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Clinical Aspects of Liver Diseases 31 Metabolic Disorders and Storage Diseases

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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 car- bohydrate (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 bro- ken 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.
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