Clinical Aspects of Liver Diseases 31 Metabolic Disorders and Storage Diseases

Clinical Aspects of Liver Diseases 31 Metabolic disorders and storage diseases

Page: Page: 1 Definition 579 9.3 Cystinosis 594 2 Pathogenesis 579 9.4 Homocystinuria 594 3 Non-alcoholic fatty liver disease 579 10 Carbohydrate storage diseases 595 3.1 Physiological aspects 579 10.1 Glycogenoses 595 3.2 Definition 580 10.2 Galactosaemia 596 3.3 Pathogenesis 580 10.3 Hereditary fructose intolerance 597 3.4 Morphology 580 10.4 Fructose-biphosphatase deficiency 597 3.4.1 Fatty infiltration 580 11 Lipid storage diseases 597 3.4.2 Fatty degeneration 582 11.1 Wolman’s disease 597 3.4.3 Phospholipidosis 582 11.2 Cholesterol ester storage disease 598 3.5 Causes 582 11.3 Cerebrotendinous xanthomatosis 599 3.6 Non-alcoholic steatohepatitis 583 11.4 Abetalipoproteinaemia 599 3.6.1 Definition 583 11.5 Hypoalphalipoproteinaemia 599 3.6.2 Epidemiology 583 11.6 Debre´’s syndrome 599 3.6.3 Pathogenesis 584 12 Sphingolipid storage diseases 599 3.6.4 Morphology 584 12.1 Gaucher’s disease 599 3.7 Diagnosis 585 12.2 Fabry’s disease 600 3.8 Prognosis 586 12.3 Gangliosidoses 601 3.9 Complications 586 12.4 Niemann-Pick disease 601 3.10 Therapy 586 12.5 Mucopolysaccharidoses 601 4 Faulty nutrition 587 12.6 Mucolipidoses 602 4.1 Malnutrition 587 13 Mucoviscidosis 602 4.2 Kwashiorkor 588 14 Zellweger’s syndrome 603 4.3 Tropical juvenile cirrhosis 588 15 Porphyrias 603 4.4 Infantile sclerosis 588 15.1 Definition 603 4.5 Obesity 588 15.2 Classification 603 4.5.1 Diabetes mellitus 589 15.3 Biochemistry 603 4.5.2 Hyperlipidaemia 589 15.4 Genetics 604 5 Reye’s syndrome 589 15.5 Clinical aspects 604 5.1 Causes 589 15.6 Erythropoietic porphyrias 605 5.2 Clinical picture 589 15.6.1 Congenital erythropoietic porphyria 605 6 Acute fatty liver of pregnancy 589 15.6.2 Erythropoietic protoporphyria 605 6.1 Clinical picture 589 15.7 Hepatic porphyrias 605 6.2 Prognosis 590 15.7.1 Acute intermittent porphyria 606 6.3 Treatment 590 15.7.2 Variegate porphyria 607 7 Mauriac’s syndrome 590 15.7.3 Hereditary coproporphyria 607 8 Protein storage diseases 590 15.7.4 Doss porphyria 607 α 8.1 1-antitrypsin deficiency 591 15.7.5 Porphobilinogen synthase defect 607 8.1.1 Clinical picture 591 15.7.6 Porphyria cutanea tarda 607 8.1.2 Diagnosis and treatment 591 15.8 Hepatoerythropoietic porphyria 610 8.2 Amyloidosis 592 16 Wilson’s disease 610 8.2.1 Clinical picture and diagnosis 592 16.1 Definition 610 8.2.2 Prognosis and treatment 593 16.2 Frequency 610 8.3 α1-antichymotrypsin deficiency 593 16.3 Pathogenesis 610 9 Amino acid storage diseases 593 16.4 Pathophysiology 611 9.1 Hereditary tyrosinaemia 593 16.5 Morphological changes 611 9.1.1 Clinical picture 593 16.5.1 Hepatic manifestation 611 9.1.2 Treatment 594 16.5.2 Extrahepatic manifestations 612 9.2 Disturbances of the urea cycle 594 16.6 Clinical picture 613

577 Page: Page: 16.7 Laboratory findings 614 17.3.2 Pathogenesis 619 16.8 Diagnostic measures 614 17.3.3 Iron toxicity 619 16.9 Prognosis 615 17.3.4 Morphology 620 16.10 Treatment 615 17.3.5 Early diagnosis 621 16.10.1 Dietary measures 615 17.3.6 Preventive diagnosis 621 16.10.2 Drug therapy 615 17.3.7 Manifestation 621 16.10.3 Dialysis therapy 616 17.3.8 Prognosis 623 16.10.4 Liver transplantation 616 17.3.9 Treatment 624 16.11 Indian childhood cirrhosis 616 18 Acquired haemochromatosis / 626 17 Haemochromatosis 617 Haemosiderosis 17.1 Definition 617 18.1 Alcohol abuse 626 17.2 Classification 617 18.2 Porphyria cutanea tarda 626 17.2.1 HFE-related haemochromatosis 617 18.3 Blood transfusion 626 17.2.2 Non-HFE-related haemochromatosis 618 18.4 Haemolytic anaemia 626 17.2.3 Aceruloplasminaemia 618 18.5 Chronic liver disease 627 17.2.4 Atransferrinaemia 618 18.6 African iron overload 627 17.2.5 Neonatal haemochromatosis 618 ț References (1Ϫ487) 627 17.3 Hereditary haemochromatosis 618 (Figures 31.1Ϫ31.27; tables 31.1Ϫ31.18) 17.3.1 Frequency 618

578 31 Metabolic disorders and storage diseases

1 Definition ᭤ In primary or secondary metabolic disorders or storage diseases, almost all metabolic functions of the Primary metabolic disorders and storage diseases are liver may be affected. caused by endogenous factors, usually a gene muta- (jaundice ؍) tion. Since the congenital defect is predominantly or Bilirubin metabolism (cholestasis ؍) exclusively located in the liver, the resulting diseases Bile acid metabolism also become manifest in this organ. Amino acid metabolism Lipid metabolism Secondary metabolic disorders and storage diseases Carbohydrate metabolism Lipoprotein metabolism are present in almost all liver diseases and occur with Copper metabolism Mucopolysaccharide metabolism Glycolipid metabolism Porphyrin metabolism more or less pronounced intensity. • They are, how- Iron metabolism Protein metabolism ever, also caused by faulty nutrition as well as by many exogenous factors or noxae Ϫ just as latent Genetically induced disorders of bilirubin metabolism metabolic disorders may generally become manifest affect (1.) bilirubin conjugation or (2.) bilirubin excre- due to such factors. tion through the canalicular membrane. This results in functional hyperbilirubinaemia. (s. tabs. 12.1, 12.4) (see Thesaurismoses are storage diseases caused by the chapter 12) accumulation of metabolic products or substances in bile acid metabolism body fluids, organs or cells as a result of metabolic Genetically induced disorders of disorders. cause non-obstructive intrahepatic cholestasis. Cholesta- sis due to primary storage diseases also belongs to this group of disorders. (s. tab. 13.4) (see chapter 13)

2 Pathogenesis 3 Non-alcoholic fatty liver disease ᭤ The pathogenic processes leading to the development of primary metabolic disorders or storage diseases are 3.1 Physiological aspects essentially caused by two mechanisms:(1.) formation of atypical macromolecules and (2.) extensive or complete Usually, the liver contains 0.8Ϫ1.5% of its wet weight in blockage of a metabolic pathway. • These pathologically the form of extractable, finely dispersed structural fats, formed macromolecules cannot be broken down or which cannot be detected by normal histological tech- secreted, with the result that they accumulate in the cells, niques. Under the light microscope, the liver fat, which including hepatocytes, or in the extracellular spaces. • is mainly made up of small droplets of triglycerides, Blockage of a metabolic pathway leads to (1.) insuffi- only becomes visible when an increase to >2Ϫ3% cient production of certain metabolites, (2.) metabolite occurs. Above this value, hepatocytes “register” this accumulation at the point of blockage, or (3.) formation event as a pathological process per se. of abnormal metabolites. This gives rise to the respective Triglycerides: Triglycerides are formed by the esterification of fatty primary metabolic disorder or storage disease. It is, acids with glycerophosphate being produced by glycolysis. • Short- however, largely unclear what kind of mechanisms are and medium-chain fatty acids from foodstuffs as well as fatty acids actually responsible for liver cell damage. derived from lipolysis within adipose tissue are bound to albumin and transported to the liver cells through the portal vein. Long- ᭤ The pathogenesis of secondary metabolic disorders chain fatty acids from foodstuffs become inserted as triglycerides in the chylomicrons within the mucosal cells of the small intestine. or storage diseases depends on the specific metabolic After having been broken down by endothelial lipoprotein lipase, influence resulting from the character of the existing the chylomicrons reach the hepatocytes in the form of remnants liver disease as well as other individual factors (e.g. mal- together with fatty acids. There, the fatty acids are beta-oxidized nutrition, alcohol abuse, chemicals, toxins). • Either a (to acetate and ketone bodies) in order to release energy or to severe deficiency or an excessive supply of nutrients can synthesize phospholipids, cholesterol ester and triglycerides. The liver cell is also capable of de-novo synthesis of fatty acids from cause persistent disorders in the hepatic metabolism and acetyl coenzyme A. Triglycerides are synthesized rapidly, particu- possibly result in morphological changes. This may also larly when there is a sufficient supply of α-glycerophosphate and trigger a latent metabolic disorder which leads to fur- acetyl coenzyme A. This also explains the influence of glucose and ther hepatocellular damage. This is especially true when insulin on the regulation of hepatocellular metabolism. High carbohydrate (and alcohol) levels increase the esterification of fatty the hepatic metabolism is compromised by a combina- acids to form glycerides. Partial conjugation of lipids and apoprot- tion of stress factors, such as are present with diabetes eins takes place at the contact surfaces (i.e. membranes) of the mellitus, obesity, alcoholism or hyperlipidaemia. smooth and rough endoplasmic reticulum, while the carbohydrate

579 Chapter 31 component is subsequently added within the Golgi complex, so factors may be responsible for the development of liver that a complete VLDL particle is formed. It is only in this form, steatosis. In this process, additive as well as potentiating and together with cellular membrane lipids, that triglycerides can be actively exported from the liver cell by way of exocytosis. Other- metabolic disorders sometimes occur, resulting in a wise, both retention and thus storage occur in the liver cell. • biochemical/morphological vicious circle. (s. tab. 31.1) VLDL particles secreted from the hepatocyte are once more broken down in the capillaries by lipoprotein lipase to form LDL and Exogenous fatty acids. In this way, the fatty acids can be reused as an energy 1. Increase in lipid uptake from the intestine source, stored in fat depots or remetabolized in the hepatocytes. • 2. Enhanced supply of glyceride precursors The lipids stored in fat depots are likewise broken down by triglyc- (glucose, fructose, galactose) eride lipase into fatty acids (and glycerin) and reach the liver cells again via the blood stream, where the same possibilities of meta- Endogenous bolization exist. • The liver cell is capable of either synthesizing or 1. Increase in peripheral lipid mobilization metabolizing lipid substances separately within itself, both in terms • Lipolysis Ȇ (ϭ triglyceride lipase activity Ȇ) of time and place. These metabolic processes may occur parallel to (by ACTH, cortisol, catecholamines, prostaglandins, and independently of each other. (s. p. 43) (s. fig. 3.8) caffeine, alcohol, nicotine) 2. Inhibition of lipid utilization in hepatocytes • β-oxidation ȇ 3.2 Definition • Fatty acid-binding protein ȇ Liver steatosis 3. Increase in lipid synthesis in hepatocytes is defined as a condition when there are • Formation of fatty acids Ȇ small or medium-sized fat droplets in singular, dissemin- • Formation of triglycerides Ȇ Ϫ ated liver cells and when the fat content is 3 10% of 4. Reduction in lipid export liver wet weight. • Fatty liver is defined as a condition • Secretion of VLDL ȇ • Ϫ ȇ when the fat storage is >10% of liver wet weight, when Synthesis of apoproteins B, C1 C3,E >50% of the hepatocytes contain fat droplets in dif- • Disturbance in gluconeogenesis ferent sizes (small to large) and when fat deposition Tab. 31.1: Pathogenesis of liver steatosis and fatty liver shows a diffuse pattern in the parenchyma. • Storage of fat in the liver cell is the most common form of morphological hepatocellular damage. 3.4 Morphology ᭤ Symptom: Low-grade fat storage in liver cells, ranging ᭤ fatty liver from the deposition of tiny to medium-sized droplets, is The earliest histological criteria of were described by W. B owman in 1842. • As early as 1861, F. T. F rerichs demon- deemed to be a mere symptom (or “metabolic siding”) strated the development of hepatic steatosis and its reversibility and therefore a harmless phenomenon. • Such a finding in dogs. He gave a detailed description of minute fat droplets can be seen as a “dynamic” (short-term) liver steatosis in liver cells and their continuous growth. Even at that time, he after a high-fat meal, particularly together with alcohol. differentiated between fatty infiltration and fatty degeneration. Indeed, he considered fatty degeneration to be more “perni- ᭤ Disease: A diffuse fatty liver showing medium and cious” than fatty infiltration. (1861, volume I, pp 285Ϫ324; figs. 41, 42) • (see below: W. S. H artroft et al., 1968) large-sized droplets is regarded as a disease when the severity increases to a point where >50% of hepatocytes are involved (ϭ “from symptom to disease”). Occasion- 3.4.1 Fatty infiltration ally, excessive fat storage occurs (up to 100% of hepatocytes involved) with a high mortality rate, e.g. in acute Fat storage in liver cells starts with tiny droplets being alcohol intoxication (s. fig. 28.5) and acute poisoning deposited inside the endoplasmic reticulum and cyto- due to chemicals or toxins. A maximum fat storage rate plasm. This fatty deposition in the form of small drop- of 24% of liver wet weight has been observed. lets without a surrounding membrane is also called fatty infiltration (type A) (W.S. Hartroft et al., 1968). (14) Ini- tially, only a few hepatocytes are affected by small-drop- 3.3 Pathogenesis let deposits, whereas later on whole clusters are grouped together, mainly at the periphery of the lobules or in When the hepatocytes are continuously inundated by the centroacinar area. • Slowly but steadily, the droplets fatty acids, from either the intestines or fat depots, their become larger, resulting in medium-droplet steatosis. The oxidative degradation or synthesis capacity may be stored fatty droplets increase further in size and eventu- reduced and triglyceride binding to lipoproteins can be ally fill the hepatocytes completely (ϭ macrovesicular depleted. This is most likely to happen whenever apo- steatosis). (20, 24, 40, 49) (s. tab. 31.2) protein synthesis or lipoprotein formation is compromised by noxae (e.g. alcohol). • Fat storage in hepato- As a result of large-droplet steatosis, the hepatocytes be- cytes is a question of equilibrium since accelerated or come enlarged, the fine cytoplasmatic structures are increased formation of triglycerides in the liver cell is destroyed and the nucleus is pushed towards the cellular not compensated by sufficient synthesis of lipoproteins membrane. The functions of the nucleus are impaired and adequate secretion of VLDL from the liver cell. • or even halted. This also results in a strong tendency of Therefore, both exogenous and endogenous pathogenic the fatty cells to develop necrosis even under mildly

580 Metabolic disorders and storage diseases

Formation of fat droplets 1. Deposits of tiny fat droplets Formation of small fat droplets ϭ small-droplet liver steatosis ȇ 2. Increase in size of fat droplets ϭ medium-droplet liver steatosis ȇ 3. Further increase in size of fat droplets Confluence of fat droplets Impairment of nuclear functions ϭ large-droplet liver steatosis ȇ ϭ mixed-droplet liver steatosis ϭ formation of fat cysts

Localization of liver steatosis Fig. 31.1: Glycogenated nuclei (so-called glycogen vacuolations of 1. peripheral 3. zonal the nuclei) in diabetes mellitus. Insert: nucleus strongly laden with 2. centroacinar 4. diffuse glycogen (Ȇ) (PAS) (s. pp 396, 526, 589, 596, 611, 620)

Liver steatosis 1. Low-grade liver steatosis ϭ ca. 5% of WW ϭ 10Ϫ15% of hepatocytes 2. Medium-grade liver steatosis ϭ 6Ϫ8% of WW ϭ 15Ϫ30% of hepatocytes 3. Pronounced liver steatosis ϭ 8Ϫ9% of WW ϭ 30Ϫ50% of hepatocytes Fatty liver 4. Severe fatty changes in liver cells ϭ 10Ϫ12% of WW ϭ >50% of hepatocytes (medium and large-droplet size, diffuse) 5. High-grade fatty changes in liver cells ϭ Ϫ Ϫ Fig. 31.2: Large-droplet (coarse-vacuolar) fatty liver in diabetes 12 17% of WW (300 500 mg/g) mellitus (preliminary stage of fat cyst formation) (HE) ϭ >70% of hepatocytes

Tab. 31.2: Formation, localization and various courses of liver steatosis resulting in the development of fatty liver (WW ϭ wet weight of liver) toxic conditions. At the same time, the hepatocyte loses more and more glycogen. Glycogen vacuolations of the nuclei form when nuclear glycogen is removed. (s. fig. 31.1) They can be observed in various diseases, most frequently in diabetes mellitus, predominantly in the area of the portal fields. • So-called fat cysts of various sizes are the result of large-droplet steatosis due to the cellular membrane being torn apart. (s. fig. 31.2) This fat-storing process results ultimately in a diffuse mixed- droplet fatty liver. (s. fig. 31.3) • Peripheral fat deposits Fig. 31.3: Pronounced mixed-droplet fatty liver (Sudan red) (zone 1) are mainly caused by infectious or toxic damage directly affecting the periphery, where the liver cells are more involved in lipid metabolism via the blood in diffuse steatosis of the whole lobule. (s. fig. 31.3) In stream. (s. fig. 31.4) • Centroacinar steatosis (zone 3) is general, the left lobe shows less homogeneous steatosis mostly found in O2 deficiency, nutrition-related damage, than the right lobe. Regionally more pronounced fatty diabetes mellitus and alcohol abuse. It is basically con- changes Ϫ which were formerly known laparoscopically sidered to be the more severe form of damage. (s. fig. as “yellow spots” (s. fig. 31.6), can be clearly detected 31.5) • Zonal steatosis occurs when only certain zones as focal (s. fig. 8.3) or segmental fatty infiltration (s. fig. or areas of a lobule are affected. • This eventually results 8.4) by means of CT. (8, 13, 17, 26, 40)

581 Chapter 31

which are surrounded by a delicate membrane. This may give the hepatocytes a foamy appearance. The nucleus remains largely unmodified in the centre of the cell. Such microvesicular degeneration can be found in various thesaurismoses, different liver conditions and numerous drug-induced diseases. (15) (s. tab. 31.3)

1. Acute fatty liver of pregnancy 2. Alcoholic foamy fat syndrome 3. Jamaican vomiting sickness (35) 4. Kwashiorkor (30, 38) 5. Reye’s syndrome 6. Thesaurismoses Ϫ cholesterol ester storage disease Ϫ disturbance of the urea cycle Fig. 31.4: Steatosis in periportal liver parenchyma. Clinical diagno- Ϫ HDV hepatitis in northern South America sis: chronic phosporus poisoning (HE) Ϫ Wolman’s disease 7. Drugs Ϫ acetylsalicylic acid Ϫ pirprofen Ϫ amineptin Ϫ tetracycline Ϫ fialuridine Ϫ valproic acid Ϫ ibuprofen Ϫ warfarin Ϫ ketoprofen etc.

Tab. 31.3: Causes of microvesicular fatty degeneration (with some references)

3.4.3 Phospholipidosis Enhanced lysosomal storage of phospholipids due to the inhibition of phospholipases is another special form of hepatic steatosis. The hepatocytes are enlarged and exhibit a distinctive foamy lucency of the cytoplasm. Fig. 31.5: Centroacinar steatosis. Clinical diagnosis: chronic alco- Crystalline inclusions and an agglomeration of myelin hol abuse (Sudan red) structures are visible in the lysosomes by electron microscopy. Mallory bodies may also be found. This idio- syncratic metabolic liver damage may even develop into cirrhosis. (s. p. 545) (s. tab. 31.4)

1. Amiodarone 5. Imipramine 2. Amitriptyline 6. Perhexiline maleate 3. Chloroquine etc. 4. Chlorpromazine

Tab. 31.4: Causes of phospholipidosis

3.5 Causes Causes of fatty liver are manifold, and combinations of causes quite common. Acquired causes are by far the Fig. 31.6: Fatty liver with pronounced, regional, thumb-sized fatty most frequent, but there are also rare causes, e.g. coeliac changes at the periphery of the left liver lobe (so-called “yellow disease (9, 25), parenteral nutrition. (28, 29) • Congenital spot”) metabolic disorders can also lead to the development of a fatty liver, as in the case of a rare thesaurismosis. • It 3.4.2 Fatty degeneration is of considerable therapeutic and prognostic importance to differentiate between an alcoholic fatty liver This form of microvesicular fat storage in hepatocytes, (AFL) and alcoholic steatohepatitis (ASH) (s. pp 529, which is also termed type B (W.S. Hartroft et al., 1968) 531) as well as between non-alcoholic fatty liver (14), is a rare but prognostically serious condition. The (NAFLD) and non-alcoholic steatohepatitis (NASH). cytoplasm is filled with small non-confluent fat particles (2, 20, 24, 36) (s. tabs. 31.5Ϫ31.7)

582 Metabolic disorders and storage diseases

1. Nutritional causes 1. Medication Carbon tetrachloride Gastric bypass Flurazepam Chloroform Hyperalimentation/obesity (1, 4, 5, 10, 19, 34, 51, 77) Glucocorticosteroids Chromium Jejunoileostomy Hydrazine DDT Malnutrition (12) Mercaptopurine Dinitrobenzene Ϫ malabsorption, starvation, kwashiorkor (30, 38) Methotrexate Dioxins Parenteral feeding (28, 29) Naproxen Hexachlorocyclohexane 2. Metabolic disorders Nifedipine Lead Diabetes mellitus (22, 34, 39) Phenylbutazone Pentachloroethane Gout Probenecid Phosphorus Hyperlipidaemia (56) Rifampicin Tetrachloroethane Thesaurismoses (s. tab. 31.6) STH Toluilendiamine 3. Alcohol Tamoxifen etc. 4. Drugs (s. tabs. 29.10; 31.7) etc. 3. Phytotoxins and 2. Chemical substances mycotoxins 5. Chemical substances (47) Antimony Aflatoxins 6. Phytotoxins, mycotoxins Arsenic Amanitins 7. Infections Chloronaphthalene Gyromitrin Bronchiectasis Chronic osteomyelitis Tab. 31.7: Liver steatosis or fatty liver due to medication, chemical Chronic tuberculosis substances or toxins (s. tab. 29.10!) Hepatitis C HIV infection Sprue NAFLD coincide, the frequency and severity of fatty Ulcerative colitis/Crohn’s disease (9, 25) liver increases. (18) Yellow fever 8. Oxygen deficiency Ϫ anaemic 3.6 Non-alcoholic steatohepatitis Ϫ cardiac Ϫ respiratory ᭤ In 1980 the term non-alcoholic steatohepatitis 9. Endocrinopathies (NASH) was introduced by J. Ludwig et al. to denote Acromegaly chronic liver disease with increased enzymatic activity Cushing’s syndrome and the histological picture of alcohol-induced hepa- Myxoedema (59) (60) 10. Liver surgery titis. • The histological feature itself was described haler Liver resection by H. T as early as 1962 in his paper “Fatty liver Primary dysfunction of a transplanted liver (45, 62) and its relationship to cirrhosis“. (76) •Overthe following years, transition from a diabetic fatty liver 11. Cryptogenic fatty liver (11) into cirrhosis was reported (S. Itoh et al., 1979) as well Tab. 31.5: Acquired causes of liver steatosis or fatty liver (includ- as from an obesity-induced fatty liver into cirrhosis ing some references) (M. Adler et al., 1979).

Abetalipoproteinaemia Mucoviscidosis Cholesterol ester storage Niemann-Pick disease 3.6.1 Definition Fructose intolerance Refsum’s disease Galactosaemia Sphingolipidosis Histologically, non-alcoholic steatohepatitis shows Glycogenoses Tyrosinaemia moderate to high-grade, mainly macrovesicular fatty Homocystinuria Weber-Christian disease degeneration of the liver cells with inflammatory Hypoalphalipoproteinaemia Wilson’s disease Mauriac syndrome Wolman’s disease infiltrates and formation of fibrosis. Cirrhosis fre- Mucolipidosis etc. quently develops. • Despite the morphological simi- larity to alcohol-induced fatty liver hepatitis, there is Tab. 31.6: Congenital causes of liver steatosis or fatty liver (so- no (noteworthy) alcohol consumption involved in called thesaurismoses) NASH. Viral or autoimmune hepatitis are not detect- The frequency of NAFLD in the general population is able either. • There are no or only moderate subjective given as 3Ϫ58%, whereby the great variability is due to complaints. The transaminases are normal or slightly socio-economic differences (average value 20Ϫ23%). increased. NASH is mostly associated with obesity The development of NAFLD is more closely correlated and/or type II diabetes, thus NASH is regarded as the with obesity than with alcohol abuse. In the case of hepatic manifestation of a metabolic syndrome. combined obesity and alcohol abuse, the frequency of Ϫ fatty liver is estimated to be 50 60%. About one third 3.6.2 Epidemiology of overweight patients suffer from type II diabetes, which in turn is responsible for the development of an Once alcohol consumption, viral hepatitis or autoim- NAFLD or it can lead to the formation of ASH and mune hepatitis have been ruled out, NASH is deemed NASH. Consequently, if several causal factors of the most common cause of a long-term increase in

583 Chapter 31

transaminases. • The information available on preva- ᭤ From present knowledge, it can be assumed that lence and general frequency is not yet sufficient. In numerous cases of cryptogenic chronic hepatitis or 2Ϫ6% of the US population, however, an increase in cryptogenic cirrhosis are attributable to the presence GPT (ALT) was detected without chronic liver disease of NASH in terms of aetiopathogenesis. being diagnosed. (55) Based on liver biopsies, a prevalence of 1.2Ϫ9.0% was determined. (70) NASH is frequently associated with obesity (ca. 40%), non-insulin- 3.6.4 Morphology dependent diabetes mellitus (ca. 20%) and hyperlipidaemia (ca. 20%). Women (particularly in middle age) are The diagnosis of NASH as well as the assessment of its more often affected than men. (51, 55, 77, 78) • NASH prognosis is most reliably derived from liver histology. • may indeed also be found in children. (61, 67, 73). In this In the lobule, steatosis is distributed mainly in a macro- context, it was associated with obesity in 83% and with vesicular and diffuse manner, but sometimes it is also a disorder of the lipid metabolism in 50% of cases, while concentrated microvesicularly and perivenously. Glyco- diabetes mellitus could only be detected in 5% of genated nuclei are commonly present. • The inflamma- patients (but with increasing frequency during the fur- tory reaction consists of granulocytic and lymphocytic ther course of life as was shown in the follow-up). (67) infiltrates, which are more frequently found in the portal and perivenous area than intralobular, with or without 3.6.3 Pathogenesis focal necrosis. Cell ballooning, Mallory’s hyaline and ubiquitin are generally present, while occasionally The development of liver steatosis is attributable to vari- megamitochondria are also found. Steatosis and mild ous exogenous and endogenous mechanisms, which may lobular chronic inflammation alone are insufficient for combine with and/or potentiate each other. (s. tab. 31.1) the diagnosis of NASH. • First of all, fibrosis appears Numerous causal factors must be considered in the within the perisinusoidal area, then additionally within pathogenesis of fatty liver. (s. tabs. 31.5, 31.7) the portal field; subsequently, it develops as bridging fibrosis giving rise to architectural remodelling, and With the increasing storage of fat, the liver cells also eventually results in cirrhosis with portal hypertension. become more and more vulnerable to noxae. Thus oxida- The histological picture of NASH can be mistaken for tive stress may cause augmented oxidation of free fatty chronic hepatitis C, steroid-treated autoimmune hepati- acids in the peroxisomes as well as enhanced activity of tis, drug-induced hepatitis or the early stage of Wilson’s cytochrome P 450 2E1. The biotoxometabolites (e.g. disease. It is even more difficult for the pathologist to malonyldialdehyde, 4-hydroxynonenal) arising during this differentiate between a cirrhosis as a result of NASH, process provoke inflammatory infiltrations and fibrosis. chronic hepatitis C and autoimmune hepatitis. Often a Second-hit hypothesis: This hypothesis has been proposed as a diagnosis of cryptogenic cirrhosis has to be made. (11, plausible explanation for the occurrence of NASH. (48, 70) • The 40, 42, 43, 44, 52, 54, 58, 61, 66, 70, 71, 73) (s. fig. 31.7) first hit is considered to be the development of fatty liver, particularly due to hyperalimentation and obesity resulting in insulin resistance. As second hit follows the mobilization of free fatty acids from fat depots and their transport to the liver cells. This leads to a massive increase of free radicals due to oxidative stress with lipid peroxidation and induction of cytokines (TNFα,TGFβ, IL6, IL8). As a result, there is a reactive formation of uncoupling protein (UCP2) with a subsequent decrease in hepatocyte ATP and a disturbance of macrophage function with higher sensitivity to endotoxin. This leads to an inflammatory reaction, cell death and the formation of fibrosis. (44, 50, 65) A genetic basis seems to be necessary as a predisposition of NASH; however, such mechanisms are still unknown. It is discussed that genes can influence the degree of oxidative stress, the severity of steatosis, the regulation of immune reactions and apoptosis. Fig. 31.7: Non-alcoholic steatohepatitis (NASH): Hydropic degen- ᭤ The pathogenesis of NASH is multifactorial, i.e. in erated hepatocytes with Mallory’s hyaline (ǟ); lymphocytic and the presence of steatosis, it is attributed to the add- granulocytic infiltration as well as activated Kupffer cells (HE) itional (even combined) influence of different noxae (e.g. oxygen deficiency, endotoxins, medicaments, chemicals, iron, biotoxometabolites). • There should ᭤ There are no morphological differences between be no laboratory findings pointing to alcohol abuse; alcoholic steatohepatitis and NASH. • In some chronic hepatitis B and C as well as autoimmune hep- 30(Ϫ50)% of patients with NASH, predominantly atitis (75) must also be ruled out. micronodular cirrhosis develops within 5 years.

584 Metabolic disorders and storage diseases

3.7 Diagnosis be reliably detected by sonography. (s. p. 117) • Often, it is difficult to differentiate focal fatty changes (circum- Clinical findings: Steatosis does not cause any subjective scribed density of the echo pattern) from malignant foci, complaints or clinical symptoms; it remains undetected so that further clarification by means of scintigraphy or is discovered incidentally when diagnostic screening (26) or CT scanning is required. Fibrosis shows an is being carried out for another disease. In this context, inhomogeneous parenchymal structure in relation to the the presence of risk factors (overweight, diabetes, gout, degree of severity. (7, 8, 13, 23, 31) (s. tab. 31.8) hyperlipidaemia, medication, malnutrition, etc.) is of considerable diagnostic importance. • Subjective com- CT: In a fatty liver, CT scanning shows diffuse density plaints may include fatigue, repletion, malaise or loss of reduction with a corresponding decrease in Hounsfield appetite. In hepatomegaly, right upper quadrant abdo- units (HU). (27) A fatty liver is markedly darker than minal discomfort may occur, especially when stooping the spleen (so-called large, grey liver). The vessels and or lying on the right side. In obesity, which is present in bile ducts are hyperdense as compared to the paren- most cases, hepatomegaly is often not palpable, so that chyma. There is a linear relationship between the extent the actual size of the liver may only be demonstrated by of fat deposition and the reduction in density. The diag- sonography (or CT). Hepatomegaly correlates with the nostic reliability of a fatty liver determined by CT is severity of the fatty liver, allowing determination of the 85Ϫ95%. Focal fatty changes or segmental fatty changes course. Splenomegaly is found in 20Ϫ25% of patients. are easy to differentiate since, in contrast to metastases, (37) • In advanced cases, skin stigmata of liver disease as they do not have any vascular branching. A 10% well as signs pointing to portal hypertension might be increase in the relative fat content results in a density in evidence. (s. tab. 31.8) reduction of 17Ϫ20 HU; i.e. in fatty changes of 80%, a density decrease to about Ϫ50 HU occurs. (s. p. 153) • Laboratory diagnostics: With increasing severity of a fatty Investigations have also been carried out to determine liver or NASH, some laboratory parameters are patho- whether it is possible to quantify the fat content of the Ϫ Ϫ logical in 80 90% of cases, i.e. 10 20% of patients show liver by MRI. (17, 21, 27) (s. tab. 31.8) normal values. There is an initial rise in γ-GT, and subsequently in GPT and GOT. As a rule, the mildly to moder- 1. Determination of potential risk factors ately increased values are detected purely by chance dur- (obesity, alcohol, diabetes, gout, malnutrition, ing a medical check-up. The DeRitis quotient is <1 (cf. hyperlipidaemia, medication, etc.) alcoholic hepatitis with >1). While this constellation in 2. Hepatomegaly itself is a useful hint of liver cell damage induced by toxins or metabolic processes, an increase in cholinesterase actu- 3. Laboratory parameters ally suggests the presence of disturbed lipid metabolism • γ-GT Ȇ, GPT Ȇ,GOTȆ • cholinesterase Ȇ or a fatty liver. Decreased functioning of the liver, detect- Ϫ galactose elimination capacity ϩ able at an early stage, can be determined by measuring the Ϫ indocyanine green test ϩ galactose elimination capacity (s. p. 95) or by applying the Ϫ alkaline phosphatase Ȇ indocyanine green test (s. p. 96); these tests may also be Ϫ ferritin Ȇ Ϫ Ȇ Ȇ Ȇ used in long-term follow-up. • Other important labora- triglycerides , cholesterol , glucose Ϫ lipid electrophoresis ϩ, leptin Ȇ, thioredoxin Ȇ tory parameters include alkaline phosphatase, bilirubin, electrophoresis, ferritin, leptin (46, 68), thioredoxin (74) 4. Sonography and parameters connected with lipid metabolism. Pro- CT gressive and severe courses correlate well with laboratory 5. Morphology values well outside the normal range. Sonographic signs • percutaneous biopsy, laparoscopy ϩ biopsy of liver steatosis indicate screening for diabetes mellitus,if necessary with the help of the oral glucose tolerance test. Tab. 31.8: Diagnosis of fatty liver or NASH, involving determina- (6, 36, 50, 52, 54, 55, 58, 72, 74) (s. tab. 31.8) tion of the degree of severity, differential diagnosis and course Sonography: Hepatomegaly can usually be confirmed by Liver biopsy: Only morphology provides a definitive sonography (vertical diameter liver enlargement in diagnosis of fatty changes in the liver cells or a fatty MCL > 11Ϫ12 cm), with the liver generally showing a liver. Apart from revealing fatty changes,itiseven plump form. The echogenicity is increased as a result of more important histologically to detect inflammatory the high number of water/fat boundary layers, and the reactions and to determine whether there is any sign of single reflexes are coarsened (in contrast to the renal progressive fibrosis (e.g. due to iron overload). (6) The parenchyma). In general, the hepatic veins are difficult result of grading and staging (43) is decisive for the to visualize. In pronounced fatty liver, sonographic signs prognosis. (s. tabs. 34.2, 34.3) • Laparoscopic evalua- of portal hypertension may appear (ϭ sinusoidal block). tion of the liver surface is of considerable diagnostic There is a positive correlation between the degree of importance, as is the targeted biopsy of hepatic areas fatty changes and the increase in echogenicity (so-called which are suspected of being pathological. large, white liver). Fatty changes below 10Ϫ20% cannot

585 Chapter 31

3.8 Prognosis underlying cause has not been identified despite all efforts (ϭ cryptogenic fatty liver) and thus no real starting point ᭤ A fatty liver has a good prognosis, since complete for therapeutic measures is given, and (3.) the specific reversibility can be achieved if the causes are fully elim- cause of fatty liver, and the occurrence of NASH in par- inated. However, existing fibrotic processes generally ticular, already has a tendency towards progression. • In remain. • A fatty liver should in no way be underesti- this case, there is evidence of liver cell necrosis and inflam- mated, since it involves many dangers: (1.) the manifold matory infiltration, both of which are reversible. How- liver cell functions may be distinctly compromised, ever, in some cases, particularly with simultaneous lipid causing unfavourable effects on the liver or the organism peroxidation, they can lead to a vicious circle with subse- as a whole; (2.) fatty changes in the liver cells make quent mesenchymal reactions. The outcome is increasing them susceptible to noxae or toxins, so that there is an fibrosis or development of cirrhosis. increased tendency towards steatonecrosis and an impaired regeneration capacity; (3.) a fatty liver re- sponds strongly to inflammatory processes with mes- 3.10 Therapy enchymal reactions; (4.) a severe fatty liver sometimes So far, no medicament has been found that can achieve a results in a narrowing of the intrahepatic vessels with normalization of the disturbed hepatocellular lipid metab- ensuing impairment of biliary flow and haemodynam- olism or bring about the release of the fat stored in liver ics, or it may even lead to the development of portal cells. hypertension. Prognosis is essentially dependent on whether the causes of fatty liver as well as any add- ᭤ Fatty liver does not require any specific therapy. itional risk factors can be eliminated. NASH develops Exclusion of the cause and elimination of additional risk into fibrosis or cirrhosis within 5Ϫ10 years in 10Ϫ40% factors Ϫ in as far as these two basic therapeutic of cases. Some 10Ϫ15% of these patients die within 10 requirements can be accomplished Ϫ usually result in years as a result of complications associated with cirrho- complete regression of steatosis. • Should these meas- sis. • Risk factors showing that NASH is progressing ures fail to bring about a regression within a period of include: age >50 years, body mass index >30, type II 3Ϫ6 months, it can be assumed that either exclusion of diabetes, hyperlipidaemia, DeRitis quotient >1, throm- the cause and elimination of risk factors have not been bopenia, and the presence of Mallory bodies. (16, 36, 50, successful or the real underlying cause was not iden- 54, 58, 66, 71) • Metastases originating from a colorectal tified, so that no effective treatment measures were actu- carcinoma are very rarely found in fatty liver. ally applied. • A lack of regression thus necessitates (1.) renewed investigation of the cause and risk factors as well as (2.) consistent implementation of the therapy 3.9 Complications that results from this! The occurrence of complications points to the fact that Strict alcohol abstinence is called for Ϫ even in those cases fatty liver should not generally be regarded as a harmless where alcohol is not the cause of fatty liver. The same disorder. A fatty liver as well as the various risk factors applies to the exact adjustment of the blood-sugar levels in may give rise to complications which occasionally mani- diabetes mellitus or the uric acid values in gout. Hyper- fest as a separate disease. (20, 36, 58, 66) (s. tab. 31.9) lipidaemia may likewise necessitate a specific drug therapy depending on the respective type and course. • In 1. Development of fatty liver hepatitis progressing to obesity due to overnutrition, it is absolutely imperative to fatty fibrosis (50%) or cirrhosis (15%) (e.g. via non- reduce weight (gradually!) by means of a low caloric diet, alcoholic steatohepatitis) based on the principles of the physiology of nutrition. 2. Formation of intrahepatic cholestasis with or Proteins and water-soluble vitamins should be adminis- without jaundice, possibly even similar to ob- tered at a higher daily dosage than is normally required. structive jaundice (3) The effect of dietary measures can be supported by orlis- 3. Fat embolism (R. Virchow, 1886) (32) tat. Regression of a fatty liver may be achieved by weight 4. Compression and narrowing of sinusoids (33) with reduction. • Given a normal body weight, reducing the potentially reversible portal hypertension Ϫ but intake of fat in the diet (below the level that is usually also with formation of collaterals and ascites needed) does not influence the regression of hepatic 5. Intrahepatic narrowing of the inferior vena cava, steatosis. (12, 27) with occurrence of leg oedema Although the therapeutical principles described 6. Hepatic insufficiency (3%) above are generally accepted knowledge, pharmacological possibilities for facilitating the release of fat Tab. 31.9: Possible complications of fatty liver from the liver cells by administering specific medication have been repeatedly sought in the past. This has Such complications must be reckoned with in fatty liver if still not been achieved Ϫ but nevertheless remains a (1.) the cause or any additional risk factors have not been visionary idea for the future. eliminated and continue to have an effect, (2.) the

586 Metabolic disorders and storage diseases

Adjuvant therapy: In view of the fact that it has hith- some proliferator-activated receptor (PPAR), led to an erto proved impossible to restore a fatty liver by improvement in the histological findings. This could means of medication, attention has focused on the imply that insulin resistance is significant in the patho- possibility of averting the pathomorphological forms genesis of NASH. (63) Atorvastatin (10 mg/day) was of damage described above (and thus the develop- effective in patients with hyperlipidaemia. Metformin ment of a complicative progression) with the help of had only little efficacy. medicaments as an adjuvant therapy. The use of ursodeoxycholic acid is advisable in cases involving a cholestatic course of NAFLD or NASH. Prevention of fibrosis is of particular importance. Three With a dosage of 13Ϫ15 mg/kg BW/day, it was possible substances have already proved their worth in the inhibi- to achieve an improvement in the transaminase values tion of fibrosis: essential phospholipids (EPL or PPC), and the fat content of the liver. An increase in dosage silymarin and UDCA. • The antifibrogenic effect of EPL to 20Ϫ25 mg/kg BW/day might be advisable. (57) has been demonstrated repeatedly in experiments; it is A phlebotomy reduces transaminase levels and increases based upon the stimulation of collagenase. (s. fig. 40.3) iron parameters in patients with NASH. This is under- • The antifibrogenic efficacy of silymarin is attributed standable, since intrahepatic iron storage correlates with to the proven inhibition and transformation of Ito cells the severity of fibrosis. as well as the reduction in gene expression of ECM and Liver transplantation may be indicated in patients with TGF-β. (s. tab. 40.13) • Recently, an antifibrogenic effect considerable cirrhosis-related complications. However, of UDCA in alcoholic liver disease was also reported. NASH can also reoccur in the transplanted liver. (45, 63) The occurrence of lipid peroxidation normally results in This observation points to a systemic disorder of the inflammatory tissue reactions and progression of the lipid metabolism. morphological process. Under experimental conditions, elimination of the free radicals responsible for lipid per- 4 Faulty nutrition oxidation has proved useful in therapy. The administration of antioxidants may thus be advisable as adjuvant A healthy liver is capable over a longer period of time of tolerat- therapy. The three most effective active agents are essen- ing considerable changes in the pattern of food intake (irregular tial phospholipids (s. fig. 40.3), N-acetylcysteine and sily- meals) or with respect to the quantity and quality of the food marin. In the case of silymarin, stimulation of super- itself. • However, even a healthy liver reacts with functional disturbances or morphological changes to long-term malnutri- oxide dismutase, inhibition of lipoxygenase, reduction tion. During a state of hunger or a period of low protein intake, in malonyl dialdehyde and decreased consumption of for example, almost all toxic substances have more severe glutathione have been demonstrated. (s. tab. 40.13) effects, while the ability of the immune system to fight infec- Administration of vitamins C and E as antioxidants led tions is likewise compromised. • General hyperalimentation results in surplus calorie supply. The excess in carbohydrates to the regression of fibrosis. (53) Likewise, probucol,an and fat usually goes together with simultaneous protein defi- agent with antioxidant properties, caused a significant ciency. In this context, both the kind of fat or carbohydrate and decrease in GPT and GOT. any imbalance between lipogenic and lipotropic substances are extremely important. The use of lipotropic substances has always been of special interest. They show a particular affinity to fats and ᭤ Animal experiments have shown that faulty nutrition, i.e. > 90% fat, < 10% protein and < 2 mg choline per day, leads to pro- have counteracted hepatic steatosis in animal experi- nounced fatty liver and even fatty cirrhosis within a few weeks. ments. • In a 12-month course of therapy involving The same changes could be observed when the protein intake patients with fatty liver, especially due to NASH, PPC remained more or less normal, while extremely little methionine led to a significant and lasting improvement and even to and choline was offered. • With a partial surplus of certain food- normalization of the increased transaminases and γGT stuffs, the special nature of the excessive nutritional components is also of considerable importance. • The term partial malnutrition within 4 weeks. (64) • Choline is substantially involved in may, for example, be associated with a pronounced protein defi- the mobilization of triglycerides from the liver cell, ciency (and thus possibly inadequate production of lipoproteins) because it uses these neutral fats to form transportable or a lack of lipotropic substances (such as methionine, choline, phospholipids. However, choline needs betaine for cystine, glycocollbetaine, pyridoxine, casein and various N- or S- methylated substances). Protein deficiency has particularly severe demethylation. Thus betaine has an important function consequences when toxic substances are absorbed at the same time in transmethylation processes of lipid metabolism. or when the organism has to fight bacterial or parasitic infections. • Resynthesis of methionine likewise requires the assis- A diseased liver reacts to both a serious deficiency in and an exces- tance of betaine. A dosage of 20 g/day (over 1 year) led sive supply of different nutrients (e.g. proteins, certain kinds of to a reduction of transaminases, liver steatosis and amino acids, various lipids, trace elements) with unfavourable or even complicative developments during the course of disease. inflammatory activity. (41) • Clofibrat proved ineffective in patients with NASH. Gemfibrozil (600 mg/day), 4.1 Malnutrition which reduces the mobilization of free fatty acids from the fat depots, brought about a decrease in transami- Functional disturbances and morphological cell damage nases. • By contrast, the use of rosiglitazone, a peroxi- of the liver can be observed after prolonged general

587 Chapter 31 malnutrition. They are fully reversible using nutritional 4.3 Tropical juvenile cirrhosis therapy. In anorexia nervosa, there may also be an This clinical picture is also caused by animal protein increase in transaminases or a pathological tendency deficiency. However, it was common practice in the shown in liver function tests. affected regions to use beaver oil as a laxative, and this Lipofuscin: The presence of lipofuscin is without pathological rele- is known to be extremely toxic to the liver. Fatty liver, vance and can be witnessed when medication is taken (e.g. phe- hepatomegaly and jaundice were observed; ultimately, nacetin, chlorpromazine) (s. p. 395) (s. fig. 21.3), with advancing age and during prolonged malnutrition. The yellowish-brown pigment cirrhosis of a more biliary type developed. granules, some 1 µ in size, are PAS-positive, orcein-negative and acid-proof. They are produced from cell-own material and stored in the centroacinar hepatocytes, i.e. between the nucleus and bile 4.4 Infantile sclerosis canaliculi (so-called centroaxial pigment pathways).

Ceroid: The presence of ceroid is occasionally observed in both This disease has mainly been encountered in Jamaica. malnutrition and in acute viral hepatitis. It is PAS-positive, orcein- Severe fatty liver with hepatomegaly developed together positive and, like lipofuscin, acid-proof. This orange-brown granu- with early ascites (but no jaundice) and an increasing lar pigment is mainly stored centroacinarly. (s. p. 397) (s. fig. 21.6) deterioration in liver synthesis performance. Death Brown atrophy: In malnutrition, the liver shows a decrease in cell occurs in liver coma. Morphologically, there was evi- and nucleus size, glycogen depletion, pigment deposits, occasional dence of fibrosis as well as veno-occlusive disease, fea- siderosis as well as proliferation of Kupffer cells. The liver as a tures which suggested a combination of protein-defi- whole becomes smaller (by as much as two thirds of its normal cient nutrition and phytotoxins. weight). Due to its pigment deposits, particularly siderin, the liver takes on a brown colour. These changes have been subsumed under the term brown atrophy (H. Popper, 1948). 4.5 Obesity 4.2 Kwashiorkor In 30Ϫ50% of cases of obesity, fatty liver is detected. A statistical evaluation of available data (1996) revealed Kwashiorkor (meaning in the Ghanaian language “a dis- that 15Ϫ17% of the German population displayed a ease which develops in a baby when it is replaced by a new body mass index of >30 (BMI ϭ body weight [in kg] Ϭ baby and is weaned from the breast onto starch paps”) body size [in m2]). Another 40% are overweight, with a illiams was first described by C. W in 1933. This disease is BMI of 25Ϫ30. (4) Thus the German population occu- caused by at diet which is extremely poor in protein, par- pies a leading position in the world with regard to the ticularly animal protein, while at the same time the supply percentage of persons who are considerably overweight. of carbohydrates and fat calories is too high. Two new The degree of obesity correlates with the severity of hypotheses of aetiology have recently emerged suggesting fatty liver. Adipose people suffering from android distri- that the disease stems from (1.) the action of excess free bution of fat (i.e. bulk of the fat in the abdominal area) olden radicals (M.N.H. G et al., 1987) or (2.) the action of also develop more pronounced fatty liver. (19) Steatosis dietary toxins, e.g. cyanogens, aflatoxins (R.G. Hendrickse, is predominantly macrovesicular and localized in zone 1991; R.P. Kamalu, 1993). Generally, manifestation is attri- 3. The increased release of fatty acids is responsible for butable to intercurrent intestinal infections. In both chil- diminished glucose utilization, whereby blood sugar dren and adults, the symptoms include dermatosis, mus- rises and insulin secretion is stimulated, with simultan- cle atrophy, oedema due to hypoalbuminaemia, eous insulin resistance. Apart from that, any excessive diarrhoea and growth retardation. The hair shows typical carbohydrates are used for liponeogenesis. The outcome depigmentation (red hair), at the same time becoming is a metabolic disorder similar to diabetes with increasing straight, thin and soft. (s. p. 80) There is severe fatty liver fatty changes in the liver; this condition is further aggra- (predominantly in zone 1), often with enormous hepato- vated by an enhanced production of endogenous corti- megaly. Striking dark red skin patches appear, mainly in sol due to adiposity, with the result that a vicious circle the periumbilical and/or inguinal areas as well as in the is established. (1, 2, 5, 10, 34, 51, 61, 77, 78) nuchal region. This skin discoloration as well as the red hair gave the illness the name “red boy”. When animal Leptin, an anti-obesity hormone, can prevent “lipotoxi- protein is supplied, particularly in the form of skimmed city” from damaging hepatocytes by limiting triglyceride milk, complete restitution can be achieved. • Kwashior- accumulation. A deficiency of leptin could be a risk kor as such does not result in liver fibrosis or cirrhosis. factor for NASH. (68) Hyperleptinaemia correlates with However, lymphocytic infiltration of the portal fields and the severity of fatty liver, but not with inflammation or progressive periportal/perilobular fibrosis (as well as pan- fibrosis. • Thioredoxin is a stress-inducible, thiol-con- creatic fibrosis and endocardial sclerosis) can often be taining protein. It is elevated in NASH compared to observed; there is also evidence of necrosis and collapse patients with simple fatty liver. There is a correlation areas as well as signs of cirrhosis. Such changes are attrib- with increasing iron accumulation in the liver cells. utable to the great susceptibility of kwashiorkor patients Therefore, the pathogenesis of NASH may be associated to infections and toxic effects (e.g. aflatoxin). (30, 38) with iron-related oxidative stress.

588 Metabolic disorders and storage diseases

4.5.1 Diabetes mellitus hypoglycaemia. Progressive CNS disturbances develop along with convulsions, clouding of consciousness and In type II diabetes, fatty liver is detectable with a fre- brain oedema. Laboratory values show a pronounced quency of 30Ϫ40%, principally due to adiposity and increase in the transaminases, distinct hyperammoni- insulin resistance. The course is generally more aggres- aemia and moderate cholestasis (without jaundice). sive with rapid progression to cirrhosis; mortality is also Striking features are elevated serum levels of alanine, higher. (39) In diabetics, fatty acid oxidation in the liver glutamine and lysine. There are severe blood coagulation cell remains undisturbed as far as coenzyme A acetate; disorders. • The tumour-necrosis factor is increased. glucose deficiency then stops any further oxidation Hepatomegaly and microvesicular fatty changes in the within the citric-acid cycle. The additional energy liver cells predominate. The hepatocytes are swollen and required has to be supplied through increased degrada- depleted of glycogen. Cell necrosis is found at the tion of fatty acids in the fat depots (ϭ lipolysis) or periphery of the lobules. The smooth endoplasmic reti- reduced storage (ϭ lipogenesis). This inevitably results culum and peroxisomes are clearly increased, while the in hyperlipidaemia, fatty liver and ketosis. Often, so- mitochondria are swollen and deformed; no signs of called glycogen vacuolization of the nuclei is found, inflammation are present. (s. fig. 31.8) Development of mainly in the vicinity of the portal fields. Ketoacidosis chronic liver disease has not been observed as yet. The increases lipolysis, causing steatosis to progress. • In a mortality rate is 30Ϫ50%. (82, 83, 84, 86Ϫ89, 92) type I diabetes, however, fatty liver is less common and is indeed only to be expected in a ketotic metabolic situation, e.g. if the diabetes is not well-regulated. The course is more favourable; the mortality rate is not influenced. (2, 22, 34, 39, 64, 78) (s. fig. 31.1) 4.5.2 Hyperlipidaemia Disorders of lipid metabolism, particularly type IV (endogenous hypertriglyceridaemia), cause fatty liver to develop. Hyperlipidaemia is present in ca. 50% of patients with sonographically determined fatty liver. (2, 56) • Likewise, patients suffering from gout are very often found to have fatty liver. Both these metabolic disorders frequently appear in combination with obesity.

Fig. 31.8: Reye’s syndrome (newborn): fine-droplet fatty changes 5 Reye’s syndrome of hepatocytes as well as glycogen depletion; no signs of inflammation (PAS) ᭤ This syndrome was described by W.R. Brain et al. in 1929. (81) In 1963 it was differentiated as a clinical pathological entity by R.D.K. Reye et al. and defined as a feverish disease of unclear aetiology in infancy. Almost half the children died of cerebral manifestations including brain oedema. (91) 6 Acute fatty liver of pregnancy ᭤ The first descriptions of acute fatty liver of pregnancy were 5.1 Causes given by H.J. Stander et al. (1934) (109); H.L. Sheehan (1940) later defined this disease as a separate syndrome. (107) Causes, which are generally linked to a genetic disposi- tion, include viral infection (e.g. influenza viruses, vari- cella) and the administration of salicylates (involved in 6.1 Clinical picture some 95% of cases). (90) • In the USA, as many as 2,900 This severe clinical picture occurs more often than has cases were reported in 1973 alone, with more than 800 previously been assumed; nowadays, however, the sur- fatalities; a further 1,207 cases were reported between vival rate is higher. Incidence is about 1 in 13,000 births. 1980 and 1997. (80) About 98% of these patients were (97, 104, 105, 114) • The cause is still unknown. Up to now, younger than 20 years of age. The frequency peak was a correlation with high-dosage intravenous tetracycline 1978 to 1980; the disease appeared predominantly in has been assumed. (98) An analogy to Reye’s syndrome December to April, i.e. during the so-called influenza is also under discussion, as this clinical picture is con- peak. It only occurs rarely nowadays: from 1994 to 1997 sidered to be part of the spectrum of pre-eclampsia. Pri- only two cases were observed. (79, 80, 82, 85, 87, 90) (s.p.271) migravidas and multigravidas are equally affected. 5.2 Clinical picture There is evidence of an already existing genetic enzyme defect (3-hydroxyacyl-CoA dehydrogenase?). (102, 111) The onset of the disease is an influenza-like, feverish Acute fatty liver of pregnancy occurs in the third trimes- syndrome. Uncontrollable vomiting results in severe ter, particularly in the 34thϪ36th week. The disease

589 Chapter 31 begins in a state of complete well-being and a hitherto Additional complications were observed during the uncomplicated pregnancy. It comprises nausea and course of disease, including pronounced cholestasis vomiting (often coffee-ground-like), polydipsia, right- (113), portal hypertension (95) and liver rupture (101). sided abdominal pain, headaches and jaundice. Pruritus is rare. Sometimes, gastrointestinal bleeding, oedema 6.2 Prognosis and ascites occur. Encephalopathy develops with neurological symptoms similar to eclampsia. Hypertension, The prognosis depends on early diagnosis and subse- tachycardia, proteinuria and oliguria as well as signs of quent early (even premature) delivery. When a pregnant acute pancreatitis are frequently observed. The whole woman in the third trimester suddenly suffers from clinical picture of the disease is characterized by complaints and/or when the laboratory liver values are multiple organ insufficiency with haemorrhagic diathe- pathological, acute fatty liver of pregnancy should be sis and fulminant hepatic failure. However, relatively suspected and other hepatobiliary diseases excluded as asymptomatic and moderate courses with jaundice have soon as possible. • The previous mortality rates for also been witnessed. mother (ca. 90%) and child (ca. 70%) have been reduced Ϫ Ϫ Laboratory values show progressive hyperbilirubinaemia to 10 35% and 7 50%, respectively. The duration of up to about 15 mg/dl, an increase in alkaline phosphatase the disease up to the death of the mother was on average (3 to 5 times above the normal range) and triglycerides as 11 days (3 days up to 6 weeks), and in cases of survival well as a rise in the transaminases up to about 500 U/l. from 2 to 8 weeks. (97, 104, 105, 106, 110) • After acute Usually, γ-GT is normal. Uric acid, which is elevated in fatty liver of pregnancy has been overcome, the liver most cases, is considered to be an early laboratory marker values normalize within a few days. There is no danger of the disease. Severe hypoglycaemias are evident. A of chronic liver damage. In subsequent pregnancies, striking feature is pronounced leucocytosis (>50,000/µl), there is mostly no tendency to relapse, and there are no with neutrophils predominating. The differential blood contraindications against further pregnancies. (93, 114) count shows giant thrombocytes, target cells and nor- However, a certain risk remains, so that the women moblasts. There is a tendency towards bleeding due to affected should be given the relevant information. Usu- thrombopenia as well as to a decrease in Quick’s value, ally, the patient prefers not to risk a further pregnancy. fibrinogen and AT III; disseminated intravascular coagulopathy is usually present. (96, 99, 105, 106) 6.3 Treatment Computer tomography provides evidence of massive Immediate delivery (per section or vaginally) is the most fatty deposits in the liver. (88, 112) • Sonography,how- important treatment. Further therapy consists of inten- ever, does not generally demonstrate such steatosis. sive medical care. (96, 106, 113) In individual cases, liver There is pronounced hepatomegaly. (94) transplantation may be indicated. (103) Liver biopsy may be required for diagnosis Ϫ unless there are any contraindications. (s. tab. 7.4) In order to detect the characteristic microvesicular (mainly 7 Mauriac’s syndrome centroacinar) fatty changes, fixation without alcohol and examination of the biopsy material in the form of This clinical picture was described by P. M auriac in 1930. a frozen section are necessary. (108) The hepatocytes are Pathogenesis is attributed to pluriglandular dysregula- swollen and resemble so-called foam cells. The nucleus is tion. In combination with difficult-to-control infantile or pyknotic. The mitochondria are deformed. (s. fig. 31.9) juvenile diabetes mellitus, secondary glycogenosis may develop due to large deposits of glycogen and fat in the hepatocytes, resulting in hepatomegaly. • In addition to considerable fluctuations between hyperglycaemia and hypoglycaemia, there is evidence of hypercholesterolaemia, hyperlipidaemia and acetonuria. The clinical picture is characterized by repeated abdominal colic, meteorism, venectasias of the abdominal wall, buffalo obesity, moon face, retarded growth and osteoporosis. Careful monitoring and stabilization of diabetes mellitus are the most essential aspects of the treatment. (115)

8 Protein storage diseases

Fig. 31.9: Microvesicular fatty changes of liver cells in acute fatty Numerous proteins are produced in the liver. Genetically liver of pregnancy (Sudan red) induced disorders of protein metabolism may cause pro-

590 Metabolic disorders and storage diseases teins to be stored in the hepatocytes or even deposited homozygous patients, nothing more than an increase in in the intestinal tract. Primary storage diseases in this the transaminases was observed. Uninhibited neutro- context include: (1.) α1-antitrypsin deficiency, (2.) amy- philic elastase results in a loss of elasticity in the lung, so loidosis, and (3.) α1-antichymotrypsin deficiency. that emphysema and obstructive pulmonary disease develop. However, a combined hepatopulmonary disease 8.1 ␣ -antitrypsin deficiency is rarely witnessed. Extrahepatic manifestations include 1 pancreas fibrosis, panniculitis, glomerulonephritis and α ᭤ The association between lung emphysema and α1-antitrypsin arterial aneurysm. • Heterozygous 1-antitrypsin defi- (α1AT) deficiency was recognized by C. B. Laurell et al. in 1963. ciency does not cause any manifest hepatic or pulmonary α The development of liver cirrhosis due to 1AT deficiency was diseases as a rule, but it is considered to be a predisposing reier first observed in children by E. F et al. in 1968 and in adults factor. Heterozygotes of type PiZ have an increased risk by N. O. Berg et al. in 1972. of HCC both in a non-cirrhotic liver and in the absence of liver disease. Heterozygous carriers are in any case This disease is biochemically more correctly termed α1-protease inhibition deficiency since the protein acts against trypsin and overrepresented in patients suffering from cryptogenic or numerous serine proteases, in particular chymotrypsin and leuco- viral chronic hepatitis and cirrhosis. A higher prevalence cyte elastase. In the pulmonary alveoli, for example, elastase inhib- of PiMZ was found in idiopathic haemochromatosis; α its the breakdown of elastin. • Serum 1AT is a glycoprotein with greater frequency was likewise observed in pregnancies 394 amino acids and 3 carbohydrate chains. It is generally synthesized in the Golgi apparatus of the hepatocytes, although small and twin births. There was a higher prevalence of PiZ in amounts are also formed in the gastrointestinal tract and in macro- polyarthritis rheumatica. (116, 120, 122, 124, 126, 127, 129, α phages. Due to gene mutation, the transport of 1AT from the 134, 135) endoplasmic reticulum (high-mannose type) to the Golgi apparatus is inhibited, so that the “secretion-competent complex” cannot ϭ α α be produced ( 1AT deficiency). (125) Thus 1AT is not transfer- 8.1.2 Diagnosis and treatment red to the blood by way of exocytosis, but remains stored in the globular deposits endoplasmic reticulum in the form of and is sub- Evidence of conjugated jaundice in neonates as well as sequently broken down. • The α1AT gene is localized on chromosome 14 q 31Ϫ32 and possesses about 75 allelic variants, which frequent bronchopulmonary infections in infants arouse are named according to the Pi nomenclature (ϭ protease inhibitor). suspicion of α1-antitrypsin deficiency. In later life, this In homozygosity, normal allele PiM regulates the formation of the genetic cause needs to be ruled out in cases of cryptogenic normal phenotype PiMM, which is present in >90% of the pop- chronic hepatitis or cirrhosis. • Reduction in the α1- ulation. • Alpha1-antitrypsin deficiency is caused by an autosomal recessive mutation of two alleles. • Homozygous defective alleles globulin fraction in electrophoresis to <2 rel.% is an im- α are: PiZZ, PiSS, PiZnull, PiPP, PiWW, Pinull, PiMmalton. They portant indicator of 1-antitrypsin deficiency, because show plasma concentrations between 0% and 15% of the normal α1AT is the main component of α1-globulins (90%). α -AT value. These homozygous combinations of defective alleles 1 Diagnosis is confirmed by determination of α1AT in the are accompanied by a high risk of pulmonary emphysema, newborn serum. Normal values range between 190Ϫ330 mg/dl or cholestasis, infantile hepatitis, cirrhosis and hepatocellular carci- Ϫ noma. • PiMS, PiMZ, PiSZ, PiFZ and PiMnull are deemed to be 80 147 IU/ml. The half-life is approx. 5 days. Values heterozygous defective alleles. In Europe, the allele type PiMZ is <20% of the normal level suggest a homozygous type, found in 3%, PiMS in 7%, and PiSZ as well as PiZZ in 1% of while a 40Ϫ70% reduction below normal points to a the population. Plasma values range between 42% and 60% of the heterozygous type. Identification of the phenotype of normal α1AT value. Heterozygosity thus causes only moderate α1AT is possible. Alpha1-AT is normally also found in and/or intermediary α1-AT deficiency, but is nevertheless considered to be a predisposing factor of liver disease. (117, 118, 120, tears, rhinal secretion, saliva, duodenal juice, bronchial 126Ϫ128, 132) secretion, cerebrospinal fluid and breast milk. • Liver histology points to cholestasis or changes in the biliary duct- 8.1.1 Clinical picture ules. PAS-positive, diastasis-resistent, 1Ϫ40 µm sized globular deposits of α1AT in the hepatocytes are typical The great variability of this clinical picture depends upon features, mainly found in the periportal area (zone 1), but allele type, age at initial manifestation and individual pro- only in homozygosity. (119, 120, 126, 133) (s. fig. 31.10) Ϫ Ϫ gression. • About 0.02 0.06% (1 : 1,500 3,500) of all Inflammatory and fibrotic reactions are detectable in the newborns are homozygous carriers of defective alleles. In vicinity, although α AT is not considered to be a toxic Ϫ 1 10 12% of these, conjugated hyperbilirubinaemia with agent. Copper content in the liver is increased. In pro- intrahepatic cholestasis and pruritus develops within the gressive fibrosis, there is generally a rise in P-III-P in the first months of life. A lethal course is possible; in most serum. The prognosis for α1-antitrypsin cirrhosis is much cases, the cholestasis present in the newborn disappears poorer than for other types of cirrhosis; the mean survival by the age of six or seven years. Hepatosplenomegaly gen- rate is reported to be 2 years after a diagnosis has been Ϫ erally persists. In 10 15% of the patients, cirrhosis is established. In 10Ϫ30% of cases, hepatic carcinoma can most likely to develop. Additional genetic or exogenous be expected. (127, 131, 136) factors are held responsible for manifestation and progression. An α1-antitrypsin deficiency of the PiZZ type Causal treatment is not yet possible, but gene therapy caused cirrhosis in 45Ϫ50% (as shown after autopsy) and may prove feasible, i.e. integration of a normal allele M liver carcinoma in 25Ϫ30% of adults. In some 50% of into the genome of the patient’s somatic cells. Substitu-

591 Chapter 31 tion with α AT (e.g. infusion or aerosol inhalation of ules (so-called amyloid tumour or paramyloid). AL amyloidosis 1 idiopathic ϭ α AT) is less promising. An increase in α AT synthesis may be: (1.) ( primary) without any associated basic 1 1 disease or (2.) reactive (ϭ secondary) in cases of multiple myeloma, has been attempted by means of androgens and oestro- Waldenström’s syndrome, Bence-Jones plasmocytoma and various gen antagonists (e.g. tamoxifen). • In progressive cirrho- type B cell tumours. sis and imminent liver failure, liver transplantation is Further differentiation distinguishes between AF amyloid (ATTR) indicated. (123, 127, 130) The five-year survival rate in (amyloid types in familial amyloidosis), endocrine EA amyloid and children was 83%. (121) Transplantation allows a pheno- AS amyloid (occasionally detected in old age in its isolated form AB amyloid β typical healing to take place. in the heart as well as in the brain) and (A 2m) (often observed in the osseous system during long-term dialysis).

8.2.1 Clinical picture and diagnosis Clinically, pronounced hepatomegaly predominates; later on, splenomegaly also develops in most cases. An increase in alkaline phosphatase is observed at a relatively early stage. Severe courses of intrahepatic cholestasis have been observed. (137, 144, 146, 147, 151, 154, 155) In most cases, these involve obstructive cholestasis due to deposits of fibrils between the sinusoidal wall and hepatocytes, so that the canaliculi and the ductules are compressed. Hepatic enzymes and liver function tests are normal or deviate only slightly from normal values. Jaundice, which appears only in the late phases, is indic-

Fig. 31.10: Serologically confirmed α1-antitrypsin deficiency type ative of a poor prognosis. A decrease in cholinesterase is PiZ in a juvenile patient (homozygosity). Globular α1-antitrypsin considered to be a sign of increasing amyloid deposition deposits in the hepatocytes (Ȇ); PiZ immunohistochemistry with with subsequent compromising of de novo synthesis. PiZ antibody ATZ11 Factor X is often decreased. • In CT scanning, a reduced contrast medium enhancement in the area of amyloid storage may be detected. Scintigraphy by means of 8.2 Amyloidosis 99mTc-sulphocolloid shows markedly decreased uptake in the spleen as compared to the liver, and also metasta- Amyloid is an insoluble protein-polysaccharide complex sis-like storage defects. (156) • The tracers 123I-SAP or consisting of fibrillary protein, AP component and gly- 99mTc-SAP show abnormal uptake into amyloid de- cosaminoglycan; this AP protein is identical with the posits. (143) In individual cases, involvement of other regular serum amyloid P (ϭ SAP). Amyloid is mainly organs (kidney (137, 140), heart, spleen (150, 152, 155), stored in the extracellular spaces. The substance shows a intestines, CNS, carpal tunnel syndrome) suggests the irchow ϭ strong affinity to iodine (R. V , 1854: “amyloid” existence of amyloidosis. Often, there is reddish-brown “starch-like”) and Congo red (H. Puchtler et al., 1962). dyschromia. (141) • Rectum biopsy, when carried out Under a polarizing microscope, amyloid shows a green expertly, provides diagnostic accuracy in 80Ϫ85% of staining with double refraction. Electron microscopy Ϫ µ cases. Aspiration biopsy from bone marrow or subcuta- reveals a fibrillary structure with 7 10 m fibres. Vari- neous abdominal fat tissue only has an accuracy of ous amyloid types can be distinguished, depending on 40Ϫ50%. (s. fig. 31.11) the different kinds of protein in the fibrils. Secondary amyloidosis is the most common form. • Autosomal dominant hereditary amyloidosis is transmitted by means of structurally altered transthyretin (TTR). Meanwhile, more than 60 mutations of TTR have been detected. The gene responsible is located on chromosome 18; a gene test is already available. (138, 141) AA amyloid appears in a generalized form and is mainly stored perireticularly in the kidney, spleen and liver. This kind of amyloidosis occurs as (1.) a congenital form in cases of familial Medi- terranean fever, (2.) an idiopathic (ϭ primary) form without any associated basic disease, and (3.) a reactive (ϭ secondary) form in chronic inflammations or tumours (e.g. Hodgkin’s disease) as well as in drug abuse and AIDS. AL amyloid (AIg) possesses fibrils composed of fragments from Ig light chains of the kappa or lambda type. This amyloid is stored pericollagenically both in a generalized and organ-localized form. Fig. 31.11: Liver amyloidosis: Perisinusoidal amyloidosis with Deposits in organs, including the liver, may take the form of nod- atrophic hepatocyte trabeculae (HE)

592 Metabolic disorders and storage diseases

Morphology: Amyloid is also stored in the small portal vein Tyrosinaemia type I is very rare (incidence 1 : 100,000 births). It is branches of the liver. Depending on the guiding fibres used by caused by an autosomal recessive defect of fumarylacetoacetate amyloid, it is possible to differentiate between perireticular and hydrolase (localized on chromosome 15 q 23Ϫ25), which impairs pericollagenous amyloidosis. The vascular amyloid involvement tyrosine degradation. Tyrosine metabolites accumulate at the point together with the solidity and fragility of the liver are the cause of where the metabolic process is compromised. This results in either occasional excessive haemorrhagic tendency (142); this condition is an acute clinical course initiated immediately after birth and usu- also given after liver biopsy. Therefore, percutaneous liver biopsy ally leading to a quick death or a chronic course in which patients must be considered as a contraindication. (s. tab. 7.4) If liver histol- reach adult age. (160, 161, 163, 164) ogy is required, the sample should be obtained by laparoscopic Tyrosinaemia type II liver biopsy, so that targeted treatment measures can be applied is caused by reduced activity of tyrosine “with visual control” should complicative bleeding occur. (s. pp aminotransferase, resulting in a greater concentration of tyrosine congenital- 157, 158) The biopsy specimen is pale pink. The liver surface in the serum. This may develop into an independent hereditary appears pale and wax-like with coarse reddish marbling. (s. fig. clinical picture or physiological hypertyrosinaemia, neonatal-transitory 31.11) which occurs in about 10% of newborns as a event. 8.2.2 Prognosis and treatment 9.1.1 Clinical picture The prognosis for amyloidosis is poor. In AL amy- The gene mutation inhibits hydrolytic cleavage of loidosis, fewer than 20% of patients had a five-year sur- fumarylacetoacetate into fumarate and acetoacetate. vival rate. A course of 1Ϫ2 years is regarded as a mean Consequently, the toxic precursors maleylacetoacetate survival period. The outcome depends mainly upon and fumarylacetoacetate accumulate in the liver and renal and cardiac amyloidosis; the prognosis regarding kidneys. They possess a reactive double bond and can the liver is determined by the development of portal therefore react with macromolecules to assume the hypertension or acute liver failure. (139) Cytostatics are properties of alkylating substances. In addition, intra- recommended for the treatment of benign or malignant cellular glutathione deficiency develops due to the stable B cell tumours in type AL amyloidosis, while melphalan complex formation with glutathione, favouring lipid per- and prednisolone are used for concomitant amyloidosis. oxidations. Enhanced formation of δ-aminolaevulinic However, therapeutic measures are generally limited. acid can also be observed during occasional attacks of The mobilization of amyloid deposits may be attempted acute intermittent porphyria (G. Mitchel et al., 1990). by administering dimethyl sulphoxide (1.5Ϫ10.0 g/day). • In secondary amyloidosis, treatment of the underlying The acute course in newborns is characterized by vomit- disease is the main issue; individual cases have been ing and diarrhoea as well as growth disturbances. Hepa- reported in which amyloidosis disappeared due to suc- tosplenomegaly, hypoalbuminaemia, hypercholesterin- cessful therapy. • In hereditary amyloidosis, the indica- aemia and hypoglycaemia as well as oedema/ascites and tion for liver transplantation is given, since the liver is coagulopathy develop very rapidly. A striking feature is indeed the main site of transthyretin synthesis. Mutant the early and marked rise in the α1-foetoprotein value transthyretin is no longer detectable in the serum after in the serum. Excretion of succinylacetone (>50 nmol/l) transplantation. (145, 148, 153, 155) Regression of extra- and delta-aminolaevulinic acid in the urine is noticeably hepatic amyloid deposits has been reported following increased. Methionine, phenylalanine and tyrosine are transplantation. clearly elevated in the serum. A slight rise in transaminases and serum bilirubin occurs. Death is due to acute liver failure. • There is histologic evidence of extensive 8.3 ␣1-antichymotrypsin deficiency necrosis, fatty infiltration, cholestasis and regenerative nodes in the liver. • Should the newborn survive the first In genetically (autosomal dominant) induced α1-antichymotrypsin deficiency, this inhibitor of serine prote- few months, the proximal renal tubule suffers complex Fanconi’s syn- ases is not secreted in sufficient quantities from the damage, resulting in the clinical picture of drome: glucosuria, aminoaciduria, phosphaturia includ- hepatocytes or alveolar macrophages. Therefore α1- antichymotrypsin is stored in these cells. The deposits ing osteomalacia, and renal tubular acidosis with poly- can be detected as cellular inclusions by light micro- uria. scopy. Patients suffering from this condition may The chronic course is characterized by a milder form. develop chronic hepatitis and cirrhosis. (157Ϫ159) The general symptoms are less pronounced, and often they do not appear before the patient reaches school age. Hepatosplenomegaly is present. Laboratory findings 9 Amino acid storage diseases include hypoalbuminaemia, coagulopathy and markedly elevated serum values of α1-foetoprotein, methionine, 9.1 Hereditary tyrosinaemia tyrosine and phenylalanine. Activity of the fumarylacetoacetate hydrolase in leucocytes, fibroblasts and ᭤ This clinical picture was described for the first time by M.D. hepatocytes is increased. • The liver is granular and firm Baber in 1956; it was identified as an enzyme deficiency by B. with a yellowish colour. Histologically, the picture is Lindblad et al. in 1977. similar to that of galactosaemia (fatty changes, tubular

593 Chapter 31 transformation, cholestasis, periportal fibrosis, central Diagnosis is based upon hyperammonaemia, which is sclerosis). Within a few months, micronodular cirrhosis detectable either spontaneously or after the oral intake is detectable with early multifocal liver cell carcinoma. of proteins Ϫ or, most obviously, following intravenous (160, 163, 166) • Fanconi’s syndrome (see above) also devel- infusion of amino acids. The respective amino acids are ops in the chronic course. Occasionally, there are symp- increased in the serum prior to the disturbed metabolic toms of peripheral neuropathy. reaction. Argininosuccinate is only detectable in the urine. A striking feature in these patients is their thin, 9.1.2 Treatment brittle hair. With defective ornithine transcarbamylase, there is an increase in orotic acid, uridine and uric acid prognosis The is determined by the early onset of acute in the urine, while the respective citrulline concentration liver failure in the newborn and, in the following is decreased. The determination of OTC activity in liver months or years, by the development of hepatocellular tissue verifies the diagnosis and facilitates a genomic liver transplantation carcinoma. (163, 167) •A is thus analysis. (172) The allopurinol test can be applied for the recommended as from the second or third year of life. identification of heterozygosity (or the mild form of (162) Dietary measures (avoidance of methionine, tyro- OTC deficiency). The liver shows steatosis, portal sine and phenylalanine as nutritional components) have inflammation and portal fibrosis. not proved particularly successful. • Good therapeutic results were achieved when 2-(2-nitro-4-trifluoromethyl- A defect in argininosuccinate synthetase coincides with benzoyl)-1-3-cyclohexanedione) (NTBC) was applied. markedly elevated citrulline values in the blood. Neither This substance is an inhibitor of 4-hydroxyphenylpyru- citrullinaemia nor a carbamylphosphate synthetase vate dioxygenase, which prevents the accumulation of defect cause liver damage. By contrast, an argininosuc- succinylacetone. (165) Even the risk of HCC develop- cinase defect leads to microvesicular steatosis and mega- ment was reduced by this substance. mitochondria with dilatation of the ER. Treatment involves a low-protein diet (0.5Ϫ0.7 g/kg 9.2 Disturbances of the urea cycle BW/day) with a sufficient supply of calories. Substitu- tion of essential amino acids (in about the same quan- Six enzymes are involved in the urea cycle: (1.) carbamoylphos- tity) is required. • The administration of benzoate phate synthetase (CPS), (2.) ornithine transcarbamylase (OTC), Ϫ (3.) argininosuccinate synthetase, (4.) argininosuccinate lyase, (5.) (0.1 0.25 g/kg BW/day), arginine hydrochloride (1 arginase, and (6.) N-acetyl glutamate synthetase Ϫ as well as mmol/kg BW/day) or sodium phenylacetate (0.3Ϫ0.5 g/ enzymes involved in supply reactions. They may be compromised kg BW/day) (phenylbutyrate tends to be more effective) by a genetic defect. Up to now, 6 congenital disorders of the urea facilitates nitrogen excretion via other metabolic path- cycle are known. The cumulative frequency is estimated at ways. (168Ϫ170) • With an enhanced excretion of orotate 1 : 8,000. • The genetic disorder is autosomal recessive; only the ornithine transcarbamylase disorder (ϭ OTC deficiency) shows a or other metabolites of pyrimidine synthesis, the admin- dominant chromosomal pattern of transmission (chromosome p istration of allopurinol leads to an increase in the excre- 21.1). This is the most frequently detected intramitochondrial tion of nitrogen via metabolites from pyrimidine synthe- defect to date (1 : 14,000). (172) • Following preliminary detoxifica- sis. Ammonia and urea precursors are eliminated by tion of ammonia at the site of formation by reaction with glutamate (whereby glutamine is formed), definitive detoxification takes haemodialysis. In individual cases, liver transplantation place in the urea cycle and by hepatic glutamine synthesis. • The is indicated. (171) urea cycle has two other functions: (1.) de-novo synthesis of arginine and (2.) regulation of the acid-base balance by consumption of bicarbonate. (s. pp 57, 58) (s. figs. 3.12, 3.15) 9.3 Cystinosis The clinical symptomatology, which is almost the same Autosomal recessive cystinosis is caused by an enzyme- in all enzymatic disturbances of the urea cycle, is caused induced blockage of cystine degradation, particularly in by hyperammonaemia. An arginase defect results in the RES lysosomes of the bone marrow, liver, spleen enhanced excretion of lysine, ornithine and cystine. and kidneys. Especially in the stellate cells of the spleen Neurological symptoms such as hyperreactivity and ath- and to a lesser extent of the hepatic lobule centres, hex- etosis followed by paresis and tetraplegia predominate. agonal and rectangular cystine crystals are found, point- In neonatal manifestation of OTC deficiency, lethargy, ing at an early stage to cystinosis. There is evidence of vomiting, refusal to take food, hyperventilation and hepatosplenomegaly and microvesicular steatosis. The hypothermia develop quickly. Death ensues in coma clinical picture of the infantile type presents as a Fan- within a few days. Manifestation in infants or adoles- coni syndrome. (s. pp 593, 597) The children affected die cents is based upon the residual activity of the defective in the first five years of life. enzyme. This course is also characterized by vomiting and lethargy. The clinical picture is aggravated by a pro- 9.4 Homocystinuria tein-rich diet, whereas protein reduction improves the clinical situation. Without treatment, death occurs in a This rare disease has an autosomal recessive inheritance hepatic coma. pattern. It is based on a deficiency of cystathion-β syn-

594 Metabolic disorders and storage diseases thase, so that homocystein and other metabolites (e.g. VLDL and LDL values are found, leading to the devel- methionine) accumulate and are eliminated in increased opment of skin and tendon xanthomas, lactate acidosis, quantities in the urine. There is evidence of disturbed a slight increase in transaminases, a tendency towards mental development and a marked tendency to throm- infection (due to leucopenia related to abnormal glu- bosis in the arterial system. Liver steatosis (mainly in cose-6-phosphatase transport), weakened skeletal zone 1) and hepatomegaly with subsequent portal fibro- muscles, bleeding tendency (due to abnormal platelet sis can be seen. function), hyperuricaemia (with possible manifestations of gout, nephrocalcinosis, kidney stones) and osteoporosis. Hyposomia with fat pads, particularly in the buc- 10 Carbohydrate storage diseases cal area, is often witnessed. Diagnosis is additionally confirmed by a glucagon test (no or inadequate rise in Carbohydrate storage diseases include: (1.) glyco- the blood sugar level) as well as fructose or galactose genoses, (2.) galactosaemia, (3.) hereditary fructose tests and liver biopsy. (s. fig. 31.12) • The occurrence of intolerance, and (4.) fructose-1,6-biphosphatase defi- adenoma or HCC is associated with an increase in fatty ciency. acid synthesis. Subtype I b is characterized above all by susceptibility to infection with leucopenia. Recurrent oral ulcers are often a cardinal symptom. The liver 10.1 Glycogenoses shows evidence of enlarged, polygonal hepatocytes with Glycogenoses are congenital metabolic diseases with enzyme bright cytoplasm and centrally located small nuclei as a defects in which glycogen cannot be broken down to glucose. This result of glycogen storage. Occasionally, Mallory bodies results in normal or structurally changed glycogen being stored in and glycogen vacuolation of the nuclei can be found. the organs in ever-increasing quantities. To date, ten types (types The hepatocytes have a pronounced (phytocell-like) cel- IϪX) have been defined. Types VIIIϪX are very rare and partly lular membrane. (175Ϫ177, 179Ϫ184) present as subgroups of the other types. • The incidence of types IϪVII ranges between 1 : 20,000 and 1 : 40,000 births with geographic differences. A relative frequency was determined from 1,192 cases: type I (23%), type II (15%), type III (21%), type IV (2.5%), type V (6%), type VI (30%) and type VII (2.5%). • Trans- mission is autosomal recessive. With regard to the extent of the enzymatic disturbance or the involvement of regulatory enzymes, pronounced heterogeneity can be observed within the individual types. • Liver disease only develops in types I, III, IV and VI. Hepatomegaly is also found in type II and in the rare types IX and X. • Differential diagnosis of glycogenoses and their subtypes is not possible simply using liver histology. However, it can be achieved by means of additional histochemistry, quantitative determination of glycogen and enzyme analysis. (174, 178, 186, 187)

Gierke’s disease (type I)

᭤ Hepatorenal glycogenosis was described for the first time by S. Van Creveld in 1928 and resolved in terms of pathological morphology by E.O.E. von Gierke in 1929. This genetic defect (localized Fig. 31.12: Gierke’s disease: phytocyte-like hepatocytes surrounded on chromosome 17) causes the complete or partial absence of glu- by a delicate network of fibrosis cose-6-phosphatase activity (subtype Ia). (179) • Enzymatic activity is only detectable after the application of detergents. There is a defect in the translocase of glucose-6-phosphatase at the endoplas- Treatment consists of prevention or elimination of hypoglycaemia. mic reticulum membrane. This defect is also found in adults (sub- In newborns and infants, this can be achieved by the continuous type Ib). • Disturbance of this microsomal phosphate/pyrophos- application of formula diets, if required via nasogastric tube feed- phate translocase may occur (subtype Ic). • Glucose-6-phosphatase ing. The administration of allopurinol may also be advisable. A is necessary for the discharge of glucose from the liver when glu- starch diet (e.g. uncooked corn starch) is then used to ensure that cose-1-phosphate is supplied by glycogenolysis. This results in an glucose is released and resorbed slowly in the intestinal tract. (173, accumulation of glucose-1-phosphate, which in turn stimulates the 177) After puberty, the course of disease is usually less pro- neosynthesis of glycogen. However, glucose-1-phosphate is also nounced. In the long term, especially in adenoma-related compli- broken down by glycolysis, with an increased formation of lactate, cations, liver transplantation may be indicated. (185) acetyl-coenzyme A and glycerol-3-phosphate. The last two are basic products for the hepatic synthesis of fatty acids and triglycer- Pompe’s disease (type II) ides. Generalized glycogenosis type II, also called Pompe’s disease (J.C. The clinical picture is characterized by hepatomegaly Pompe, 1932), is caused by a deficiency of lysosomal acidic ␣1,4 due to deposits of glycogen and triglycerides and by glucosidase. This enzyme is responsible for the degradation of gly- marked kidney enlargement (no splenomegaly as occurs cogen and maltose within the lysosomes. Glycogen is accumulated in all organs, particularly in the heart, but also in the liver. The in lipoidosis or cirrhosis). • Severe metabolic disorders disease may occur in the newborn (death due to heart failure, often such as hypoglycaemia and hyperlipidaemia (triglycer- within the first 12 months of life), but may also become manifest in ides, free fatty acids, cholesterol) as well as increased infants and adults. • Clinical symptoms include weakened skeletal

595 Chapter 31 muscles, hyperlipidaemia, increased values of the muscle enzymes phy and motor dysfunctions as well as dilative cardio- aldolase and CK, macroglossia as well as pronounced cardiomeg- myopathy may be observed. The disease can also take a aly and moderate hepatomegaly. Mental development is not impaired. The glucagon test is normal; hypoglycaemia does not protracted course, so that the patient even reaches ado- occur. Diagnosis is confirmed by the detection of reduced enzyme lescence. • There is no specific course of treatment. Liver activity in biopsy material obtained from the liver or muscle. Vacu- transplantation is indicated, whereby a surprisingly pos- oles can be demonstrated in the liver cells. • No specific treatment itive effect on extrahepatic complications and growth is known. The genetical engineering of acid glucosidase (rhGAA) (185) could become a new form of therapy in future. In the later stages retardation can be expected. of life, the prognosis quoad vitam is determined by heart failure, pneumonia and respiratory insufficiency. Hers’ disease (type VI)

Hepatic glycogenosis ers Cori’s disease (type III) (type VI) (G.H. H , 1959) is due to hepatic phosphorylase deficiency. Subtype VIa is caused by a lack of phosphorylase-B kinase, Hepatomuscular glycogenosis (G.B. Forbes, 1952; G.H. Hers, 1959) is and it is transmitted by the x-chromosomal glycogen phos- caused by a deficiency of amylo-1,6-glucosidase (debranching recessive route. Subtype VIb shows a deficiency in phorylase, enzyme). Consequently, degradation of the glycogenic branched and its transmission is autosomal recessive. In the mus- chains is impaired, yielding an abnormal residual molecule (limit culature, the analogous enzyme is, however, intact. Nevertheless, dextrinosis). Gluconeogenesis from lactate is possible. In Forbes there is pronounced genetic and phenotypical heterogeneity. subtype, deposits of the markedly branched glycogen (with short clinical picture external chains) are observed in the heart, liver and musculature; The shows moderate hepatomegaly. The in Forbes-Hers subtype, they are found in the hepatocytes only. normal glycogen is stored in focal form at the periphery Further subtypes (up to III F) have been described. of the lobules. There is a mixed pattern of small and large hepatocytes, giving the picture of an irregular Clinical symptoms include hepatomegaly, increased mosaic. Hypoglycaemia occurs only during fasting. No transaminases, hypoglycaemia (glucose may be released other biochemical deviations are observed. The progno- from glycogen when the terminal glucose fragments split sis is relatively good when dietary instructions are off), hyperlipidaemia and moderate lactate acidosis. The adhered to. Mental functions are normal. glucagon tolerance test is positive (ϭ no increase in blood sugar); the galactose test and the fructose test are normal. Histologically, the liver shows numerous glyco- Type IX and type X gen vacuolizations of the nuclei (s. fig. 31.1), slight These benign glycogenoses are due to a defect in hepatic phospho- steatosis and periportal fibrosis (also transition to cir- rylase kinase or cAMP-dependent phosphorylase kinase. Glycogen rhosis). Adenomas frequently appear. • The treatment is deposited unevenly in the hepatocytes; there is evidence of hepa- consists of frequent small meals rich in carbohydrates tomegaly with fine-droplet steatosis and occasional fibrosis. Hyperlipidaemia and elevated GPT values are present. In the and proteins plus additional dietary corn starch prepa- course of time, the patient is able to catch up on physical growth, rations. and hepatomegaly recedes.

Andersen’s disease (type IV) 10.2 Galactosaemia Liver-cirrhotic, reticulo-endothelial glycogenosis type IV (D.A. Andersen, 1956) is a defect of the branching enzyme amylo-1,4-1,6- Hereditary galactose intolerance (A. v. Reuss, 1908; F. Göppert, 1917) transglucosidase. There is a disturbance in the formation of glyco- is caused by an autosomal recessive disorder in galactose metabo- gen side-chains, which results in the production of a low-branched lism. • Type II is characterized by an enzyme defect in galactose- glycogen with long side-chains (amylopectinosis). This abnormal 1-phosphate uridyltransferase. (Type I, caused by a defect of galac- structure causes low solubility, resulting in the deposition of the tokinase, only affects the eyes and is therefore not discussed here.) malstructured glycogen in the hepatocytes at the periphery of the Transferase deficiency affects several organs, particularly the liver, lobule in the form of eosinophilic or colourless, granular, PAS- and results in severe damage. Galactonate and galactite develop as positive substances. This abnormal glycogen has a cellulotoxic toxic metabolites, which are deposited in the tissues; galactite is effect. It is also deposited in the spleen, lymph nodes and RES. also detectable in the urine. (188, 191) Clinical symptoms include hepatosplenomegaly and The prevalence of the disease is about 1:35,000 to increased transaminases as well as an occasional rise in 1:70,000 births. With the help of neonate screening, the cholestasis-indicating enzymes. Histologically, the liver defect can be discovered and treated at an early stage. • specimen shows a number of giant cells, cell necrosis The enzyme coding for transferase is on chromosome 9 and cholestasis. The abnormal glycogen stored in the p13; there are various mutations and pronounced poly- hepatocytes can to a certain extent be removed by dia- morphisms. Accordingly, several variants displaying dif- stasis digestion, and it takes on a violet stain when in ferent kinds of enzymatic activities have been described contact with iodine (in contrast to the usual reddish- in many different places (the Duarre, Rennes, Los Ange- brown colour); PAS staining is positive. Diagnosis can les and Chicago variants as well as the Caucasian and also be reached using rectal biopsy: macrophages with Negroid variants). Usually, the defect can only be globular inclusions containing amylopectin are found. detected by means of the galactose tolerance test. A The further course is determined by portal hypertension healthy person oxidizes 30Ϫ50% of orally administered with the formation of ascites and a haemorrhagic ten- galactose to CO2 in 5 hours, whereas in transferase defi- dency. In addition, diminished reflexes, muscular atro- ciency, only 0Ϫ8% is oxidized. • Galactonate causes syn-

596 Metabolic disorders and storage diseases thesis disorders of glycoproteins and glycolipids in the is observed in babies and infants. • During adolescence liver cell by the consumption of UDP. Due to the accu- and in adults, a chronic course may develop, charac- mulation of galactose-1-phosphate, the consumption of terized by hepatomegaly, hypophosphataemia, hypo- phosphate is increased with a subsequent decrease in glycaemia, blood coagulation disorders and an increase ATP and gluconeogenesis. • The deposits of galactose- in transaminases as well as jaundice and moderate cho- 1-phosphate in the proximal renal tubular cells lead to lestasis. Phosphaturia results in osteomalacia. Hyper- the development of Fanconi’s syndrome (glucosuria, magnesaemia is a striking feature. • Histological findings aminoaciduria, phosphaturia, acidosis) (s. pp 593, 594). include a fatty liver with liver cell necrosis and increasing fibrosis; the liver cell plates show tubular trans- The clinical picture sets in immediately after birth, as formation. Giant cells are often found. At a later stage, soon as milk (including breast milk) is given. The symp- cirrhosis develops. (193, 195Ϫ197) • When the intake of toms are vomiting, diarrhoea, no weight gain and galac- fructose (or sorbitol) is avoided, even patients with a tosuria. As early as the second week, pronounced hepa- homozygous genotype are symptom-free. The diagnosis tomegaly (or hepatosplenomegaly) is observed, often is based upon the determination of liver aldolase B or accompanied by jaundice and cholestasis. The findings on the fructose tolerance test: correspond to those in haemolysis. Transaminases are elevated, liver functions are increasingly compromised, Method: Oral administration of 200 mg/kg BW fructose in a and metabolic acidosis is generally in evidence. Cata- 20% solution over a period of 30 minutes. After establishing racts develop. • The diagnosis is confirmed by galacto- the initial values, both glucose and phosphate are determined suria and a rise in galactose and galactose-1-phosphate every 10 minutes; after 1 hour, the intervals are extended to 30 minutes. The test findings are pathological when serum glucose concentrations in the blood as well as reduced transfer- decreases to <40 mg/dl and phosphate to <1.5 mg/dl. Hypo- ase activity in the erythrocytes. • Histologically, the liver glycaemia requires an immediate i.v. glucose infusion. shows mixed-droplet fatty changes, cholestasis with duc- tular proliferations, liver cell necrosis, collapse of reticu- Treatment consists of completely avoiding fructose and lar fibre structures as well as pseudoglandular and/or commercially available cane sugar as well as excluding tubular transformation processes of the liver cell plates sorbitol from i.v. infusions. When this regime is strictly around the canaliculi. Within a period of 3Ϫ6 months, adhered to, prognosis is good and life expectancy unaf- micronodular cirrhosis develops, followed by ascites and fected. increasing liver insufficiency. (189, 190, 192) Treatment is successful when the disease is recognized 10.4 Fructose-1,6-biphosphatase deficiency early enough and when nutrition is free of galactose and lactose, so that the prognosis is generally considered to Due to the autosomal recessively inherited reduction in fructose- 1,6-biphosphatase activity in the liver, the gluconeogenesis of lac- be favourable. Organ damage can be halted or indeed tate, glycerine and glucogenic amino acids is inhibited. If fructose prevented completely; occasionally, there is (partial) or glycerine are supplied, phosphate and bicarbonate are con- recession. The UDP galactose required for cell metab- sumed in higher quantities and lactate production is increased. olism is supplied from UDP glucose. (192) This results in metabolic acidosis. The clinical picture is much less pronounced than in 10.3 Hereditary fructose intolerance hereditary fructose intolerance (type aldolase B). When fructose is supplied or when infections develop, the Hereditary fructose intolerance is caused by an autosomal reces- affected children may suffer from metabolic disorders, fructose-1-phosphate aldolase sive hereditary defect of the enzyme . such as hypoglycaemia, nausea, vomiting, diarrhoea, Whenever fructose is supplied, severe hypoglycaemia and functional disorders occur in the liver, kidneys and CNS. • The preva- hyperventilation, convulsions, lactate acidosis and keto- lence is estimated at 1:20,000 births. As with galactose intolerance, sis. The glucagon tolerance test is pathological (ϭ no the gene which codes aldolase B is also localized on chromosome increase in blood sugar). • Histology shows a fatty liver. 9. This enzyme defect causes fructose-1-phosphate to accumulate Diagnosis can be confirmed by measuring the fructose- in the liver and tissue. The cleavage of fructose-1,6-biphosphate is only slightly compromised since the enzymes aldolase A and C are 1,6-biphosphatase activity in the liver tissue. available for this process. • The consumption of phosphate and Treatment consists of completely avoiding fructose and, ATP in the tissue results in various functional disorders: (1.) inhibition of gluconeogenesis in the liver and kidneys, (2.) increase in if necessary, in correcting metabolic acidosis, electro- lactate in the serum with metabolic acidosis, (3.) decrease in pro- lytes and blood sugar values. tein synthesis in the liver, and (4.) functional disorders of the proximal tubular cells with development of Fanconi’s syndrome.(s.pp 593, 594) (193, 194, 196, 198) 11 Lipid storage diseases The clinical picture is characterized by nausea, vomiting, diarrhoea, abdominal pain, dizziness and hypoglyc- 11.1 Wolman’s disease aemia, not only following the intake of fructose (oral, Xanthomatosis, an autosomal recessive inherited disorder, was intravenous), but also after sorbitol infusions (sorbitol described by A. Abramov, S. Schorr and M. Wolman in 1956. Proba- is converted to fructose in the organism). Growth failure bly, this rare clinical picture (about 40 cases have been reported to

597 Chapter 31

date) was already published by H. Dienst and H. Hamperl as early as 1927. Some cases may indeed have been attributed erroneously to Niemann-Pick disease. • Wolman’s disease is caused by a considerable reduction or complete absence of intra-lysosomal lipase activity. In acid pH, the lipase catalyzes the hydrolytic cleavage of cholesterol esters and triglycerides in the lysosomes. This enzyme defect results in an excessive storage of cholesterol esters and triglycerides in the abdominal organs, skin and nervous system. The mutant gene for isoenzyme A of acidic lysosomal lipase is located on chromosome 10. In homozygotes, lipase activity in the liver is reduced to less than 10% of the normal value, in heterozygotes to around 50%. • The enzyme defect is responsible for (1.) storage of cholesterol esters and triglycerides in the hepatocytes, Kupffer cells and macrophages as well as in various other body cells, and (2.) disturbance of cholesterol homoeostasis in the blood, since the lysosomes release an insufficient quantity of free cholesterol into the cytosol. For this reason, the regulation of cholesterol metabolism in the cytosol is considerably impaired: (1.) inadequate or Fig. 31.13: Cholesterol ester storage disease. Fine-droplet fatty no inhibition of the synthesis of cholesterol and the LDL receptor, changes in the hepatocytes. Widely extensive small and larger lipid and (2.) inadequate or no stimulation of cholesterol esterification vacuoles in the liver cells and foam cells of the portal field (Sudan with saturated fatty acids. black) (s. fig. 21.5). Same patient as in fig. 31.14 The clinical picture, which is already manifested in early infancy, comprises vomiting, diarrhoea, growth failure and meteorism. Hepatosplenomegaly and anaemia develop rapidly. Multiple xanthomas of the skin appear. CT scanning shows enlarged adrenal glands (due to xanthomatous redifferentiation), often with finely spot- ted calcifications. Deposits of cholesterol esters, triglycerides and, to a certain extent, phospholipids are found in the spleen, liver, small intestine, lymph nodes, lungs, skin and nervous system. The foam cells detectable in the bone marrow differ from Pick cells in that they lack sphingomyelin. Transaminases are increased; liver function is markedly compromised. Death usually ensues within the first year of life. (199Ϫ201)

11.2 Cholesterol ester storage disease Fig. 31.14: Light yellowish-red, smooth surface in fatty liver due to cholesterol ester storage (13-year-old girl). Same patient as in Cholesterol ester storage disease (CESD) was first described by fig. 31.13 D. S. Fredrickson in 1966. No more than 20 cases of this very rare disease have been reported to date, with twice as many girls being affected as boys. • Just like Wolman’s disease,itis of the liver ranges between 22% and 28%. • Laboratory transmitted as an autosomal recessive mutation with the gene findings show a slight increase in transaminases and bile chromosome 10. localization on Due to this defect, degradation acids as well as reduced liver function. In most cases, of cholesterol esters and triglycerides in the lysosomes is inhibited. Therefore, these lipids are stored in the hepatocytes, Kupf- jaundice is observed. Markedly augmented concentra- fer cells and macrophages as well as in other somatic cells. tions of cholesterol, triglycerides and LDH are charac- Although CESD displays the same biochemical and metabolic teristic. (204) Foam cells can be found in the bone mar- disorders as Wolman’s disease, it is less severe. It does not row. Diagnosis is confirmed by determination of become evident until adulthood. lysosomal acidic lipase in the leucocytes and skin fibroblasts. • Corresponding to the high lipid content, the ᭤ It was possible for us to describe this clinical picture in liver surface has an orange-yellowish colour, as does the detail from our own observations of a 13-year-old girl. We liver specimen. (205) The lipid drops found in the hepa- detected a very high content of cholesterol ester in the tocytes and Kupffer cells are surrounded by a lysosomal biopsy sample and a deficiency of lysosomal Ͱ-naphthyl- membrane; they replace the cytoplasm and nucleus. In acetate esterase in the fibroblast culture. (205) (s. figs. polarized light, the hepatocellular lipids show birefrin- 21.5; 31.13, 31.14) gence of the Maltese cross type. The hepatocytes con- Initially, the clinical picture is largely asymptomatic. The tain finely floccular, PAS-positive glycogen deposits. In average age of the patients reported to date was 6.5 all, the prevalent picture is that of mixed-droplet fatty years at the time of diagnosis. Striking features are changes. (205) In the further course, hepatic fibrosis or hepatomegaly and, occasionally, splenomegaly. (206) micronodular cirrhosis develop. Both the course and The cholesterol ester content of the liver can be up to prognosis depend on whether cirrhosis develops and 10% of the liver wet weight, while the total lipid content what its concomitant complications are. (202, 203, 265)

598 Metabolic disorders and storage diseases

11.3 Cerebrotendinous xanthomatosis medium-chain fatty acids (MTC diet) with strict avoid- This disease is caused by an autosomal recessive gene mutation ance of other fats. Fat-soluble vitamins have to be sub- (localization on chromosome 2) and leads to an enzyme defect in stituted (if necessary, orally in high doses). mitochondrial steroid-27 hydroxylase. The enzyme itself is responsible for the breakdown of cholesterol side-chains in bile acid synthesis. Such a defect results in the formation of cholestanol, a 11.5 Hypoalphalipoproteinaemia reduction product of cholesterol. It is deposited in various organs, particularly in the tendons and in the nervous system, because the ᭤ In 1961 D. S. Fredrickson et al. described an autosomal reces- substance cannot be broken down adequately. Deposition takes sive disease called hypo- or analphalipoproteinaemia. This lipid place conjointly with cholesterol. (209, 210) storage disease is also known as Tangier disease Ϫ named after the small Tangier Island in Chesapeake Bay/Maryland Ϫ where The clinical picture is characterized by xanthomas, par- it was first observed in two siblings. The cause is probably a synthesis defect α ticularly on the tendons (especially the Achilles tendon). genetic in the apoproteins of 1-lipoproteins. Xanthomas consist of cholesterol and cholestanol. The enzyme defect also results in disturbed vitamin D The most important clinical feature is the storage of metabolism. Osteoporosis is thus observed quite often, cholesterol esters in the lymph nodes, tonsils, spleen and with a tendency towards spontaneous fractures. (208) liver. (221) The noticeably enlarged tonsils are of a dis- Striking clinical features are cerebral functional disor- tinctive yellowish or orange colour. There is evidence ders (from deviant behaviour to severe dementia, motor of lymphadenopathy and hepatosplenomegaly as well as disturbances and convulsions) as well as peripheral polyneuropathy. PAS-positive foam cells or foamy Kupf- neurological symptoms caused by cholestanol deposits. fer cells are found in the bone marrow, lymph nodes and (211) High concentrations of apolipoprotein B and liver. • Laboratory findings show an increase in triglycer- cholestanol are found in the CSF. (213) • Treatment is ide and cholesterol values, α1-lipoprotein deficiency and based on the administration of chenodeoxycholic acid moderate jaundice; occasionally, thrombopenia and leu- (750 mg/day). Effectiveness is improved if HMG-CoA copenia are observed. • The prognosis is generally good. reductase inhibitors (e.g. pravastatin) are used concomi- Therefore, the disease is often diagnosed for the first tantly. (207, 212) time in adulthood. (222, 223)

11.4 Abetalipoproteinaemia 11.6 Debre´’s syndrome

In this autosomal recessive disease, the disorder does not involve This metabolic disorder with simultaneous storage of fat and gly- the gene on chromosome 2, which is responsible for apoprotein cogen in the liver was described by A.R. Debre´ et al. in 1934. Within assembly, but the MTP gene (microsomal triglyceride transfer pro- a few weeks of birth, infants suffer from considerable hepato- tein), which is localized on chromosome 4 q 22Ϫ24. In the endo- megaly (without splenomegaly). There is evidence of hyperlipid- plasmic reticulum, MTP transfers cholesterol esters, triglycerides aemia with hypercholesterolaemia, a tendency towards fasting and phospholipids to the nascent apoprotein B. This process is hypoglycaemia, and disturbed glucose mobilization following a prerequisite for the transport of the complete lipoproteins (e.g. exposure to insulin or adrenaline. • It should be noted, however, chylomicrons, VLDL) to the Golgi complex and their secretion that this form of glycolipidosis has still not been reliably classified. into the blood via subsequent exocytosis. In the case of MTP deficiency, lipoprotein particles are not secreted, with the result that any superfluous apoprotein B is broken down in the endoplasmic reticulum. (214, 216, 219, 220) 12 Sphingolipid storage diseases Even in infants fed with high-fat milk, the clinical picture is characterized by malabsorption leading to fatty The biochemical group of sphingolipids comprises: stools and diarrhoea. This results in a deficiency of fat- sphingomyelin, cerebroside, sulphatide, gangliosides, soluble vitamins with all the respective complications. ceramide trihexosides, etc. Depending on the substance • Reduced elimination of lipids from the liver leads to stored, differentiation is made between (1.) glucosyl cer- hepatomegaly with large-droplet fatty changes, possibly amidoses (e.g. gangliosidoses, ceramide trihexosidosis, causing the formation of fat cysts and larger fat pools. cerebrosidoses, sulphatidosis), (2.) phosphoryl cer- (s. fig. 31.2) Splenomegaly often occurs due to fat stor- amidoses (e.g. sphingomyelinosis), and (3.) mucopoly- age in the macrophages of the spleen as well as to portal saccharidoses. hypertension, which may be caused by an increased resistance in the sinusoids in cases of fatty liver. (215, 12.1 Gaucher’s disease 217) Development of cirrhosis has also been reported. • As far as laboratory findings are concerned, a marked ᭤ This form of glucosyl ceramidosis is the longest known lipid decrease in cholesterol (usually <40 mg/dl) and trigly- storage disease. It was described by P.C.E. Gaucher as early as cerides (usually <10 mg/dl) is relevant for the diagnosis; 1882 and recognized as a separate entity with systemic character by F. Schlagenhaufer in 1907. VLDL (ϭ pre-beta lipoproteins) are not found. The haemogram shows deformed (e.g. crenated) erythro- The condition is an autosomal recessive disease with reduced activ- cytes due to their altered membrane lipids. (218) • Treat- ity of the lysosomal β-glucocerebrosidase. (Instead of an enzyme ment is based on the administration of triglycerides with defect, the cause may be the absence of cofactor saposin C.) The

599 Chapter 31

relevant gene is localized on chromosome 1. There is considerable genetic heterogeneity. While some gene mutations are responsible for more frequent neurologic and severe courses, others have been recognized, particularly in older patients, as causing a late onset and more moderate course of disease. The gene mutations are detectable with varying frequency in different ethnic groups. Due to the enzyme defect, sphingolipids are only broken down to the level of the glucocerebroside, whereby this glycolipid is subsequently stored. Prevalence is 1 : 30,000 Ϫ 1 : 50,000 Glucocerebroside is stored predominantly in the RES cells, but also in the spleen, hepatocytes, bone marrow and lymph nodes; rod-like tubules (20Ϫ40 nm) develop. • The storage of glucocerebroside leads to the formation of so-called Gaucher cells. These oval or polygonal cells are characterized by their light, striated (“crumpled”) cytoplasm and a swollen cell body with a decentralized Fig. 31.15: Gaucher’s disease. Gaucher cells (sphingolipid-storing nucleus; occasionally, there are two or more hyperchro- macrophages) within the liver parenchyma (arrow), shown here as matic nuclei at the periphery. Apart from glucocerebro- pale-blue cells with an internal structure similar to cigarette paper (PAS) side, Gaucher cells also contain lysosomal acidic phosphatase. They are PAS-positive, 20Ϫ100 µm in size and grouped together within the hepatic lobule; in some areas, the cells fill the sinusoids and are likewise found For a successful course of treatment, β-glucocerebrosi- in the portal fields, where they originate from histio- dase gained from the placenta or recombinant imiglu- cytes. cerase can be used as an intravenous infusion every Ϫ Type I second week. (225 227, 230, 234, 236) • A novel form of (chronic visceral type): This is the most common oral treatment with N-butyldeoxynojirimycin over a course and may manifest at any time in life; most often, period of up to 12 months produced good results. Fur- however, it occurs between the ages of 20 and 40. The ther trials with this substance, which inhibits the synthe- patients are able to lead relatively normal lives. Clinical sis of glucocerebrosides, are justified. Diarrhoea was a features include pronounced hepatosplenomegaly, oste- frequent side effect (79%). (228) • Following liver trans- algia with spontaneous fractures, backache and pain in plantation, there was a regression in glucosylceramide the extremities, fever and haematopoetic disorders deposition in the extrahepatic organs Ϫ the metabolic (microcytic anaemia, leucopenia, thrombopenia with defect was not corrected however. (244) Long-term fol- haemorrhagic diathesis). The transaminases and the low-up showed good results after bone-marrow trans- liver function values are usually normal; alkaline phos- plantation. (238) phatase is increased. Portal hypertension and ascites may occur due to obstruction or compression of the Type II (acute infantile neurological type): Type II becomes mani- sinusoidal pathway. (233) After a course of several years, fest within the first few months of life. Splenomegaly followed by yellowish brown, patchy pigmentations (containing mel- hepatomegaly can be observed at a very early stage. A striking feature is the cerebral and neurological symptomatology. The anin) appear in the face, particularly at the root of the affected child usually dies within the first year of life due to nose, and on the legs. Yellowish grey pingueculae may bronchopulmonary infection. be present around the eyes (nasal or bilateral). Diagno- Type III sis is confirmed by the detection of acidic phosphatase (chronic juvenile neurological type): At the onset of the disease, splenomegaly and, subsequently, hepatomegaly are in the cells and a reduced activity of glucocerebrosidase observed. Gaucher cells are found in the bone marrow at an early in leucocyte suspensions or fibroblast cultures. Mean- stage. There are severe cerebral and neurological disorders. while, the various types of Gaucher’s disease can be identified by PCR. There are no neurologic symptoms. The cholesterol level is normal. (229, 231, 232, 235) •Prog- 12.2 Fabry’s disease nosis is determined by haematological complications, an increased susceptibility to infections and a higher rate The enzymatic defect in glycoprotein and lipid metabolism in this disease, which is based on X-chromosomal transmission, is most of lymphoproliferative diseases. Transition to cirrhosis likely to be ␣-galactosidase-A deficiency. Storage products consist has often been observed, as have bleeding oesophageal of sphingolipids, mainly GL-3. They are principally stored in the varices. (224, 233, 237, 239, 241) kidneys, vascular walls and smooth musculature, but also in the liver (stellate cells, portal macrophages, vascular endothelium). ᭤ We were able to observe a family with 6 children, 4 of These affected cells take on a yellowish-brown colour. The hepato- whom (3 boys and 1 girl) suffered from Gaucher’s disease. cytes are finely vacuolated; the Kupffer cells and macrophages are I examined one of the children laparoscopically. All 4 chil- hypertrophic and contain cholesterol and lipofuscin. • The clinical picture, which usually begins with swelling of and burning pains dren showed pronounced hepatosplenomegaly with symp- in the limbs as well as skin changes and corneal opacity, was simul- toms of abdominal organ displacement; splenectomy was taneously described by J. Fabry and by W. A nderson in 1898. • carried out in good time. (240) (s. fig. 31.15) Treatment with recombinant agalsidase beta has proved successful.

600 Metabolic disorders and storage diseases

12.3 Gangliosidosis sis as well as cholestasis develop. The affected child dies Among other things, gangliosidosis may also affect the liver. The before reaching the age of 2 years. (244, 248) deposition of gangliosides (particularly of the GM1 and GM2 type) Type B is often characterized by neonatal cholestasis, in the liver causes hepatomegaly to develop. In 1964 B.H. Landing et al. described familial neurovisceral lipidosis as a disease in its own which disappears in the later course of disease. The con- right, although this entity had probably been observed by J. Caffey dition becomes manifest in childhood and progresses as early as 1951. The type of metabolic disorder was defined by slowly. Hepatosplenomegaly develops, as does cirrhosis rien G J.S. O’B et al. in 1965. It is in fact an autosomal recessive M1 with portal hypertension. (245) The lungs occasionally gangliosidosis of the infantile generalized type I. The disease is caused by β-galactosidase A, B and C deficiency, so that the cleav- display a miliary picture due to the interstitial storage age of the terminal galactose of both the ganglioside GM1 and the of sphingomyelin; chronic bronchitis is often observed. mucopolysaccharides is inhibited. These abnormal products are No neurological or cerebral symptoms are in evidence. then stored. Foam cells with PAS-positive substances develop, The haemogram shows anaemia and thrombopenia. • which in turn involves the total RES and hence the stellate cells and portal histiocytes as well. Progressive hepatomegaly is present. Treatment with allogeneic bone marrow transplantation Familial neurovisceral lipidosis causes the death of the child in the has been reported. (246) first or second year of life. (Type II GM1 gangliosidosis is consid- Type C ered to be a juvenile type without visceral involvement.) is characterized by a slow course with neurological symptoms and gradual mental deterioration. A rare G gangliosidosis hexosamidase A M2 is caused by a deficiency of event is the development of neonatal cholestasis (243) or and B. It was described for the first time by K. Sandhoff et al. as Sandhoff’s disease in 1968. This biochemical variant (type II) an HCC (242). largely corresponds to Tay-Sachs disease, which is also autosomal Type E sea-blue histiocytes syn- recessive. Renal globoside (ceramide trihexoside) is stored in the is also known as the visceral organs, particularly in the liver and spleen. Hepatomegaly drome and is considered to be a special form of Nie- is present, occasionally with splenomegaly. The lysosomes within mann-Pick disease found in adults. The stored, ceroid- the hepatocytes become considerably larger until they are as big like, acid-proof and PAS-positive pigment shows a sea- as the nucleus and show lamellar structures. blue colour on Giemsa staining. Hepatosplenomegaly is present; thrombopenia is likewise in evidence due to bone marrow involvement. Cirrhosis may develop. The 12.4 Niemann-Pick disease prognosis is considered to be good. (243) ᭤ In 1914 A. Niemann described a type of storage disease which, however, he did not recognize. In 1926 L. Pick differentiated this clinical picture from Gaucher’s disease and called it “lipid 12.5 Mucopolysaccharidoses cellular splenomegaly”. The substance predominantly stored was identified as sphingomyelin by E. Klenk in 1934. Thus, this These are congenital disturbances in the enzymatic condition is a kind of phosphoryl ceramidosis. degradation of acidic mucopolysaccharides (MPS) by the lysosomes. Four types of mucopolysaccharides (gly- The disease is based upon a deficiency of the lysosomal cosaminoglycam, dermatan sulfate, heparan sulfate, enzyme sphingomyelinase, mainly in the RES cells. This chondroitin-6 sulfate) are stored, ultimately compromis- autosomal recessive enzyme defect results in sphingomy- ing all organs and tissues. In addition, ganglioside is elin being stored in the liver (hepatocytes, Kupffer cells, stored in the CNS. Depending on the respective disease, portal macrophages), spleen, bone marrow and lungs. varying distribution patterns can be found, with storage These pale storage cells, the so-called Pick cells (20Ϫ40 forms occurring individually or in combination. To date, µm) display a mulberry-like, alveolate structure, and, in ten individual forms have been identified; others, how- addition to sphingomyelin, contain cholesterol and tri- ever, have remained unclassified. In all forms, there is glycerides as well as pigment ceroid (s. fig. 21.6). The increased elimination of the above-mentioned MPS in cell inclusions are granular and double-refractory. Due the urine. • Six out of a total of ten forms are accom- to vacuolation, the Pick cells look like foam cells. • panied by liver involvement (storage in the hepatocytes, Meanwhile, five biochemical and clinical types have Kupffer cells and portal macrophages as well as vacuoli- been differentiated (types AϪE); type A is equivalent to zation of the cytoplasm) and hepatomegaly. The liver is the classical Niemann-Pick disease observed in infants. firm and has a bluish-yellow or greyish-yellow colour. To date, some 200 cases have been reported. The stored mucopolysaccharides are PAS-positive, but not diastasis-resistant. During a longer course, fibrosis Type A is already present in infancy. The following develops and cirrhosis may occur. symptoms rapidly develop: anorexia, vomiting, weight Pfaundler-Hurler syndrome loss, growth retardation, hepatosplenomegaly, lymph- (type I-H): This syndrome is caused by an α-L-iduronidase deficiency (M. v. Pfaundler, 1920; G. Hurler, adenopathy, profuse sweating, a brownish-yellow waxy 1920). It is autosomal recessive and panethnic, with an incidence complexion and a pronounced cerebral and neurolog- of approx. 1: 100,000 live births. A major cause of morbidity and ical symptomatology (muscular hypotonia, areflexia, mortality is respiratory insufficiency together with cardiac com- deafness, loss of sight). In about 5 % of cases, cherry- promise (valvular dysfunction). red spots with yellowish prominence can be found on Ullrich-Scheie’s syndrome (type V): This is also characterized by the fundus of the eye. Liver cell damage and cell necro- an α-L-iduronidase deficiency, but it does not appear before school

601 Chapter 31

age (O. Ullrich et al., 1943; H. G. Scheie et al., 1962). Further symp- also involved. The affected hepatocytes are similar to so-called toms are above-normal growth and head size, chronic otitis, ground glass cells and mostly found at the periphery of the lobules. chronic rhinitis, hepatosplenomegaly, corneal clouding, ankylosis The coarse granular and lamellar cytoplasmic inclusions are and mental retardation. PAS-positive glycoprotein-mucopolysaccharide particles, also known as Lafora bodies (C.R. Lafora, 1911). Liver biopsy shows ᭤ These forms overlap in symptomatology and cannot signs of unspecific reactive hepatitis and fibrosis. Death occurs in be distinguished by enzyme or urinary assays. • A new infancy. therapy for α-L-iduronidase deficiency using enzyme replacement (ϭ laronidase) as i.v. infusion has proved safe and efficacious (J. Wraith et al., 2004). Hunter’s syndrome (type II): Initially, this disease was erroneously 13 Mucoviscidosis classified as type I-H. Its nosological independence and X- chromosomal recessive transmission were recognized in 1964 (A. cystic fibrosis (CF) ja Mucoviscidosis or is indeed one of the most N ). The disease is based on a deficiency of L-iduron-sulphate common autosomal recessive diseases. It is characterized by the sulphatase and sulphoiduronate sulphatase. The syndrome may production of a viscous secretion in the excretory glands. Accord- appear in a moderate or severe form. ingly, pancreatic cystic fibrosis can be observed in the pancreatic Sanfilippo’s syndrome (type III): This syndrome exhibits a similar area and cylindrical bronchiectases in the pulmonary area. The clinical picture as described above with at least two different inspissation of bile and mucus leads to obstruction of the bile enzyme defects: heparan-sulphamidase deficiency (type A) and N- canaliculi and subsequently to cholestasis. The gene product is acetyl-α-D-glucosamidase deficiency (type B) and possibly types characterized as cystic fibrosis transmembrane regulator (CFTR). CorDaswell(S.J.Sanfilippo et al., 1963). (252) The gene defect, which is located on chromosome 7, causes a disorder of the intracellular transport of chloride ions (probably Morquio’s syndrome (type IV): This syndrome is a result of a also of chloride ion secretion) and thus triggers the occurrence of galactosamine-6-sulphatase deficiency (type A) or a beta-galactos- CF. The incidence of mucoviscidosis is about 1 : 2,000Ϫ4,500. idase deficiency (type B) (L. Morquio, 1929; J. F. Brailsford, 1929). liver Maroteaux-Lamy syndrome In protracted disease, the becomes involved in (type VI): This syndrome is due to an Ϫ arylsulphatase B deficiency. It appears in a severe or moderate 20 25% of cases. Rarely, a symptomatic hepatobiliary form (P. Maroteaux et al., 1965). disease, mostly in the form of fatty liver but also as focal biliary cirrhosis, occurs in the first few weeks of life. Proliferation of the ductuli and dilatation of the intra- 12.6 Mucolipidoses lobular bile ducts can be detected. As a result of this, crumbly products are deposited and the lumina are Mucolipidoses are characterized by a combined meta- completely sealed off. These retained crumbly products bolic disorder of mucopolysaccharides, lipids, and glyco- have not yet been differentiated more specifically; they proteins. Lysosomal storage and foamy swollen Kupffer are, however, PAS-positive and mucin-negative and con- cells with hepatomegaly may be seen. In some of the sist mainly of precipitated protein. Hepatomegaly is due numerous types, the underlying enzymatic defects have to macrovesicular steatosis. Inflammatory changes in not yet been detected. • Type II is also called Leroy syn- the bile canaliculi and the small bile ducts with chole- drome (J.G. Leroy et al., 1967). Due to distinctive cyto- stasis and infiltration of the portal fields can be plasmic inclusions in fibroblast cultures, this disorder is observed. (250, 254) With progressive proliferation of the also known as “inclusion cell disease” (J.G. Leroy et al., ductules and liver fibrosis, there is a rise in γ-GT, AP 1971). Foamy altered stellate cells, macrophages and also and 5’ NU. In the further course, a slight increase in epithelioid foam cell granulomas are found. transaminases as a sign of hepatocellular damage is detectable. A score can be used for the sonographic Fucosidosis, being a so-called mucolipidosis, can be grouped among the mucopolysaccharidoses. It is due to α-fucosidase defi- diagnosis of liver involvement in CF. (258) Scintigraphy ciency (localized on chromosome 1p 34). The storage products are may be applied for the quantification of impaired secre- deposited in the form of granular or lamellar inclusions in the tion. (256) Liver function is assessed by means of ChE, lysosomes. This autosomal recessive disorder was first observed by Quick’s value, GEC (s. p. 108) and ICG tests (s. p. 108). urand an oof P. D et al. in 1967 and clarified by F. V H et al. in 1968. Gene mutation can easily be confirmed by direct genetic Besides hepatomegaly, splenomegaly may also sometimes occur. screening with allele-specific oligonucleotides. The Mannosidosis, first observed by P.-A. Öckerman in 1967, is caused inflammatory and reactive-fibrosing processes may α by -mannosidase deficiency. The gene defect (autosomal reces- ultimately result in necrotizing cholangitis and multilob- sive) is localized on chromosome 19p, 13, 2-q12. Hepatospleno- megaly, steatosis and perisinusoidal fibrosis are in evidence. PAS- ular biliary cirrhosis, possibly with bleeding oesopha- positive vacuoles, consisting of lysosomally stored substances, are geal varices; the frequency is reported to be 5Ϫ20%. found in the cytoplasm of the hepatocytes. (250, 254, 255) • The only effective therapy is gene replace- Mucosulphatidosis is caused by arylsulphatase deficiency (types A, ment. (253, 259) Symptomatically, liver damage and cho- B and C). Metachromatic granules are found mostly in portal lestasis can be reduced by UDCA. (249) It is also advis- macrophages and less frequently in hepatocytes or Kupffer cells. able to use essential phospholipids as long-term therapy. (257) In severe cases, there may be an indication for liver Lafora’s disease (H. Unverricht et al., 1891) is regarded as an autosomal recessive enzyme defect. A striking feature are the transplantation or indeed combined liver-lung trans- severe CNS disorders. The myocardium, liver and musculature are plantation. (251)

602 Metabolic disorders and storage diseases

14 Zellweger’s syndrome ulatory disturbance of porphyrin and haem synthesis together with the induction of ALA synthase within the This cerebro-hepatorenal syndrome was described by P. hepatocyte. The acute forms are less frequent, but are Bowen, C. S. Lee, H. Zellweger and R. Lindenberg in 1964 associated with a higher risk. Only acute hepatic por- on the basis of observations originally made by Zell- phyrias show convulsive gastrointestinal and neuropsy- weger. (260) It is an autosomal recessive disease, with a chiatric symptoms. Chronic hepatic porphyrias are due lack of peroxisomes due to a mutation of the mRNA to congenital or acquired enzyme defects; they are the peroxisome-assembly factor 1. In this complex syn- most frequent forms and always involve liver damage. • drome, there are various malformations with disturb- Only the erythropoietic forms are accompanied by acute ances in the amino-acid balance and β-oxidation of long phototoxic reactions. Skin changes are found in two chain fatty acids as well as iron metabolism resulting from forms of hepatic porphyrias: variegate porphyria and a disorder of bile acid synthesis at the side chain. (261, porphyria cutanea tarda. (s. tab. 31.10) 262) The blood shows hypersiderinaemia, and there are increases of different intensity regarding alanine, lysine, Primary porphyrias may arise from a hereditary defect in any of the eight enzymes δ isoleucine, methionine, phenylalanine and serine. Signs involved in haem synthesis: (1.) -aminolaevulinic acid synthase (which causes a sideroblastic anaemia), (2.) porphobil- of substantial cholestatic liver damage, siderosis, portal inogen synthase, (3.) porphobilinogen deaminase, (4.) uroporphyri- inflammation, fibrosis and the potential development of nogen III synthase, (5.) uroporphyrinogen decarboxylase, (6.) cirrhosis are evident. (263Ϫ265) (s. p. 234) coproporphyrinogen oxidase, (7.) protoporphyrinogen oxidase, and (8.) ferrochelatase. • An important branching point in haem synthesis is the transformation of porphobilinogen (by PBG deaminase) into pre-uroporphyrinogen. The latter is transformed by uroporphyrinogen III synthase into uroporphyrinogen III; in the case of reduced enzyme activity, uroporphyrinogen I is spontaneously formed and 15 Porphyrias subsequently eliminated in the urine. (309) (s. fig. 3.2) 15.1 Definition ᭤ Secondary porphyrias are symptomatic and hepatic porphyrias. (309) They are coproporphyrinurias with Porphyrias are metabolic disorders caused by heredi- simultaneously increased protoporphyrin concentra- tary enzyme defects or acquired disorders of haem tions in blood plasma. For prophylactic, prognostic and synthesis. These result in the increased formation of therapeutic reasons, it is important to differentiate porphyrins and porphyrinogens and their precursors, between primary (hereditary) porphyria and secondary which are either stored in the tissue or excreted in the (symptomatic) coproporphyrinuria. • Only in copropor- urine or faeces. The term porphyria is derived from phyrinuria caused by lead intoxication and in tyrosin- the Greek “porphuros”, which means purple and aemia can δ-aminolaevulinaciduria be found at the describes the purple-red crystalline porphyrins. • same time. The alcohol-liver-porphyrinuria syndrome is Depending on the underlying enzyme defect or the the most important form of secondary porphyrinuria. respective aetiopathogenesis, porphyrias become clin- In chronic alcohol abuse, secondary coproporphyrinuria ically manifest with neurological, photocutaneous, may develop into chronic hepatic porphyria. (281) • cerebral, cardiovascular, abdominal or hepatic symp- Some 30% of patients suffering from chronic liver disease tomatology. develop pathological coproporphyrinuria during the further course. (s. tab. 31.11)

15.2 Classification 15.3 Biochemistry

᭤ Primary porphyrias are caused by hereditary enzyme Glycine and succinyl coenzyme A are the initial substrates for porphy- defects in haem synthesis. They can be differentiated rin synthesis, from which δ-aminolaevulinic acid (ALA) is formed clinically into acute and chronic porphyrias as well as with the help of ALA synthase. This is the first biosynthetic step and hepatic erythropoietic takes place in the mitochondria. Porphobilinogen (PBG) develops pathogenetically into and por- in the cellular cytosol due to the connection of 2 mol ALA. Uro- phyrias. Secondary porphyrias are symptomatic por- porphyrinogen is then formed from 4 mol PBG; this is subsequently phyrias present in various diseases or caused by poison- decarboxylated, thus producing coproporphyrinogen. Further ing or chemical substances, particularly alcohol. • decarboxylation takes place within the mitochondria, leading to the Depending on the preferred manifestation site of the production of protoporphyrin. Due to its lipophilic qualities, the latter is not filtered by the kidneys and is therefore subject to enterohep- enzyme defect, either in the hepatocytes or erythrocytes atic circulation. With the help of ferrochelatase, iron is stored and (bone marrow), the porphyrias are subdivided into haem is formed. • Haem is the final product of porphyrin synthesis, hepatic, erythropoietic and hepatoerythropoietic forms. which may take place in all cells. It is required as a prosthetic group However, this classification is not always strictly appli- by enzymes or pigments (catalase, cytochrome, haemoglobin, myo- course of disease, globin, etc.). By way of feedback, haem regulates the limiting cable. • Based on the acute and chronic enzyme ALA synthase and thus the whole porphyrin synthesis. The forms may be differentiated in primary hepatic porphyr- activity of ALA synthase is increased by various drugs (s. tab. 31.13), ias. The acute form is characterized by a congenital reg- chemical agents and endogenous metabolic products. • Induction of

603 Chapter 31

Primary porphyrias International Enzyme defect Hereditary abbreviations transmission

Erythropoietic porphyrias 1. Congenital erythropoietic porphyria CEP Uroporphyrinogen III synthase autosomal recessive (Günther’s disease) 2. Erythropoietic protoporphyria EPP Ferrochelatase autosomal dominant Hepatic porphyrias 1. Acute hepatic porphyrias • Acute intermittent porphyria AIP Uroporphyrinogen I synthase autosomal dominant • Variegate porphyria VP Protoporphyrinogen oxidase autosomal dominant • Hereditary coproporphyria HCP Coproporphyrinogen oxidase autosomal dominant • Doss porphyria DP Aminolaevulinic acid dehydratase autosomal recessive • Porphobilinogen synthase defect PS Porphobilinogen synthase autosomal recessive 2. Chronic hepatic porphyrias • Porphyria cutanea tarda PCT Uroporphyrinogen III decarboxylase autosomal dominant • Hepatoerythropoietic porphyria HEP Uroporphyrinogen III decarboxylase autosomal recessive

Tab. 31.10: Primary (erythropoietic, hepatic, hepatoerythropoietic) porphyrias

ALA synthase can be suppressed by glucose. Due to the short half- ᭤ The colourless porphyrinogens easily convert to life of ALA synthase of 70Ϫ80 minutes, inhibition or induction of this enzyme very quickly affects haem synthesis. Haem deficiency coloured red-fluorescent uroporphyrins at 366 nm due to an enzyme defect causes an increase in δ-aminolaevulinic when there is a sufficient amount of oxygen. This acid. Free haem is either integrated into various apoproteins or it causes a red colour in the urine, which becomes intervenes as a haem repressor with the nuclear gene chain, which darker (burgundy red) when left in contact with air. • leads to the formation of specific mRNA for ALA synthase. • Syn- thesis and consumption of haem are synchronized precisely. The The red-fluorescent specimen obtained by liver biopsy organism produces some 300 mg haem per day, with only 1% being in chronic hepatic porphyria is impressive. (s. pp 145, excreted unused in the urine or faeces. (271, 273, 300, 309) (s. p. 34) 158) (s. fig. 7.10) (s. tab. 3.3)

15.4 Genetics

Secondary coproporphyrinurias and protoporphyrinaemias Primary porphyrias are genetically determined, whereby their expression varies in intensity, i.e. there is either a reduction in or 1. Poisoning instability of the enzyme affected by gene mutation. A total loss • Alcohol of enzyme activity or a lack of enzyme protein is inconsistent with • Heavy metals the viability of the organism. Transmission is autosomal dominant Ϫ lead, arsenic, iron, gold in five forms of porphyrias, but autosomal recessive in congenital • Chemical agents erythropoietic porphyria (CEP), hepatoerythropoietic porphyria Ϫ benzenes, hydrocarbons, etc. (HEP) and the so-called Doss porphyria. (s. tab. 31.10) • Any type 2. Liver diseases of porphyria may be caused by various gene mutations, which • Acute and chronic hepatitis, alcohol-induced fatty liver, results in pronounced genetic heterogeneity. Two different types cirrhosis, cholestasis, haemochromatosis of porphyria may even become manifest within one family. The 3. Blood diseases penetrance of the relevant gene mutation is low, so that about 80% • Haemolytic anaemia, sideroachrestic anaemia, aplastic of the persons involved are without clinical or laboratory findings. anaemia, pernicious anaemia, leukaemia, Hodgkin’s dis- The probability of the enzyme defect being passed on to a child is ease, etc. about 50%. (274, 278, 284, 290, 308, 309) Infectious diseases 4. ᭤ However, not only genetic factors figure prominently Diabetes mellitus 5. in the manifestation of porphyria, but also endogenous 6. Hereditary metabolic defects and exogenous causes such as alcohol (281), medica- • Benign recurrent cholestasis • Dubin-Johnson syndrome ments, stress situations, fasting, intoxication, metabolic • Rotor’s syndrome products, effects of light and chemical agents (e.g. poly- • Tyrosinaemia type I halogenized biphenyls, dioxin). • In Turkey, about 4,000 7. Neoplastic diseases people contracted hepatocutaneous porphyria after eat- 8. Cardiac infarction ing wheat contaminated with the fungicide hexachloro- 9. Pregnancy benzene. (s. p. 565) 10. Starvation 11. Iron metabolism disturbances 12. Medication (s. tab. 31.13) 15.5 Clinical aspects

Tab. 31.11: Secondary (symptomatic, acquired) disorders of por- In cases of suspected hepatic porphyria, instant orienta- phyrin metabolism tion is gained by examining the urine for evidence of δ-

604 Metabolic disorders and storage diseases aminolaevulinic acid (ALA) and porphobilinogen (PBG) 15.6.1 Congenital erythropoietic porphyria (CEP) Ϫ using the Watson-Schwartz test (C.J. Watson et al., 1941) This clinical picture is also termed Günther’s disease (H. Günther, oesch Ϫ or Hoesch test (K. H , 1947) as well as for the pres- 1911). About 200 cases have been described so far. An autosomal ence of porphyrins. (Hoesch test: 2 ml Ehrlich’s reagent ϩ recessive deficiency of uroporphyrinogen III synthase (chromo- 3 drops of urine ϭ pinkish-red discoloration after shak- some 10q25) results in augmented accumulation of porphyrin iso- ing, revealing positive evidence of porphobilinogen.) • mers of type I, which cannot be used biologically. In particular, differentiation this causes an increase in uroporphyrin with the occurrence of flu- Further of porphyrins excreted in the urine orocytes (most of all erythrocytes, but occasionally also hepato- and faeces or present in plasma and erythrocytes as well cytes). A red discolouration of urine is already observed in infants. as of the distribution pattern of porphyrin metabolites is Exposure to the sun leads to severe burns with the formation of necessary; for this purpuse, thin-layer chromatography, blisters (the content of which may fluoresce) and necroses. Pro- nounced mutilations on the face and hands develop in the course ion-exchange chromatography and HPLC are available. • of time. The teeth are discoloured reddish-brown due to the depo- Identification of asymptomatic gene carriers, which is of sition of porphyrins in dentine. Haemolytic anaemia with spleno- particular importance for preventive measures, can be megaly may develop. • CEP causes neither neurologic disorders nor achieved by determining the enzymes involved in porphy- (substantial) liver damage. rin synthesis. 15.6.2 Erythropoietic protoporphyria (EPP) The symptomatology of porphyrias is of such com- plexity and variability that there is always a danger An autosomal dominant ferrochelatase deficiency of misinterpretation. Wrongly indicated laparotomy causes enhanced accumulation of protoporphyrin due to suspected acute abdomen entails a high risk. within the erythrocytes. The gene for ferrochelatase has The initiation of incorrect treatment measures may been detected on chromosome 18q21. EPP is considered also have grave consequences. Owing to the extremely to be the third most frequent porphyria (1 : 100,000). complex interdisciplinary symptomatology, an emer- (315) Red-fluorescing erythrocytes form as a result of the gency due to porphyria must be interpreted in terms high porphyrin content. EPP becomes manifest already of surgery, internal medicine or neurology, and in childhood, but the course of disease may be latent depending on the results obtained, the patient is for a long time. Exposure to the sun causes strong skin referred to the corresponding department. • Por- reactions, such as painful erubescence, oedema and blis- phyria can imitate numerous diseases. ters. After long-term insolation, permanent skin infiltrations are observed. The prognosis is generally good. • The liver is damaged considerably by increasing deposits 15.6 Erythropoietic porphyrias of porphyrins. Cholestasis as well as liver fibrosis and The enzymatic metabolic defect is mainly restricted to the erythro- cirrhosis may become manifest. Pigment gallstones can cytes or bone marrow. Two distinct clinical pictures can be dif- occur. Acute liver failure with a fatal outcome has also ferentiated: congenital erythropoietic porphyria (CEP) and erythro- been reported. (272, 293, 307) • Treatment consists of the poietic protoporphyria (EPP) (W. Kosenow et al., 1953; I.A. Magnus administration of β-carotene and vitamin E in order to et al., 1961). From a hepatological point of view, only EPP is capture the oxygen radicals which are present in greatly important. (s. tab. 31.12) increased numbers in the skin following exposure to sunlight and thus to prevent the triggering of phototoxic CEP EPP reactions. Administration of chenodeoxycholic acid, cholestyramine and glucose (>300 g/day) is likewise Urine Total porphyrins ϩϩϩ N/v recommended. Liver transplantation may be indicated. Uroporphyrin ϩϩ N/v (270, 274, 277, 278, 280, 291, 296, 298, 303, 304, 306, 309, 317, Coproporphyrin ϩ N/v 319) Porphobilinogen N N ALA N N Faeces Total porphyrins ϩϩ ϩ 15.7 Hepatic porphyrias Uroporphyrin ϩ N/v Coproporphyrin ϩ v Hepatic porphyrias show the following characteristics: Protoporphyrin ϩϩϩ (1.) intermittent course, (2.) increased ALA synthase Erythrocytes activity, and (3.) acute attacks induced or manifesting Total porphyrins ϩϩϩ ϩϩϩ during the latency period due to numerous causes such Uroporphyrinogen I ϩϩϩ N/v as alcohol (281), hunger, carbohydrate deficiency, hor- Coproporphyrin ϩϩ N/v mones, stress, intoxication, metabolic products and ϩϩ ϩϩϩ Protoporphyrin medicaments. (s. tab. 31.13) • The diagnosis is based Plasma upon the clinical symptomatology and the excretion ϩϩ ϩ Total porphyrins pattern of the porphyrins or their precursors in the urine Tab. 31.12: Constellation of findings in erythropoietic porphyrias and faeces as well as their concentrations in the erythro- (v ϭ variable, N ϭ normal) cytes and plasma. (s. tab. 31.14)

605 Chapter 31

Alcohol Lofepramine 31.13] and xenobiotics, alcohol abstinence). A diet rich Allopurinol Medrogestone in carbohydrates is important as a preventive measure, Amiodarone Meprobamate because this reduces ALA activity in the liver. • It is Barbexaclon Mesuximide essential to examine other family members in order to Barbiturates Methyldopa Benegrid Metoclopramide recognize any potential genetic carriers or to identify a Carbamazepine Metronidazole relative afflicted by porphyria which is still in the latency Carbromal Nalidixic acid phase. Such persons are likewise informed about the dis- Chloramphenicol Nicethamide ease, particularly with respect to potential manifestation Chlordiazepoxides Nifedipine factors, and they also receive a porphyria pass. Chlormezanone Nitrofurantoin Chloroquine Oral contraceptives Chlorpropamide Oestrogens Acute hepatic porphyrias Clonazepam Oxazepam Clonidine Paramethadione There are pathophysiological and clinical transitions Cyclophosphamide Pentazocines between all forms of acute hepatic porphyrias. Due to Danazol Pentetrazol the complex clinical symptomatology, including abdom- Dapsone Phenacetin inal, neurological and cardiovascular findings, misinter- Diazepam Phenoxybenzamine Dichloralphenazone Phensuximide pretations are possible, and often the diagnosis is made Diclofenac Phenylbutazone too late. Skin symptoms are observed when porphyrins Dimenhydrinate Phenytoin have accumulated in the tissue, causing reactive oxygen Ergotamine preparations Piroxicam intermediates to form following exposure to sunlight. In Ethosuximide Primidone all acute hepatic porphyrias, the excretion of δ-aminolae- Eucalyptus oil Progesterone Fern extract Pyrazinamide vulinic acid, porphobilinogen and porphyrins is increased Flufenamic acid Pyrazolone derivatives in the urine. However, no augmentation in the excretion Frusemides Pyrimethamine of PBG is observed in defective PBG synthase. Even Gestagens Ranitidine genetically identified acute hepatic porphyrias may Glibenclamide Rifampicin Gliquidone Spironolactone remain latent for a considerable period of time. Their Glutethimide Steroids frequency is given at about 5:100,000, with remarkable Griseofulvin Sulphonamides geographic variations. There are four (or five) different Halothane Sulthiame forms of acute hepatic porphyria. (309, 312) (s. tab. 31.10) Hydralazine Theophyllines Ibuprofen Tolbutamide 15.7.1 Acute intermittent porphyria (AIP) Imipramines Trimethadione Ketoconazole Valproic acid Lidocaine etc. This disease, considered to be the second most frequent form of porphyria, occurs 3Ϫ4 times more often in Tab. 31.13: Drugs which are able to trigger acute hepatic por- women than in men. The peak rate is between the ages phyria (AIP, VP, HCP) with differing degrees of risk (s. tab. 31.10) of 20 and 40 years. This autosomal dominant form is responsible for a deficiency in porphobilinogen deami- AIP VP HCP PCT nase (uroporphyrinogen I synthase). The genetic defect of this enzyme is localized on chromosome 11q24. Sev- Urine eral genetic variants (>4) exist. The frequency of gene ϩϩ ϩϩ ϩϩ ϩϩϩ Total porphyrins defects shows geographic variations. Manifestation of Uroporphyrins ϩϩϩϩϩϩ Coproporphyrins ϩϩ ϩϩ ϩϩ ϩ AIP is also caused by numerous exogenous or endoge- Porphobilinogen ϩǞϩϩϩ ϩǞϩϩϩ ϩǞϩϩϩ N nous factors (see above). In women, the first clinical β-ALA ϩǞϩϩϩ ϩǞϩϩϩ ϩǞϩϩϩ N manifestation is often associated with the premenstrual Faeces phase. Some women suffer from cycle-related episodes Coproporphyrin N/v ϩ ϩϩϩ N/v of the disease. The overall frequency of AIP is 5Ϫ10: Protoporphyrin ϩϩϩϩN/v 100,000. • There are five cardinal symptoms, which may ϩ ϩ Uroporphyrin N/v /v N/v appear with widely differing intensity: (1.) cardiovascu- Plasma lar findings such as tachycardia, hypertension and ϩǞϩϩ ϩǞϩϩ Total porphyrins N/v N/v changes in the ECG, (2.) intermittent and diffuse abdo- Tab. 31.14: Porphyrin and porphyrin precursor content in urine minal pain, often localized in the lower abdomen, which and faeces for the differentiation of hepatic porphyrias (v ϭ vari- may take the form of colic, including vomiting and able, N ϭ normal) (s. tab. 31.10) ileus-like features, (3.) severe obstipation, largely unresponsive to treatment (onset mostly during puberty), ᭤ Patients suffering from hepatic porphyria receive a (4.) peripheral neurological and muscular disorders, porphyria pass as well as all important information refer- which may result in pareses or paralyses, and (5.) neuro- ring to the disease; in particular, they must be well tic or psychotic behaviour (confusion, depression, anxi- informed about risk factors leading to manifestation ety, hallucinations, delirium and coma). In cases of (e.g. avoidance of porphyria-inducing drugs [s. tab. hyponatraemia (insufficient ADH secretion), encepha-

606 Metabolic disorders and storage diseases

lopathy may become manifest (B. Dixon, 1997). If cardio- and internal as well as neurological symptoms similar to AIP vascular and psychiatric symptoms coincide, the picture (women > men). Therefore, VP is also called “mixed porphyria”. Skin symptoms (increased photosensitivity, vulnerability, forma- may be misinterpreted as a thyrotoxic crisis, particularly tion of blisters, pigmentation, hypertrichosis) are observed in 85% because the serum values of T3 and T4 are increased in of patients, beginning mostly between the ages of 20 and 30 years. approximately 20% of patients suffering from AIP. The Constipation, vomiting and hypertension are even more common causes of the clinical symptoms are thought to be in PV than in AIP. Growth is retarded. • Laboratory findings show relatively high increases in total porphyrins, porphobilinogen and abnormal biochemical stimuli, triggering dysregulations ALA, particularly in acute attacks. Enhanced excretion of copro- in peripheral and autonomic innervation. However, porphyrin in the urine and faeces is observed, even in the preclin- there are no skin changes in AIP, and there is no photo- ical period. The following are considered to be characteristic fea- sensitivity. (268) tures of VP: (1.) increased excretion of porphyrin-peptide (x- porphyrin) in faeces and (2.) maximum absorption of porphyrins Occasionally, the liver is also involved: slight increases in in the plasma at 626 nm, while the maximum is 619 nm in all other the transaminases and bilirubin, and possibly impaired porphyrias. • The liver biopsy sample shows no red fluorescence. No significant or even characteristic histological liver changes are excretory functions as well. Initially the hepatocytes in evidence. • Factors triggering an acute attack correspond to reveal ultrastructural changes, and later slight steatosis those found in AIP. The prognosis is quite good when these noxae and siderosis. The liver bioptate shows no signs of red are avoided. (279, 297) fluorescence. In AIP, there is a high risk of cirrhosis and liver cell carcinoma developing. (266, 269, 294) In some 15.7.3 Hereditary coproporphyria (HC) patients suffering from such conditions, liver transplan- This is an autosomal dominant coproporphyrinogen oxidase defi- tation has proved successful. ciency (chromosome 3 q 12). The frequency is 1 : 100,000. An ᭤ Acute attacks increase in porphyrins, coproporphyrin and porphobilinogen is often coincide with oliguria and hyponatraemia. found in the urine. This form of acute hepatic porphyria is very It is relatively simple to demonstrate the enhanced excretion of rare. Its clinical course is largely identical to that of AIP, whereby porphobilinogen in the urine by means of the Watson-Schwartz acute gastrointestinal and neuropsychiatric symptoms predomi- test or Hoesch test. Urinary excretion of ALA is increased. In nate. However, they are less pronounced and cannot be detected about 60% of cases, the urine takes on a burgundy-red colour as with the same frequency as in AIP and VP. Skin symptoms (in a result of uro- and coproporphyrin when allowed to stand (due about 30% of cases) include photosensitivity, pigmentation and to the action of light and O2). For evaluating prognosis and pre- hypertrichosis. The liver displays red fluorescence due to the accu- ventive measures, it is important to consider the different AIP disease phases: mulation of porphyrin (s. fig. 7.10), but no morphological damage. (1.) enzymatic defect, (2.) compensated latency period Coexistence with PCT has been described. (282) with moderate excretion of porphyrins, (3.) decompensated latency period with stronger excretion of porphyrins and discrete clinical symptomatology, and (4.) resultant clinical period with acute por- 15.7.4 Doss porphyria (DP) phyria syndrome. When PBG is discharged in small amounts dur- This rare, autosomal recessive form of porphyria is based on 5’- ing remission, no acute episodes need to be feared as a rule. • aminolaevulinic acid dehydratase deficiency (chromosome 9q34). Misdiagnoses may include: acute abdomen, ileus, pancreatitis and A symptomatic disease only occurs in homozygotes or double het- peritonitis (ϭ beware of laparotomy!) as well as poliomyelitis, psy- erozygotes. No more than seven cases have been described to date. chosis, hysteria, hypertonic crisis, thyrotoxic crisis, heart attack, Urinary excretion of ALA and coproporphyrin is increased; etc. • A prognosis is difficult to make regarding an acute attack, greater amounts of protoporphyrin accumulate in the erythrocytes. which may be life-threatening. An acute sporadic attack has to Neuropathy develops, as in AIP. Repeated severe neurological cri- be treated immediately. Morphological damage to nerves and also ses may necessitate liver transplantation. Heterozygotes are con- demyelination can develop after a long period of paralysis siderably endangered by lead, because lead inhibits ALA and thus following an acute attack. The regression of these forms of damage triggers the manifestation of porphyria (ϭ plumboporphyria). often takes many months. Residual defects may remain, mostly in the hands and feet. If corresponding preventive measures are carried out to curtail the factors triggering the disease, the prognosis 15.7.5 Porphobilinogen synthase defect is quite favourable. This rare form shows a very varied symptomatology. The disease Treatment ϫ may become manifest during puberty with severe pain or it may consists of i.v. glucose infusions (2 2,000 th haem arginate present later in life (beyond the 5 decade) with the clinical picture ml, 20% per day) plus administration of of moderate polyneuritis. ALA as well as uroporphyrins and (3 mg/kg BW/day on four consecutive days and at vary- coproporphyrins are augmented in the urine, whereas no abnor- ing sites of injection) (s. p. 846), possibly with simultan- malities are evident in faeces or plasma. eous administration of metalloporphyrin (for the inhibition of haemoxygenase) (276, 301) as well as intensive Chronic hepatic porphyrias care measures and administration of cimetidine (292) or Chronic hepatic porphyrias appear in two variants: (1.) iron. In cases with peripheral or CNS symptoms, porphyria cutanea tarda and (2.) hepatoerythropoietic prednisolone (100 mg/day) may be administered in add- porphyria. Chronic hepatic porphyria develops in about ition. (267, 289, 295, 296, 312, 313, 318) 10% of patients suffering from chronic liver disease. (s. tabs. 31.10, 31.11) 15.7.2 Variegate porphyria (VP)

Porphyria variegata is caused by protoporphyrinogen oxidase defi- 15.7.6 Porphyria cutanea tarda (PCT) ciency. Transmission is autosomal dominant (chromosome 1 q 23). The frequency is 1 : 100,000. • The clinical picture is characterized This is the most common form of porphyria (prevalence by skin changes similar to PCT (men > women), abdominal pain 20Ϫ50 : 100,000). The primary enzyme defect is a uro-

607 Chapter 31 porphyrinogen III decarboxylase deficiency. The coded disease and liver cell carcinoma. Chronic liver disease is gene for the enzyme defect is on chromosome 1q34. found in 30Ϫ40% of patients with PCT. (285, 305) PCT is characterized by pronounced genetic hetero- The pathogenesis of PCT is thus caused by a combin- geneity. • As far as its transmission is concerned, two ation of four factors: forms can be differentiated: (1.) familial form (type 2), which is characterized by an autosomal dominant trans- 1. Defective uroporphyrinogen decarboxylase mission route with heterozygote enzyme deficiency 2. Realization and provocation factors (about 50% enzyme activity) in all tissues (e.g. erythro- 3. Accumulation of UCP and HCP in the liver cytes, liver, fibroblasts) Ϫ other family members are fre- 4. Liver disease quently affected as well; (2.) acquired form (type 1), which is also autosomal dominant, displays a uroporph- Clinical picture: The clinical picture is characterized by yrinogen decarboxylase deficiency, but only in the liver skin lesions and liver damage. • The skin changes usually (normal enzymatic activity in erythrocytes). This “spo- begin between the ages of 40 and 70 years. Photosensi- radic” type occurs about six times as often as the famil- tivity is due to porphyrin deposits in the skin, where ial form. Probably, there is also a third form of PCT, their distribution pattern resembles that in the urine and namely another familial form, in which, however, the serum. The lesions are so typical that there are hardly inheritance is not confirmed. The URO-D in the hepa- any misinterpretations. They are found at locations tocytes is normal (100%) in these patients. The enzyme exposed to light such as the dorsal surface of the hands defect seems to be limited to the liver. (284) It is (not yet) and fingers, face, neck, auricle and hairless areas of the possible to differentiate clinically between these forms. head. The following forms are evident: (1.) vesiculated ᭤ As is the case with all hepatic porphyrias except HEP, additional erosive blisters of 2 mm to 3 cm in size, which “migrate” realization factors such as (1.) alcohol, (2.) oestrogens, and (3.) when subjected to pressure (ϭ Nikolsky’s phenomenon), haemodialysis (together with a genetically induced enzyme defect) (2.) bloody scabs after the blisters have ruptured, with a are required for the clinical manifestation of PCT. Alcohol may poor tendency to heal, but only a slight inclination to cause the manifestation of PCT due to the induction of MEOS and an alcohol-related increase in iron in the liver. However, (4.) secondary bacterial infection, (3.) healed vesiculated pharmacons (particularly lipophilic medicaments) may also be erosive blisters with atrophic scar formation and blotchy responsible for PCT, e.g. barbiturates, diazepam, hydantoin, hyper- or depigmentation as well as whitish epithelial rifampicin, antipyrin, cyclophosphamide (299), hexachloroben- cysts, the size of a pinhead, filled with pearly bodies, (4.) zene. (s. p. 565) These substances also trigger induction of the cyto- hypertrichosis and facial cyanosis as well as melanotic chrome P 450 system, but no regulatory disorder of haem synthesis, so there is no compensatory increase in ALA synthase. A rise hyperpigmentation, (5.) chronic actinic skin changes in PBG and ALA is therefore not detectable in the urine; this (premature skin ageing, cutis rhomboidalis, elastosis), means that no neuropsychiatric symptoms appear in PCT. • Apart and (6.) pseudosclerodermia on skin areas exposed to from that, there are substances which act as provocation factors, sunlight. (s. figs. 4.13; 31.16) e.g. xenobiotics, steroids, lead, iron and mercury. Iron interferes with porphyrin metabolism by inhibiting uroporphyrinogen decarboxylase and probably the subsequent ferrochelatase as well, so that PCT becomes manifest. While these factors trigger an acute life-threatening porphyric process in acute hepatic porphyrias, they are generally well tolerated in PCT (e.g. all drugs), at least for a short period of time. (285, 309) While PCT was formerly observed with greater frequency in men (peak rate between the third and fifth decade), the ratio between the sexes nowadays is assumed to be 1:1, with women occasionally being even more prone to the disease. This situation is possibly attributable to oestrogen intake (e.g. contraceptives) and increased alcohol consumption among women. Obviously, hepatic siderosis is a prerequisite for the expression of the “sporadic” form. The frequency of PCT is estimated to be 1% of the population in the age groups 30Ϫ70 years. Predisposition: The additional liver damage caused by the accumulation of urocarboxyporphyrins (UCP) and heptacarboxyporphyrins (HCP) in hepatic tissue is a prerequisite for clinically manifest PCT. Several forms of liver disease increase susceptibility to PCT, e.g. viral hepatitis B, and more particularly type C (286, 287, 302, Fig. 31.16: Skin changes (face, front part of the neck) in porphyria 309), fibrosis, siderosis, cirrhosis, alcohol-induced liver cutanea tarda (s. fig. 4.13)

608 Metabolic disorders and storage diseases

Liver damage is clinically recognizable as hepatomegaly. UV examinations (366 nm), to which every liver bioptate There is an increase in transaminases, GDH, γ-GT,serum should be subjected, the red fluorescence has different iron (increased saturation of transferrin) with secondary intensities, facilitating classification into PCT groups polycythaemia, and occasionally alkaline phosphatase. AϪD: types A and B (no clinical symptoms) show dot- Reduced liver function is evident due to decreased cholin- like fluorescence, type C (latent PCT) has mostly reticu- esterase. • Depending on the duration and progression of lar fluorescence, and type D (manifest PCT) is charac- PCT, changes in the liver surface range from a faded lobu- terized by homogeneous red fluorescence. (s. fig. 7.10!) lar pattern on a reddish-brown coloured liver to finely (s. pp 145, 158) • In the further course, scar tissue or granulated areas with fine whitish fibrosis on a diffuse micronodular cirrhosis develop. There is a greater risk blue-grey surface colour (due to porphyrin deposits) and of hepatocellular carcinoma (15Ϫ25%) (due to concom- brownish speckled areas as well as flat tuberous surfaces itant HBV or HCV infection as well as haemochro- with scar formation. (s. fig. 31.17) matosis?). (305, 309Ϫ311) Diagnosis of PCT is based upon skin changes with characteristic anamnesis and detection of porphyrins in the urine and faeces. (s. tab. 31.14) There is evidence of increased uroporphyrins, particularly heptacarboxy- porphyrin and coproporphyrin in the urine as well as elevated uroporphyrin in the faeces and plasma. Dark red discolouration of the urine resulting from enhanced release of porphyrin (>15 µmol/day) has frequently been observed. Subclinical forms can be detected three times more frequently using targeted diagnostics! • In most cases, HLA-A3 and HLA-B7 (as in haemochromatosis) are present in the serum. Serum iron is elevated. The undoubtedly important role of iron in the pathogenesis of PCT has still not been clarified. Mutations of the HFE gene in haemochromatosis (C 282 Y, H 63 D) are also much more numerous in PCT. Probably, these Fig. 31.17: Chronic active hepatitis in porphyria cutanea tarda. (and other?) mutations cause an enhanced resorption Dispersed light reflection, capsular fibrosis with pronounced net- of iron from the intestine. (284, 310) • There is a close like fibrosis. Spider-like subcapsular neovascularization coincidence of PCT and HCV infection (mainly genotype I b). A considerable geographical variation in fre- Histology shows deposits of needle-like porphyrins and quency has been reported, from which an average of large-droplet fatty changes in the hepatocytes, moderate HCV positivity in PCT patients of about 45% can be iron deposits in the hepatocytes and Kupffer cells as determined. Interactions between the two diseases have well as signs of non-specific reactive hepatitis. (s. fig. not been clarified as yet; however, it is striking that both 31.18) conditions generally show siderosis as well as being influenced to a particularly unfavourable degree by alcohol. (284, 287, 288, 302) Sonography: Even at an early stage of porphyria, ring- shaped foci with marginal hyperechoic ring and central hypoechoic reflexes can be detected. (s. fig. 31.19)

Fig. 31.18: Chronic porphyria: uncharacteristic lobular hepatitis histomorphologically correlating to increased liver enzyme levels (HE)

Fig. 31.19: Chronic hepatic porphyria: Sonographically, multiple, In the bluish-grey areas, the porphyrin content is three ring-shaped foci with marginal hyperechoic ring and central hypo- to four times higher than in the lighter liver sections. In echoic reflexes. (Completely reversible after alcohol abstinence)

609 Chapter 31

These foci result from porphyrin deposition and are The first therapeutic attempts to eliminate the increased often only discovered by chance since there is no evi- copper content of the tissue by way of chelating agents dence of a chronic porphyria. They can be mistaken for go back to J. N. Cumings (1948) and D. Denny-Brown et al. tumours or metastases; neither the foci nor their neigh- (1951). For this purpose, dimercaprol and ethylene- bouring parenchyma are hypervascularized. Following diaminetetraacetic acid (EDTA) were used. Treatment abstinence of alcohol and avoidance of oestrogens, they with potassium sulphide was recommended by M.M. are completely reversible. • In a chronic porphyria, there Wintrobe et al. in 1954. The final breakthrough came is frequently a uniform increase in density due to diffuse with examinations carried out by J.M. Walshe (1956),who porphyrin storage. recognized the copper-binding properties of β,β-dimeth- Treatment comprises avoidance of trigger factors (alco- ylcysteine (penicillamine). Another copper-chelating hol, oestrogens, sunlight, etc.) and application of sun- substance, trientin-dihydrochloride, was introduced by alshe blocks. • Venesection with its withdrawal of iron results J.M. W in 1969. (389) The therapeutic effectiveness in inhibition of ALA synthetase, while uroporphyrino- of zinc in patients suffering from Wilson’s disease had chouwink gen III decarboxylase activity is increased. This blood- been reported as early as 1961 (G. S ), while the letting therapy is based on 500 ml per week, after 4Ϫ6 therapeutic principle itself was described at a later date oogenraad weeks at monthly intervals. As an alternative, plasma- by T. U. H et al. (1978). (343) pheresis has also been applied. • Chloroquine (2 x 50 mg/ day) is administered every second day for 6Ϫ12 months; 16.1 Definition it combines biochemically with porphyrins in the hepatocytes, thus improving the elimination of porphyrins Wilson’s disease is a genetically determined, autoso- from the liver. Venesection and chloroquine therapy mal recessive copper storage disease with a reduced may be carried out jointly. • Alkalization of the renal discharge of copper into the bile. Due to pathological metabolism enhances the elimination of porphyrins via copper deposits in the liver and brain as well as vari- the kidneys. (296) ous other organs, sequelae develop above all in the 15.8 Hepatoerythropoietic porphyria (HEP) liver and CNS. The other affected organs are generally involved in the disease as late manifestation. This is a very rare form of chronic hepatic porphyria. The chromosomal defect is still not fully clarified. As with PCT, the enzymatic defect is a deficiency of uroporphyrinogen decarboxylase. However, the genetic defect is homozygous. It may also be caused by exoge- 16.2 Frequency nous factors. HEP manifests in early childhood with high photosensitivity, sclerodermia, hypertrichosis and The incidence rate is 1:100,000 inhabitants/year. The anaemia. • The liver shows red fluorescence. Histologi- prevalence of this disease in patients with manifestation cally, siderosis and non-specific hepatitis are found. is estimated at 1:30,000 and in heterozygote symptom Ϫ Development of cirrhosis is possible. • No effective ther- carriers at 1:100 to 1:200 of the population, i.e. 5 30 apy is known. (314, 316) patients/1 million inhabitants. • Wilson’s disease appears in childhood, adolescence and early adulthood. Initial occurrence before the 5th or after the 35th year of life is 16 Wilson’s disease considered to be an exception. However, mild courses of disease have also been diagnosed beyond the age of ᭤ The first clinical and morphological description of the dis- (321, 323) ease was published by S.A.K. Wilson in 1912. (394) This article 50. Most patients develop the first clinical did not mention the previous reports by K. F. O. Westphal (1883) symptoms around the age of 15. Geographical or race- and A. von Strümpell (1898); they distinguished between the related differences in frequency have not been reported. neuropsychiatric picture of the disease, assigning to it the rather However, a higher incidence is found in regions with unfortunate term “pseudosclerosis”, derived from multiple scle- strong consanguinity (e.g. Sardinia, Israel). rosis, which was already clearly defined at that time. • In 1921 H.C. Hall maintained that Wilson’s disease and pseudosclerosis were actually one and the same thing and that it was even hereditary; he coined the term “hepatolenticular degeneration”. 16.3 Pathogenesis • The storage of copper in the liver and brain was postulated by A. Rumpel in 1913 and confirmed by F. Haurowitz in 1930. The The metabolic defect in Wilson’s disease is located in brown-green colour of the corneal ring described by B. Kayser the liver on chromosome 13 close to the esterase-D leischer (1902) (347) and B. F (1902) (337, 338) is due to copper locus (ATP 7B). (325, 346, 359) Apparently, this is a genet- erlach umings deposits, as was confirmed by W. G in 1934. J. N. C ically determined disturbance of hepatobiliary copper (1948) identified copper as the cause of disease. Hypercupriuria was first described by B.M. Mantelbrote et al. (1948) and hypo- discharge due to a defect in lysosomal copper-trans- cupraemia by A.G. Bearn et al. (1952). This abnormality in cop- porting ATPase, which is localized in the trans-Golgi per metabolism was clarified by the detection of hypoceruloplas- network. As a result, apoceruloplasmin cannot be minaemia (I.H. Scheinberg et al., 1952). In 1960 A.G. Bearn loaded with copper, and is therefore degraded. The demonstrated the recessive autosomal transmission. reduced secretion of ceruloplasmin explains the low

610 Metabolic disorders and storage diseases copper level in the serum. So far, more than 250 dif- copper may also be bound intracellularly to another pro- ferent mutations of Wilson’s gene have been described. tein that has only recently been detected. (327, 358) This disorder may be located (1.) in the area of the sinusoidal membrane (transfer into the blood via ceruloplasmin) or (2.) in the area of the canalicular membrane (transfer into the bile via copper-binding 16.4 Pathophysiology ATPase). About 80% of the copper absorbed enterally The toxicity of copper is due to (1.) its binding to SH groups of is excreted via the bile, while in Wilson’s disease, the cysteine, which is converted into an irreversible form by oxidation, biliary excretion is reduced to 10Ϫ20%. Neither reab- and (2.) the fact that it is responsible for the formation of reactive sorption of copper excreted via the bile nor intestinal oxygen intermediates (e.g. hydroxyl radicals), resulting in lipid peroxidation, which, in turn, is responsible for functional and struc- (332, 370, 385, 395) copper resorption are increased. tural disturbances of biomembranes. (342) In addition, a reduction In the first 3Ϫ4 months of life, the newborn usually shows findings in vitamin E likewise encourages the occurrence of lipid peroxid- concerning copper metabolism which correspond to those found ations. • Initially, copper is diffusely distributed in the cytosol and in Wilson’s disease. It is therefore assumed that the conversion of then stored in the hepatocellular lysosomes. At this point, it can foetal copper metabolism to that normally found later on in life is also be demonstrated histochemically. Rapid transfer from the effected by a control gene. From birth onwards, 10Ϫ20 mg copper cytosol to the lysosomes may lead to increased lipid peroxidation are accumulated every year. It usually takes 6Ϫ15 years before with cell necrosis. (370, 383) • Abrupt discharge of copper from the clinical symptoms become apparent as a result of the cumulative lysosomes into the bloodstream results in intravasal haemolysis and copper deposition. • In siblings, there may be considerable differ- widespread liver cell necroses with fulminant hepatitis. ences regarding clinical and laboratory findings. It can therefore be concluded that exogenous or endogenous factors modify the genetically determined process or alter the gene expression within the families involved. There is genetic heterogeneity. 16.5 Morphological changes Copper: Ϫ The daily intake from food is 0.8 2.0 mg; it 16.5.1 Hepatic manifestation is released into the portal vein via copper-transporting ATPase. The transport of copper, which is toxic in its Electron-microscopically, the mitochondria Ϫ an essen- free form, is effected by the binding to ceruloplasmin, tial target of toxic copper Ϫ show swelling and altered albumin and transcuprin. • Copper is bound to reduced morphology, separation of external and internal mem- glutathione and metallothionein in the hepatocytes and branes, greater density of the matrix, and granular or distributed to various organelles or incorporated into vacuolic inclusions. The peroxisomes are characterized enzymes. The biological effects of copper are manifold by their increase in size and altered form as well as a and essential for some cellular functions. (s. p. 50) Cop- granular matrix. Secretion of lipids is reduced. These per is toxic not only in its free form, but also in cases structural changes result in discernible steatosis of the of overload (e.g. cirrhosis in childhood due to the con- hepatocytes. • The lysosomes grow in number and size; sumption of water from copper pipes). Copper homoe- finally, they decay and release lysosomal enzymes. (350) ostasis is regulated via biliary excretion (normal value: Apart from that, structural changes in the endoplasmic about 1.2Ϫ2.0 mg/day), so that the normal value in reticulum and cytoskeleton can be observed (ϭ stage I). serum is 75Ϫ130 µg/dl. (321, 323, 370, 383, 386) (s. p. 102) Histologically, Ceruloplasmin binds eight copper atoms per molecule fine-droplet, ultimately also large-drop- and is of an intense blue colour. The coding gene is let, fatty changes of the hepatocytes in the peripheral lobules and the occasional formation of Mallory bodies localized on chromosome 3. (396) Ceruloplasmin is the most important transport protein for copper in circulat- can be found. There are no signs of fat cysts. Steatosis ing blood (about 75Ϫ95% binding capacity). Another subsides with increasing duration of disease. The lyso- important function of this protein is the catalysis of oxi- somes, meanwhile overloaded with copper, are depos- dative metabolic reactions; it also possesses antioxida- ited mainly at the bile pole of the hepatocytes and tive features for the elimination of reactive oxygen inter- resemble lipofuscin-like pigment bodies. Degenerative mediates. (s. tab. 3.25) The normal value in serum is changes in the hepatocytes, hypertrophy of Kupffer cells 20Ϫ35 mg/dl. and an accumulation of glycogen in the nuclei with formation of glycogen vacuolations can be observed. (s. fig. The reduction in the serum value of ceruloplasmin led to the 31.1) • Rapid intracellular redistribution of copper assumption that a primary synthesis disturbance was of particular pathogenic importance. There are several observations which con- causes extensive cell necrosis. In this intermediate stage tradict this hypothesis, suggesting that the disturbance in cerulo- (ϭ stage II), inflammatory reactions (very probably of plasmin synthesis is probably a secondary consequence of the an autoimmune nature) and proliferations of the bile underlying metabolic defect. The introduction of copper into ceru- ducts are evident. The histological picture Ϫ as well as loplasmin is possibly inhibited as a result of a dysfunctional apo- the laparoscopic image of the liver surface Ϫ may at protein of ceruloplasmin. this point correspond to that of chronic hepatitis. (s. fig. Transcuprin is another transport protein for copper in 31.20) The late stage shows increased fibrogenesis with circulating blood (about 7% binding capacity). • Apart variable fibre contents, and micronodular cirrhosis from being bound to glutathione and metallothionein, develops (ϭ stage III). (s. figs. 31.21, 31.22)

611 Chapter 31

nation of the liver bioptate. The detection of copper is possible by means of (unreliable) rhodanine staining, while the copper bound to metallothionein in the lysosomes is demonstrable by orcein staining (likewise not reliable). The copper content of the liver (normal 15Ϫ55 µg/g dry weight) may indeed rise to 3,000 µg/g. If untreated, Wilson’s disease shows rapid progression, also in the liver. (339, 349, 355, 378, 382) With an effective therapeutic reversal of copper deposition, the copper balance can be restored. The patient returns to an asymptomatic course of Wilson’s disease. However, the organ damage that has hitherto occurred is irreversible (ϭ stage IV). The morphological spectrum may therefore range from steatosis, acute hepatitis, fulminant course, chronic Fig. 31.20: Chronic hepatitis in Wilson’s disease. Pronounced “sim- hepatitis, aggressive episodes in chronic hepatitis and ian cleft” with barely recognizable hepar succenturatum (s. p. 15) liver fibrosis through to micronodular cirrhosis. Com- plete cirrhosis can already exist in children aged 4Ϫ5 years. • The development of hepatocellular carcinoma is extremely rare (360); it is assumed that copper has a protective effect against malignant transformation. (391, 393)

16.5.2 Extrahepatic manifestations After complete saturation of the copper-binding capacity of the liver, the copper absorbed from food can no longer be taken up by the liver. This means that copper is stored in the brain, skeletal system, heart, cornea and kidneys Ϫ as is also the case when copper stored in the hepatocytes is released into the circulation on a large scale due to extensive liver cell necrosis. (339) CNS: Fig. 31.21: Explanted liver with micronodular cirrhosis in Wilson’s Copper deposits affect the whole CNS. Degener- disease (18-year-old woman presenting with acute liver failure) (Si- ation and tissue loss as well as atrophy of the lenticular rius) nucleus prevail. Occasionally, there are also small necrotic foci with a diffuse spot-like distribution. Micro- cavernous lesions occur due to the destruction of nerve cells. Myelinized fibres and oligodendrocytes are present, but there is also cellular hyperplasia and hypertrophy of astrocytes rich in protoplasm. The cerebral changes detectable in CT scanning do not correlate with the degree of severity of the functional disturbances (320, 335); however, there is a close correlation between the lesions detected by MRI and certain neurological findings. (350, 366, 376, 388) (s. p. 615) Eyes: Copper is deposited in the form of a copper-sul- phur complex in Descemet’s membrane on the back of the cornea. Fine copper granules are observed, first as moderate colour changes at the upper limbus, then also Fig. 31.22: Cirrhosis in Wilson’s disease. Numerous copper de- at the lower limbus, with the ultimate development of a posits in periportal liver epithelia (Rhodanine) complete brown-green ring, 1Ϫ3 mm in width. (337, 338, 347) The Kayser-Fleischer corneal ring is nearly always The distribution of copper in the liver is concentrated found in adults with principally neurological and psy- in the peripheral lobules, but its pattern is nevertheless chological problems, whereas it is generally not present irregular (even in advanced stages): there may be areas in juveniles with a hepatic course. The best way to detect with very high copper concentrations adjacent to this ring is by slit-lamp examination. (s. fig. 4.17) The regions which are almost copper-free; this can give rise existence of such a ring is not in itself proof of Wilson’s to false-negative findings during histochemical exami- disease, as it is also found in CDNC-induced cirrhosis

612 Metabolic disorders and storage diseases and primary sclerosing cholangitis; its absence does not, patients show symptoms between the 6th and 20th year however, exclude Wilson’s disease. • Occasionally of life Ϫ occasionally, however, as late as the 4th decade. (10Ϫ20%), a sunflower cataract is observed on the lens About half the patients develop the disease before the (E. Siemerling et al., 1922): a central gold-brown copper age of 15. Sometimes, above-average growth in height is deposit in the frontal lens capsule with radial emanation observed. Based on the prevailing symptoms, three clin- into the posterior capsule areas. (328) Visual acuity is ical forms can be differentiated: (1.) hepatic,(2.) neuro- not compromised by these changes. Successful treat- logical, and (3.) mixed courses. The hepatic form is ment leads to the regression of both ocular findings, observed almost exclusively in children between the ages making it possible to evaluate the course of disease (as of 6 and 15, while the neurological form predominates well as to monitor inadequate treatment). in adults. • Asymptomatic courses are usually diagnosed Kidneys: Dysfunction of the proximal tubule may occur only by chance. (326, 330, 339, 341, 364, 370, 377, 379, 381) as a late manifestation of Wilson’s disease. Epithelial Early diagnosis is essential. This is true both for the flattening, a loss of the brush-border membrane, mito- recognition of heterozygous carriers and for the diag- chondrial anomalies and fatty cellular changes can be nosis of asymptomatic homozygous carriers Ϫ often, observed. These findings are, in turn, responsible for the two groups can only be differentiated by using proteinuria with a predominance of hyperaminoaciduria complicated methods (e.g. specific DNA markers, zman (L. U et al., 1948). Enhanced calciuria and phosphat- gene linkage analysis, 64Cu kinetics). (345, 351) uria may cause osteomalacia as well as hypoparathyroidism. (329, 344) Glucosuria and uricosuria, if present, ᭤ Once the diagnosis of Wilson’s disease has been con- are without clinical relevance. Due to decreased bicar- firmed beyond doubt, all other family members have to bonate resorption, tubular acidosis may occur, with a be examined as well. During this process, occasional tendency towards osteomalacia as well as the develop- cases of a presymptomatic course of disease are ment of nephrocalcinosis and renal stones (in some 15% detected. A reduction of ceruloplasmin in serum may of cases). (344, 356, 392) The intensity of the copper even be present in carriers of heterozygous features. deposits in the kidneys correlates closely with the cellu- Genetic analysis can provide a diagnosis in some 95% lar changes and functional disorders. • The glomerular of cases, even prenatally. function is not compromised, with the result that substances normally excreted in the urine are not retained. Liver diseases Skeleton: Renal phosphate diabetes associated with Hepatic disorders are a prominent feature of Wilson’s hypercalciuria may lead to osteomalacia or osteoporo- disease in childhood and adolescence. In the early sis. Likewise, inflammatory or degenerative arthrosis is stages, a fatty liver is often observed, the aetiology of thought to be a late manifestation of Wilson’s disease. which is at first unclear. • A slight increase in the trans- (354) Often, these developments are combined with aminases may be the first biochemical sign, before any intra-articular calcium deposits and chondromalacia, in other symptoms appear. • In acute hepatitis of varying particular patellar chondromalacia. Bone fractures are degrees of severity, Wilson’s disease must always be frequently observed even with minor traumas. Calcifica- ruled out. • In the natural course of disease, chronic tion may occur in articular cartilage, capsule and tendi- active hepatitis may be found in the initial phase. In nous insertions, and deposits of calcium pyrophosphate terms of clinical and laboratory examination, it can only dihydrate can appear in the intervertebral disks. be distinguished from other forms of chronic active hep- Myocardium: Copper deposits in the myocardium causes atitis by way of aetiology-specific findings. (s. fig. 31.20) interstitial fibrosis, the sclerosing of small vessels and • Fulminant hepatitis, which is observed quite often, focal inflammatory or degenerative lesions. This results in shows rapid progression with the development of pro- cardiac arrhythmia and cardiomyopathy. nounced jaundice; there is evidence of increased copper Bone marrow: Leucopenia and thrombopenia may be a values in the serum and urine, while ceruloplasmin in result of bone-marrow damage caused by copper de- the blood is decreased or normal. Ascites and growing posits, although this can also be due to splenomegaly. liver insufficiency are evident. (335) Transaminases are only slightly elevated. A marked reduction in alkaline Skin and muscles: Acute rhabdomyolysis (362) as well as phosphatase is considered to be a characteristic feature. dermatomyositis are considered to be rare manifesta- (374) At the same time, haemolysis is often present due tions of Wilson’s disease. • Occasionally, there is evi- to an abrupt discharge of cytosolic copper into the dence of hyperpigmentation as well as acanthosis nigri- bloodstream. Fulminant hepatitis in Wilson’s disease is cans. Bluish, lunular discolorations of the nails, so- usually fatal if there is no chance of liver transplanta- called azure lunulae, are rare. (322) (s. p. 84) tion. (333, 334, 339, 340, 353, 358, 368, 375, 380) • Liver cirrho- 16.6 Clinical picture sis develops slowly. (s. figs. 31.21, 31.22) Non-specific general complaints and skin stigmata of liver disease (s. The symptoms of Wilson’s disease can hardly ever be fig. 4.21), which are typical in chronic forms, as well as recognized before the age of six. In most cases, the the symptoms and sequelae of portal hypertension are

613 Chapter 31 evident. In association with thrombopenia, cutaneous 16.7 Laboratory findings and mucosal bleeding may occur due to synthesis disor- When there are clinical signs suggesting the presence of ders of the coagulation factors. Occasionally, recurrent Wilson’s disease or corresponding differential diagnostic bouts of jaundice (generally due to haemolysis) are considerations, diagnosis (or diagnosis by exclusion) is observed. An acute necrotizing episode may have a established by laboratory parameters. AP is normal or fatal outcome. slightly increased. The GPT/GOT quotient is generally Neurological and psychiatric disorders >4.(330, 339Ϫ341, 357, 381, 390, 397) (s. tab. 31.15) Neurological symptoms are not observed before an Ceruloplasmin in the serum ȇ (Ͻ 20 mg/dl) advanced stage of disease is reached, particularly in Copper content of the liver Ȇ (Ͼ 250 µg/g) older juveniles or adults. In their case history, half of Copper in the urine Ȇ (Ͼ 70 µg/day) these patients have not shown any signs of haemolytic Free copper in the serum Ȇ (Ͼ 25 µg/dl) anaemia or hepatic symptoms which could have pointed Penicillamine test (600 mg) ϩ (Ͼ 300 µg/6h) to Wilson’s disease. However, a very discrete symptom- Total copper in the serum ȇ (Ͻ 70 µg/dl) atology at the onset progresses continuously and ultimately characterizes the clinical picture of untreated Tab. 31.15: Decisive laboratory criteria for the diagnosis and fol- Wilson’s disease. (320, 371, 381, 397) • Psychiatric symp- low-up of Wilson’s disease toms (personality changes, behavioural disorders, neuro- Ϫ ses, psychoses) are detected in 55 65% of cases. • A Ceruloplasmin: Usually, the serum value of ceruloplasmin is below drop in performance at school may be one of the first 20 mg/dl in homozygous Wilson’s disease; however, in about 15% signs of Wilson’s disease. • The following symptoms are of such symptomatic patients, the values are found in the lower found in varying degrees of intensity and in different normal range (20Ϫ30 mg/dl). In about 15% of heterozygous combinations (although some of the late features are patients without manifestation of the disease, a slight decrease in the ceruloplasmin value is also observed. When the value is >30 no longer observed nowadays due to effective treatment mg/dl, Wilson’s disease can usually be ruled out. Nevertheless, in techniques which are generally initiated at an early strongly compromised liver function, the ceruloplasmin value stage): increases due to hyperoestrogenism, which develops subsequently and stimulates ceruloplasmin synthesis in the liver. A decrease to Ϫ unsteady gait, balance disturbance, uncoordinated <20 mg/dl is not confirmation of Wilson’s disease. Decreased movements, grimacing values are also found in nephrosis, Menkes’ disease, aceruloplas- Ϫ minaemia (J.D. Gitlin, 1998), malabsorption syndrome, etc. dysarthria, scanning speech, palilalia Increased values Ϫ are observed in cholestasis, during pregnancy, dysphagia, salivation, raising and retracting of the with oral contraceptives, in malignant and inflammatory pro- upper lip cesses, etc. Ϫ dysgraphia, micrographia Ϫ Cupruria: In pronounced liver cell decay, there is not only a rise in seizures the copper value in serum, but more particularly in the amount of Ϫ tremor, athetosis, resting and intention tremor, copper excretion in the urine. Cupruria of <50 µg/day rules out nystagmus, rigor, flexion contractures, spasticity the presence of Wilson’s disease (differential diagnosis: e.g. kidney Ϫ personality changes, behavioural disorders, neuro- disease). • The penicillamine test has proved successful: after tic or psychotic symptoms (including forgetful- administration of 600 mg penicillamine, copper excretion increases to >300 µg/6 hr (>600 µg/24 hr). However, it should be noted that ness, irritability, emotional lability, inability to this test may show similar positive results in cholestatic liver dis- keep a distance) eases. Ϫ hypomimia and amimia, mask-like face Copper content of the liver: The diagnosis of Wilson’s disease is confirmed by determination of the liver copper content (normal: Haemolysis 20Ϫ50 µg/g dry weight) using atomic absorption spectrometry. First of all, the puncture instruments and glass vessels have to be In about 15% of patients suffering from Wilson’s dis- free of copper (cleaned with a 0.1 EDTA solution). An in- ease, haemolysis with corresponding jaundice can be homogenous distribution of copper in the liver, particularly in cases of cirrhosis, has to be taken into account. • In addition, an observed, sometimes as a relapse and occasionally as a increased hepatic copper content can also be detected in other liver haemolytic crisis. (s. tab. 12.3) The release of large diseases, e.g. bile-duct atresia, primary biliary or primary scleros- amounts of copper from necrotized liver cells causes ing cholangitis, bile-duct obstruction, chronic hepatitis, neoplasm, α copper-induced damage to erythrocytes with subsequent 1-antitrypsin deficiency, Gilbert’s disease, Dubin-Johnson syndrome. haemolysis (due to enzyme deficiency). Haemolysis may even constitute the first manifestation of Wilson’s disease (333, 334, 365) and precede the hepatic findings by 16.8 Diagnostic measures several years. Usually, it is transitory and self-limiting. In severe cases, this non-spherocytic, Coombs-negative, ᭤ Suspicion: Detection of acute or chronic liver disease intravascular haemoloysis may be combined with of unclear aetiology (in particular fatty liver) and/or haemoglobinuria. • Chronic haemolysis can lead to the haemolysis, and/or neurological or psychological peculi- formation of pigment gallstones. arities in children above the age of 6, in juveniles and in

614 Metabolic disorders and storage diseases adults up to the age of 40 suggest the suspected presence 16.9 Prognosis of Wilson’s disease (“give it thought”). The prognosis depends essentially on early diagnosis ᭤ Hints: Detection of a Kayser-Fleischer corneal ring and consistent treatment. (357, 370) If untreated, Wilson’s (in the early phase by slit-lamp examination) is con- disease is fatal. When treatment is initiated too late, sidered to be the most important clinical finding of irreversible, chronic damage is inevitable and the prog- early treatment manifest Wilson’s disease. (s. fig. 4.17) nosis is poor. However, when is applied at an initial stage, the prognosis for Wilson’s disease is ᭤ Confirmation: The diagnosis is verified by laboratory relatively good; remissions over a period of 7 years have parameters (determination of the serum values of cop- even been reported. (One of our own patients has now per and ceruloplasmin as well as of copper excretion in been in remission for more than 20 years.) The prognosis the urine, if necessary also by means of the penicillam- is particularly favourable if copper excretion therapy is ine test) and by demonstration of the copper content of already started in the preclinical phase. Compared to the liver, with simultaneous differentiation of existing the normal population, the life expectancy of the liver damage. patients is not compromised if the therapy is successful. After recovery, the patient’s general condition and phys- ᭤ Organ involvement: The type and extent of organ ical performance is usually unimpaired. involvement is determined by a broad spectrum of examinations. To a certain degree, these examinations are also important for monitoring progress and therapy. 16.10 Treatment (s. tab. 31.16) Early diagnosis and thus early treatment form the basis for (1.) establishing copper homoeostasis which is as 1. Liver stable as possible, (2.) avoiding chronic or irreversible laboratory parameters organ damage, (3.) supporting the regression of still liver biopsy/laparoscopy reversible lesions, and (4.) improving (perhaps even nor- copper content of the liver malizing) functional disorders. Therapy must be contin- 2. CNS ued lifelong, since copper reaccumulates, with the result EEG, ENG, EMG (CT), MRI that Wilson’s disease becomes manifest, and there is a 3. Eyes slit-lamp examination danger of acute liver failure. (326, 339, 340, 371, 381, 390) 4. Kidneys calciuria, phosphaturia, glucosuria, 16.10.1 Dietary measures aminoaciduria, tubular acidosis 5. Sonography Nutrition should be low in copper. Patients must avoid liver status, portal hypertension, foodstuffs and beverages containing copper, e.g. edible kidney stones, nephrocalcinosis, offal, nuts, cocoa products, mushrooms, potato crisps, gallstones rye flour, oat flakes, beans, dried figs, certain types of 6. Skeleton cheese, meat and fish, pineapple, mineral water (see rele- osteomalacia, osteoporosis, vant lists as to the composition of foodstuffs and copper chondrocalcinosis, arthropathy content in food). Vegetarian food, from which copper 7. Blood thrombocytes, leucocytes, cannot be easily mobilized, is therefore recommended. • coagulation factors, Cooking utensils containing copper should not be used. signs of haemolysis (s. tab. 12.3) • Alcohol is strictly forbidden. 8. Heart ECG 16.10.2 Drug therapy echocardiography D-penicillamine: The first-choice medication is D-peni- Tab. 31.16: Diagnostic measures for detecting the type and extent alshe of organ involvement in Wilson’s disease cillamine (J.M. W , 1956). By forming copper chelate, it not only causes a reversal of copper deposition and cupruria (see penicillamine test), but also induces metal- At an advanced stage, sonography yields a metastasis- lothionein synthesis, whereby the toxicity of the remain- like picture: fatty degeneration together with areas of ing copper is reduced, even though the copper content fibrosis (ϭ echogenic) and normal parenchyma (ϭ in the liver does not sink. Penicillamine reduces the hypoechoic). activity of lysil oxidase, thus diminishing the deposition of collagen. As a result, however, the skin unfortunately An MRI brain scan may demonstrate typical changes becomes fragile and wounds heal more slowly. • The such as atrophy and densification in the basal ganglia initial dose is adapted to the individual and ranges from and the lenticular nucleus (i.e. in the putamen and the 900Ϫ1,200 (Ϫ1,800) mg/day. The medication is given in globus pallidus). The cause of the particular sensitivity 3(Ϫ4) single doses per day, which have to be taken half of these regions is unknown. an hour before meals. Therapeutic success is to be

615 Chapter 31 expected after 6 months at the earliest: there is a con- cacy is lower. Iron-deficiency anaemia can occur. The siderable and continuous improvement with regard to substance is commercially available in the USA. (369) • abdominal complaints, neurological and psychological Further chelating agents being tested include 2,3,2-tetra- disorders, opthalmic findings and laboratory param- mine, APD and tetrathiomolybdate. eters. Occasionally, an initial worsening of the neurological symptoms is observed (most likely due to excessive 16.10.3 Peritoneal dialysis copper mobilization), which, however, ultimately results in a constant improvement in the neurological status if In acute copper toxicosis (378), peritoneal dialysis has also been treatment is carried on consistently. Whether or not the successfully implemented with simultaneous administration of penicillamine. In order to bridge the time until liver transplanta- treatment has actually been successful can only be deter- tion can be carried out, plasmapheresis and haemofiltrations are mined after about 2 years. • The removal of copper recommended. deposits is reflected in a normalization of copper excretion in the urine (after 2 days without medication) and 16.10.4 Liver transplantation serum parameters regarding copper metabolism. At this Ϫ stage, a maintenance dose of 600 900 mg/day can be In a fulminant course of Wilson’s disease or an advanced administered. Any interruption of treatment should not stage of cirrhosis with complications or in cases where exceed a period of several weeks, since this would defi- medication is not feasible, the only remaining alternative nitely result in a renewed overload of the organism with is liver transplantation. After successful transplantation, copper and possibly lead to acute and dangerous all clinical findings and laboratory parameters improve, relapses. Treatment with penicillamine is continued even and even neurological disorders become reversible. during pregnancy; breastfeeding is, however, not recom- Transplantation is a causal therapy, which confirms that mended. the primary metabolic defect of Wilson’s disease is In 20Ϫ25% of cases, side effects are observed, depending mainly located in the liver. (348) This means that no copper- on the dose (hypersensitivity reactions, aphthous lesions, arthral- releasing medication is required following transplanta- gia, nausea, fever). All in all, treatment of Wilson’s disease with tion. (324, 352, 361, 363, 372, 375, 384) penicillamine is considered to be successful and safe. If penicillamine is not well tolerated or if serious side effects are observed (e.g. kidney or bone-marrow damage, polyneuropathy, pemphi- gus), treatment must be discontinued. • Penicillamine usually 16.11 Indian childhood cirrhosis causes pyridoxin deficiency, so that substitution (25Ϫ40 mg/day) is recommended, particularly as chronic liver damage also leads to This condition, which is confined to India, leads to the vitamin B6 deficiency. • If necessary, electrolytes and trace elements also have to be substituted. development of childhood cirrhosis; it is fatal in almost all cases. Its aetiology is unknown. The condition affects Zinc: Treatment with zinc is considered to be an alterna- children of both sexes between the ages of 1Ϫ3 years. tive therapy for mobilizing copper deposits (T.U. Hoogen- Its familial occurrence points to genetic factors. There raad et al., 1978). (343) Zinc causes inhibition of intestinal is increased copper ingestion through food and milk as copper resorption and stimulates the synthesis of metal- well as from household utensils. Alkaloids may also be lothionein in the liver and intestinal mucosa. The recom- involved in aetiopathogenesis. • Initially, the symptoms mended dosage is 3 (Ϫ4) ϫ 50 mg/day, one hour before include increased appetite, restlessness, sleep distur- meals. The duration of administration and the dose are bances, bright and sticky stools as well as hepatomegaly. adjusted in line with therapeutic success. Zinc can also Kayser-Fleischer rings are not present. Serum cerulo- be used in long-term treatment (i.e. maintenance of cop- plasmin is normal. The further course is characterized per homoeostasis) following the initial release of copper by jaundice, oedema and ascites, bouts of fever and liver deposits by means of penicillamine. Side effects have atrophy. • The histological picture is similar to acute been reported in the form of gastrointestinal com- alcoholic hepatitis, but without fatty degeneration. Mal- plaints. There is an increase in AP as well as amylase lory’s hyaline, which is surrounded by polymorphonu- and lipase. (367, 387) clear leucocytes, is detectable in 80Ϫ90% of hepatocytes. Potassium sulphide: A decrease in intestinal copper resorption can The liver shows the highest content of copper so far also be achieved by the administration of potassium sulphide (3 ϫ verified in humans; it is located in the cytoplasm. As 20 mg/day) (M.M. Wintrobe et al., 1954). However, this therapy is a result of low-grade liver cell regeneration, only small not readily accepted by patients because the substance has a bad taste and very unpleasant smell. nodules are formed in the extensive, dense connective tissue, so that micronodular cirrhosis results. • Therapy Triethylene tetramine: The copper-chelating agent tri- is based on a strict reduction in copper intake and the ethylene tetramine (trientine) can be considered as an administration of D-penicillamine. (399) alternative therapy to penicillamine (J.M. Walshe, 1982). Non-Indian childhood cirrhosis: (389) The initial dose is 3Ϫ4 ϫ 600 mg/day; the recom- This similar condition, found in ϫ other countries, is indistinguishable from Indian childhood cirrho- mended maintenance dose is 2 600 mg/day, adminis- sis. Therefore, it is also called copper-related liver disease. A genetic tered about one hour before meals. The side effects are defect is probably involved. Any correlation with increased copper similar to those observed with penicillamine, but effi- ingestion is unlikely. (398)

616 Metabolic disorders and storage diseases

17 Haemochromatosis Hereditary (primary) haemochromatosis

᭤ The first observation of haemochromatosis was made by Th. HFE-related haemochromatosis Bonnet (1679). The first clinical case was described by A. Trous- type 1 Hereditary haemochromatosis seau (1865) with the three main symptoms of iron storage diseases: diabetes mellitus, bronze pigmentation of the skin and cirrhosis. Non-HFE-related haemochromatosis In 1871 C.E. Troisier termed this condition “la cirrhose pigmen- type 2 Juvenile haemochromatosis taire dans le diabe`te sucre´”. In 1877 H. Quincke detected iron type 3 deposits in the liver parenchyma of these patients and called this Italian variant clinical picture “siderosis”. For the same condition, V. H anot and type 4 Autosomal dominant form hauffard A.M. C (1892) coined the term “cirrhose hypertrophique Aceruloplasminaemia pigmentaire dans le diabe`te sucre´”. In 1895 P. M arie also described this illness as “diabe`te bronze´”. The term “haemochro- Atransferrinaemia matosis” was suggested by F. D. v. Recklinghausen in 1889. (469) Neonatal haemochromatosis (inherited /acquired?) Since 1935, haemochromatosis has been regarded as a genetically determined entity in itself and hypogonadism was added as a Acquired (secondary) haemochromatosis fourth cardinal symptom by J.H. Sheldon. (iron content of the liver > 0.5 g/100 g liver WW) ț extreme iron intake due to dietary habits 17.1 Definition e.g. Bantu disease or African iron overload (together with genetic basis), dietary iron overload Haemochromatosis (HC) is a hereditary disease ț extreme iron intake due to therapy (autosomal recessive) affecting the iron metabolism. e.g. frequent blood transfusions, chronic haemo- It refers to pronounced iron deposition, predomi- dialysis nantly in the liver (>50% of the total iron in the ț haemolytically induced body), but also in other organs, such as pancreas, e.g. thalassaemia spleen, heart, endocrinium, bone marrow, lymph ț metabolically induced nodes, salivary glands, basal skin layers and gastroin- e.g. tyrosinaemia, porphyria cutanea tarda, testinal epithelia. • In addition to these hereditary Zellweger’s syndrome, glycogenoses, lipidoses, (HFE-related) or idiopathic (non-HFE-related) pri- paraneoplastic ferritin production mary forms, there are numerous acquired secondary (such as in bronchiolar carcinoma) forms of HC. At first, the cells of the RES become laden with iron. Only when the capacity of the RES Haemosiderosis is exceeded is there iron deposition in the parenchy- ț liver siderosis mal cells; this leads to damage of the respective (iron content of the liver < 0.5 g/100 g liver WW) organs. (s. tab 31.17) e.g. chronic alcohol damage, portocaval anastomoses, hepatitis C, cirrhosis Haemosiderosis (HS) denotes iron storage in the ț pulmonary haemosiderosis organism, whereby iron deposition in the liver is <0.5 ț renal siderosis g/100 g liver WW. Iron deposition occurs almost ex- e.g. paroxysmal haemoglobinuria clusively in the RES; parenchymal cells are rarely ț affected. Haemosiderosis exists in two forms: (1.) cerebral siderosis absolute HS resulting in generalized iron deposition e.g. Alzheimer’s disease, Huntington’s in the body as a whole, or (2.) relative HS localized chorea, Pick’s atrophy in a certain organ with the rest of the body showing Tab. 31.17: Classification of haemochromatosis and haemosidero- normal iron distribution. Haemosiderosis does not sis (WW ϭ wet weight) cause haemochromatosis. (s. tab. 31.17) termed HLA-H gene and later on called HFE gene (J.N. Feder et al., 1996). The exact interpretation of the letters 17.2 Classification HFE is unknown (human ferritin?). In about 90% of Hereditary haemochromatosis (HC) can be differenti- patients with haemochromatosis, a homozygote point ated in one HFE-related and three non-HFE-related mutation (Cys 282 Tyr) in the HFE gene is evident. A Ϫ types as well as in a few other forms. (s. tab. 31.17) further point mutation (His 63 Asp) is found in 5 10% of HC patients. Its role in iron metabolism is still not 17.2.1 HFE-related haemochromatosis clarified. This mutation is often observed in HC together with a heterozygote status for Cys 282 Tyr Type 1 is the classic HFE-related form of HC. It has an mutation (so-called compound heterozygosity). For autosomal recessive inheritance pattern. The gene muta- these two point mutations the terms C 282 Y and H 63 tion is localized on chromosome 6, directly next to the D have been used. • The phenotype of HC in northern A-locus of the HLA system. (426, 427) It was originally Europe and the USA comprises the genotypes: (1.) C

617 Chapter 31

282 Y / C 282 Y (85Ϫ95%), (2.) wildtype / wildtype ally, there was a serious iron deficiency in serum (5Ϫ8%), (3.)C282Y/H63D(ϭ compound heterozy- together with marked iron storage in the tissue. (s. tab. gosity) (<5%), (4.) C 282 Y / wildtype (<2%), (5.)H63 31.17) D / wildtype (<2%), and (6.) H 63 D / H 63 D (<1%). In southern European populations, the frequency of C 282 Y homozygosity is lower (ca. 65%). • The localiza- 17.2.5 Neonatal haemochromatosis tion of the HFE gene on chromosome 6 has no close Neonatal haemochromatosis was first described by H. association to the receptor protein synthesis of ferritin Cottier in 1957. This fatal form of HC starts in utero (chromosomes 11 and 19), transferrin (chromosome 3) and must be differentiated from the above-mentioned or the iron-regulating factor (chromosome 9). (403, 429, genetically induced types; it does not represent a variant 448, 459, 468) (s. tab. 31.17) of HC. Genetic markers are not known and the basic underlying defect is still unclarified (inherited/ 17.2.2 Non-HFE-related haemochromatosis acquired?). “Sporadic” cases have also been observed. Both sexes are affected with the same frequency. Even Type 2 juvenile haemochromatosis is the . This rare form at birth, newborns have pronounced ferritin values, of iron storage can be differentiated from type 1 by an jaundice, cholestasis, coagulopathy, oedemas and ascites earlier onset of clinical symptoms. It becomes manifest as well as cirrhosis with iron storage. The babies affected prior to the age of 30. Both sexes are affected equally. die generally within the first few days or weeks. Patho- The gene defect is localized on chromosome 1q (A. genetically, irregular transport of iron through the pla- oetto R et al., 1999). Compared to type 1, cardiomyopathy centa or dysregulated iron metabolism in the foetal liver and hypogonadism are more frequent, the course of dis- cells is assumed to be responsible. The following therapy ease is more severe and cardiac-induced death is more can be recommended: acetylcysteine (100 mg/kg BW/ common. HFE mutations are absent, and there is no day i.v. for 7 days), α-tocopherol (25 U/kg BW/day association with the HLA system. This form of HC has orally), desferrioxamine (30 mg/kg BW/day i.v. infusion an autosomal recessive inheritance. (s. tab. 31.17) over 8 hours until the serum ferritin is <500 µg/l), sel- Type 3 is the Italian variant of haemochromatosis. The enium (3 µg/kg BW i.v. by continuous infusion) and µ gene defect is localized on chromosome 7 q 22 and prostaglandin E1 (0.4 g/kg BW i.v.). Liver transplan- affects transferring receptor 2 (D. Girelli et al., 2001). This tation, if successful, is curative. (411, 439, 447, 456) (s. form of HC probably has an autosomal recessive inheri- tab. 31.17) tance. The histomorphological and clinical findings are similar to those of type 1. (466) (s. tab 31.17) Type 4 is an autosomal dominant variant of HC. It has 17.3 Hereditary haemochromatosis only been observed in Italy. The gene defect is located on chromosome 2 q 32 and affects the iron export pro- HFE-related haemochromatosis, which is synonymous with type 1, is the most frequent and most important tein ferroportin (O.T. Njajou et al., 2001). In contrast to types 1 and 3, there is early iron storage in the macro- form of HC. The following chapter refers to this clin- phages. A characteristic feature are the markedly in- ical feature. creased values of ferritin together with a slight elevation of transferrin saturation. (s. p. 98) (s. tab. 31.17) 17.3.1 Frequency

17.2.3 Aceruloplasminaemia Hereditary haemochromatosis (HC) has an incidence of 0.25Ϫ0.5% in the Caucasian population. After Gilbert’s Aceruloplasminaemia is a very rare, autosomal recessive disease, HC is the most common hereditary liver dis- disease with diffuse iron overload. It is caused by a ease. Men are affected 5Ϫ10 times more frequently than mutation of the ceruloplasmin gene. This leads to women. The gene mutation on chromosome 6 occurs excessive iron storage, mainly in the brain, liver and with a frequency of 1:10 to 1:20 for the heterozygous pancreas. The principal symptoms are increased serum type and of 1:200 up to 1:400 for the homozygous type, ferritin, decreased serum iron and transferrin saturation as far as this can be detected by current methods. The as well as extrapyramidal disturbances, retinal degener- number of those affected with manifest HC is strongly ation, cerebellar ataxia and diabetes mellitus. (486Ϫ488) influenced by racial as well as exogenous factors (e.g. (s. tab. 31.17) diet, alcohol, personal habits), which is an explanation for the variations in frequency between 1:500 to 1:4,000. 17.2.4 Atransferrinaemia Prevalence of the HC gene in the normal population is estimated as being 6Ϫ7%. If both parents are heterozy- Atransferrinaemia is likewise a very rare inherited syn- gous carriers, the probability of the children being drome. The first and only case involving a seven-year- homozygous is 1:4 and heterozygous 1:2. (403, 407, 410, old girl was described in 1961 (L. Heilmeyer et al.). Clinic- 428, 452, 483)

618 Metabolic disorders and storage diseases

Ϫ About 1:500 persons in Germany are carriers of HC, however, the amount is 3 5 mg/day. Thus HC produces an annual iron surplus of 500Ϫ1,000 mg. • Resorption of bivalent iron homozygous HC. However, the number of clinically takes place in the mucosal cells of the duodenum and proximal detected cases of HC only corresponds to a ratio of jejunum. There, it is oxidized by ferroxidases into trivalent iron 1:5,000. A considerable number of homozygous car- and bound (by means of apoferritin) reversibly to water-soluble ˚ riers are diagnosed and treated far too late. • In 1% ferritin (molecular weight 460,000, 50 A in diameter, iron content about 20%). A single molecule of ferritin may contain up to 4,500 of patients with newly detected diabetes mellitus and atoms of iron. The synthesis of ferritin, which enters the cell via in 3Ϫ15% of cirrhotic patients, the respective disease ferritin receptors, is stimulated by iron; the site of synthesis is the is aetiologically attributable to HC. RES. Ferritin is also formed on the polysomes of the hepatocytes and broken down in the lysosomes. The plasma ferritin value correlates with the total amount of iron stored in the body. Enteral 17.3.2 Pathogenesis iron resorption is controlled by the intracellular ferritin concentration: there is a negative correlation between these two quantities. ᭤ Iron storage is about 0.07 g per year in heterozygous In HC, ferritin is considerably decreased in or absent from the mucosal cells; there may be disturbed regulation of ferritin gene carriers. In homozygous men, however, it is about ten expression, i.e. ferritin-determined dysregulation is observed. (414, times higher (0.6 g), whereas the rate in homozygous 426) • A second (but labile) intracellular storage form of iron is women is only 0.16 g due to loss of iron during menstru- haemosiderin, a water-insoluble pigment of Fe(III) hydroxide (ca. ation, pregnancy and breastfeeding. Generally, men 37%), protein, carbohydrate, lipids, copper and calcium. Haemo- have stored a total of 20Ϫ30gironbytheageof50.As siderin is formed during the lysosomal breakdown of ferritin, a Ϫ process by which released iron can be stored in the lysosomes. It from 5 8 g, progredient organ damage begins. (434, 460, is mainly stored in the peripheral area of the lobules and in the 468, 477) (s. fig. 31.23) portal fields. In contrast to ferritin, haemosiderin shows a positive Berlin-blue reaction. (s. figs. 31.25, 31.26) • Intracellular iron is, to A defect in the HFE gene leads to overenhanced (unde- a certain extent, bound to transferrin, which is mainly produced sired) intestinal iron absorption. Thus the enteral in the hepatocytes. It is considered to be a carrier molecule for absorption of iron is at a higher level in HC (2 to 4- extracellular iron. Only one third of the total iron-binding capacity of transferrin (normal 250Ϫ370 µg/dl) is iron-saturated. The satu- fold) because of this dysregulation, although the iron ration capacity beyond this normal degree of transferrin saturation content of the organism is increased. After being above is called free (latent) iron-binding capacity. There is a negative cor- average for several years, iron uptake returns to normal, relation between the amount of iron in the organism and the even in HC patients. However, following venesection, transferrin synthesis rate. The absorption of transferrin into the target cells occurs by means of a specific receptor. (418, 434, 448, the iron absorption in HC increases again. This disorder 453, 454, 464) (s. pp 49, 98) is primarily caused by the HFE mutation present in the crypts of the small intestine cells, where iron uptake An additional pathogenetic factor (apart from excessive iron supply usually occurs. • Iron absorption is regulated by the or alcohol abuse) is vitamin C, which has different effects: on the iron-responsive-elements-binding-protein. This IRE-BP one hand, it enhances intestinal iron resorption as well as iron excretion from the RES, but on the other hand, it is broken down shows a normal function in HC, since its gene is not due to an iron overload, which results in subsequent vitamin C localized on chromosome 6. In contrast, there is a dis- deficiency. • Alcoholic beverages may support the development of turbance of the association between C 282 Y mutation haemochromatosis when the respective iron content is considerably of HFE and the β-microglobulin, so that the normal increased (depending on the iron content of the soil or of the function of HFE is reduced. In addition, the defect drinking water used in their production). Furthermore, alcohol- induced folate deficiency may cause ineffective erythropoiesis with HFE gene does not interact with the transferrin recep- enhanced endogenous iron storage. • A genetic association also tor 1, with the result that iron is more easily absorbed exists between HC and Ͱ1-antitrypsin deficiency syndrome as well in the cell. Both the transmembranous protein Nramp 2 as porphyria cutanea tarda, which leads to a more rapid develop- and the iron reductase (Dcyt ϭ duodenal cytochrome ment of cirrhosis. • Any rise in iron storage is due to a disturbed iron balance: if the daily supply continues to be higher than the B) are considered as apical iron transporters. • Intestinal daily loss, the individual organs will absorb iron in line with their uptake of iron is still influenced by the basolateral iron respective storage capacity. transporter ferroportin 1, whose gene defect causes type 4 HC. Iron is also transported by the multi-copper-iron- oxidase hephaistin, which creates the connection be- 17.3.3 Iron toxicity tween iron and copper transport. • Transferrin receptor It was O. Warburg (1928) who first observed the toxic effects of 2 is also involved in the regulation of intestinal iron “free” (ionized) iron on cell metabolism. Increased acid phos- transport; in the case of a gene defect, it is responsible phatase, decreased glucose-6-phosphatase, disturbances in oxi- for the development of type 3 HC. The modes of action dative cell metabolism as well as augmented glycolytic break- behind iron absorption and iron transport based on the down processes in the liver and cardiac muscle cells have since been reported. • There are three molecular mechanisms which above-mentioned (and other?) proteins have only been are important for the toxic effects of free iron on cell metabol- partially clarified. (414, 418, 453, 454, 464, 477) ism: (1.) increased formation of reactive oxygen intermediates (with release of lysosomal enzymes and indirect stimulation of Iron metabolism: Iron is the sixth most abundant element in the fibrogenesis) (s. p. 67), (2.) direct stimulation of collagen synthe- universe; it has two oxidation states: Fe(II) and Fe(III). Normal sis (with enhanced fibrogenesis) (s. p. 403), and (3.) changes in diet Ϫ accounts for 10 30 mg iron/day, with about 1.5 mg/day of or damage to DNA (with the possible induction of carcinogen- this amount being stored mainly in the bone marrow, skeletal mus- esis). (s. fig. 31.23) culature and liver (hepatocytes, Kupffer cells, endothelial cells); in

619 Chapter 31

Fig. 31.23: Postulated pathogenetic and morphological cascade of damage in HC

17.3.4 Morphology grouped into islet-like structures. Within the tylotic connective tissue, very fine epithelial tubuli, also known as After being transported in increased quantities to the pseudo bile ducts, are found; they are more strongly liver, iron is mostly stored as haemosiderin and ferritin loaded with iron pigments than are the preformed bile in the hepatocytes of the lobular periphery. Initially, this ducts. These pseudo bile ducts are seen as minimal and liver cell siderosis does not impair the function of hepa- ineffective attempts to regenerate the parenchyma, tocytes, as iron is absorbed by lysosomes. Iron storage although the constant iron supply prevents epithelial commences in lobular zone 1 and progresses to zone 3. substitution. This leads to the development of almost Gradually, the cells of the whole lobule become involved uniform, micronodular (later on mixed-nodular) and in iron deposition, mainly in the form of centroaxial very coarse pigment cirrhosis, which is rich in fibres and pigment pathways, with enhanced iron deposition in the poor in regeneration. (s. figs. 31.24Ϫ31.26) periportal area (haemosiderin granules). (422, 442) When the storage capacity of the lysosomes has been exhausted (usually with a liver iron content of >4,000 µg/ g wet weight), there are unspecific inflammatory reactions in the portal field and lobular periphery, including single-cell necrosis as well as activation of fibroblasts and macrophages. Siderin, released from necrotized hepatocytes, is absorbed by Kupffer cells, which are usually increased in number and arranged in a nodular form. Coarse, grained siderosis of stellate cells likewise points to the extent of liver cell necrosis (ϭ sideronecrosis). This phase may be called acute siderophile hepatitis. (421) Occa- sionally, there is formation of giant siderosomes and glycogen vacuolations of the nuclei in the hepatocytes of the peripheral lobules. (s. fig. 31.1) • Some excess iron is transported into the bile ducts and stored in their epi- Fig. 31.24: Haemochromatotic cirrhosis: micronodular, slate-grey thelial cells. The fainter and more finely granulated pig- to brownish discolouration, rich in septate fibrosis, marked neovascularization mentation (compared to hepatocytes) is important for the morphological diagnosis of HC. The inflammatory mesenchymal reactions in the portal ᭤ The morphological damage in other iron-storing field and lobular periphery induce extremely low-cell organs (particularly the pancreas, heart and endocrin- perilobular and tylotic fibrosis. (425, 442) Slowly, star- ium) follows pathological mechanisms similar to those shaped portal fibrosis, so-called holly-leaf fibrosis, devel- in the liver. These organs also show brown tissue ops. This morphological picture, similar to that of changes with increasing fibrosis. HFE is expressed in all chronic hepatitis, was termed chronic siderophile hepati- tissues involved in HC. • In HC, zinc is also stored in tis by H. Kalk (1962). • The hepatic lobules are gradually the liver at up to eight times the normal levels.

620 Metabolic disorders and storage diseases

For the early diagnosis of HC, it has proved very useful to determine the hepatic iron index: iron content of the liver (in µmol/g dry weight) divided by age (given in years) (M.L. Bassett et al., 1984). A ratio of >2.0 suggests HC, while a ratio of <1.5 points to heterozygous HC or chronic alcoholic liver disease. (472, 478) Depending on the results obtained, subsequent determination of the phenotype or even of the genotype, if necessary, will follow (analogous to preventive diagnosis).

᭤ In the future, non-invasive liver-iron quantification (measuring the magnetic susceptibility as in “magnetic biopsy”) by way of SQUID biosusceptimeter (BTi ferritometer) as a quick and sensitive method Fig. 31.25: Micronodular cirrhosis due to hereditary (HFE-re- will open up new possibilities of early detection and lated) haemochromatosis (Berlin blue) therapy control.

17.3.6 Preventive diagnosis The detection of HC requires targeted preventive diagnosis of family members (including siblings) and close relatives. First of all, HFE genotyping is carried out by determining the C 282 Y mutation. Determination of the C 282 Y mutation shows a similarly high diagnostic sensitivity as a liver biopsy; HFE genotyping is therefore of the utmost importance for family screening. In heterozygosity, however, liver biopsy should be per- formed as a diagnostic marker instead of HFE genotyping. (403, 407Ϫ410, 417, 429, 434, 451, 458, 467, 468, 471, 473) • The phenotype varies considerably and is influenced by Fig. 31.26: Cirrhosis in hereditary haemochromatosis. Massive a number of factors (alcohol abuse, oestrogens, dietary siderosis in hepatocytes and in epithelia of preformed bile ducts iron intake, loss of iron, etc.). Elucidation of the pheno- (arrows) (Berlin blue) type focuses on the determination of transferrin saturation and ferritin concentration in the blood. With increased values, liver biopsy is indicated: an iron 17.3.5 Early diagnosis content of >1.7 mg/g dry weight points to HC, while a value of >4.5 mg/g or an iron index of >2.0 confirms For successful treatment and thus also for prognosis, the presence of HC and is also an indication for therapy. it is of the utmost importance to detect HC in its early phase. At this stage, however, neither subjective HLA system: This system may have one of three constellations:(1.) complaints nor clinical findings are apparent. The when two alleles (A3 and B14 or B7) of the relative are identical Ϫ to those of the patient, there is a high risk of HC occurring (ϭ development of symptoms is slow and gradual in annual check-ups are required); (2.) with only one HLA allele of men, not before the age of 30; in women, usually not the relative being identical to that of the diseased person, there is before the menopause. • It is only by chance that an merely a minor risk of manifestation (ϭ check-ups every 4Ϫ5 years increase in serum iron (>160 µg/dl), ferritin (>200 µg/ are sufficient); (3.) if neither allele of the relative is identical to dl) or transferrin saturation (>45%) occasionally those of the patient, there is no risk that the disease will become manifest (ϭ no further check-ups are required). (427, 443) • It becomes evident. The combined determination of fer- should be noted, however, that the formerly recommended deter- ritin and transferrin saturation has a sensitivity of mination of the HLA types (A3, B7, B14) is no longer common. 90Ϫ95%, although specificity is lower. (s. tab. 31.18) These purely accidental findings, which initially appear as moderate deviations from normal values, are by no 17.3.7 Manifestation means conclusive, but they are nevertheless suggestive Subjective complaints of HC. • However, hepatic siderosis can likewise be detected incidentally in liver biopsy, sometimes with When the organism is constantly overloaded with iron, an iron content of >1.7 mg/g dry weight, allowing subjective complaints gradually develop (in 5Ϫ40% of the additional option of determining the hepatic iron cases). These present a variety of uncharacteristic fea- index. (406, 408, 410, 417, 458) tures, varying from individual to individual.

621 Chapter 31

Fatigue (40؊60%) Impaired potency (10؊20%) heart, particularly of the ventricles, to thicken; apart -Abdominal pain (30؊40%) Nausea (10؊20%) from that, necrosis of the cardiac muscle cells with sub -Stress dyspnoea (20؊30%) Diarrhoea (5؊10%) sequent fibrosis can be observed. Dilatative cardiomy Weight loss (15؊25%) Meteorism (5؊10%) opathy is accompanied by tachyarrhythmias. Cases of (Heart problems (15؊25%) Dysmenorrhoea (5؊10% Arthralgia (15؊25%) Proneness to infection (5؊10%) sudden death have been described. Considerable Thirst (10؊20%) improvement is generally achieved by the release of iron deposits. The aetiology of cardiomyopathy can be clarified by myocardial biopsy. (416, 462, 470, 482) Clinical findings 5. Arthropathy: Initially, the small joints (finger, toe and During the development of the disease, clinical findings wrist) are affected. Subsequently, the large joints (knee, appear which can be attributed to those organs primar- shoulder and hip) also become involved in the clinical ily involved in iron storage and to their respective dam- picture of arthrosis. The patients complain at an early aging mechanisms. (402, 407, 417, 429, 452, 458, 467) stage (in 30Ϫ50% of cases) of arthralgia located in the areas described above, but there seems to be no correla- 1. Liver involvement (>90%) Cutaneous pigmentation (60؊80%) tion with the degree of iron overload. X-ray scanning .2 -Diabetes mellitus (60؊80%) shows subchondral cysts and sclerotic changes, narrow .3 -Cardiomyopathy (20؊50%) ing of the articular space, hypertrophic bone prolifera .4 Arthropathy (20؊50%) tions, chondrocalcinosis, and osteoporosis (particularly .5 Endocrinopathy (20؊50%) when hypogonadism is present). This kind of damage in .6 the joints, cartilaginous parts and adjacent bones is 1. Liver involvement: The liver is enlarged and of firm caused by the formation of calcium phosphate crystals consistency. Skin stigmata of liver disease occur with within the synovial cells, mainly due to iron-induced varying degrees of intensity. (s. p. 80) Portal hyperten- pyrophosphatase inhibition. Venesection treatment has sion with splenomegaly (30Ϫ50%), oesophageal varices little effect on arthropathy. (404, 474) and ascites develop. • Laboratory findings may include 6. Endocrinopathy: a slight increase in transaminases, P-III-P and IgG Pronounced iron deposition can be values as well as borderline pathological ICG and galac- found in the thyroid and parathyroid glands, the anter- tose tests. (s. p. 108) Occasionally, CA 19-9 levels are ior lobe of the hypophysis and the adrenal cortex. Tes- ticular atrophy is caused by insufficiency of the anterior moderately increased. Vitamin E is reduced. (440) A striking feature is the detection of normal parameters lobe of the hypophysis, particularly since only a small despite the presence of manifest cirrhosis. The existence (perivascular) amount of iron, or no iron at all, is depos- of cirrhosis with a ferritin value of <1,000 µg/l is ited in the testes. Hypogonadism (loss of libido, men- strual disorders, impotency) may regress after the unlikely. • Determination of α1-foetoprotein is recommended at long intervals. removal of iron deposits. In addition, signs of hypothyroidism, hypoparathyroidism and slight insufficiency 2. Cutaneous pigmentation: “Bronze diabetes” (s. p. 616) of the adrenal cortex are found. Biochemical evidence is rare. The colour of the skin is usually grey-brown, showing decreased serum values of the relevant hor- particularly in areas exposed to light, but also in axillae mones (gonadotropins, testosterone, oestrogens, aldo- and conjunctivae as well as in the genital area and oral sterone, thyroid hormones) may provide an overview of cavity. The dirty grey discolouration is due to increased the underlying endocrinopathy. Gynaecomastia has not melanin and enhanced iron storage, particularly in the been observed. (419, 445) sweat glands. Pigmentation is most striking along the lines of the palms. (s. fig. 4.12!) (s. p. 84) Laboratory findings 3. Diabetes mellitus: A glucose tolerance disorder is There are many reasons why laboratory parameters of detectable at an early stage. Subsequently, 60Ϫ70% of iron metabolism may deviate from normal values; they the patients develop the distinct clinical picture of dia- should always be checked to facilitate the differential betes, including diabetic complications (retinopathy, diagnosis of HC or of acquired haemochromatosis and polyneuropathy, nephropathy, arteriopathy). The β-cells haemosiderosis. • In cases of HC, there are various devi- show iron deposition and fibrosis, in contrast to the α- ations from normal values. (406, 410, 417, 458, 467) (s. cells (so that glucagon secretion is still normal). It tab. 31.18) remains unclear whether an additional genetic defect is The determination of serum iron concentration often present in the β-cells. Usually, there is peripheral insulin shows normal values over a long period of manifest HC. resistance, which often becomes reversible as a result of In suspected HC, repeated examinations may be neces- successful treatment. With progressive destruction of sary due to daily fluctuations and circadian rhythms in the β-cells, insulin-dependent diabetes mellitus develops. the serum iron concentration as well as in factors influ- 4. Cardiomyopathy: Iron deposition in the myocardium encing laboratory procedures. It is only in the later and/or the conduction system causes the walls of the course of HC that serum iron is constantly and signifi-

622 Metabolic disorders and storage diseases

cantly increased. In 1953 H. Kalk described hyper- Hypochromic anaemia with poikilocytosis may point to siderinaemia as the typical fifth cardinal symptom of disturbed erythropoiesis as a result of iron overload. • HC. • When serum iron continues to fall, liver carci- Transferrin deficiency may, however, also be causally noma can be suspected. related to this disease. The determination of transferrin saturation (after 12 While the deferoxamine test (s. p. 99) is often considered obsolete, it can nevertheless serve as another stone in the mosaic and prove hours of fasting) supports a strong suspicion of mani- helpful in the diagnostics or follow-up of HC, since it is an iron fest HC when the value is >55%, while a saturation of chelation test that is easy to apply, free of side effects and inexpen- >75% is almost diagnostic proof of homozygosity. This sive. In healthy persons, this test reveals a urinary iron excretion method is also considered to be a reliable screening test. of <1Ϫ2 mg; in haemosiderosis, the excreted amount is <4 mg, A value of >55% shows a specificity and sensitivity of and in HC >4 mg. (461) 92% for HC. With a value of >50% in women and A gastric mucosa biopsy may facilitate differentiation between HC >60% in men, the ferritin level should be checked as and secondary haemochromatosis, yet this examination is also ϭл well. An increased saturation value calls for liver biopsy, regarded as obsolete today. (Iron in macrophages with HC , with secondary HC ϭ ȆȆ.) whereas a normal value requires a follow-up after 1Ϫ2 years. Imaging techniques The total iron-binding capacity (TIBC) of transferrin can be calculated from the transferrin concentration in µg/dl or µmol/l: CT determination of increased liver density due to iron transferrin x 1.41 or transferrin x 25.2. This gives a normal value overload in haemochromatosis yields values of 80Ϫ140 for men of 268Ϫ436 µg/dl or 48Ϫ78 µmol/l and for women of Hounsfield units (ϭ white liver). The deposition of 1 g Ϫ µ Ϫ µ 257 402 g/dl or 46 72 mol/l. • The difference between TIBC iron causes an increase in density of 1 HU. CT densi- and the amount of iron found before Fe3ϩ and magnesium carbon- ate are added is called free iron-binding capacity. This is the FIBC tometry makes it possible to monitor the course of the which is possible beyond the normal saturation capacity of about blood-letting therapy. (463) (s. p. 173) • In MRI, a one third of the transferrin. • The transferrin saturation (in %) haemochromatotic liver appears dark grey to black (ϭ can be calculated as follows: serum iron (µg/dl) x 100 divided by dark liver) due to signal loss depending on the iron transferrin (mg/dl) x 1.25. • A free IBC of Յ 50 µg/dl, i.e. transferrin saturation of >62%, suggests the presence of HC. content. (s. fig. 8.8) With an iron concentration of 1 mg/ g liver tissue, accuracy is 95Ϫ100%. (405, 415, 436, 438, The ferritin value corresponds well to the total value of 450) (s. p. 177) • Both examination techniques are of body iron, whereby 1 µg/l ferritin is equivalent to about great importance in detecting liver cell carcinoma. • By 7.5 mg body iron. The sensitivity of the ferritin value in using the newly developed SQUID biosusceptimeter HC is 85% and the specificity is 95%. A value of >700 (BTi ferritometer), even more reliable quantification of µg/l points both to the presence of HC and to the devel- liver iron is expected. opment of liver fibrosis or cirrhosis. In contrast, a normal ferritin value and normal transferrin saturation rule Liver biopsy and laparoscopy out HC in about 95% of cases. (s. tab. 31.18) Laparoscopically, a dark brown liver surface with augmented fibrosis can be seen. (s. fig. 31.23) • Quantitative Normal values Haemochromatosis measuring of iron in the liver bioptate is the most reliable technique for diagnosing haemochromatosis. If 1. Serum iron possible, this kind of biopsy should be carried out under Ϫ µ Men 59 158 g/dl laparoscopic guidance, and two biopsy punches should 10.6Ϫ28.3 mol/l Ͼ 180 µg/dl be taken. The first sample is designed to serve as a histo- Women 37Ϫ145 µg/dl Ͼ 32 µmol/l 6.6Ϫ26.0 µmol/l logical specimen as well as to detect iron and iron localization, while the second sample is used for quantitative Ferritin 2. iron determination. • At the same time, the hepatic iron Men 35Ϫ217 µg/l Ͼ 300 µg/l Women 23Ϫ110 µg/l index is calculated arithmetically. This index also facilitates the differential diagnosis of chronic alcoholic dis- Transferrin 3. ease, which is not always an easy task, particularly at Men 210Ϫ340 mg/dl Ͼ 500 mg/dl Women 200Ϫ310 mg/dl the cirrhotic stage (index < 1.4, in HC > 2.0). (449, 481) Saturation 16Ϫ45% Heterozygotes Ͼ 55% 17.3.8 Prognosis Homozygotes Ͼ 70% The following three factors are of decisive importance Hepatic iron index 4. for course and prognosis: iron content of the liver (µmol/g) ϭ Ͼ 2.0 age (years) 1. early diagnosis 5. Deferoxamine test 2. consistent long-term treatment 500 mg i.m./iron excretion rate Ͼ 4 mg/6 hr 3. close (life-long) cooperation between patient and physician Tab. 31.18: Biochemical findings in hereditary haemochromatosis

623 Chapter 31

᭤ Therapeutic results will be better if the morpholog- developing liver cell carcinoma in HC is about 200 times ical damage is less severe and the other organs have higher than in the normal population. Nevertheless, car- not been seriously affected. • It is necessary to regard cinogenicity is not necessarily related to the presence of HC treatment as a life-long procedure requiring the cirrhosis, nor to appropriate therapy or non-treatment joint therapeutic involvement of the patient and the (cf. potential cocarcinogens, alcohol or hepatitis general practitioner or specialist. (457) viruses). HCC development is mainly multilocular. Manifestation of a sarcoma has only rarely been Ϫ Untreated HC has a slow course and follows certain observed. The latency period is reported to be 20 30 patterns in its progression; spontaneous regressions are years. Follow-up with sonography and AFP determina- not to be expected. The 5-year survival rate after estab- tion at six-month intervals is indicated. HCC can also lishing the diagnosis is only 18%. The mean survival rate develop some years after complete iron depletion. Long- was about 1.5 years in 1935, about 4.4 years after the term iron overload acts as a cocarcinogen, apparently introduction of insulin treatment, and 8.2 years with by way of DNA impairment. (412, 413, 423, 430, 432, 435, consistent venesection therapy. (484) 441, 446, 455, 479) However, with early diagnosis and consistent treatment, ᭤ In HC, the frequency of extrahepatic carcinoma may HC has a good prognosis. In a comparison of treated also be increased: in one Italian study, the figure was versus untreated patients with HC, 5-year survival rates 3.7%. This correlation, which has also been assumed by of 89% (vs. 33%) or 92%, with an overall 10-year sur- other authors, raises the question as to whether there vival rate of 76% were observed. When cirrhosis was are additional cocarcinogenic factors, such as alcohol already manifest, the survival rate was only 62% after or hepatitis viruses. (475) • It is a striking feature that 10 years, whereas it was 93% in non-cirrhotic patients. • alcoholism is much more frequently observed in patients We believe that normal life expectancy is indeed a realis- with HC than in people suffering from liver cirrhosis or tic perspective. One of our patients died after 19 years of from hepatic carcinoma of different genesis. • It is also consistent treatment of causes apparently unrelated to remarkable that prevalence of HBsAg and anti-HCV is HC. two and three times higher respectively in HC patients than in the normal population. Presumably, the func- The greater the effectiveness of iron depletion, the more tion of the immune system is blocked by iron. This likely it is that morphological liver changes or even would help to explain the high carcinoma rate in fibrosis and hepatic transformation processes will be patients with HC, due to the procarcinogenicity of HBV reversed. • Portal hypertension and oesophageal varices and HCV on the one hand and of iron on the other may regress in the same way, and a decisive improve- hand. • In cases of iron overload, yersiniosis should also ment in diabetic metabolism is often observed. One of be considered as a typical concomitant infection, possi- our patients with diabetes mellitus showed a normal diur- bly with the development of liver abscesses: iron is of nal blood sugar profile after 8 years of consistent treat- exceptional importance for the metabolism of yersinia ment, while the glucose tolerance test (monitored over and to a considerable extent conducive to their growth. longer periods of time) only produced a moderately (401, 480) (s. p. 476) pathological result. • In contrast, arthropathy appears to be unresponsive to treatment and may cause consider- 17.3.9 Treatment able suffering. The paramount aim of treatment is to reach a negative The main causes of death in HC are the following devel- iron balance. This must be achieved before complica- opments which aggravate the clinical picture (particu- tions due to the chronic iron overload have their effect larly when alcohol consumption is continued): on the predisposed organs. • The extreme uncontrolled increase in iron absorption is treatable by adjuvant meas- 1. complicative diabetes mellitus ures, albeit with limited success. 2. cardiac insufficiency 3. primary liver cell carcinoma Venesection treatment 4. hepatic coma, liver failure 5. bleeding oesophageal varices Venesection treatment (W.D. DAVIS et al., 1950) is the 6. intercurrent infections method of choice; it is the most effective therapy. Blood- 7. acute abdomen letting of about 500 ml blood frees the body of some 250 mg iron. With an average accumulation of >25 g ᭤ The correlation between hepatocellular carcinoma and iron, weekly venesection should be considered over a haemochromatosis was described by M.J. Stewart in period of at least 2 years. • In patients with haemochro- 1922. Primary liver cell carcinoma is thought to be the matosis (without simultaneous anaemia), blood-letting most common cause of death in haemochromatosis. Its of 500 ml is carried out once a week until the serum frequency is reported to range between 6Ϫ42% or ferritin value has normalized. Experience shows that the 7.3Ϫ18.9% (mean value approx. 14%), i.e. the risk of de-ironing of the body using this technique takes about

624 Metabolic disorders and storage diseases

18 months. Blood-letting is well-tolerated, and the measure, but it nevertheless has a certain effect: low-iron patient’s physical capacity is usually not affected. In nutrition corresponds to 2Ϫ3 venesections per year! • general, the haemoglobin value does not fall below 12g/ Every kind of adjuvant therapy should be used as a matter dl. • By the time the respective blood values (ferritin level of principle Ϫ nothing can be said against such measures. and transferrin saturation) normalize, a considerable (2.) This is also true of the daily consumption of black quantity of iron has been discharged. At this stage, tea (1 cup with 5 g tea in the morning and at lunchtime). blood-letting can be reduced to 2Ϫ3 times per 3 months, Tea is deemed to be an iron-chelating agent (iron tan- provided the ferritin value and transferrin saturation nate), which significantly reduces the resorption of iron, continue to remain within the normal range. Subse- particularly in a low-iron diet Ϫ with or without ascor- quently, 3Ϫ4 venesections per year usually suffice in bic acid or milk added. (424, 444) • We have always made order to maintain the iron balance. • Plasmapheresis is sure that these adjuvant measures are strictly adhered to. not required, since the plasmaproteins removed by blood-letting are easily replaced by the organism. (3.) Deferoxamine can also be used as an adjuvant agent Nevertheless, in isolated cases, plasmapheresis may in the initial treatment phase to reinforce venesection become necessary due to a cirrhosis-induced decrease in therapy. This is administered as an i.m. injection of 500 protein synthesis. The haemoglobin content should not mg/week, usually by the family doctor, about 2Ϫ3days (or only for a short period of time) fall below 11.5Ϫ12.0 before blood-letting is carried out. g/dl, and the protein concentration should not fall Abstention from alcohol below 6.0 g/dl. (406, 417, 420, 429, 445, 452, 458, 467) The (4.) is absolutely essential and number of venesections per year required to maintain the must be strictly adhered to. This is not only because of iron balance must be adhered to lifelong. Blood-letting the minor amounts of iron usually found in alcoholic therapy must never be discontinued! beverages, but also in order to avoid additional alcohol- induced lipid peroxidation and further stimulation of Deferoxamine fibrosis already caused by iron. This specific iron-chelating agent is obtained from acti- (5.) The use of antioxidants is plausible from a pharma- nomyces cultures. In a dose of 1.5 g, it is capable of cological point of view, since lipid peroxidation due to mobilizing about 25 mg iron, i.e. the same amount as iron intake may indeed lead to further tissue damage. during a 500 ml venesection. • An indication may be (460) Silymarin (e.g.2x140Ϫ170 mg), vitamin E (e.g. given, even if only temporarily, when blood-letting can- 100Ϫ200 mg) or β-carotene are good choices due to not be carried out (e.g. anaemia, cardiac insufficiency). their lack of side effects and plausibility of efficacy. Deferoxamine binds iron in the tissue and in the serum; (6.) HC patients who are HBV-negative should be excretion occurs via the urine and faeces. However, the actively immunized against hepatitis B. • As far as pos- biological half-life of about 10 minutes is quite short, sible, patients should avoid any risk of HCV infection. i.e. after this time only half the pharmacon is still effective, but with decreasing intensity. Oral administration Normalization of the respective serum parameters, is ineffective. For this reason, subcutaneous injection is stabilization of the body’s iron content at 3Ϫ5 g and required as a slow infusion of 12 hours (using a portable improvement in the organ damage are to be expected Ϫ infusion pump). With a daily dose of 25 50 mg/kg BW, in quite a short period of time when blood-letting removal of iron deposits will probably be successful. • therapy (if necessary, with deferoxamine as an option Local irritations have been observed as side effects. Ocu- in long-term treatment) and adjuvant treatment lotoxicity (initial visual loss) may be evident, depending measures (which may serve to support or speed up on the dose. Neurotoxic disturbances usually only occur the successful outcome) are carried out consistently. Ϫ when the dose is higher than 2 3 g/day (>90 mg/kg The fact that better results can be achieved if the BW). This type of treatment is more complicated, less above-mentioned measures are applied has been Ϫ effective and much more expensive it is intended as shown by several impressive and carefully conducted an alternative only when there is no possibility of vene- studies. Therapeutic removal of iron overload is in section treatment. • In the foreseeable future, we can any case not bound to a time factor! Generally, the iron-chelating agents expect the development of other faster and more constant the iron removal process is, which will meet the ideal standards: oral administration, the better. • Hypogonadism and arthropathies are less higher efficiency, lower costs and fewer side effects. susceptible to treatment. Given the basic possibility of fibrosis regression, a certain optimism in this Adjuvant treatment measures respect is definitely justified. (1.) Low-iron nutrition is a fundamental requirement (there is practically no iron-free form of nutrition). Simultaneous treatment However, intake of foodstuffs rich in iron is contraindi- cated when the iron balance has to be maintained. The At the same time, consideration has to be given to the iron balance is not influenced to any great extent by this treatment of complaints or sequelae of organic mani-

625 Chapter 31 festations, such as careful regulation of diabetes, man- deposition, the more pronounced courses are charac- agement of cardiac insufficiency or dysrhythmia, hor- terized by stronger brownish cutaneous pigmentation, mone substitution, pain therapy in arthropathy, etc. hypogonadism, glucose intolerance and hepatomegaly together with increased iron and ferritin values in the Liver transplantation serum. This results in a similar symptomatology to that found in HC, only with a hepatic iron index clearly In principle, the indication for liver transplantation is below 2.0. Blood-letting therapy is successful and reli- limited to individual cases suitable for surgery (i.e. only able within a relatively short period of time. Iron deposi- in cases of early diagnosis and appropriate treatment). tion occurs mainly in the Kupffer cells, while the hepa- Unlike in Wilson’s disease, the genetic defect is not tocytes and the septa are largely free of iron. removed by transplantation, and the transplanted liver may store iron again. • Consequently, a genuine indication is only given in acute liver failure and in an oper- 18.2 Porphyria cutanea tarda able carcinoma restricted to the liver. The final stages of In porphyria cutanea tarda, iron deposition in the liver cirrhosis certainly continue to justify a transplantation, is generally low to moderate, predominantly in the hepa- although the indication in this case is not based on HC, tocytes of the acinar periphery. The cause is thought to but on the fact that the diagnosis was established too be reduced activity of uroporphyrinogen decarboxylase late and/or that treatment was inadequate or not carried resulting in decreased synthesis of porphyrin and haem. out at all. In young men with severe iron overload, a However, this variant of hepatic siderosis only becomes swift liver transplantation is always indicated. (433, 465) manifest as a result of various triggering factors. Treat- A number of grave mistakes may occur in the treatment ment is also based on venesection. of HC. These include: 1. delay in reaching a precise diagnosis (including 18.3 Blood transfusion quantitative determination of iron in the liver Transfusional haemosiderosis (R.M. Kark, 1937) can bioptate) occur following numerous blood transfusions. There are 2. blood-letting therapy carried out too hesitantly 200Ϫ250 mg iron in 500 ml (ϭ 1 unit) blood. Thus or inadequately numerous units (more than 50Ϫ60) must be transfused 3. failure to carry out a family examination (prevent- before siderin is clinically recognizable. It is initially ive diagnosis) deposited in the RES of the bone marrow, spleen and 4. merely monitoring family members who (still) liver, ultimately in the hepatocytes as well. show no signs of manifest disease instead of treating them properly 18.4 Haemolytic anaemia In all haemolytic anaemias, especially the genetically 18 Acquired haemochromatosis/ related forms, siderin is firstly deposited in Kupffer cells. haemosiderosis The extent of siderosis depends on the duration and severity of the haemolysis. (s. fig. 31.27) In long-term Acquired (“secondary”) haemochromatosis is caused by haemolysis, iron is also stored increasingly in hepato- other diseases/conditions characterized by iron overload cytes. In such cases, the morphological and clinical pic- resulting from excessive iron storage in the organism ture of haemochromatosis can develop. (e.g. due to diet, medical treatment or haemolysis). The term acquired haemochromatosis should not be used unless the iron content of the liver is >0.5 g/100g wet weight. The causes are manifold. • In these patients, there is occasionally an HLA constellation which is identical to that of HC or a family history of iron storage. Therefore, it is postulated that these patients might be heterozygous HC carriers or that there might be another hitherto undetected triggering factor or a genetic defect in addition. (s. tab. 31.17)

18.1 Alcohol abuse The most common cause (about 30% of cases) of hepatic siderosis is alcohol-induced liver disease. Its Fig. 31.27: Siderosis of Kupffer cells in haemolytic anaemia (Ber- aetiology is unknown. With this form of acquired iron lin blue)

626 Metabolic disorders and storage diseases

18.5 Chronic liver disease 19. Kral, J.G., Schaffner, F., Pierson, R.N.jr., Wang, J.: Body fat topogra- phy as an independent predictor of fatty liver. Metabolism 1993; 42: 548Ϫ551 Haemosiderosis can be found in several chronic liver 20. Kuntz, E.: Fatty liver Ϫ a morphological and clinical review. Med. Welt 1999; 50: 406Ϫ413 diseases, such as chronic hepatitis (especially HVC lead- 21. Levenson, H., Greensite, F., Hoefs, J., Friloux, L., Applegate, G., Silva, ing to a reduced response rate to α-interferon), late- E., Kanel, G., Buxton, R.: Fatty infiltration of the liver: quantification with phase-contrast MR imaging at 1.5 T vs biopsy. Amer. J. Roent- stage cirrhosis, spontaneous or surgical portal-systemic genol. 1991; 156: 307Ϫ312 shunts, and non-alcoholic steatohepatitis. 22. Marchesini, G., Brizi, M., Morselli-Labate, A.M., Bianchi, G., Bugi- anesi, E., McCullogh, A.J., Forlani, G., Melchionda, N.: Association of nonalcoholic fatty liver disease with insulin resistance. Amer. J. Med. 1999; 107: 450Ϫ455 18.6 African iron overload 23. Mathiesen, U.L., Franzen, L.E., Aselius, H., Resjo, M., Jacobsson, L., Foberg, U., Fryden, A., Bodemar, G.: Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis In rural sub-Saharan Africa, there is a kind of beer in asymptomatic patients with mild/moderate abnormalities of liver which is traditionally brewed in iron vats. The daily iron transaminases. Dig. Dis. Sci. 2002; 34: 516Ϫ522 24. Mofrad, P., Contos, M.J., Haque, M., Sargeant, C., Fisher, R.A., overload can amount to as much as 200 mg with mark- Luketic, V.A., Sterling, R.K., Shiffman, M.L., Stravitz, R.T., Sanyal, edly increased iron absorption (T.H. Bothwell et al., 1965). A.J.: Clinical and histologic spectrum of non-alcoholic fatty liver disease associated with normal ALT values. Hepatology 2003; 37: • Such a condition is also observed in South Africa 1286Ϫ1292 25. Naschitz, J.E., Yeshurun, D., Zuckerman, E., Arad, E., Boss, J.H.: Mas- among the black population. Their diet consists of por- sive hepatic steatosis complicating adult celiac disease: report of a case ridge fermented in iron pots with an acid pH value (V.R. and review of the literature. Amer. J. Gastroenterol. 1987; 82: ordeuk 1186Ϫ1189 G et al., 1986). • In both conditions, absorption of 26. Newman, J.S., Oates, E., Arora, S., Kaplan, M.: Focal spared area in iron is facilitated by various factors, e.g. protein or vita- fatty liver simulating a mass. Scintigraphic evaluation. Dig. Dis. Sci. 1991; 36: 1019Ϫ1022 min C deficiency, alcohol abuse, acidic diet. It has been 27. Nomura, F., Ohnishi, K., Ochiai, T., Okuda, K.: Obesity-related nonal- suggested that such iron overload is triggered by genetic coholic fatty liver: CT features and follow-up studies after low-calorie diet. Radiology 1987; 162: 845Ϫ847 factors. (437) 28. Nussbaum, M.S., Li, S, Bower, R.H., McFadden, D.W., Dayal, R., Fischer, J.E.: Addition of lipid to total parenteral nutrition prevents hepatic steatosis in rats by lowering the portal venous insulin/glucagon References: ratio. J. Parent. Ent. Nutr. 1992; 16: 106Ϫ109 29. Quigley, E.M.M.M., Marsh, N., Shaffer, J.L., Markin, R.S.: Hepatobi- Fatty liver liary complications of total parenteral nutrition. Gastroenterology 1. Andersen, T., Gluud, C.: Liver morphology in morbid obesity: a litera- 1993; 104: 286Ϫ301 ture study. Int. J. Obes. 1984; 8: 97Ϫ106 30. Roediger, W.E.W.: New views on the pathogenesis of kwashiorkor: 2. Angelico, F., del Ben, M., Conti, R., Francioso, S., Feole, K., Maccioni, methionine and other amino acids. J. Pediatr. Gastroenterol. Nutr. D., Antonini, T.M., Alessandri, C.: Non-alcoholic fatty liver syndrome: 1995; 21: 130Ϫ136 a hepatic consequence of common metabolic diseases. J. Gastroenterol. 31. Saverymuttu, S.H., Joseph, A.E.A., Maxwell, J.D.: Ultrasound scan- Hepatol. 2003; 18: 588Ϫ594 ning in the detection of hepatic fibrosis and steatosis. Brit. Med. J. 3. Ballard, H., Bernstein, M., Farras, J.I.: Fatty liver presenting as 1986; 292: 13Ϫ15 obstructive jaundice. Amer. J. Med. 1961; 30: 196Ϫ201 32. Schulz, F., Hildebrand, E.: Exzessive generalisierte Fettembolie bei 4. Bedogni, G., Miglioli, L., Battistini, N., Masutti, F., Tiribelli, C., akut dystrophischer Fettleber. Med. Klin. 1977; 72: 59Ϫ63 Bellentani, S.: Body mass index is a good predictor of an elevated 33. Seifalian, A.M., Piasecki, C., Agarwal, A., Davidson, B.R.: The effect alanine transaminase level in the general population: hints from the of graded steatosis on flow in the hepatic parenchymal microcircula- Dionysos study. Dig. Liver Dis. 2003; 35: 648Ϫ652 tion. Transplantation 1999; 68: 780Ϫ784 Braillon, A., Capron, J.P., Herve´, M.A., Degott, C., Quenum, C.: 5. Liver 34. Silverman, J.F., Pories, W.J., Caro, J.F.: Liver pathology in diabetes in obesity. Gut 1985; 26: 133Ϫ139 mellitus and morbid obesity. Clinical, pathological, and biochemical 6. Burt, A.D., Mutton, A., Day, C.P.: Diagnosis and interpretation of considerations. Path. Ann. 1989; 24: 275Ϫ302 Ϫ steatosis and steatohepatitis. Semin. Diagn. Pathol. 1998; 15: 246 258 35. Tanaka, K., Kean, E.A., Johnson, B.: Jamaican vomiting sickness. Bio- 7. Caturelli, E., Squillante, M.M., Andriulli, A., Cedrone, A., Cellerino, C., Pompili, M., Manoja, E.R., Rapaccini, G.L.: chemical investigation of two cases. New Engl. J. Med. 1976; 295: Hypoechoic lesions in 461Ϫ467 the “bright liver”: a reliable indicator of fatty change. A prospective 36. Teli, M.R., James, O.F.W., Burt, A.D., Bennett, M.K., Day, C.P.: The study. J. Gastroenterol. Hepatol. 1992; 7: 469Ϫ472 Chong, V.F., Fan, Y.F.: natural history of non-alcoholic fatty liver: a follow-up study. Hepato- 8. Ultrasonographic hepatic pseudolesions: nor- logy 1995; 22: 1714Ϫ1719 mal parenchyma mimicking mass lesions in fatty liver. Clin. Radiol. 37. Tsushima, Y., Endo, K.: Spleen enlargement in patients with nonalco- 1994; 49: 326Ϫ329 Ϫ Christl, S.U., Müller, J.G.: holic fatty liver Correlation between degree of fatty infiltration in 9. Fatty liver in adult celiac disease. Dtsch. liver and size of spleen. Dig. Dis. Sci. 2000; 45: 196Ϫ200 Med. Wschr. 1999; 124: 691Ϫ694 Waterlow, J.C.: Clain, D.J., Lefkowitch, J.H.: 38. Kwashiorkor revisited: the pathogenesis of oedema in 10. Fatty liver disease in morbid obesity. kwashiorkor and its significance. Trans. R. Soc. Trop. Med. Hyg. 1984; Gastroenterol. Clin. North Amer. 1987; 16: 239Ϫ252 Ϫ Clark, J.M., Diehl, A.M.: 78: 436 441 11. Nonalcoholic fatty liver disease. An under- 39. Younossi, Z.M., Gramlich, T., Matteoni, C.A., Boparai, N., McCullogh, recognized cause of cryptogenic cirrhosis. J. Amer. Med. Ass. 2003; A.J.: Non-alcoholic fatty liver disease in patients with type 2 diabetes. 289: 3000Ϫ3004 Ϫ Dixon, J.B., Bhathal, P.S., Hughes, N.R., O’Brien, P.E.: Clin. Gastroenterol. Hepatol. 2004; 2: 262 265 12. Nonalcoholic 40. Zafrani, E.S.: Non-alcoholic fatty liver disease: an emerging pathologi- fatty liver disease: Improvement in liver histological analysis with cal spectrum. Virch. Arch. 2003; 444: 3Ϫ12 weight loss. Hepatology 2004; 39: 1647Ϫ1654 13. Giorgio, A., Francica, G., Aloisio, T., Tarantino, L., Pierri, P., Pellicano, M., Buscarini, L., Livraghi, T.: Multifocal fatty infiltration of the liver Non-alcoholic steatohepatitis mimicking metastatic disease. Gastroenterol. Internat. 1991; 4: 41. Abdelmalek, M.F., Angulo, P., Jorgensen, R.A., Sylvestre, P.B., Lindor, 169Ϫ172 K.D.: Betaine, a promising new agent for patients with nonalcoholic 14. Hartroft, W.S., Sugioka, E., Porta, E.A.: Nutritional types of fatty steato-hepatitis: results of a pilot study. Amer. J. Gastroenterol. 2001; livers in experimental animals and man. 5. Meeting-Internat. Assoc. 96: 2711Ϫ2717 Study of the Liver. Karlsbad 1968 42. Angulo, P., Keach, J.C., Batts, K.P., Lindord, K.D.: Independent predic- 15. Hautekeete, M.L., Degott, C., Benhamou, J.-P.: Microvesicular tors of liver fibrosis in patients with non-alcoholic steatohepatitis. Hep- steatosis of the liver. Acta Clin. Belg. 1990; 45: 311Ϫ326 atology 1999; 30: 1356Ϫ1362 16. Jepsen, P., Vilstrup, H., Mellemkjall, L., Thulstrup, A.M., Olsen, J.H., 43. Brunt, E.M., Janney, C.G., DiBisceglie, A.M., Neuschwander-Tetri, Baron, J.A., Sorensen, H.T.: Prognosis of patients with a diagnosis of B.A., Bacon, B.R.: Nonalcoholic steatohepatitis: A proposal for grad- fatty liver. A registry-based cohort study. Hepato-Gastroenterol. 2003; ing and staging the histological lesions. Amer. J. Gastroenterol. 1999; 50: 2101Ϫ2104 94: 2467Ϫ2474 17. Kemper, J., Jung, G., Poll, L.W., Jonkmanns, C., Luthen, R., Moedder, 44. Caldwell, S.H., Swerdlow, R.H., Khan, E.M., Iezzoni, J.C., Hespen- U.: CT and MRI findings of multifocal hepatic steatosis mimicking heide, E.E., Parks, J.K., Parker, W.D.: Mitochondrial abnormalities in malignancy (case report). Abdom. Imag. 2002; 27: 708Ϫ710 non-alcoholic steatohepatitis. J. Hepatol. 1999; 31: 430Ϫ434 18. Kojima, S., Watanabe, N., Numata, M., Ogawa, T., Matsuzaki, S.: 45. Carson, K., Washington, M.K., Treem, W.R., Clavien, P.A., Hunt, Increase in the prevalence of fatty liver in Japan over the past 12 years: C.M.: Recurrence of non-alcoholic steatohepatitis in a liver transplant analysis of clinical background. J. Gastroenterol. 2003; 38: 954Ϫ961 recipient. Liver Transpl. Surg. 1997; 3: 174Ϫ176

627 Chapter 31

46. Chitturi, S., Farrell, G., Frost, L., Kriketos, A., Lin, R., Liddle, C., 75. Tajiri, K., Takenawa, H., Yamaoka, K., Yamane, M., Marumo, F., Sato, Samarasinghe, D., George, J.: Serum leptin in NASH correlates with C.: Nonalcoholic steatohepatitis masquerading as autoimmune hepati- hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? tis. J. Clin. Gastroenterol. 1997; 25: 538Ϫ540 Hepatology 2002; 36: 403Ϫ409 76. Thaler, H.: Die Fettleber und ihre pathogenetische Beziehung zur Le- 47. Cotrim, H.P., Andrade, Z.A., Parana, R., Portugal, M., Lyra, L.G., berzirrhose. Virch. Arch. Path. Anat. 1962; 335: 180Ϫ210 Freitas, L.A.R.: Nonalcoholic steatohepatitis: a toxic liver disease in 77. Yang, S.Q., Lin, H.Z., Lane, M.D., Clemens, M., Diehl, A.M.: Obesity industrial workers. Liver 1999; 19: 299Ϫ304 increases sensitivity to endotoxin liver injury: implications for the 48. Day, C.P., James, O.F.W.: Steatohepatitis: a tale of two “hits”? Gastro- pathogenesis of steatohepatitis. Proc. Nat. Acad. Sci. 1997; 94: enterology 1998; 114: 842Ϫ845 2557Ϫ2562 49. Denk, H., Stumptner, C., Fuchsbichler, A., Zatloukal, K.: Alcoholic 78. Zamin, I., Alves-de-Mattos, A., Zettler, C.G.: Nonalcoholic steato- and nonalcoholic steatohepatitis. Histopathologic and pathogenetic hepatitis in nondiabetic obese patients. Can. J. Gastroenterol. 2002; considerations. Pathologe 2001; 22: 388Ϫ398 16: 303Ϫ307 50. Diehl, A.M.: Nonalcoholic steatohepatitis. Semin. Liver Dis. 1999; 19: 221Ϫ229 Reye’s syndrome 51. Eriksson, S., Eriksson, K.-F., Bondesson, L.: Nonalcoholic steatohepa- 79. Arrowsmith, J.B., Kennedy, D.L., Kuritsky, J.N., Faich, G.A.: National titis in obesity: a reversible condition. Acta Med. Scand. 1986; 220: patterns of aspirin use and Reye’s syndrome reporting United States, 83Ϫ88 1980 to 1985. Pediatrics 1987; 79: 858Ϫ863 52. George, D.K., Goldwurm, S., MacDonald, G.A., Cowley, L.L., Walker, 80. Belay, E.D., Bresee, J.S., Holman, R.C., Khan, A.S., Shahriari, A., N.I., Ward, P.J., Jazwinska, E.C., Powell, L.W.: Increased hepatic iron Schonberger, L.B.: Reye’s syndrome in the United States from 1981 concentration in non-alcoholic steatohepatitis is associated with through 1997. New Engl. J. Med. 1999; 340: 1377Ϫ1382 increased fibrosis. Gastroenterology 1998; 114: 311Ϫ318 81. Brain, W.R., Hunter, D., Turnbull, H.M.: Acute meningo-encephalo- 53. Harrison, S.A., Torgerson, S., Hayashi, P., Ward, J., Schenker, S.: Vita- myelitis of childhood: report of six cases. Lancet 1929/I: 221Ϫ227 min E and vitamin C treatment improves fibrosis in patients with non- 82. Casteels-van Daele, M., Eggermont, E.: Reye’s syndrome. Brit. Med. J. alcoholic steatohepatitis. Amer. J. Gastroenterol. 2003; 98: 2485Ϫ2490 1994; 308: 919Ϫ920 54. Itoh, S., Yougel, T., Kawagoe, K.: Comparison between non-alcoholic 83. Da Silveira, E.B.V., Young, K., Rodriguez, M., Ameen, N.: Reye’s syn- steatohepatitis and alcoholic hepatitis. Amer. J. Gastroenterol. 1987; drome in a 17-year-old male. Is this disease really disappearing? Dig. 82: 650Ϫ654 Dis. Sci. 2002; 47: 1959Ϫ1961 55. James, O., Day, C.: Non-alcoholic steatohepatitis: another disease of 84. Gauthier, M., Guay, J., Lacroix, J., Lortie, A.: Reye’s syndrome: a affluence. Lancet 1999; 353: 1634Ϫ1636 reappraisal of diagnosis in 49 presumptive cases. Amer. J. Dis. Child. 56. Koruk, M., Savas, C., Yilmaz, O., Taysi, S., Karokok, M., Gündogdu, 1989; 143: 1181Ϫ1185 C., Yilmaz, A.: Serum lipids, lipoproteins and apolipoprotein levels in 85. Hall, S.M., Plaster, P.A., Glasgow, J.F., Hancock, P.: Preadmission patients with nonalcoholic steatohepatitis. J. Clin. Gastroenterol. 2003; antipyretics in Reye’s syndrome. Arch. Dis. Child. 1988; 63: 857Ϫ866 37: 177Ϫ182 86. Hardie, R.M., Newton, L.H., Bruce, J.C., Glasgow, J.F.T., Mowat, A.P., 57. Laurin, J., Lindor, K.D., Cripin, J.S., Gossard, A., Gores, G.J., Ludwig, Stephenson, J.B.P., Hall, S.M.: The changing clinical pattern of Reye’s J.: Ursodeoxycholic acid or clofibrate in the treatment of non-alco- syndrome 1982Ϫ1990. Arch. Dis. Childh. 1996; 74: 400Ϫ405 holic-induced steatohepatitis: a pilot study. Hepatology 1996; 23: 87. Heubi. J.E., Partin, J.C., Partin, J.S., Schubert, W.K: Reye’s syndrome: 1464Ϫ1467 current concepts. Hepatology 1987; 7: 155Ϫ164 58. Lee, R.G.: Nonalcoholic steatohepatitis: a study of 49 patients. Hum. 88. Hilty, M.D., McClung, H.-J., Haynes, R.E., Romshe, C.A., Sherard, Pathol. 1989; 20: 594Ϫ598 E.S.: Reye’s syndrome in siblings. J. Pediatr. 1979; 94: 576Ϫ579 59. Liangpunsakul, S., Chalasani, N.: Is hypothyroidism a risk factor for 89. Meythaler, J.M., Varma, R.R.: Reye’s syndrome in adults. Diagnostic non-alcoholic steatohepatitis? J. Clin. Gastroenterol. 2003; 37: considerations. Arch. Intern. Med. 1987; 147: 61Ϫ64 340Ϫ343 90. Pinsky, P.F., Hurwitz, E.S., Schonberger, L.B., Gunn, W.J.: Reye’s syn- 60. Ludwig, J., Viggiano, T.R., McGill, D.B., Oh, B.J.: Nonalcoholic stea- drome and aspirin. Evidence for a dose-response effect. J. Amer. Med. tohepatitis: Majo Clinic experiences with a hitherto unnamed disease. Ass. 1988; 260: 657Ϫ661 Majo Clin. Proc. 1980; 55: 434Ϫ438 91. Reye, R.D.K., Morgan, G., Baral, J.: Encephalopathy and fatty degen- 61. Molleston, J.P., White, F., Teckman, J., Fitzgerald, J.F.: Obese children eration of the viscera. A disease entity in childhood. Lancet 1963/II: with steatohepatitis can develop cirrhosis in childhood. Amer. J. 749Ϫ751 Gastroenterol. 2002; 97: 2460Ϫ2462 92. Stillmann, A., Gitter, H., Shillington, D., Sobonya, R., Payne, C.M., 62. Molloy, R.M., Komorowski, R., Varma, R.R.: Recurrent non-alcoholic Ettinger, D., Lee, M.S.: Reye’s syndrome in the adult: case report and steatohepatitis and cirrhosis after liver transplantation. Liver Transpl. review of the literature. Amer. J. Gastroenterol. 1983; 78: 365Ϫ368 Surg. 1997; 3: 177Ϫ178 63. Neuschwander-Tetri, B.A., Brunt, E.M., Wehmeier, K.R., Oliver, D., Acute fatty liver of pregnancy Bacon, B.R.: Improved nonalcoholic steatohepatitis after 48 weeks of 93. Barton, J.R., Sibai, B.M., Mabie, W.C., Shanklin, D.R.: Recurrent treatment with the PPAR-gamma ligand rosiglitazone. Hepatology acute fatty liver of pregnancy. Amer. J. Obstet. Gynec. 1990; 163: 2003; 38: 1008Ϫ1017 534Ϫ538 64. Ohbayashi, H.: Twelve-month chronic administration of polyenephos- 94. Campillo, B., Bernuau, J., Witz, M.-O., Lorphelin, J.-M., Degott, C., phatidylcholine (EPL) for improving hepatic function of fatty liver Rueff, B., Benhamou, J.-P.: Ultrasonography in acute fatty liver of patients. Progr. Med. 2004; 24: 1751Ϫ1756 pregnancy. Ann. Intern. Med. 1986; 105: 383Ϫ384 65. Perez-Carreras, M., del Hoyo, P., Martin, M.A., Rubio, J.C., Martin, 95. Castells, A., Feu, F., Bruix, J., Salo, J., Bosch, J., Rodes, J.: Hiperten- A., Castellano, G., Colina, F., Arenas, J., Solis-Herruzo, J.A.: Defective sion portal transitoria en la esteatosis hepatica aguda del embarazo. hepatic mitochondrial respiratory chain in patients with nonalcoholic Gastroenterol. Hepatol. 1993; 16: 489Ϫ491 steatohepatitis. Hepatology 2003; 38: 999Ϫ1007 96. Fischer, J., Stoll, P., Müller, F., Weber, P.: Akute Schwangerschafts- 66. Powell, E.E., Cooksley, W.G., Hanson, R., Searle, J., Halliday, J.W., fettleber Ϫ Differentialdiagnostik und supportive Therapie. Schweiz. Powell, L.W.: The natural history of non-alcoholic steatohepatitis: a Med. Wschr. 1992; 122: 817Ϫ820 follow-up study of forty-two patients for up to 21 years. Hepatology 97. Hoare, C.D., Malatjalian, D.A., Badley, B.W., Sidorov, J.J., Williams, 1990; 11: 74Ϫ80 C.N.: Acute fatty liver of pregnancy: a review of maternal morbidity 67. Roberts, E.A.: Nonalcoholic steatohepatitis in children. Curr. Gastro- in 13 patients seen over 12 years in Nova Scotia. Can. J. Gastroenterol. enterol. Rep. 2003; 5: 253Ϫ259 1994; 8: 81Ϫ87 68. Saibara, T.: “Insuffient” leptin production for the fat mass: a risk 98. Kunelis, C.T., Peters, J.E., Edmondson, H.A.: Fatty liver of pregnancy factor for nonalcoholic steatohepatitis in obese patients? J. Gastro- and its relation to tetracycline therapy. Amer. J. Med. 1985; 38: enterol. 2003; 38: 522Ϫ523 359Ϫ377 69. Savas, M.C., Koruk, M., Pirim, I., Yilmaz, O., Karakok, M., Taysi, 99. Mabie, W.C.: Acute fatty liver of pregnancy. Gastroenterol. Clin. N. S., Yilmaz, A.: Serum ubiquitin levels in patients with nonalcoholic Amer. 1992; 21: 951Ϫ960 steatohepatitis. Hepato-Gastroenterol. 2003; 50: 738Ϫ741 100. McKee, C.M., Weir, P.E., Foster, J.H., Murnaghan, G.A., Callender, 70. Sheth, S.G., Gordon, F.D., Chopra, S.: Nonalcoholic steatohepatitis. M.E.: Acute fatty liver of pregnancy and diagnosis by computed Ann. Intern. Med. 1997; 126: 137Ϫ145 tomography. Brit. Med. J. 1986; 292: 291Ϫ292 71. Shimada, M., Hashimoto, E., Kaneda, H., Noguchi, S., Hayashi, N.: 101. Minuk, G.Y., Lui, R.C., Kelly, J.K.: Rupture of the liver associated Nonalcoholic steatohepatitis: risk factors for liver fibrosis. Hepatol. with acute fatty liver of pregnancy. Amer. J. Gastroenterol. 1987; 82; Res. 2002; 24: 429Ϫ438 457Ϫ460 72. Sorbi, D., Boynton, J., Lindor, K.D.: The ratio of aspartate aminotrans- 102. Moise, K.J., Shah, D.M.: Acute fatty liver of pregnancy: etiology of ferase to alanine aminotransferase: potential value in differentiating fetal distress and fetal wastage. Obstetr. Gynec. 1987; 69: 482Ϫ485 non-alcoholic steatohepatitis from alcoholic liver disease. Amer. J. 103. Ockner, S.A., Brunt, E.M., Cohn, S.M., Krul, E.S., Hanto, D.W., Gastroenterol. 1999; 94: 1018Ϫ1021 Peters, M.G.: Fulminant hepatic failure caused by acute fatty liver of 73. Struben, V.M.D., Espenheide, E.E., Caldwell, S.H.: Nonalcoholic stea- pregnancy treated by orthotopic liver transplantation. Hepatology tohepatitis and cryptogenic cirrhosis within kindreds. Amer. J. Med. 1990; 11: 59Ϫ64 2000; 108: 9Ϫ13 104. Reyes, H., Sandoval, L., Wainstein, A., Ribalta, J., Donoso, S., Smok, 74. Sumida, Y., Nakashima, T., Yoh, T., Furutani, M., Hirohama, A., Kaki- G., Rosenberg, H., Meneses, M.: Acute fatty liver of pregnancy: a clin- saka, Y., Nakajima, Y., Ishikawa, H., Mitsuyoshi, H., Okanoue, T., ical study of 12 episodes in 11 patients. Gut 1994; 35: 101Ϫ106 Kashima, K., Nakamura, H., Yodoi, J.: Serum thioredoxin levels as a 105. Riely, C.A., Latham, P.S., Romero, R., Duffy, T.P.: Acute fatty liver of predictor of steatohepatitis in patients with nonalcoholic fatty liver pregnancy. A reassessment based on observations in nine patients. disease. J. Hepatol. 2003; 38: 32Ϫ38 Ann. Intern. Med. 1987; 106: 703Ϫ706

628 Metabolic disorders and storage diseases

106. Sandhu, B.S., Sanyal, A.J.: Pregnancy and liver disease. Gastroenterol. 136. Zhou, H., Ortiz-Pallardo, M.E., Ko, Y., Fischer, H.-P.: Is heterozygous Clin. N. Amer. 2003; 32: 407Ϫ436 alpha-1-antitrypsin deficiency type PiZ a risk factor for primary liver 107. Sheehan, H.L.: The pathophysiology of acute yellow atrophy and carcinoma? Cancer 2000; 88: 2668Ϫ2676 delayed chloroform poisoning. J. Obstetr. Gynaec. Brit. Emp. 1940; 47: 49Ϫ62 Amyloidosis 108. Sherlock, S.: Acute fatty liver of pregnancy and the microvesicular fat 137. Arkenau, H.T., Widjaja, A.: An unusual case of cholestasis and makro- diseases. Gut 1983; 24: 265Ϫ269 hematuria in a 52-year-old patient. Med. Klin. 2002; 97: 480Ϫ483 109. Stander, H.J., Cadden, J.F.: Acute yellow atrophy of liver in pregnancy. 138. Caballeria, J., Bruguera, M., Sole, M., Campistol, J.M., Rodes, J.: Amer. J. Obstetr. Gynec. 1934; 28: 61Ϫ69 Hepatic familial amyloidosis caused by a new mutation in the AL 110. Tan, A.C.I.T.L., van Krieken, J.H.J.M., Peters, W.H.M., Steegers, gene: clinical and pathological features. Amer. J. Gastroenterol. 2001; E.A.P.: Acute fatty liver in pregnancy (case report). Neth. J. Med. 96: 1872Ϫ1876 2002; 60: 370Ϫ373 139. Diel, R., Krüger, C.: Primäre Amyloidose als seltene Ursache einer 111. Treem, W.R., Rinaldo, P., Hale, D.E., Stanley, C.A., Millington, D.S., akuten Leberinsuffizienz. Dtsch. Med. Wschr. 1988; 113: 1433Ϫ1436 Hyams, J.S., Jackson, S., Turnbull, D.M.: Acute fatty liver of preg- 140. Frank, H., Krammer, M., Fierlbeck, W., Rieß, R., Geiger, H.: Unusual nancy and long-chain 3-hydroxyacyl coenzyme A dehydrogenase defi- hepatorenal symptoms in amyloidosis. Med. Klin. 1999; 94: 274Ϫ278 ciency. Hepatology 1994; 19: 339Ϫ345 141. Gertz, M.A., Kyle, R.A.: Hepatic amyloidosis: clinical appraisal in 77 112. Van Le, L., Podrasky, A.: Computed tomographic and ultrasono- patients. Hepatology 1997; 25: 118Ϫ121 graphic findings in women with acute fatty liver of pregnancy. J. 142. Harrison, R.F., Hawkins, P.N., Roche, W.R., MacMahon, R.F.T., Reprod. Med. 1990; 35: 815Ϫ817 Hubscher, S.G.: “Fragile” liver and massive hepatic haemorrhage, due 113. Yang, W.W., Shen, Z.J., Peng, G.D., Chen, Y.G., Jiang, S.F., Kang, to hereditary amyloidosis. Gut 1996; 38: 151Ϫ152 S.Y., Wu, J.C.: Acute fatty liver of pregnancy: diagnosis and manage- 143. Hawkins, P.N., Pepys, M.B.: Imaging amyloidosis with radiolabelled ment of 8 cases. Chin. Med. J. 2000; 113: 540Ϫ543 SAP. Eur. J. Nucl. Med. 1995; 22: 595Ϫ599 114. Zürcher, K.: Unkomplizierte Zweitschwangerschaft nach akuter 144. Hoffmann, M.S., Stein, B.E., Davidian, M.M., Rosenthal, W.S.: Schwangerschaftsfettleber. Schweiz. Med. Wschr. 1995; 125: 1003Ϫ1005 Hepatic amyloidosis presenting as severe intrahepatic cholestasis: a case report and review of the literature. Amer. J. Gastroenterol. 1988; Mauriac syndrome 83: 783Ϫ785 115. Mandell, F., Berenberg, W.: The Mauriac syndrome. Amer. J. Dis. 145. Holmgren, G., Ericzon, B.G., Groth, C.G., Stein, L., Suhr, O., Ander- Child. 1974; 127: 900Ϫ902 sen, O., Wallin, B.G., Seymour, A., Richardson, S., Hawkins, P.N., Petys, M.B.: Clinical improvement and amyloid regression after liver ␣1-antitrypsin deficiency Bell, H., Schrumpf, E., Fagerhol, M.K.: transplantation in hereditary transthyretin amyloidosis. Lancet 1993; 116. Heterozygous MZ alpha-1- Ϫ antitrypsin deficiency in adults with chronic liver disease. Scand. J. 341: 1113 1116 Ϫ 146. Iwai, M., Ishii, Y., Mori, T., Harada, Y., Kitagawa, Y., Kashiwadani, Gastroenterol. 1990; 25: 778 792 M., Ou, O., Okanoue, T., Kashima, K.: 117. Carrell, R.W., Lomas, D.A.: Mechanisms of disease-Alpha-1-antitryp- Cholestatic jaundice in two patients with primary amyloidosis. Ultrastructural findings of the liver. sin deficiency. A model for conformational diseases (review). New Ϫ Engl. J. Med. 2002; 346: 45Ϫ53 J. Clin. Gastroenterol. 1999; 28: 162 166 Crystal, R.G.: α 147. Jorquera Plaza, F., Fernandez Gundin, M.J., Espinel Diez, J., Munoz 118. 1-antitrypsin deficiency, emphysema and liver disease. Nunez, F., Herrera Abian, A., Garcia Lagarto, E., Olcoz Goni, J.L.: Genetic basis and strategies for therapy. J. Clin. Invest. 1990; 85: Ϫ Ictericia colestasica como forma de presentacion de una amiloidosis 1343 1352 Ϫ 119. Deutsch, J., Becker, H., Auböck, L.: Histopathological features of liver sistemica. Rev. Esp. Enferm. Dig. 1997; 89: 859 861 148. Kumar, K.S., Lefkowitch, J., Russo, M.W., Hesdorffer, C., Kinkhab- disease in alpha-1 antitrypsin deficiency. Acta Paediatr. 1994; 393 wala, M., Kapur, S., Emond, J.C., Brown, R.S.: (Suppl.): 8Ϫ12 Successful sequential liver and stem cell transplantation for hepatic failure due to primary 120. Eriksson, S., Elzouki, A.-N.: α1-Antitrypsin deficiency. Baill. J. Ϫ AL amyloidosis. Gastroenterology 2002; 122: 2026Ϫ2031 Gastroenterol. 1998; 12: 257 273 Llovat, L.B., Persey, M.R., Madhoo, S., Hawkins, P.N.: 121. Filipponi, F., Soubrane, O., Labrousse, F., Devictor, D., Bernard, O., 149. The liver in Valayer, J., Houssin, D.: Liver transplantation for end-stage liver dis- systemic amyloidosis: insights from 123I serum amyloid P component α scintigraphy in 484 patients. Gut 1998; 42: 727Ϫ734 ease associated with 1-antitrypsin deficiency in children: pre- Mainenti, P.P., D’Agostino, L., Soscia, E., Romano, M., Salvatore, M.: transplant natural history, timing and results of transplantation. J. 150. Ϫ Hepatic and splenic amyloidosis: dual-phase spiral CT findings. Hepatol. 1994; 20: 72 78 Ϫ 122. Fischer, H.-P., Ortiz-Pallardo, M.E., Ko, Y., Esch, C., Zhou, H.: Abdom. Imag. 2003; 28: 688 690 151. Mohr, A., Miehlke, S., Klauck, S., Röcken, C., Malfertheiner, P.: Hepa- Chronic liver disease in heterozygous α1-antitrypsin deficiency PiZ. J. Hepatol. 2000; 33: 883Ϫ892 tomegaly and cholestasis as primary clinical manifestations of an AL- 123. Francavilla, R., Castellaneta, S.P., Hadzic, N., Chambers, S.M., Port- kappa amyloidosis. Europ. J. Gastroenterol. Hepatol. 1999; 11: mann, B., Tung, J., Cheeseman, P., Heaton, N.D., Mieli-Vergani, G.: 921Ϫ925 Monzawa, S., Tsukamoto, T., Omata, K., Hosoda, K., Araki, T., Sugi- Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the 152. Ϫ mura, K.: A case with primary amyloidosis of the liver and spleen: era of pediatric liver transplantation. J. Hepatol. 2000; 32: 986 992 Ϫ 124. Löhr, H.F., Schlaak, J.F., Dienes, H.P., Lorenz, J., Meyer zum Büschen- radiologic findings. Eur. J. Radiol. 2002; 41: 237 241 felde, K.-H., Gerken, G.: 153. Nowak, G., Westermark, P., Wernerson, A., Herlenius, G., Sletten, K., Liver cirrhosis associated with heterozygous Ericzon, B.G.: alpha-1-antitrypsin deficiency type PiMS and autoimmune features. Liver transplantation as rescue treatment in a patient Ϫ with primary AL kappa amyloidosis. Transpl. Internat. 2000; 13: Digestion 1995; 56: 41 45 Ϫ 125. Lomas, D.A., Mahadeva, R.: Alpha(1)-antitrypsin polymerization and 92 97 154. Peters, R.A., Koukoulis, G., Glimson, A., Portamnn, B., Westaby, D., the serpinopathies: pathobiology and prospects for therapy (review). J. William, R.: Clin. Invest. 2002; 110: 1585Ϫ1590 Primary amyloidosis and severe intrahepatic cholestatic Mowat, A.P.: jaundice. Gut 1994; 35: 1322Ϫ1325 126. Alpha-1-antitrypsin deficiency (PiZZ): features of liver Sandberg-Gertzen, H., Ericzon, B.G., Blomberg, B.: involvement in childhood. Acta Paediatr. 1994; 393 (Suppl.): 13Ϫ17 155. Primary amy- 127. Perlmutter, D.H.: Alpha1-antitrypsin deficiency. Curr. Treat. Option. loidosis with spontaneous splenic rupture, cholestasis, and liver failure Gastroenterol. 2000; 3: 451Ϫ456 treated with emergency liver transplantation. Amer. J. Gastroenterol. Perlmutter, D.H.: 1998; 93: 2254Ϫ2256 128. Liver injury in alpha(1)-antitrypsin deficiency: an Straub, R.F., Boyer, T.D.: aggregated protein induces mitochondrial injury (review). J. Clin. 156. The liver-spleen scan in systemic amy- Ϫ loidosis: a clue to the diagnosis. J. Clin. Gastroenterol. 1993; 16: Invest. 2002; 110: 1579 1583 Ϫ 129. Pittschieler, K., Massi, G.: Liver involvement in infants with PiSZ phe- 340 343 notype of ?1-antitrypsin deficiency. J. Pediatr. Gastro. Nutrit. 1992; ␣1-antichymotrypsin deficiency 15: 315Ϫ318 157. Callea, F., Brisigotti, M., Fabbretti, G., Bonino, F., Desmet, V.J.: 130. Prachalias, A.A., Kalife, M., Francavilla, R., Muiesan, P., Dhawan, A., Hepatic endoplasmatic reticulum storage diseases. Liver 1992; 12: Baker, A., Hadzic, D., Mieli-Vergani, G., Rela, M., Heaton, N.D.: Liver 357Ϫ362 transplantation for alpha-1-antitrypsin deficiency in children. 158. Eriksson, S., Lindmark, B., Lilja, H.: Familial α1-antichymotrypsin Transplant. Internat. 2000; 13: 207Ϫ210 deficiency. Acta Med. Scand. 1986; 220: 447Ϫ453 131. Propst, T., Propst, A., Dietze, O., Judmaier, G., Braunsteiner, H., Vogel, 159. Lindmark, B., Eriksson, S.: Partial deficiency of α1-antichymotrypsin W.: Prevalence of hepatocellular carcinoma in alpha-1-antitrypsin defi- is associated with chronic cryptogenetic liver disease. Scand. J. ciency. J. Hepatol. 1994; 21: 1006Ϫ1011 Gastroenterol. 1991; 26: 508Ϫ512 132. Sifers, R.N., Finegold, M.J., Woo, S.L.C.: Molecular biology and genetic of α1-antitrypsin deficiency. Semin. Liver Dis. 1992; 12: Hereditary tyrosinaemia 301Ϫ310 160. Dehner, L.P., Snover, D.C., Sharp, H.L., Ascher, N., Nakhleh, R., Day, 133. Steiner, S.J., Gupta, S.K., Croffie, J.M., Fitzgerald, J.F.: Serum levels D.L.: Hereditary tyrosinemia type I (chronic form): Pathologic find- of alpha(1)-antitrypsin predict phenotypic expression of the alpha(1)- ings in the liver. Hum. Path. 1989; 20: 149Ϫ158 antitrypsin gene. Dig. Dis. Sci. 2003; 48: 1793Ϫ1796 161. Demers, S.I., Russo, P., Lettre, F., Tanguay, R.M.: Frequent mutation 134. Sveger, T., Eriksson, S.: The liver in adolescents with α1-antitrypsin reversion inversely correlates with clinical severity in a genetic liver deficiency. Hepatology 1995; 22: 514Ϫ517 disease, hereditary tyrosinemia. Hum. Pathol. 2003; 34: 1313Ϫ1320 135. Yoon, D., Kueppers, F., Genta, R.M., Klintmalm, G.B., Khaoustov, V.I., 162. Freese, D.K., Tuchman, M., Schwarzenberg, S.J., Sharp, H.L., Rank, Yoffe, B.: Role of alpha-1-antichymotrypsin deficiency in promoting J.M., Bloomer, J.R., Ascher, N.L., Payne, W.D.: Early liver transplan- cirrhosis in two siblings with heterozygous alpha-1-antitrypsin defi- tation is indicated for tyrosinemia type I. J. Paediatr. Gastroenterol. ciency phenotype SZ (case report). Gut 2002; 50: 730Ϫ732 Nutr. 1991; 13: 10Ϫ15

629 Chapter 31

163. Grompe, M.: The pathophysiology and treatment of hereditary tyro- 192. Schweitzer, S., Shin, Y., Jakobs, C., Brodehl, J.: Long-term outcome in sinemia type 1. Semin. Liver Dis. 2001; 21: 563Ϫ571 134 patients with galactosaemia. Eur. J. Pediatr. 1993; 152: 36Ϫ43 164. Kvittingen, E.A.: Hereditary tyrosinemia type I Ϫ an overview. Scand. Ϫ Fructose intolerance J. Clin. Lab. Invest. 1986; 46: 27 34 Ali, M., Rellos, P., Cox, T.M.: 165. Lindstedt, S., Holme, E., Lock, E.A., Hjalmarson, O., Strandvik, B.: 193. Hereditary fructose intolerance. J. Med. Genet. 1998; 35: 353Ϫ365 Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydro- Chandramouli, V., Kumaran, K., Ekberg, K., Wahren, J., Landau, B.R.: xyphenylpyruvate dioxygenase. Lancet 1992; 340: 813Ϫ817 194. 166. Macvicar, D., Dicks-Mireaux, C., Leonard, J.V., Wight, D.G.D: Quantitation of the pathways followed in the conversion of fructose to glucose in the liver. Metabolism 1993; 42: 1420Ϫ1423 Hepatic imaging with computed tomography of chronic tyrosinaemia Mock, D.M., Perman, J.A., Thaler, M.M., Morris, R.C.: type 1. Brit. J. Radiol. 1990; 63: 605Ϫ608 195. Chronic fruc- 167. Van Spronsen, F.J., Thomasse, Y., Smith, G.P.A., Leonard, J.V., Clay- tose intoxication after infancy in children with hereditary fructose ton, P.T., Fidler, V., Berger, R., Heymans, H.S.A.: Hereditary tyro- intolerance. A cause of growth retardation. New Engl. J. Med. 1983; 309: 764Ϫ770 sinemia type I: a new clinical classification with difference in prognosis Odie`vre, M., Gentil, C., Gautier, M., Alagille, D.: on dietary treatment. Hepatology 1994; 20: 1187Ϫ1191 196. Hereditary fructose intolerance in childhood. Diagnosis, management and course in 55 Disturbances of the urea cycle patients. Amer. J. Dis. Childh. 1978; 132: 605Ϫ608 168. Berry, G.T., Steiner, R.D.: Long-term management of patients with 197. Stormon, M.O., Cutz, E., Furuya, K., Bedford, M., Yerkes, L., Tolan, urea cycle disorders. J. Pediatr. 2001; 138: 56Ϫ60 D.R., Feigenbaum, A.: A six-month-old infant with liver steatosis. J. 169. Maestri, N.E., Brusilow, S.w., Clissold, D.B., Bassett, S.S.: Long-term Pediatr. 2004; 144: 258Ϫ263 treatment of girls with ornithine transcarbamylase deficiency. New 198. Tolan, D.R.: Molecular basis of hereditary fructose intolerance: mut- Engl. J. Med. 1996; 335: 855Ϫ859 ations and polymorphisms in the human aldolase B gen. Hum. Mut. 170. Mönch, E., Hoffmann, G.F., Przyrembel, H., Colombo, J.-P., Wermuth, 1995; 6: 210Ϫ218 B., Leonard, J.V.: Diagnosis and treatment of ornithine transcarbamylase (OTC)-deficiency. Mschr. Kinderheilkd. 1998; 146: 652Ϫ658 Wolman’s disease 171. Todo, S., Starzl, T.E., Tzakis, A., Benkov, K.J., Kalousek, F., Saheki, 199. Fitoussi, G., Ne`gre-Salvayre, A., Pieraggi, M.-T., Salvayre, R.: New T., Tanikawa, K., Fenton, W.A.: Orthotopic liver transplantation for pathogenetic hypothesis for Wolman’s disease: possible role of oxidized urea cycle enzyme deficiency. Hepatology 1992; 15: 419Ϫ422 low-density lipoproteins in adrenal necrosis and calcification. Bio- 172. Tuchman, M., Matsuda, I., Munnich, A., Malcolm, S., Strautnieks, S., chem. J. 1994; 301: 267Ϫ273 Briede, T.: Proportions of spontaneous mutations in males and females 200. Lin, H.J., Jie, L.K., Ho, F.C.S.: Accumulation of glyceryl ether lipids with ornithine transcarbamylase deficiency. Amer. J. Med. Genet. in Wolman’s disease. J. Lipid. Res. 1976; 17: 53Ϫ56 1995; 55: 67Ϫ70 201. Wolf, H., Nolte, K., Nolte, R.: Wolman-Syndrom. Mschr. Kinderheilk. Ϫ Glycogen storage diseases 1973; 121: 697 698 173. Bodamer, O.A., Feillet, F., Lane, R.E., Lee, P.J., Dixon, M.A., Halliday, Cholesterol ester storage disease D., Leonard, J.V.: Utilization of cornstarch in glycogen storage disease 202. Beaudet, A.L., Ferry, G.D., Nichols, B.F.jr., Rosenberg, H.S.: Choles- type Ia. Eur. J. Gastroenterol. Hepatol. 2002; 14: 1251Ϫ1256 terol ester storage disease: clinical, biochemical, and pathological 174. Burchell, A.: Glycogen storage diseases and the liver. Baill. Clin. studies. J. Pediatr. 1977; 90: 910Ϫ914 Gastroenterol. 1998; 12: 337Ϫ353 203. Kale, A.S., Ferry, G.D., Hawkins, E.P.: End-stage renal disease in a 175. Conti, J.A., Kemeny, N.: Type Ia glycogenosis associated with hepato- patient with cholesteryl ester storage disease following successful liver cellular carcinoma. Cancer 1992; 69: 1320Ϫ1322 transplantation and cyclosporine immunosuppression. J. Pediatr. 176. De Moor, R.A., Schweizer, J.J., van Hoek, B., Wasser, M., Vink, R., Gastroenterol. Nutrit. 1995; 20: 95Ϫ97 Maaswinkel-Mooy, P.D.: Hepatocellular carcinoma in glycogen storage 204. Kelly, D.R., Hoeg, J.M., Demosky S.J.jr., Brewer, H.B.jr.: Characteriza- disease type IV. Arch. Dis. Childh. 2000; 82: 479Ϫ480 tion of plasma lipids and lipoproteins in cholesteryl ester storage dis- 177. Fernandes, J.: Glycogen storage disease: recommendations for treat- ease. Biochem. Med. 1985; 33: 29Ϫ37 ment. Europ. J. Pediat. 1988; 147: 226Ϫ228 205. Kuntz, H.D., May, B., Schejbal, V., Assmann, G.: Cholesterinester- 178. Lee, P., Mather, S., Owens, J., Leonard, J., Dicksmireaux, C.: Hepatic Speicherkrankheit der Leber. Leber Magen Darm 1981; 11: 258Ϫ263 ultrasound findings in the glycogen storage diseases. Brit. J. Radiol. 206. Limbach, A., Steppberger, K., Naumann, A., Sandig, K., Lohse, P., Kel- 1994; 67: 1062Ϫ1066 ler, E.: Cholesteryl ester storage disease as cause of hepatomegaly in 179. Lei, K.-J., Pan, C.-J., Liu,J.-L., Shelly, L.L., Yang Chou, J.: Structure- childhood. Mschr. Kinderheilk. 2003; 151: 953Ϫ956 function analysis of human glucose-6-phosphatase, the enzyme defi- cient in glycogen storage disease type Ia. J. Biol. Chem. 1995; 270: Cerebrotendinous xanthomatosis 11882Ϫ11886 207. Berginer, V.M., Salen, G., Shefer, S.: Long-term treatment of cerebro- 180. Limmer, J., Fleig, W.E., Leupold, D., Bittner, R., Ditschuneit, H., Beger, tendinous xanthomatosis with chenodeoxycholic acid. New Engl. J. H.G.: Hepatocellular carcinoma in type I glycogen storage disease. Med. 1984; 311: 1649Ϫ1652 Hepatology 1988; 8: 531Ϫ537 208. Berginer, V.M., Shany, S., Alkalay, D., Berginer, J., Dekel, S., Salen, 181. Marfaing-Koka, A., Wolf, M., Boyer-Neumann, C., Meyer, D., Odie`vre, G., Tint, G.S., Gazit, D.: Osteoporosis and increased bone fractures in T., Labrune, T.: Increased levels of hemostatic proteins are independent cerebrotendinous xanthomatosis. Metabolism 1993; 42: 69Ϫ74 of inflammation in glycogen storage disease type Ia. J. Pediatr. 209. Cali, J.J., Hsieh, C.L.,Franke, U., Russel, D.W.: Mutations in the bile Gastroenterol. Nutr. 2003; 37: 586Ϫ570 acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendi- 182. Martin, K., Schlotter, B., Müller-Höcker, J., Loeschke, K., Pongratz, nous xanthomatosis. J. Biol. Chem. 1991; 266: 7779Ϫ7783 D., Folwaczny, C.: 26-year old female patient with elevated liver 210. Javitt, N.B.: Bile acid synthesis from cholesterol: regulatory and auxil- enzymes. Z. Gastroenterol. 2002; 40: 885Ϫ890 iary pathways. FASEB J. 1994; 8: 1308Ϫ1311 183. Parker, P., Burr, I., Slonimi, A., Ghishan, F.K., Greene, H.: Regression 211. Leitersdorf, E., Meiner, V.: Cerebrotendinous xanthomatosis. Curr. of hepatic adenomas in type Ia glycogen storage disease with dietary Opin. Lipidol. 1994; 5: 138Ϫ142 therapy. Gastroenterology 1981; 81: 534Ϫ536 212. Nakamura, T., Matsuzawa, Y., Takemura, K., Kubo, M., Miki, H., 184. Rosh, J.R., Collins, J., Groisman, G.M., Schwersenz, A.H., Schwartz, Tarui, S.: Combined treatment with chenodeoxycholic acid and pravas- M., Miller, C.M., LeLeiko, N.S.: Management of hepatic adenoma in tatin improves plasma cholestanol levels associated with marked glycogen storage disease Ia. J. Pediatr. Gastroenterol. Nutrit. 1995; regression of tendon xanthomas in cerebrotendinous xanthomatosis. 20: 225Ϫ228 Metabolism 1991; 40: 741Ϫ746 185. Selby, R., Starzl, T.E., Yunis, E., Todo, S., Tzakis, A.G., Brown, B.I., 213. Salen, G., Berginer, V.M., Shore, V., Horak, I., Horak, E., Tint, G.S., Kendall, R.S.: Liver transplantation for type I and type IV glycogen Shefer, S.: Increased concentrations of cholestanol and apolipoprotein storage disease. Eur. J. Pediatr. 1993; 152 (Suppl. 1) 71Ϫ76 B in the cerebrospinal fluid of patients with cerebrotendinous xantho- 186. Siciliano, M., de Candia, E., Ballarin, S., Vecchio, F.M., Servidei, S., matosis. New Engl. J. Med. 1987; 316: 1233Ϫ1238 Annese, R., Landolfi, R., Rossi, L.: Hepatocellular carcinoma compli- Abetalipoproteinaemia cating liver cirrhosis in type IIIa glycogen storage disease. J. Clin. 214. Black, D.D., Hay, R.V., Rohwer-Nutter, P.L., Ellinas, H., Stephens, Gastroenterol. 2000; 31: 80Ϫ82 J.K., Sherman, H., Teng, B.-B., Whitington, P.F., Davidson, N.O.: Talente, G.M., Coleman, R.A., Alter, C., Baker, L., Brown, B.I., Can- Intes- 187. tinal and hepatic apolipoprotein B gene expression in abetalipopro- non, R.A., Chen, Y.-T., Crigler, J.F., Ferreira, P., Haworth, J.C., Her- Ϫ man, G.E., Issenman, R.M., Keating, J.P., Linde, R., Roe, T.F., Senior, teinemia. Gastroenterology 1991; 101: 520 528 215. Castellano, G., Garfia, C., Gomez-Coronado, D., Arenas, J., Manza- B., Wolfsdorf, J.I.: Glycogen storage disease in adults. Ann. Intern. nares, J., Colina, F., Solis-Herruzo, J.A.: Ϫ Diffuse fatty liver in familial Med. 1994; 120: 218 226 heterozygous hypobetalipoproteinemia. J. Clin. Gastroenterol. 1997; Galactose intolerance 25: 379Ϫ382 188. Berry, G.T., Nissim, I., Lin, Z., Mazur, A.T., Gibson, J.B., Segal, S.: 216. Gregg, R.E., Wetterau, J.R.: The molecular basis of abetalipoproteine- Endogenous synthesis of galactose in normal men and patients with mia. Curr. Opin. Lipidol. 1994; 5: 81Ϫ86 hereditary galactosaemia. Lancet 1995; 346: 1073Ϫ1074 217. Hagve, T.-A., Myrseth, L.-E., Schrumpf, E., Blomhoff, J.-P., Christo- 189. Kumar, M., Yachha, S.K., Gupta, R.K.: Neonatal cholestasis syndrome phersen, B., Elgjo, K., Gjone, E., Prydz, H.: Liver steatosis in hypobe- due to galactosemia. Ind. J. Gastroenterol. 1996; 15: 26Ϫ27 talipoproteinemia. A case report. J. Hepatol. 1991; 13: 104Ϫ111 190. Monk, A.M., Mitchell, A.J.H., Milligan, D.W.A., Holton, J.B.: The 218. Linton, M.F., Farese, R.V., Young, S.G.jr.: Familial hypobetalipopro- diagnosis of classical galactosaemia. Arch. Dis. Childh. 1977; 52: teinemia. J. Lipid. Res. 1993; 34: 521Ϫ541 943Ϫ946 219. Rader, D.J., Brewer, H.B.: Abetalipoproteinemia: New insights into 191. Reichhard, J.K.V.: Mutations in galactosemia. Amer. J. Hum. Genet. lipoprotein assembly and vitamin E metabolism from a rare genetic 1995; 57: 978Ϫ979 disease. J. Amer. Med. Ass. 1993; 270: 865Ϫ869

630 Metabolic disorders and storage diseases

220. Wetterau, J.R., Aggerbeck, L.P., Bouma, M.E., Eisenberg, C, Munck, 247. Yerusalem, B., Sokol, R.J., Narkewicz, M.R., Smith, D., Ashmead, A., Hermier, M., Gay, G., Rader, D.J., Gregg, R.E.: Absence of micro- J.W., Wenger, D.A.: Niemann-Pick disease type C in neonatal cholesta- somal triglyceride transfer protein in individuals with abetalipopro- sis at a North American center. J. Pediatr. Gastroenterol. Nutrit. 2002; teinemia. Science 1992; 258: 999Ϫ1001 35: 44Ϫ50 Hypoalphalipoproteinaemia 248. Zhou, H., Linke, R.P., Schaefer, H.E., Möbius, W., Pfeifer, U.: Pro- 221. Gheorghiu, T., Assmann, G., Schaefer, H.E.: Endoscopic findings in gressive liver failure in a patient with adult Niemann-Pick disease asso- Ϫ ciated with generalized AL amyloidosis. Virchows Arch. 1995; 426: Tangier disease. Endoscopy 1976; 8: 164 169 Ϫ 222. Huth, K., Kracht, J., Schoenborn, W., Fuhrmann, W.: Tangier-Krank- 635 639 heit (Hypo-α-lipoproteinämie). Dtsch. Med. Wschr. 1970; 95: Mucoviscidosis Ϫ 2357 2361 249. Colombo, C., Battezzati, P.M., Podda, M., Bettinardi, N., Giunta, A.: 223. Velicia Llames, M.R., Gonzalez Hernandez, J.M., Sanz Santa Cruz, C., Fernandez Orcajo, P., Martinez Barrero, F.: Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a Elevacion de gammaglu- double blind multicenter trial. Hepatology 1996; 23: 1484Ϫ1490 tamiltranspeptidasa en pacientes con hipoalfalipoproteinemia y disli- 250. Colombo, C., Battezzati, P.M., Crosignani, A., Morabito, A., Con- pemias tipo IIa compensadas. Gastroenterol. Hepatol. 1995; 18: stantini, D., Padoan, R., Giunta, A.: Ϫ Liver disease in cystic fibrosis: a 319 322 prospective study on incidence, risk factors, and outcome. Hepatology Gaucher’s disease 2002; 36: 1374Ϫ1382 224. Aderka, D., Garfinkel, D., Rothem, A., Pinkhas, J.: Fatal bleeding from 251. Couetil, J.P., Houssin, D.P., Dousset, B.E., Chevalier, P.G., Guinvarch, esophageal varices in a patient with Gaucher’s disease. Amer. J. A., Loumet, D., Achkar, A., Carpentier, A.F.: Combined heart-lung- Gastroenterol. 1982; 77: 838Ϫ839 liver, double lung-liver, and isolated liver transplantation for cystic 225. Barton, N.W., Brady, R.O., Dambrosia, J.M., Di Bisceglie, A.M., Dop- fibrosis in children. Transpl. Int. 1997; 19: 33Ϫ39 pelt, S.H., Hill, S.C., Mankin, H.J., Murray, G.J., Parker, R.I., Argoff, 252. Dray-Charrier, N., Paul, A., Veissiere, D., Mergey, M., Scoazec, J.-Y., C.E., Grewal, P.P., Yu, K.-T.: Replacement therapy for inherited Chapeau, J., Brahimi-Horn, C., Housset, C.: Expression of cystic fibro- enzyme deficiency: macrophage targeted glucocerebrosidase for sis transmembrane conductance regulator in human gallbladder epi- Gaucher’s disease. New Engl. J. Med. 1991; 324: 1464. thelial cells. Lab. Invest. 1995; 73: 828Ϫ836 226. Beck, M., Valadares, E.R., Lotz, J.: Gaucher’s disease. Therapy by 253. Gelman, M.S., Kopito, R.R.: Rescuing protein conformation: prospects intravenous infusions of modified glucocerebrosidase. Clin. Invest. for pharmacological therapy in cystic fibrosis (review). J. Clin. Invest. 1993; 71: 78. 2002; 110: 1591Ϫ1597 227. Beutler, E.: Gaucher’s disease: new molecular approaches to diagnosis 254. Hultcrantz, R., Mengarelli, S., Strandvik, B.: Morphological findings and treatment. Science 1992; 256: 794Ϫ799 in the liver of children with cystic fibrosis: a light and electron micro- 228. Cox, T., Lachmann, R., Hollak, C., Aerts, J., van Weely, S., Hrebicek, scopical study. Hepatology 1986; 6: 881Ϫ889 M., Platt, F., Butters, T., Dwek, R., Moyses, C., Gow, I., Elstein, D., 255. Lindblad, A., Glaumann, H., Strandvik, B.: Natural history of liver Zimran, A.: Novel oral treatment of Gaucher’s disease with N-butyl- disease in cystic fibrosis. Hepatology 1999; 30: 1151Ϫ1158 deoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lan- 256. O’Connor, P.J., Southern, K.W., Bowler, I.M., Irving, H.C., Robinson, cet 2000; 355: 1481Ϫ1485 P.J., Littlewood, J.M.: The role of hepatobiliary scintigraphy in cystic 229. Fallet, S., Grace, M.E., Sibille, A., Mendelson, D.S., Shapiro, R.S., fibrosis. Hepatology 1996; 23: 281Ϫ287 Hermann, G.; Grabowski, G.A.: Enzyme augmentation in moderate to 257. Strandvik, B., Hultcrantz, R.: Liver function and morphology during life-threatening Gaucher’s disease. Pediat. Res. 1992; 31: 496Ϫ502 long-term fatty acid supplementation in cystic fibrosis. Liver 1994; 230. Figueroa, M.L., Rosenbloom, B.E., Kay, A.C., Garver, P., Thurston, 14: 32Ϫ36 D.W., Koziol, J.A., Gelbart, T., Beutler, E.: A less costly regimen of 258. Williams, S.G.J., Evanson, J.E., Hodgson, M.E., Boultbee, J.E., Wes- alglucerase to treat Gaucher’s disease. New Engl. J. Med. 1992; 327: taby, D.: An ultrasound scoring system for the diagnosis of liver disease 1632Ϫ1636 in cystic fibrosis. J. Hepatol. 1995; 22: 513Ϫ521 231. Harzer, K.: Enzymic diagnosis in 27 cases with Gaucher’s disease. Clin. 259. Yang, Y., Raper, S.E., Cohn, J.A., Engelhardt, J.F., Wilson, J.M.: An Chim. Acta 1980; 106: 9Ϫ15 approach for treating the hepatobiliary disease of cystic fibrosis by 232. Heilbronner, H., Wurster, K.G., Harzer, K.: Pränatale Diagnose der somatic gene transfer. Proc. Nat. Acad. Sci. USA 1993; 90: 4601Ϫ4605 Ϫ Gaucher-Krankheit. Dtsch. Med. Wschr. 1981; 106: 652 654 Zellweger’s syndrome 233. James, S.P., Stromeyer, F.W., Chang, C., Barranger, J.A.: Liver abnor- 260. Danks, D.M., Tippett, P., Adams, C., Campbell, P.: Cerebro-hepato- malities in patients with Gaucher’s disease. Gastroenterology 1981; Ϫ 80: 126Ϫ133 renal syndrome of Zellweger. J. Pediatr. 1975; 86: 382 387 Kohn, D.B., Nolta, J.A., Weinthal, J., Bahner, I., Yu, X.J., Lilley, J., 261. Eyssen, H., Eggermont, E., van Eldere, J., Jaeken, J., Parmentier, G., 234. Janssen, G.: Crooks, G.M.: Toward gene therapy for Gaucher’s disease. Human Bile acid abnormalities and the diagnosis of cerebro- hep- Ϫ ato-renal syndrome (Zellweger’s syndrome). Acta Paediatr. Scand. Gene Ther. 1991; 2: 101 105 Ϫ 235. Mistry, P.K.: Genotype/phenotype correlations in Gaucher’s disease. 1985; 74: 539 544 Ϫ 262. Mathis, R.K., Watkins, J.B., van Szczepanik-van Leeuwen, P., Lott, Lancet 1995; 346: 982 983 I.T.: 236. Niederau, C., Holderer, A., Heintges, T., Strohmeyer, G.: Glucocere- Liver in the cerebro-hepato-renal syndrome: defective bile acid synthesis and abnormal mitochondria. Gastroenterology 1980; 79: brosidase for treatment of Gaucher’s disease: first German long-term Ϫ results. J. Hepatol. 1994; 21: 610Ϫ617 1311 1317 Peters, S.P., Lee, R.E., Glew, R.H.: 263. Moser, A.E., Sing, I., Brown, F.R., Solish, G.I., Kelley, R.I., Benke, P.J., 237. Gaucher’s disease, a review. Medi- Moser, H.W.: cine 1977; 56: 425Ϫ442 The cerebrohepatorenal (Zellweger) syndrome. Increased 238. Ringden, O., Groth, C.-G., Erikson, A., Bäckman, L., Granqvist, S., levels and impaired degradation of very-long-chain fatty acids and Mansson, J.-E., Svennerholm, L.: Long-term follow-up of the first suc- their use in prenatal diagnosis. New Engl. J. Med. 1984; 310: 1141Ϫ1146 cesful bone marrow transplantation in Gaucher’s disease. Transplanta- Müller-Höcker, J., Bise, K., Endres, W., Hübner, G.: tion 1988; 46: 66Ϫ70 264. Zur Morphologie 239. Stone, R., Benson, J., Tronic, B., Brennan, T.: Hepatic calcifications in und Diagnostik des Zellweger-Syndroms. Virch. Arch. Path. Anat. 1981; 393: 103Ϫ114 a patient with Gaucher’s disease. Amer. J. Gastroenterol. 1982; 77: Santos, M.J., Moser, A.B., Drwinga, H., Moser, H.W., Lazarow, P.B.: 95Ϫ98 265. 240. Tjhen, K.Y., Zillhardt, H.W.: M. Gaucher Typ 1. Verlauf von 4 Ge- Analysis of peroxisomes in lymphoblasts: Zellweger’s syndrome and a patient with a deletion in chromosome 7. Pediatr. Res. 1993; 33: schwistererkrankungen vor und nach Splenektomie. Pädiat. Prax. Ϫ 1977; 18: 247Ϫ260 441 444 241. Zimran, A., Sorge, J., Gross, E., Kubitz, M., West, C., Beutler, E.: Porphyrias Prediction of severity of Gaucher’s disease by identification of mut- Andant, C., Puy, H., Bogard, C., Faivre, J., Soule´, J.C., Nordmann, Y., Ϫ 266. ations at DNA level. Lancet 1989/II: 349 352 Deybach, J.C.: Hepatocellular carcinoma in patients with acute hepatic Niemann-Pick disease porphyria: frequency of occurrence and related factors. J. Hepatol. 242. Birch, N.C., Radio, S., Horslen, S.: Metastatic hepatocellular carci- 2000; 32: 933Ϫ939 noma in a patient with Niemann-Pick disease, type C. J. Pediatr. 267. Andersson, C., Thunell, S., Floderus, Y., Forsell, C., Lundin, G., Anvret, Gastroenterol. Nutr. 2003; 37: 624Ϫ626 M., Lannfelt, L., Wetterberg, L., Lithner, F.: Diagnosis of acute 243. Putterman, C., Zelingher, J., Shouval, D.: Liver failure and the sea-blue intermittent porphyria in northern Sweden: an evaluation of mutation histiocyte/adult Niemann-Pick disease. Case report and review of the analysis and biochemical methods. J. Intern. Med. 1995; 237: 301Ϫ308 literature. J. Clin. Gastroenterol. 1992; 15: 146Ϫ149 268. Andersson, C., Innala, E., Backstrom, T.: Acute intermittent porphyria 244. Smanik, E.J., Tavill, A.S., Jacobs, G.H., Schafer, I.A., Farquhar, L., in women: clinical expression, use and experience of exogenous hor- Weber, F.L., Mayes, J.T., Schulack, J.A., Petrelli, M., Zirzow, G.C., mones. A population-based study in northern Sweden. J. Intern. Med. Oliver, K.L., Miller, S.P.F., Brady, R.O.: Orthotopic liver transplanta- 2003; 254: 176Ϫ183 tion in two adults with Niemann-Pick and Gaucher’s disease: implica- 269. Bjersing, L., Andersson, C., Lithner, F.: Hepatocellular carcinoma in tions for the treatment of inherited metabolic disease. Hepatology patients from northern Sweden with acute intermittent porphyria: 1993; 17: 42Ϫ49 morphology and mutations. Canc. Epidem. Biomark. Prev. 1996; 5: 245. Tassoni, J.P., Fawaz, K.A., Johnston, D.E.: Cirrhosis and portal hyper- 393Ϫ397 tension in a patient with adult Niemann-Pick disease. Gastroenterol- 270. Bloomer, J.R., Rank, J.M., Payne, W.D., Snover, D.C., Sharp, H.L., ogy 1991; 100: 567Ϫ569 Zwiener, R.J., Carithers, R.L.: Follow-up after liver transplantation for 246. Vellodi, A., Hobbs, J.R., O’Donnell, N.M., Coulter, B.S., Hugh-Jones, protoporphyric liver disease. Liver Transplant. Surg. 1996; 4: 269Ϫ275 K.: Treatment of Niemann-Pick disease type B by allogeneic bone mar- 271. Bloomer, J.R.: Liver metabolism of porphyrins and haem. J. Gastro- row transplantation. Brit. Med. J. 1987; 295: 1375Ϫ1376 enterol. Hepatol. 1998; 13: 324Ϫ329

631 Chapter 31

272. Bonkovsky, H.L., Schned, A.R.: Fatal liver failure in protoporphyria. 304. Rank, J.M., Carithers, R., Bloomer, J.: Evidence for neurological dys- Synergism between ethanol excess and the genetic defect. Gastroenter- function in end-stage protoporphyric liver disease. Hepatology 1993; ology 1986; 90: 191Ϫ201 18: 1404Ϫ1409 273. Bonkovsky, H.L., Barnard, G.F.: Diagnosis of porphyric syndromes: a 305. Salata, H., Cortes, J.M., Enriquez de Salamanca, R., Oliva, H., Castro, practical approach in the era of molecular biology. Semin. Liver Dis. A., Kusak, E., Carreno, V., Hernandez Guio, C.: Porphyria cutanea 1998; 18: 57Ϫ65 tarda and hepatocellular carcinoma. Frequency of occurrence and 274. Brenner, D.A., Didier, J.M., Frazier, F., Christensen, S.R., Evans, G.A., related factors. J. Hepatol. 1985; 1: 477Ϫ487 Dailey, H.A.: A molecular defect in human protoporphyria. Amer. J. 306. Samuel, D., Boboc, B., Bernuau, J., Bismuth, H., Benhamou, J.P.: Liver Hum. Genet. 1992; 50: 1203Ϫ1210 transplantation for protoporphyria. Evidence for the predominent role 275. Bruguera, M.: Liver involvement in porphyria. Semin. Dermatol. 1986; of the erythropoetic tissue in protoporphyria overproduction. Gastro- 5: 178Ϫ185 enterology 1988; 95: 816Ϫ819 276. Cable, E.E., Cable, J.W., Bonkovsky, H.L.: Depression of hepatic delta- 307. Sarkany, R.P.E., Alexander, G.J.M., Cox, T.M.: Recessive inheritance aminolevulinate synthase by heme and metalloporphyrins: relationship of erythropoietic protoporphyria with liver failure. Lancet 1994; 343: to inhibition of heme oxygenase. Hepatology 1993; 18: 119Ϫ127 1394Ϫ1396 277. Cox, T.M., Alexander, G.J.M., Sarkany, R.P.E.: Protoporphyria. 308. Sassa, S., Kappas, A.: Molecular aspects of the inherited porphyrias. Semin. Liver Dis. 1998; 18: 85Ϫ93 J. Intern. Med. 2000; 247: 169Ϫ178 278. Dailey, H.A., Sellers, V.M., Dailey, T.A.: Mammalian ferrochelatase: 309. Scarlett, Y.V., Brenner, D.A.: Porphyrias. J. Clin. Gastroenterol. 1998; expression and characterization of normal and two human proto- 27: 192Ϫ198 porphyria ferrochelatases. J. Biol. Chem. 1994; 269: 390Ϫ395 310. Siersema, P.D., Rademakers, L.H.P.M., Cleton, M.I., ten Kate, F.J.W., 279. Da Silva, V., Simonin, S., Deybach, J.C., Puy, H., Nordmann, Y.: Varie- de Bruijn, W.C., Marx, J.J.M., Wilson, H.J.P.: The difference in liver gate porphyria: diagnostic value of fluometric scanning of plasma por- pathology between sporadic and familial forms of porphyria cutanea phyrins. Clin. Chim. Acta 1995; 238: 163Ϫ168 tarda: the role of iron. J. Hepatol. 1995; 23: 259Ϫ267 280. Doss, M.O., Frank, M.: Hepatobiliary implications and complications 311. Stockinger, L.: Elektronenmikroskopische Befunde bei Leberbiopsien in protoporphyria: a 20-year study. J. Clin. Biochem. 1989; 22: bei Porphyria cutanea tarda. Wien. Zschr. Inn. Med. 1996; 47: 223Ϫ239 459Ϫ465 281. Doss, M.O., Kühnel, A., Groß, U., Sieg, I.: Hepatic porphyrias and 312. Tefferi, A., Colgan, J.P., Solberg, L.A.: Acute porphyrias: diagnosis alcohol. Med. Klin. 1999; 94: 314Ϫ328 and management. Mayo Clin. Proc. 1994; 69: 991Ϫ995 282. Doss, M.O., Gross, U., Puy, H., Doss, M., Kuhnel, A., Jacob, K., Dey- 313. Tenhunen, R., Mustajoki, P.: Acute porphyria: treatment with heme. bach, J.C., Nordmann, Y.: Coexistence of hereditary coproporphyria Semin. Liver Dis. 1998; 18: 53Ϫ55 and porphyria cutanea tarda: a new type of a dual porphyria. Med. 314. Toback, A.C., Sassa, S., Poh-Fitzpatrick, M.B., Schechter, J., Zaider, Klin. 2002; 97: 1Ϫ5 E., Harber, L.C., Kappas, A.: Hepatoerythropoietic porphyria: clinical, 283. Egger, N.G., Goeger, D.E., Payne, D.A., Miskovsky, E.P., Weinman, biochemical, and enzymatic studies in a three-generation family lin- S.A., Anderson, K.E.: Porphyria cutanea tarda. Multiplicity of risk eage. New Engl. J. Med. 1987; 316: 645Ϫ650 factors including HFE mutations, hepatitis C, and inherited uropor- 315. Todd, D.J.: Molecular genetics of erythropoietic protoporphyria. Pho- phyrinogen decarboxylase deficiency. Dig. Dis. Sci. 2002; 47: 419Ϫ426 toderm. Photoimmun. Photomed. 1998; 14: 70Ϫ73 284. Elder, G.H.: Porphyria cutanea tarda. Semin. Liver Dis. 1998; 18: 316. Verneuil de, H., Bourgeois, F., de Rooij, F., Siersema, P.D., Wilson, 67Ϫ76 J.H., Grandchamp, B., Nordmann, Y.: Characterization of a new muta- 285. Fargion, S., Sergi, C., Bissoli, F., Fracanzani, A.L., Suigo, E., Carraz- tion (R 292 G) and a deletion at the human uroporphyrinogen decar- zone, A., Roberto, C., Cappellini, M.D., Fiorelli, G.: Lack of association boxylase locus in two patients with hepatoerythropoietic porphyria. Ϫ between porphyria cutanea tarda and α1-antitrypsin deficiency. Europ. Hum. Genet. 1992; 89: 548 552 J. Gastroenterol. Hepatol. 1996; 8: 387Ϫ391 317. Wagner, S., Doss, M.O., Wittekind, C., Bäcker, U., Meessen, D., 286. Fargion, S., Fracanzani, A.L.: Prevalence of hepatitis C virus infection Schmidt, F.W.: Erythrohepatische Protoporphyrie mit rasch pro- in porphyria cutanea tarda. J. hepatol. 2003; 39: 635Ϫ638 gredienter Leberzirrhose. Dtsch. Med. Wschr. 1989; 114: 1837Ϫ1841 287. Ferri, C., Baicchi, U., La Civita, L., Greco, F., Zigneco, A.L., Manns, 318. Wassif, W.S., Deacon, A.C., Floderus, Y., Thunell, S., Peters, T.J.: M.P.: Hepatitis C virus-related autoimmunity in patients with por- Acute intermittent porphyria: diagnostic conundrums. Eur. J. Clin. phyria cutanea tarda. Eur. J. Clin. Invest. 1993; 23: 851Ϫ855 Chem. Clin. Biochem. 1994; 32: 915Ϫ921 288. Gisbert, J.P., Garcia-Buey, L., Pajares, J.M., Moreno-Otero, R.: Preva- 319. Wells, M.M., Golitz, L.E., Bender, B.J.: Erythropoietic protoporphyria lence of hepatitis C virus infection in porphyria cutanea tarda: system- with hepatic cirrhosis. Arch. Dermatol. 1980; 116: 429Ϫ432 atic review and meta-analysis. J. Hepatol. 2003; 39: 620Ϫ627 289. Gorchein, A.: Drug treatment in acute porphyria. Brit. J. Clin. Pharma- Wilson’s disease col. 1997; 44: 427Ϫ434 320. Akil, M., Brewer, G.J.: Psychiatric and behavioral abnormalities in 290. Grandchamp, B., Puy, H., Lam oril, J., Deybach, J.C., Nordmann, Y.: Wilson’s disease. Adv. Neurol. 1995; 65: 171Ϫ178 Review: Molecular pathogenesis of hepatic acute porphyrias. J. 321. Badii, M., Wong, H., Steinbrecher, U.P., Freeman, H.J.: Wilson’s dis- Gastroenterol. Hepatol. 1996; 11: 1046Ϫ1052 ease in an elderly patient. Can. J. Gastroenterol. 1995; 9: 78Ϫ80 291. Groß, U., Frank, M., Doss, M.O.: Hepatic complications of erythropoi- 322. Bearn, A.G., McKusick, V.A.: Azure lunulae. An unusual change in the etic protoporphyria. Photoderm. Photoimmun. Photomed. 1998; 14: fingernails in two patients with hepatolenticular degeneration (Wilson’s 52Ϫ57 disease). J. Amer. Med. Ass. 1958; 166: 904Ϫ906 292. Horie, Y., Norimoto, M., Tajima, F., Sasaki, H., Nanba, E., Kawasaki, 323. Bellary, S.V., van Thiel, D.H.: Wilson’s disease: a diagnosis made in H.: Clinical usefulness of cimetidine treatment for acute relapse in two individuals greater than 40 years of age. J. Okla. State Med. Assoc. intermittend porphyria. Clin. Chim. Acta 1995; 234: 171Ϫ175 1993; 86: 441Ϫ444 293. Ishibashi, A., Ogata, R., Sakisaka, S., Kumashiro, R., Koga, Y., Mitsuy- 324. Bellary, S.V., Hassanein, T., van Thiel, D.H.: Liver transplantation for ama, K., Kuromatsu, R., Uchimura, Y., Ijuin, H., Tanaka, K., Iwao, T., Wilson’s disease. J. Hepatol. 1995; 23: 373Ϫ381 Ishii, K., Sata, M., Inoue, Y., Kin, Y., Oizumi, K., Nishida, H., Imai- 325. Bowcock, A.M., Farrer, L.A., Herbert, J.M., Agger, M., Sternlieb, I., zumi, T., Tanikawa, K.: Erythropoietic protoporphyria with fatal fail- Scheinberg, I.H., Buys, C.H.C.M., Scheffer, H., Frydman, M., Chajek- ure. J. Gastroenterol. 1999; 34: 405Ϫ409 Saul, T., Bonne-Tamir, B., Caralli-Sforza, L.L.: Eight closely linked 294. Kauppinen, R., Mustajoki, P.: Acute porphyria and hepatocellular car- loci place the Wilson’s disease locus within 13q14-q21. Amer. J. cinoma. Brit. J. Cancer 1988; 57: 117Ϫ120 Human. Genet. 1988; 43: 664Ϫ674 295. Kauppinen, R., Mustajoki, P.: Prognosis of acute porphyria: occurrence 326. Brewer, G.J.: Practical recommendations and new therapies for Wil- of acute attacks, precipitating factors, and associated diseases. Medi- son’s disease. Drugs 1995; 50: 240Ϫ249 cine 1992; 71: 1Ϫ13 327. Bull, P.C., Thomas, G.R., Rommens, J.M., Forbes, J.R., Wilson Cox, 296. Kauppinen, R., Timonen, K., Mustajoki, P.: Treatment of the porphyr- D.: The Wilson’s disease gene is a putative copper transporting P-type ias. Ann. Med. 1994; 26: 31Ϫ38 ATPase similar to the Menkes gene. Nat. Genet. 1993; 5: 327Ϫ337 297. Logan, G.M., Weimer, M.K., Ellefson, M., Pierach, C.A., Bloomer, 328. Cairns, J.E., Wiliams, H.P., Walshe, J.M.: “Sunflower cataract” in Wil- J.R.: Bile porphyrin analysis in the evaluation of variegate porphyria. son’s disease. Brit. Med. J. 1969/III: 95Ϫ96 New Engl. J. Med. 1991; 324: 1408Ϫ1411 329. Carpenter, T.O., Carnes, D.L.jr., Anast, C.S.: Hypoparathyroidism in 298. MacDonald, D.M., Germain, D., Perrot, H.: The histopathology and Wilson’s disease. New Engl. J. Med. 1983; 309: 873Ϫ877 ultrastructure of liver disease in erythropoetic protoporphyria. Brit. J. 330. Cauza, E., Maier-Dobersberger, T., Polli, C., Kaserer, K., Kramer, L., Dermatol. 1981; 104: 7Ϫ17 Ferenci, P.: Screening for Wilson’s disease in patients with liver diseases 299. Manzione, N.C., Wolkoff, A.W., Sassa, S.: Development of porphyria by serum ceruloplasmin. J. Hepatol. 1997; 27: 358Ϫ362 cutanea tarda after treatment with cyclophosphamide. Gastroenterol- 331. Dameron, C.T., Harrison, M.D.: Mechanisms for protection against ogy 1988; 95: 1119Ϫ1122 copper toxicity. Amer. J. Clin. Nutr. 1998; 67 (Suppl.): 1091Ϫ1097 300. Moore, M.R.: Biochemistry of porphyria. Int. J. Biochem. 1993; 25: 332. Davis, W., Chowrimootoo, G.F.E., Seymour, C.A.: Defective biliary 1353Ϫ1368 copper excretion in Wilson’s disease: the role of caeruloplasmin. Eur. 301. Mustajoki, P., Nordmann, Y.: Early administration of heme arginate J. Clin. Invest. 1996; 26: 893Ϫ901 for acute porphyric attacks. Arch. Intern. Med. 1993; 153: 2004Ϫ2008 333. De Andrade, D.R., Fujito Neto, F.G., Vieira, G.S., Tiberio, I.F., Warth, 302. Navas, S., Bosch, O., Castillo, I., Marriott, E., Carreno, V.: Porphyria M.P., Carlich, I.: Acute hemolytic crisis followed by fulminant hepatic cutanea tarda and hepatitis C and B viruses infection: a retrospective failure with fatal outcome, as a first clinical manifestation of Wilson’s study. Hepatology 1995; 21: 279Ϫ284 disease. Rev. Hosp. Clin. Fac. Med. Sao Paulo 1994; 49: 69Ϫ75 303. Poh-Fitzpatrick, M.B.: Clinical features of the porphyrias. Clin. Der- 334. Degenhardt, S., Blomhard, G., Hefter, H., Kreuzpaintner, G., Linde- matol. 1998; 16: 251Ϫ264 mann, W., Lobeck, H., Schnaith, E., Stremmel, W., Grabensee, B.:

632 Metabolic disorders and storage diseases

Hämolytische Krise mit Leberversagen als Erstmanifestation eines 363. Rakela, J., Kurtz, S.B., McCarthy, J.T., Ludwig, J., Ascher, N.L., Morbus Wilson. Dtsch. Med. Wschr. 1994; 119: 1421Ϫ1426 Bloomer, J.R., Claus, P.L.: Fulminant Wilson’s disease treated with 335. Duvoux, C.: Severe hepatitis during Wilson’s disease. Gastroenterol. post-dilution hemofiltration and orthotopic liver transplantation. Gas- Clin. Biol. 2004; 28 (Suppl. 5): 202Ϫ205 troenterology, 1986; 90: 2004Ϫ2007 336. Erhardt, A., Hoffmann, A., Hefter, H., Häussinger, D.: HFE gene mut- 364. Roberts, E.A., Schilsky, M.L.: A practice guideline on Wilson disease. ations and iron metabolism in Wilson’s disease. Liver 2002; 22: Hepatology 2003; 37: 1475Ϫ1492 474Ϫ478 365. Roche-Sicot, J., Benhamou, J.-P.: Acute intravascular hemolysis and 337. Fleischer, B.: Zwei weitere Fälle von grünlicher Verfärbung der Kor- acute liver failure associated as a first manifestation of Wilson’s dis- nea. Klin. Mbl. Augenheilk. 1903; 41: 489Ϫ491 ease. Ann. Intern. Med. 1977; 86: 301Ϫ303 338. Fleischer, B.: Die periphere braungrünliche Hornhautverfärbung als 366. Roh, J.K., Lee, T.G., Wie, B.A., Lee, S.B., Park, S.H., Chang, K.H.: Symptom einer eigenartigen Allgemeinerkrankung. Münch. Med. Initial and follow-up brain MRI findings and correlation with the clin- Wschr. 1909; 56: 1120Ϫ1123 ical course in Wilson’s disease. Neurology 1994; 44: 1064Ϫ1068 339. Gitlin, J.D.: Wilson disease (review). Gastroenterology 2003; 125: 367. Rossaro, L., Sturniolo, G.C., Giacon, G., Montino, M.C., Lecis, P.E., 1868Ϫ1877 Schade, R.R., Corazza, G.R., Trevisan, C.: Zinc therapy in Wilson’s Gollan, J.L., Gollan, T.J.: disease: observations in five patients. Amer. J. Gastroenterol. 1990: 340. Wilson disease in 1998: genetic, diagnostic Ϫ and therapeutic aspects. J. Hepatol. 1998; 28: 28Ϫ36 85: 665 668 Gow, P.J., Smallwood, R.A., Angus, P.W., Smith, A.L., Wall, A.J., Se- 368. Sallie, R., Katsiyiannakis, L., Baldwin, D., Davies, S., O’Grady, J., 341. Mowat, A., Mieli-Vergani, G., Williams, R.: well, R.B.: Diagnosis of Wilson’s disease: an experience over three Failure of simple biochem- decades. Gut 2000; 46: 415Ϫ419 ical index to reliably differentiate fulminant Wilson’s disease from other Gu, M., Cooper, J.M., Butler, P., Walker, A.P., Mistry, P.K., Dooley, causes of fulminant liver failure. Hepatology 1992; 16: 1206Ϫ1211 342. Scheinberg, I.H., Jaffe, M.E., Sternlieb, I.: J.S., Schapira, A.H.V.: Oxidative-phosphorylation defects in liver of 369. The use of trientine in pre- Ϫ venting the effects of interrupting penicillamine therapy in Wilson’s patients with Wilson’s disease. Lancet 2000; 356: 469 474 Ϫ Hoogenraad, T.U., van den Hamer, C.J.A., van Hattum, J.: disease. New Engl. J. Med. 1987; 317: 209 213 343. Effective 370. Schilsky, M.L.: Wilson disease: genetic basis of copper toxicity and treatment of Wilson’s disease with oral zinc sulphate: two case reports. natural history. Semin. Liver Dis. 1996; 16: 83Ϫ95 Brit. Med. J. 1984; 289: 273Ϫ276 Schoen, R.E., Sternlieb, I.: Hoppe, B., Neuhaus, T., Superti-Furga, A., Forster, I., Leumann, E.: 371. Clinical aspects of Wilson’s disease. Amer. 344. J. Gastroenterol. 1990; 85: 1453Ϫ1457 Hypercalciuria and nephrocalcinosis, a feature of Wilson’s disease. 372. Schumacher, G., Platz, K.P., Mueller, A.R., Neuhaus, R., Steinmüller, Nephron 1993; 65: 460Ϫ462 T., Bechstein, W.O., Becker, M., Luck, W., Schuelke, M., Neuhaus, P.: Houwen, R.H.J., Roberts, E.A., Thomas, G.R., Cox, D.W.: 345. DNA Liver transplantation: treatment of choice for hepatic and neurological markers for the diagnosis of Wilson’s disease. J. Hepatol. 1993; 17: Ϫ Ϫ manifestation of Wilson’s disease. Clin. Transplant. 1997; 11: 217 224 269 276 373. Sen, S., Felldin, M., Steiner, C., Larsson, B., Gillett, G.T., Olausson, 346. Huster, D., Hoppert, M., Lutsenko, S., Zinke, J., Lehmann, C., M., Williams, R., Jalan, R.: Albumin dialysis and molecular adsor- Mössner, J., Berr, F., Caca, K.: Defective cellular localization of bents recirculating system (MARS) for acute Wilson’s disease (case mutant ATP 7B in Wilson’s disease patients and hepatoma cell lines. report). Liver Transplant. 2002; 8: 962Ϫ967 Gastroenterology 2003; 124: 335Ϫ345 374. Shaver, W.A., Bhatt, H., Combes, B.: Low serum alkaline phosphatase 347. Kayser, B.: Über einen Fall von angeborener grünlicher Verfärbung activity in Wilson’s disease. Hepatology 1986; 6: 859Ϫ863 der Cornea. Klin. Mbl. Augenheilk. 1902; 40: 22Ϫ25 375. Stampfl, D.A., Munoz, S.J., Moritz, M.J., Rubin, R., Armenti, V.T., 348. Kreuzpainter, G., Lauchart, W., Frenzel, H., Stremmel, W., Berges, W., Jarrell, B.E., Maddrey, W.C.: Heterotopic liver transplantation for ful- Pichlmayr, R., Strohmeyer, G.: Orthotope Lebertransplantation bei minant Wilson’s disease. Gastroenterology 1990; 99: 1834Ϫ1836 Morbus Wilson und akuter Leberinsuffizienz. Dtsch. Med. Wschr. 376. Starosta-Rubinstein, S., Young, A.B., Kluin, K., Hill, G., Aisen, A.M., 1988; 113: 1097Ϫ1100 Gabrielsen, T., Brewer, G.J.: Clinical assessment of 31 patients with 349. Ludwig, J., Moyer, T.P., Rakela, J.: The liver biopsy diagnosis of Wil- Wilson’s disease. Correlations with structural changes on magnetic res- son’s disease. Methods in pathology. Amer. J. Clin. Pathol. 1991; 102: onance imaging. Arch. Neurol. 1987; 44: 365Ϫ370 443Ϫ446 377. Steindl, P., Ferenci, P., Dienes, H.P., Grimm, G.; Pabinger, I., Madl, 350. Magalhaes, A.C., Caramelli, P., Menezes, J.R., Lo, L.S., Bacheschi, C., Maier-Dobersberger, Th., Hernetz, A., Dragosics, B., Meryn, S., L.A., Barbosa, E.R., Rosemberg, L.A., Magalhaes, A.: Wilson’s disease: Knoflach, P., Granditsch, G., Gangl, A.: Wilson’s disease in patients MRI with clinical correlation. Neuroradiology 1994; 36: 97Ϫ100 presenting liver disease Ϫ a diagnostic challenge. Gastroenterology 351. Maier-Dobersberger, T., Mannhalter, C., Rack, S., Granditsch, G., Ka- 1997; 113: 212Ϫ218 serer, K., Korninger, L., Steindl, P., Gangl, A., Ferenci, P.: Diagnosis of 378. Sternlieb, I.: Hepatic copper toxicosis. J. Gastroenterol. Hepatol. 1989; Wilson’s disease in an asymptomatic sibling by DNA linkage analysis. 4: 175Ϫ181 Gastroenterology 1995; 109: 2015Ϫ2018 379. Sternlieb, I.: Wilson’s disease and pregnancy. Hepatology 2000; 31: 352. Mason, A.L., Marsh, W., Alpers, D.: Intractable neurological Wilson’s 531Ϫ532 disease treated with orthotopic liver transplantation. Dig. Dis. Sci. 380. Strand, S., Hofmann, W.J., Grambihler, A., Hug, H., Volkmann, M., 1992; 38: 1746Ϫ1750 Otto, G., Wesch, H., Mariani, S.M., Hack, V., Stremmel, W., Krammer, 353. McCullough, A.J., Fleming, C.R., Thistle, J.L., Baldus, W.P., Ludwig, P.H., Galle, P.R.: Hepatic failure and liver cell damage in acute Wil- J., McCall, J.T., Dickson, E.R.: Diagnosis of Wilson’s disease pre- son’s disease involve CD 95 (APO-1/Fas)-mediated apoptosis. Nat. senting as fulminant hepatic failure. Gastroenterology 1983; 84: Med. 1998; 4: 588Ϫ593 161Ϫ167 381. Stremmel, W., Meyerrose, K.-W., Niederau, C., Hefter, H., Kreuz- painter, G., Strohmeyer, G.: 354. Menerey, K.A., Eider, W., Brewer, G.J., Braunstein, E.M., Schumacher, Wilson’s disease: clinical presentation, H.R., Fox, I.: treatment, and survival. Ann. Intern. Med. 1991; 115: 720Ϫ726 The arthropathy of Wilson’s disease: clinical and patho- Stromeyer, F.W., Ishak, K.G.: logical features. J. Rheumatol. 1988; 15: 331Ϫ337 382. Histology of the liver in Wilson’s disease. Myers, B.M., Prendergast, F.G., Holman, R., Kuntz, S.M., LaRusso, A study in 34 cases. Amer. J. Clin. Pathol. 1980; 73: 12Ϫ24 355. Tao, T.Y., Gitlin, J.D.: N.F.: Alterations in hepatocyte lysosomes in experimental hepatic cop- 383. Hepatic copper metabolism: insights from Ϫ genetic disease. Hepatology 2003; 37: 1241Ϫ1247 per overload in rats. Gastroenterology 1993; 105: 1814 1823 Terajima, H., Tanaka, K., Okajima, K., Inomata, Y., Yamaoka, Y.: 356. Nakada, S.Y., Brown, M.R., Rabinowitz, R.: Wilson’s disease pre- 384. senting as symptomatic urolithiasis: a case report and review of litera- Timing of transplantation and donor selection in living-related liver Ϫ transplantation for fulminant Wilson’s disease. Transplant. Proc. 1995; ture. J. Urol. 1994; 152: 978 979 Ϫ Nazer, H., Ede, R.J., Mowat, A.P., Williams, R.: 27: 1177 1178 357. Wilson’s disease: clin- 385. Thomas, G.R., Forbes, J.R., Roberts, E.A., Walshe, J.M., Cox, D.W.: ical presentation and use of prognostic index. Gut 1986; 27; The Wilson’s disease gene: spectrum of mutations and their conse- 1377Ϫ1381 Ϫ Okada, T., Morise, T., Takeda, Y., Mabuchi, H.: quences. Nat. Genet. 1995; 9: 210 217 358. A new variant dele- 386. Turnland, J.R.: Human whole-body copper metabolism. Amer. J. Clin. tion of a copper-transporting P-type ATPase gene found in patients Nutr. 1998; 67: 960Ϫ964 with Wilson’s disease presenting with fulminant hepatic failure. J. 387. Veen, C., van den Hamer, C.J.A., de Leeuw, P.W.: Zinc sulphate therapy Gastroenterol. 2000; 35: 278Ϫ283 Petrukhin, K., Fischer, S.G., Pirastu, M., Tanzi, R.E., Chernov, I., for Wilson’s disease after acute deterioration during treatment with 359. low-dose D-penicillamine. J. Intern. Med. 1991; 229: 549Ϫ552 Devoto, M., Brzustowicz, L.M., Cayanis, E., Vitale, E., Russo, J.J., 388. Vogl, T.J., Steiner, S., Hammerstingl, R., Schwarz, S., Kraft, E., Wein- Matseoane, D., Boukhgalter, B., Wasco, W., Figus, A.L., Loudianos, J., zierl, M., Felix, R.: MRT der Leber bei Morbus Wilson. RöFo. 1994; Cao, A., Sternlieb, I., Evgrafov, O., Parano, E., Pavone, L., Warburton, 160: 40Ϫ45 D., Ott, J., Penchaszadeh, G.K., Scheinberg. I.H., Gilliam, T.C.: Map- 389. Walshe, J.M.: Treatment of Wilson’s disease with trientine (triethylene ping, cloning and genetic characterization of the region containing the tetramine) dihydrochloride. Lancet 1982/I: 643Ϫ647 Wilson’s disease gene. Nat. Genet. 1993; 5: 338Ϫ343 390. Walshe, J.M: Diagnosis and treatment of presymptomatic Wilson’s dis- 360. Polio, J., Enriquez, R.E., Chow, A., Wood, W:M., Atterbury, C.E.: He- ease. Lancet 1988/II: 435Ϫ437 patocellular carcinoma in Wilson’s disease: Case report and review of 391. Walshe, J.M., Waldenstrom, E., Sams, V., Nordlinder, H., Westermark, the literature. J. Clin. Gastroenterol. 1989; 11: 220Ϫ224 K.: Abdominal malignancies in patients with Wilson’s disease. Quart. 361. Polson, R.J., Rolles, K., Calne, R.Y., Williams, R., Madsden, D.: Rever- J. Med. 2003; 96: 657Ϫ662 sal of severe neurological manifestations of Wilson’s disease following 392. Wieber, D.O., Wilson, D.M., McLeod, R.A., Goldstein, N.P.: Renal orthotopic liver transplantation. Quart. J. Med. 1987; 64: 685Ϫ691 stones in Wilson’s disease. Am. J. Med. 1979; 67: 249Ϫ254 362. Probst, A., Propst, T., Feichtinger, H., Judmaier, G., Willeit, J., Vogel, 393. Wilkinson, M.L., Portmann, B., Williams, R.: Wilson’s disease and he- W.: Copper-induced acute rhabdomyolysis in Wilson’s disease. Gastro- patocellular carcinoma: Possible protective role of copper. Gut 1983; enterology 1995; 108: 885Ϫ887 24; 767Ϫ771

633 Chapter 31

394. Wilson, S.A.K.: Progressive lenticular degeneration: A familiar nervous 423. Deugnier, Y.M., Guyader, D., Crantock, L., Lopez, J.-M., Turlin, B., disease associated with cirrhosis of the liver. Brain 1912; 34: 295Ϫ509 Yaouanq, J., Jouanolle, H., Campion, J.-P., Launois, B., Halliday, J.W., 395. Yamaguchi, Y., Heiny, M.E., Gitlin, J.D.: Isolation and characteriza- Powell, L.W., Brissot, P.: Primary liver cancer in genetic hemochro- tion of a human liver cDNA as a candidate gene for Wilson’s disease. matosis: a clinical pathological and pathogenetic study of 54 cases. Biochem. Biophys. Res. Commun. 1993; 197; 271Ϫ277 Gastroenterology 1993; 104: 228Ϫ234 396. Yang, F., Naylor, S.L., Lum, J.B., Cutshaw, St., McCombs, J.L., 424. Disler, P.B., Lynch, S.R., Charlton, R.W., Torrance, J.D., Bothwell, Haberhaus, K.H., McGill, J.R., Adrian, G.S., Moore, J.L., Barnett, T.H., Walker, R.B., Mayet, F.: The effect of tea on iron absorption. D.R., Bowman, B.H.: Characterisation, mapping and expression of the Gut 1975; 16: 193Ϫ200 human caeruloplasmin gene. Proc. Natl. Acad. Sci. USA 1986; 83: 425. Diwakaran, H.H., Befeler, A.S., Britton, R.S., Brunt, E.M., Bacon, 3257Ϫ3261 B.R.: Accelerated hepatic fibrosis in patients with combined hereditary 397. Yarze, J.C., Martin, P., Munoz, S.J., Friedman, L.S.: Wilson’s disease. hemochromatosis and chronic C infection. J. Hepatol. 2002; 36: Current status. Amer. J. Med. 1992; 92: 643Ϫ654 687Ϫ691 426. Dugast, I.J., Papadopoulus, P., Zappone, E., Jones, C., Theriault, K., Indian childhood cirrhosis Handelman, G.J., Benarous, R., Drysdale, J.W.: Identification of two 398. Baker, A., Gormally, S., Saxena, R., Baldwin, D., Drumm, B., Bonham, human ferritin H genes on the short arm of chromosome 6. Genomics J., Portmann, B., Mowat, A.P.: Copper-associated liver disease in child- 1990; 6: 204Ϫ211 hood. J. Hepatol. 1995; 23: 538Ϫ543 427. Edwards, C.Q., Griffen, L.M., Dadone, M.M., Skolnick, M.H., Kush- 399. Bavdekar, A.R., Bhave, S.A., Pradhan, A.M., Pandit, A.N., Tanner, ner, J.P.: Mapping the locus for hereditary hemochromatosis: localiza- M.S.: Long term survival in Indian childhood cirrhosis treated with tion between HLA-B and HLA-A. Amer. J. Genet. 1986; 38: 805Ϫ811 D-penicillamine. Arch. Dis. Childh. 1996; 74: 32Ϫ35 428. Edwards, C.Q., Griffen, L.M., Goldgar, D., Drummond, C., Skolnick, M., Kushner, J.P.: Prevalence of hemochromatosis among 11 065 pre- Haemochromatosis sumably healthy blood donors. New Engl. J. Med. 1988; 318: 400. Adams, P.C., Searle, J.: Neonatal hemochromatosis: a case and review 1355Ϫ1362 of the literature. Amer. J. Gastroenterol. 1988; 83: 422Ϫ425 429. Eijkelkamp, E.J., Yapp, T.R., Powell, L.W.: HFE-associated hereditary 401. Adams, P.C., Gregor, J.: Hemochromatosis and yersiniosis. Canad. J. hemochromatosis. Can. J. Gastroenterol. 2000; 14: 121Ϫ125 Ϫ Gastroenterol. 1990; 4: 160 162 430. Elmberg, M., Hultcrantz, R., Ekborn, A., Brandt, L., Olsson, R., Lind- 402. Adams, P.C., Deugnier, Y., Moirand, R., Brissot, P.: The relationship gren, S., Lööf, L., Stal. P., Wallerstedt, S., Almer, S., Sandberg-Gertzen, between iron overload, clinical symptoms, and age in 410 patients with H., Askling, J.: Ϫ Cancer risk in patients with hereditary hemochro- genetic hemochromatosis. Hepatology 1997; 25: 162 166 matosis and in their first-degree relatives. Gastroenterology 2003; 125: 403. Adams, P.C., Kertesz, A.E., McLaren, C.E., Barr, R., Bamford, A., Ϫ Chakrabarti, S.: 1733 1741 Population screening for hemochromatosis: a compar- 431. Failla, M., Giannattasio, C., Piperno, A., Vergani, A., Grappiolo, A., ison of unbound iron-binding capacity, transferrin saturation, and Gentile, G., Meles, E., Mancia, G.: Radial artery wall alterations in C282Y genotyping in 5,211 voluntary blood donors. Hepatology 2000; genetic hemochromatosis before and after iron depletion therapy. Hep- 31: 1160Ϫ1164 Ϫ Aellen, P., Guerne, P.-A., Zenagui, D., Vischer, T.L.: atology 2000; 32: 569 573 404. L’arthropathie 432. Fargion, S., Fracanzani, A.L., Piperno, A., Braga, M., D’Alba, R., de l’hemochromatose: manifestation souvent inaugurale de la maladie. Ronchi, G., Fiorelli, G.: Prognostic factors for hepatocellular carci- Schweiz. Med. Wschr. 1992; 122: 842Ϫ849 Ϫ Alustiza, J.M., Artetxe, J., Castiella, A., Agirre, C., Emparanza, P., noma in genetic hemochromatosis. Hepatology 1994; 20: 1426 1431 405. 433. Farrell, F.J., Nguyen, M., Woodley, S., Imperial, J.C., Garcia-Kennedy, Otazua, P., Garcia-Bengoechea, M., Barrio, J., Mujica, F., Recondo, R., Man, K., Esquivel, C.O., Keeffe, E.B.: J.A.: Outcome of liver transplan- MR quantification of hepatic iron concentration. Radiology tation in patients with hemochromatosis. Hepatology 1994; 20: 2004; 230: 479Ϫ484 Ϫ Bacon, B.R.: 404 410 406. Diagnosis and management of hemochromatosis. Gastro- 434. Fletcher, L.M., Halliday, J.W.: Haemochromatosis: understanding the enterology 1997; 113: 995Ϫ999 Baer, D.M., Simons, J.L., Staples, R.L., Rumore, G.J., Morton, C.J.: mechanism of disease and implications for diagnosis and patient man- 407. agement following the recent cloning of novel genes involved in iron Hemochromatosis screening in asymptomatic ambulatory men 30 metabolism. J. Intern. Med. 2002; 251: 181Ϫ192 years of age and older. Amer. J. Med. 1995; 98: 464Ϫ468 Balan, V., Baldus, W., Fairbanks, V., Michels, V., Burritt, M., Klee, G.: 435. Fracanzani, A.L., Conte, D., Fraquelli, M., Taioli, E., Mattioli, M., 408. Losco, A., Fargion, S.: Screening for hemochromatosis: a cost-effectiveness study based on Increased cancer risk in a cohort of 230 patients 12,258 patients. Gastroenterology 1994; 107; 453Ϫ459 with hereditary hemochromatosis in comparison to matched control 409. Beutler, E., Felitti, V., Gelbart, T., Ho, N.: The effect of HFE genotypes patients with non-iron-related chronic liver disease. Hepatology 2001; 33: 647Ϫ651 on measurements of iron overload in patients attending a health Gandon, Y., Olivie, D., Guyader, D., Aube, C., Oberti, F., Sebille, V., appraisal clinic. Ann. Intern. Med. 2000; 133: 329Ϫ337 436. Bhavnani, M., Lloyd, D., Bhattacharyya, A., Marples, J., Elton, P., Dlugnier, Y.: Non-invasive assessment of hepatic iron stores by MRI. 410. Ϫ Worwood, M.: Screening for genetic hemochromatosis in blood sam- Lancet 2004; 363: 357 362 Ϫ 437. Gangaidzo, I.T., Moyo, V.M., Saungweme, T., Khumalo, H., Chara- ples with raised alanine aminotransferase. Gut 2000; 46: 707 710 kupa, R.M., Gomo, Z.A.R., Loyevsky, M., Stearman, R., La Vaute, T., 411. Blisard, K.S., Bartow, S.A.: Neonatal hemochromatosis. Hum. Path. Ϫ Enquist, E.G., Rouault, T.A., Gordeuk, V.R.: Iron overload in urban 1986: 17: 376 383 Ϫ 412. Blumberg, R.S., Chopra, S., Ibrahim, R., Crawford, J., Farraye, F.A., Africans in the 1190s. Gut 1999; 45: 278 283 Zeldis, J.B., Berman, M.D.: 438. Guayder, D., Gandou, Y., Robert, J.Y., Heautot, J.F., Jouanolle, H., Primary hepatocellular carcinoma in idio- Jacquelinet, C., Messner, M., Deugnier, Y., Brissot, P.: pathic hemochromatosis after reversal of cirrhosis. Gastroenterology Magnetic reso- 1988; 95: 1399Ϫ1402 nance imaging and assessment of liver iron content in genetic hemo- Boige, V., Castera, L., de Roux, N., Ganne-Carrie, N., Ducot, B., Pellet- chromatosis. J. Hepatol. 1992; 15: 304Ϫ308 413. Hardy, L., Hansen, J.L., Kushner, J.P., Knisely, A.S.: ier, G., Beaugrand, M., Buffet, C.: Lack of association between HFE 439. Neonatal hemo- gene mutations and hepatocellular carcinoma in patients with cirrho- chromatosis. Genetic analysis of transferrin-receptor, H-apoferritin, Ϫ and L-apoferritin loci and of the human leukocyte antigen class I sis. Gut 2003; 52: 1178 1181 Ϫ 414. Bonkovsky, H.L., Slaker, D.P., Bills, E.B., Wolf. C.D.: Iron and the region. Amer. J. Pathol. 1990; 137: 149 153 liver. Amer. J. Med. Sci. 1991; 301: 32Ϫ43 440. Herbay, v.A., de Groot, H., Hegi, U., Stremmel, W., Strohmeyer, G., Sies, H.: 415. Bonkovsky, H.L., Rubin, R.B., Cable, E.E., Davidoff, A., Pels Rijcken, Low vitamin E content in plasma of patients with alcoholic T.H., Stark, D.D.: liver disease, hemochromatosis and Wilson’s disease. J. Hepatol. 1994; Hepatic iron concentration: noninvasive estimation Ϫ by means of MR imaging techniques. Radiology 1999; 212: 227Ϫ234 20: 41 46 416. Candell-Riera, J., Seres, L., Gonzales, J.B., Batille, J., Permanyer-Mir- 441. Hsing, A.W., McLaughlin, J.K., Olsen, J.H., Mellemkjar, L., Wachol- alda, G., Garcia-del-Castillo, H., Soler-Soler, J.: Cardiac hemochro- der, S., Fraumemi, J.F.jr.: Cancer risk following primary hemochromatosis: beneficial effects of iron removal therapy. Amer. J. Cardiol. matosis: a population-based cohort study in Denmark. Int. J. Cancer 1983; 52: 824Ϫ829 1995; 60: 160Ϫ162 417. Crawford, D.H.G., Leggett, B.A., Powell, L.W.: Haemochromatosis. 442. Hübscher, S.G.: Iron overload, inflammation and fibrosis in genetic Baill. Clin. Gastroenterol. 1998; 12: 209Ϫ225 haemochromatosis. (editorial) J. Hepatol. 2003; 38: 521Ϫ525 418. Cremonesi, P., Acebron, A., Raja, K.B., Simpson, R.J.: Iron absorption: 443. Jouanolle, A.M., Gandou, G., Je´ze´quel, P., Blayau, M., Campion, M.L., Biochemical and molecular insights into the importance of iron species Yaouanq, J., Mosser, J., Fergelot, P., Chauvel, B., Bouric, P., Carn, G., for intestinal uptake. Pharm. Toxicol. 2002; 91: 97Ϫ102 Andrieux, N., Gicquel, I., Le Gall, J.-Y., David, V.: Haemochromatosis 419. Cundy, T., Butler, J., Bomford, A., Williams, R.: Reversibility of hypo- and HLA-H. Nat. Genet. 1996; 14: 251Ϫ252 gonatotrophic hypogonadism associated with genetic haemochro- 444. Kaltwasser, J.P., Werner, E., Schalk, K., Hansen, C., Gottschalk, R., matosis. Clin. Endocrin. 1993; 38: 617Ϫ620 Seidl, C.: Clinical trial on the effect of regular tea drinking on iron 420. Davis, W.D., Arrowsmith, W.R.: The effect of repeated bleeding in hem- accumulation in genetic haemochromatosis. Gut 1998; 43: 699Ϫ704 ochromatosis. J. Lab. Clin. Med. 1950; 36: 814Ϫ815 445. Kelly, T.M., Edwards C.Q., Meikle, A.W., Kushner, J.P.: Hypogo- 421. De Bont, B., Walker, A.C., Carter, R.F., Oldfield, R.K., Davidson, G.P.: nadism in hemochromatosis: reversal with iron depletion. Ann. Intern. Idiopathic hemochromatosis presenting as acute hepatitis. J. Pediatr. Med. 1984; 101: 629Ϫ632 1987; 110: 431Ϫ434 446. Kew, M.D.: Pathogenesis of hepatocellular carcinoma in hereditary 422. Deugnier, Y.M., Lore´al, O., Turlin, B., Guyader, D., Jouanolle, H., hemochromatosis: occurence in noncirrhotic liver. Hepatology 1990; Moirand, R., Jacquelinet, C., Brissot, P.: Liver pathology in genetic 11: 1086Ϫ1087 hemochromatosis: a review of 135 homozygous cases and their bioclin- 447. Knisely, A.S., Mieli-Vergagni, G., Whitington, P.F.: Neonatal hemo- ical correlations. Gastroenterology 1992; 102: 2050Ϫ2059 chromatosis. Gastroenterol. Clin. N. Amer. 2003; 32: 877Ϫ889

634 Metabolic disorders and storage diseases

448. Lebron, J.A., Bennett, M.J., Vaughn, D.E., Chirino, A.J., Snow, P.M., 469. Recklinghausen, v.F.D.: Über Hämochromatose. Berlin. Klin. Wschr. Mintier, G.A., Feder, J.N., Bjorkman, P.J.: Crystal structure of the 1889; 26: 925 hemochromatosis protein HFE and characterization of its interaction 470. Rivers, J., Garrahy, P., Robinson, W., Murphy, A.: Reversible cardiac with transferrin receptor. Cell 1998; 93: 111Ϫ123 dysfunction in hemochromatosis. Amer. Heart J. 1987; 113: 216Ϫ217 449. Ludwig, J., Batts, K.P., Moyer, T.P., Baldus, W.P., Fairbanks, V.F.: Liver 471. Rossi, E., Henderson, S., Chin, C.Y.B., Olynyk, J., Beilby, J.P., Reed, biopsy diagnosis of homozygous hemochromatosis: A diagnostic algo- W.D., Jeffrey, G.P.: Genotyping as a diagnostic aid in genetic rithm. Mayo Clin. Proc. 1993; 68: 263Ϫ267 haemochromatosis. J. Gastroenterol. Hepatol. 1999; 14: 427Ϫ430 450. Macfarlane, J.D., Vreugdenhil, G.R., Doornbos, J., van der Voet, G.B.: 472. Sallie, R.W., Reed, W.D., Shilkin, K.B.: Confirmation of the efficacy Idiopathic haemochromatosis: magnetic resonance signal intensity of hepatic tissue iron index in differentiating genetic hemochromatosis ratios permit non-invasive diagnosis of low levels of iron overload. from alcoholic liver disease complicated by alcoholic hemosiderosis. Netherl. J. Med. 1995; 47: 49Ϫ53 Gut 1991; 32: 207Ϫ210 McCune, C.A., Ravine, D., Worwood, M., Jackson, H.A., Erans, H.M., 451. 473. Sanchez, M., Villa, M., Ingelmo, M., Sanz, C., Bruguera, M., Ascas, Hutton, D.: Screening for hereditary haemochromatosis within families C., Oliva, R.: Ϫ Population screening for hemochromatosis: a study in and beyond. Lancet 2003; 362: 1897 1898 5370 Spanish blood donors. J. Hepatol. 2003; 38: 745Ϫ750 452. McDonnell, S.M., Preston, B.L., Jewell, S.A., Barton, J.C., Edwards, Schumacher, H.R., Straka, P.C., Krikker, M.A., Dudley, A.T.: C.Q., Adams, P.C., Yip, R.: 474. The A survey of 2,851 patients with hemochro- arthropathy of hemochromatosis: recent studies. Ann. N.Y. Acad. Sci. matosis: symptoms and response to treatment. Amer. J. Med. 1999; 1988; 526: 224Ϫ233 106: 619Ϫ624 McLaren, G.D., Nathanson, M.H., Jacobs, A.: 475. Shaheen, N.J., Silverman, L.M., Keku, T., Lawrence, L.B., Rohlfs, 453. Regulation of intestinal E.M., Martin, C.F., Galanko, J., Sandler, R.S.: iron absorption and mucosal iron kinetics in hereditary hemochro- Association between Ϫ hemochromatosis (HFE) gene mutation carrier status and the risk of matosis. J. Lab. Clin. Med. 1991; 117: 390 401 Ϫ 454. Melefors, Ö., Hentze, M.W.: Iron regulatory factor Ϫ the conductor colon cancer. J. Nat. Canc. Inst. 2003; 95: 154 159 Ϫ 476. Sigurdsson, l., Reyes, J., Kocoshis, S.A., Hansen, T.W.R., Rosh, J., of cellular iron regulation. Blood Rev. 1993; 7: 251 258 Knisely, A.S.: 455. Morcos, M., Dubois, S., Bralet, M.P., Belghiti, J., Terris, B.: Primary Neonatal hemochromatosis: outcomes of pharmacologic and surgical therapies. J. Pediatr. Gastroenterol. Nutrit. 1998; 26: liver carcinoma in genetic hemochromatosis reveals a broad histologi- Ϫ cal spectrum. Amer. J. Clin. Path. 2001; 116: 738Ϫ743 85 89 456. Muiesan, P., Rela, M., Kane, P., Dawan, A., Baker, A., Ball, C., Mowat, 477. Stremmel, W., Riedel, H.D., Niederau, C., Strohmeyer, G.: Pathogenesis A.P., Williams, R., Heaton, N.D.: Liver transplantation for neonatal of genetic haemochromatosis. Eur. J. Clin. Invest. 1993; 23: 321Ϫ329 haemochromatosis. Arch. Dis. Childh. 1995; 73: 178Ϫ180 478. Summers, K.M., Halliday, J.W., Powell, L.W.: Identification of homo- 457. Niederau, C., Fischer, R., Pürschel, A., Stremmel, W., Häussinger, D., zygous hemochromatosis subjects by measurement of hepatic iron Strohmeyer, G.: Long-term survival in patients with hereditary hemo- index. Hepatology 1990; 12: 20Ϫ25 chromatosis. Gastroenterology 1996; 110: 1107Ϫ1119 479. Terada, T., Nakamura, Y.: Iron negative foci in siderotic macroregener- 458. Niederau, C.: Hereditary haemochromatosis. Internist 2003; 44: ative nodules in human cirrhotic liver. A marker of incipient neoplastic 191Ϫ207 lesion. Arch. Path. Lab. Med. 1989; 113: 916Ϫ920 459. Nielsen, P., Carpinteiro, S., Fischer, R., Cabeda, J.M., Porto, G., 480. Vadillo, M., Corbella, X., Pac, V., Fernandez-Viladrich, P., Pujol, R.: Gabbe, E.E.: Prevalence of the C282Y-and the H 63 D-mutations in Multiple liver abscesses due to Yersimia enterocolitica discloses pri- the HFE-gene in patients with hereditary haemochromatosis and in mary hemochromatosis: Three case report and review. Clin. Inf. Dis. control subjects from Northern Germany. Brit. J. Haematol. 1999; 1994; 18: 938Ϫ941 103: 842Ϫ845 481. Villeneuve, J.-P., Bilodeau, M., Lepage, R., Cote, J., Lefebre, M.: Vari- 460. Niemela, O., Parkkila, S., Britton, R.S., Brunt, E., Janney, C., Bacon, ability in hepatic iron concentration measurements from needle-biopsy B.: Hepatic lipid peroxidation in hereditary hemochromatosis and specimens. J. Hepatol. 1996; 25: 172Ϫ177 alcoholic liver injury. J. Lab. Clin. Med. 1999; 133: 451Ϫ460 482. Westra, W.H., Hruban, R.H., Baughman, K.L., Olson, J.L., Porterfield, 461. Olivieri, N.F., Berriman, A.M., Tyler, B.J., Davis, S.A., Francombe, J.K., Mitchell, M.C., Hutchins, G.M.: Progressive hemochromatotic W.H., Liu, P.P.: Reduction in tissue iron stores with a new regime of cardiomyopathy despite reversal of iron deposition after liver trans- continuous ambulatory intravenous deferoxamine. Amer. J. Hematol. plantation. Amer. J. Clin. Path. 1993; 99: 39Ϫ44 Ϫ 1992; 41: 61 63 483. Willis, G., Wimperis, J.Z., Lonsdale, R., Fellows, I.W., Watson, M.A., 462. Olson, L.J., Edwards, W.D., Holmes, D.R.jr., Miller, F.A.jr., Nordstrom, Skipper, L.M., Jennings, B.A.: L.A., Baldus, W.P.: Incidence of liver disease in people with Endomyocardial biopsy in hemochromatosis: clini- HFE mutations. Gut 2000; 46: 401Ϫ404 copathologic correlates in six cases. J. Amer. Coll. Cardiol. 1989; 13: 484. Wojcik, J.P., Speechley, M.R., Kertesz, A.E., Chakrabarti, S., Adams, 116Ϫ120 P. C. : Olynyk, J., Hall, P., Sallie, R., Reed, W., Shilkin, K., Mackinnon, M.: Natural history of C 282 Y homozygotes for hemochromatosis. 463. Can. J. Gastroenterol. 2002; 16: 297Ϫ302 Computerized measurement of iron in liver biopsies: a comparison Ϫ with biochemical iron measurement. Hepatology 1990; 12: 26 30 Acaeruloplasminaemia 464. Philpott, C.C.: Molecular aspects of iron absorption: insights into the Ϫ 485. Lore´al, D., Turein, B., Pigeon, C., Moisan, A., Ropert, M., Morice, P., role of HFE in hemochromatosis. Hepatology 2002; 35: 993 1001 Gandon, Y., Jouanolle, A.-M., Ve´rin, M., Hider, R.C., Yoshida, K., Bris- 465. Pillay, P., Tzoracoleftherakis, E., Tzakis, A.G., Kakizoe, S., van Thiel, D.H., Starzl, T.E.: sot, P.: Aceruloplasminemia: new clinical, pathophysiological and ther- Orthotopic liver transplantation for hemochro- Ϫ matosis. Transplant. Proc. 1991; 23: 1888Ϫ1889 apeutic insights. J. Hepatol. 2002; 36: 851 856 466. Piperno, A., Arosio, C., Fossati, L., Vigano, M., Trombini, P., Vergani, 486. Mariani, R., Arosio, C., Pelucchi, S., Grisoli, M., Piga, A., Trombini, A., Mancia, G.: Two novel nonsense mutations of HFE gene in five P., Piperno, A.: Iron chelation therapy in aceruloplasminemia: study unrelated Italian patients with hemochromatosis. Gastroenterology of a patient with a novel missense mutation (case report). Gut 2004; 2000; 119: 441Ϫ445 53: 756Ϫ758 467. Powell, L.W.: Hereditary hemochromatosis and iron overload diseases. 487. Yoshida, K., Furihata, K., Takeda, S., Nakamura, A., Yamamoto, K., J. Gastroenterol. Hepatol. 2002; 17 (Suppl.): 191Ϫ195 Morita, H., Hiyamuta, S., Ikeda, S., Shimizu, N., Yanagisawa, N.: A 468. Ramrakhiani, S., Bacon, B.R.: Hemochromatosis. Advances in molecu- mutation in the ceruloplasmin gene is associated with systemic hemo- lar genetics and clinical diagnosis. J. Clin. Gastroenterol. 1998; 27: siderosis in humans. Nature Genet. 1995; 9: 267Ϫ272 41Ϫ46

635