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Home , GRACILE syndrome, Hemojuvelin, Iron overload, Juvenile hemochromatosis, Transferrin receptor 2

33 Disorders of , , and Eve A. Roberts

33.1 Introduction

Metabolic diseases associated with abnormal disposition of metals are generally rare, with the exception of hereditary hemochromatosis (HFE1) in northern European populations. They are highly disparate disorders.

I 33.1 Wilson disease Wilson disease (hepatolenticular degeneration) is an autosomal recessive dis- order of copper disposition in the and certain other organs, notably the brain, kidneys, mammary glands, and placenta. It is associated with copper overload in the liver and secondary accumulation of copper in certain parts of the brain, cornea (Kaiser-Fleischer ring), and in the kidneys, , and synovia. Wilson disease can present as , progressive neurological disease, or psychiatric illness (Roberts and Schilsky 2003). The hepatic presentation usually occurs at younger ages. Wilson disease is fatal if not treated, but with ef- fective treatment, especially if commenced early (ideally in the presymptomatic stage), the outlook for a normal healthy life is excellent. If a specific treatment must be discontinued because of adverse side-effects, alternate treatment must be substituted. Treatment should be continued through pregnancy. Dietary management by itself is inadequate, but foods containing very high concen- trations of copper (shellfish, nuts, chocolate, mushrooms, and organ meats) should be avoided, especially in the 1st year of treatment. Liver transplantation is indicated for patients unresponsive to medical treatment and for those with fulminant hepatic failure.

I 33.2 Menkes disease is a rare (1:250,000) complex disorder of copper disposition leading to systemic copper insufficiency. The major features of Menkes disease involve neurodegeneration, vascular (usually arterial) abnormalities, and ab- normal hair structure (pili torti: occasioning the disease’s alternative name of “kinky hair” syndrome). Detailed examination of the hair shaft reveals typical changes. Treatment with copper supplementation provided as subcutaneous in- 354 Disorders of Copper, Zinc, and Iron Metabolism jections of copper-histidine (Sarkar et al. 1993; Christodoulou et al. 1998) must be started before 3 weeks of age if severe neurological disease is to be avoided. Preemptive treatment of male sibs subsequent to the proband in a family may produce the best clinical outcome. Life expectancy in Menkes disease is reduced, usually to less than 10 years. A mild variant of Menkes disease has been reported with later onset of symptoms and relative sparing of the central nervous system. Although these children may have the same facies, typical skin and hair abnormalities, their neurological disease is often limited to ataxia and dysarthria. The biological basis for this milder form of Menkes disease is not known.

I 33.3 This is a mild allelic form of Menkes disease, whose phenotypic mechanism is unknown.

I 33.4 Acrodermatitis enteropathica This rare autosomal recessive disorder presents clinically with a constellation of findings: typical rash involving the perineum and perianal region, hands, and feet; , alopecia, and visual disorders (photophobia). Poor growth and recurrent infections, associated with immunodeficiency, may occur. Most patients do not have all the possible clinical features. The disorder typically becomes evident at the time of weaning. The diagnosis is usually confirmed by finding very low concentrations of serum zinc; urinary zinc excretion is also very low. Classic acrodermatitis enteropathica is due to in the ZIP4 implicated in zinc uptake (Dufner-Beattie et al. 2003). Treatment is with zinc replacement and is life-long and may need to be increased in times of increased growth demands, such as during adolescence or pregnancy. A skin disorder resembling acrodermatitis enteropathica has been associ- ated with the urea cycle defect involving ornithine transcarbamylase (Lee et al. 2002).

I 33.5 Congenital with hepatic zinc accumulation An infantile cholestatic liver disease with hepatic zinc accumulation has been described in North American Indians mainly from Ontario, Canada, most of whom belonged to a single extended kindred. Two unrelated North American Indian children appeared to have extrahepatic clinically and at laparotomy (Phillips et al. 1996). The pathogenesis of this zinc-overload liver disease is not known. Treatment is general management of chronic cholestatic liver disease and orthotopic liver transplantation if indicated. Introduction 355

I 33.6 Hemochromatosis The term “hemochromatosis” refers to iron accumulation in parenchmyal cells of the liver and other tissues. Approximately 90% of primary hemochromatosis is due to mutations in the HFE gene. Other types of primary hemochromatosis are rare. Secondary hemochromatosis is usually related to congenital hemolytic requiring chronic transfusion or to dietary excess in a genetically sus- ceptible individual (Bantu ).

G 33.6.1 Hereditary hemochromatosis, classic form Classic hereditary hemochromatosis with abnormal iron uptake from the in- testinal tract is due to mutations in the gene HFE on 6 near the HLA-A region (Feder et al. 1996). Classic hereditary hemochromatosis usually becomes symptomatic in men at 40–50 years of age, somewhat later in women. Arthropathy, cardiac disease, and pituitary dysfunction (with loss of libido) are important early extrahepatic manifestations; skin pigmentation and mellitus tend to be later features. Liver disease is common and may lead to cir- rhosis and . Early diagnosis (based on elevated fasting saturation and serum , abnormal serum aminotransferases, and positive genetic testing) permits reduction of total body iron load by phle- botomy (Tavill 2001). Treatment is indicated even if has developed, and symptoms relating to extrahepatic disease may improve on treatment. supplements should be avoided.

G 33.6.2 This iron-accumulation disease usually becomes symptomatic in adolescence (Camaschella et al. 2002). Although the liver is involved as in classic heredi- tary hemochromatosis, affected individuals usually have severe cardiac disease which dominates the clinical presentation. Arthropathy and may also be present. The typical biochemical profile includes extremely high serum ferritin and transferrin saturation. The genetic basis HFE2 is on chro- mosome 1q21 (Papnikolaou et al. 2004). Its gene product, , may affect expression. A clinically indistinguishable disease has recently been described in two kindred with mutations in hepcidin, a that plays a role in regulating intestinal iron absorption (Roetto et al. 2002). Treatment with phlebotomy is indicated.

G 33.6.3 TFR2 deficiency This rare form of hemochromatosis is due to mutations in the -2 gene (on 7q22). Clinical features are similar to those found with mutations in HFE (Roetto et al. 2002). 356 Disorders of Copper, Zinc, and Iron Metabolism

G 33.6.4 deficiency This is an important cause of hereditary hemochromatosis not related to the HFE . The disorder is inherited in an autosomal dominant pattern (Mon- tosi et al. 2001; Njajou et al. 2001). Patients present with anemia, diabetes, and . The serum ferritin is elevated but transferrin saturation is normal. Di- agnosis depends on genetic sequencing. Treatment is by phlebotomy is difficult because of anemia.

G 33.6.5 Perinatal hemochromatosis Perinatalhemochromatosis(alsoknownasneonatalhemochromatosisorneona- tal iron-storage disorder) comprises a group of disorders with similar clinical appearance: neonatal accompanied by in the liver, , heart, and other organs except the reticuloendothelial system (Gold- fischer et al. 1981; Knisely et al. 2003). The extent of organ damage indicates prenatal injury. The disease mechanism is not known. In some cases congenital infection with parvovirus B19 may be the etiology; nevertheless, when possi- ble etiologies have been excluded, a group of cases remains with an apparent genetic, or at least familial, basis. Mutations in HFE are not implicated. Most affected infants present shortly after birth, although a few have been diagnosed later in the neonatal period (Kelly et al. 2001), with classic chronic- pattern neonatal liver failure. The liver and certain other organs (pancreas, kidneys, adrenal glands, and heart – not the reticuloendothelial system) show marked iron accumulation. Histologically apparent iron deposition in salivary glands on buccal or evidence of iron overload by magnetic resonance imaging of the liver and pancreas supports the diagnosis. Supportive treatment in a neonatal intensive care unit is essential; liver trans- plantation is usually required. A multiple-drug regimen, called the “antioxidant cocktail” (Shamieh et al. 1993), has been used extensively with some success. Not all infants respond to this regimen (Sigurdsson et al. 1998), but early in- stitution of treatment may favor success. Monitoring subsequent pregnancies closely appears critically important. Surviving infants appear to stabilize clin- ically; they may develop cirrhosis or have no residual liver disease. Incidental hepatocellular carcinoma has been reported in three infants. Recurrent iron accumulation in the liver graft occurred in one infant after transplantation.

G 33.6.6 Perinatal hemochromatosis with renal tubular dysgenesis This condition is not necessarily a separate disorder from perinatal hemochro- matosis. In addition to neonatal liver failure with characteristics of perinatal hemochromatosis, proximal convoluted tubules are abnormal (Bale et al. 1994). The prognosis is even more guarded than for perinatal hemochromatosis. Introduction 357

G 33.6.7 Trichohepatic-enteric syndrome Thisconstellationofhairabnormalities,hepaticdysfunctionwithironoverload, and intractable diarrhea has been reported in one or two families (Verloes et al. 1997). This syndrome may be related to perinatal hemochromatosis, but its basis has not been determined.

G 33.6.8 GRACILE syndrome (Fellman syndrome) GRACILE syndrome was first reported in Finnish kindreds but has since been identified in Turkish and British patients. The classic clinical features include growth retardation, cholestatic liver disease, hepatic iron overload, severe , and early death (Fellman et al. 1998). This rare disorder is due to mutations in the BCS1L gene, which encodes a protein in the mitochondrial inner membrane essential for assembly of complex III in the mitochondrial respiratory chain (Visapaa et al. 2002). Treatments used thus far have proven ineffective.

I 33.7 Defective production is inherited as an autosomal recessive dis- order; the ceruloplasmin gene is on 3q25. Ceruloplasmin is a ferroxidase; in its absence copper disposition remains normal, but iron accumulation occurs in the liver and in other organs. Patients with aceruloplasminemia develop ane- mia, retinal degeneration, diabetes mellitus, and neurodegeneration involving the cortex and basal ganglia, manifested as ataxia (most common), involun- tary movement disorders, parkinsonism, and dementia (Miyajima et al. 2003). Symptoms typically begin in the third and fourth decades. Treatment of the iron overload is difficult, in part because ceruloplasmin is involved in the mecha- nism by which iron exits tissues, and aceruloplasminemia may be refractory to chelating agents such as desferroxamine. 358 Disorders of Copper, Zinc, and Iron Metabolism

33.2 Nomenclature

Disease Defect Gene OMIM No.

33.1 Wilson disease Hepatic Cu overload; defective synthesis of ATP7B 277900 (hepatolenticular holoceruloplasmin and inefficient biliary degeneration) excretion of Cu 33.2 Menkes disease Systemic Cu deficiency; defective intestinal up- ATP7A 309400 take of Cu; decreased synthesis of Cu-containing enzymes 1. “Classic” form – 2. “Mild” form (atypical) – 33.3 Occipital Horn syndrome Defective extrahepatic Cu disposition as for ATP7A 304150 Menkes disease 33.4 Acrodermatitis Systemic Zn deficiency due to abnormal intestinal ZIP4 201100 enteropathica absorption of Zn 33.5 Congenital Unknown –– cholestasis with hepatic zinc accumulation 33.6 Hemochromatosis 33.6.1 1. Classic form, Systemic Fe overload due to excess intestinal HFE 235200 HFE-deficient (HFE1) absorption of Fe 33.6.2 2. Juvenile form (HFE2) Systemic Fe overload, mechanism uncertain HFE2 602390 33.6.3 Transferrin receptor-2 Systemic Fe overload due to transferrin receptor TFR2 604250 deficiency (HFE3) dysfunction 33.6.4 Ferroportin deficiency Systemic Fe overload with defective cellular SLC11A3 606069 (HFE4) export 33.6.5 Perinatal Hepatic/extrahepatic Fe overload sparing reticu- –– hemochromatosis loendothelial system, mechanism unknown 33.6.6 Perinatal hemochromato- Unknown –– sis with renal tubular dys- genesis 33.6.7 Trichohepato-enteric Unknown – 222470 syndrome 33.6.8 GRACILE syndrome Hepatic Fe overload with mitochondrial BSC1L 603358 dysfunction 33.7 Aceruloplasminemia Greatly decreased production of ceruloplasmin Cp 604290 Treatment 359

33.3 Treatment

33.1 Wilson disease d-Penicillamine: 1000–1500 mg per day in two or three divided doses initially, with 750 or 1000 mg used for maintenance therapy. Tolerability may be en- hanced by beginning with incremental doses, 250–500 mg per day, increased by 250 mg increments every 4–7 days to a maximum of 1000–1500 mg per day in 2–4 divided dosages. Dosing in children is 20 mg/kg per day rounded off to the nearest 250 mg and given in two or three divided doses. Food inter- feres with efficacy.a Neurological disease may deteriorate, usually transiently, when treatment is commenced. Adverse effects occur in 20–30% of patients necessitating discontinuing penicillamine and substituting trientine or zinc: early sensitivity reaction with fever/rash/proteinuria; leukopenia, thrombo- cytopenia, aplastic anemia; late nephrotoxicity with proteinuria; lupus-like syndrome; various dermatological abnormalities (Roberts and Schilsky 2003) Trientine: 750–1500 mg per day in two or three divided doses initially, with 750 or 1000 mg used for maintenance therapy. Dosing in children is 20 mg/kg per day rounded off to the nearest 250 mg and given in two or three divided doses. Food interferes with efficacy.a Neurological disease occasionally deteriorates transiently when treatmentis commenced. Adverse reactions are rare: anemia, extremely rare aplastic anemia, , loss of taste, rashes. Zinc salts (sulphate; gluconate; acetate) to provide 50 mg elemental Zn tid. Children’s dose is 25 mg elemental Zn tid. Minimal dosing frequency is bid. Food interferes with efficacy.a Adverse reactions are uncommon, mainly gas- tritis with . 33.2 Menkes disease 1. “Classic” form Copper-histidine subcutaneous injection: 50–150 µg/kg per day. Typical dosage is 100 µg/kg per day in newborns and 1 mg/day in older children. 2. “Mild” form (atypical) Copper-histidine subcutaneous injection as above 33.3 Occipital Horn syndrome Copper-histidine subcutaneous injection as above 33.4 Acrodermatitis Zinc salts (sulphate; gluconate; acetate) to provide initially 5–10 mg elemental enteropathica Zn/kg per day. Response is usually rapid, with improvement in skin lesions beginning within 24–48 h of starting treatment. Complete resolution and restoration of normal hair growth may take 2–4 weeks. Thereafter mainte- nance does is 1–2 mg elemental Zn/kg per day by mouth. 33.5 Congenital cholestasis with Standard treatment for chronic cholestatic liver disease, then orthotopic liver hepatic zinc accumulation transplantation if indicated 33.6 Hemochromatosis 33.6.1 1. Classic form, Phlebotomytoremove500 mL ofbloodweeklyorbiweeklyuntilserumferritin HFE-deficient (HFE1) < 50 µg/l, then decrease frequency to once every 2–4 months to maintain serum ferritin in 25–50 µg/l range 33.6.2 2. Juvenile form (HFE2) Same as for HFE1 33.6.3 Transferrin receptor-2 Same as for HFE1 deficiency (HFE3) 33.6.4 Ferroportin deficiency Phlebotomy as for HFE1 except that interval should be extended to every 3–4 (HFE4) weeksorastolerated 360 Disorders of Copper, Zinc, and Iron Metabolism

33.6.5 Perinatal “Antioxidant cocktail”: N-acetylcysteine (140 mg/kg by mouth or nasogas- hemochromatosis tric tube as a loading dose then 70 mg/kg every 4 h to a total of 17–21 doses); selenium 2–3 µg/kg per day intravenously over 24 h for ∼ 4weeks; α-tocopheryl polyethylene glycol succinate 20–30 IU/kg per day given by mouth in two equally divided doses for ∼ 4 weeks or longer; prostaglandin E1 as a continuous intravenous infusion (0.4–0.6 µg/kg per hour) for 2–4 weeks; desferroxamine (30 mg/kg per day) by continuous intravenous infusion over 8 h daily until the serum ferritin is < 500 µg/l. Note that prostaglandin E1 cannot be administered if the ductus arteriosus is patent. Orthotopic liver transplantation, if indicated 33.6.7 Perinatal hemochromato- No specific treatment sis with renal tubular dysgenesis 33.6.7 Trichohepato-enteric No specific treatment syndrome 33.6.8 GRACILE syndrome No specific treatment 33.7 Aceruloplasminemia Phlebotomy as for HFE1 or as tolerated; hematocrit should be checked before each phlebotomy and it should be no lower than 20% below its starting value; desferroxamine a Best if taken 1 h before or 2 h after meals but closer proximity to meals (with possible dose adjustment) is acceptable if required for adequate compliance. Alternative Therapies/Experimental Trials 361

33.4 Alternative Therapies/Experimental Trials

33.1 Wilson disease Tetrathiomolybdate, alone or in combination with zinc (Brewer et al. 2003) – note significant risk of , hepatotoxicity and brain toxicity Vitamin E (α-tocopherol) 33.2 Menkes disease 1. “Classic” form None 2. “Mild” form (atypical) None 33.3 Occipital Horn syndrome None 33.4 Acrodermatitis enteropathica None 33.5 Congenital cholestasis with hepatic zinc ac- None; liver transplantation may be necessary cumulation 33.6 Hemochromatosis 33.6.1 1. Classic form, HFE-deficient (HFE1) None 33.6.2 2. Juvenile form (HFE2) None 33.6.3 Transferrin receptor-2 deficiency (HFE3) None 33.6.4 Ferroportin deficiency None 33.6.5 Perinatal hemochromatosis Gamma-globulin infusions to mother during latter half of pregnancy 33.6.6 Perinatal hemochromatosis with renal Antioxidant cocktail; combined liver + kidney transplantation tubular dysgenesis 33.6.7 Trichohepato-enteric syndrome Antioxidant cocktail; combined liver + intestinal transplanta- tion 33.6.8 GRACILE syndrome Intravenous administration of apotransferrin followed by ex- change transfusion; antioxidant cocktail 33.7 Aceruloplasminemia Vitamin E (α-tocopherol)

33.5 Follow-up/Monitoring

33.1 Wilson disease Clinical review and physical examination every 6–12 months; serum AST,ALT, ALP, GGT, conjugated bilirubin, albumin, International Normalized Ratio (INR), serum Cu and ceruloplasmin, complete count, urinalysis every 6–12 months Twenty-four-hour urinary copper excretion every 12–18 months if on stable dose of medication: for patients taking d-pencillamine or trientine, it should be 3–8 µmol (200–500 µg) per day, and for patients on any zinc salt it should be no more than 1.2 µmol (75 µg)perday For patients taking zinc serum zinc or 24-h urinary zinc excretion every 12 months 33.2 Menkes disease 1. “Classic” form Clinical follow-up relates to major features of the disease: seizures, neurode- generation, arterial abnormalities, bone and joint disorders. Efficacy of treat- ment is determined by normalization of serum copper and ceruloplasmin and 24-h urinary copper excretion. Exceptionally: measurement of hepatic parenchymal copper concentration may be required to assess efficacy of treat- ment 2. “Mild” form (atypical) As for classic Menkes disease 362 References

33.3 Occipital Horn syndrome As for classic Menkes disease 33.4 Acrodermatitis Clinical examination to ensure normal skin and hair.SerumZn concentrations enteropathica should be measured every 6–12 months; 24-h urinary excretion of Zn should be measured every 1–2 years. Serum Cu should be measured every 6–12 months, and the complete blood count should be monitored regularly to check for development of a Cu-deficiency anemia. Zn supplementation expected to be life-long; pregnancy or use of oral contraceptive pill may increase Zn demands 33.5 Congenital cholestasis with Routine surveillance for progressive liver disease hepatic zinc accumulation 33.6 Hemochromatosis 33.6.1 1. Classic form, Clinical examination to monitor hepatic and extrahepatic disease; serum HFE-deficient (HFE1) ferritin, fasting transferrin saturation, and complete blood count every 3–4 months or more often depending on maintenance phlebotomy requirements; screening for hepatocellular carcinoma mandatory in any patient with cir- rhosis 33.6.2 2. Juvenile form (HFE2) Same as HFE1 33.6.3 Transferrin receptor-2 Same as HFE1 deficiency (HFE3) 33.6.4 Ferroportin deficiency Same as HFE1 (HFE4) 33.6.5 Perinatal Clinical review and physical examination every 3–12 months; serum AST, hemochromatosis ALT, ALP, GGT, conjugated bilirubin, albumin, INR, complete blood count, urinalysis, , transferrin saturation and ferritin at each visit. Liver sonogram every 2–4 years 33.6.6 Perinatal hemochromato- As for perinatal hemochromatosis, if infant survives sis with renal tubular dys- genesis 33.6.7 Trichohepato-enteric As for perinatal hemochromatosis, if infant survives syndrome 33.6.8 GRACILE syndrome As for perinatal hemochromatosis, if infant survives 33.7 Aceruloplasminemia Regular clinical review and physical examination for neurological disease; regular ophthalmologic examination of retina; serum ferritin and transferrin saturation; complete blood count to monitor anemia; serum AST, ALT, ALP, GGT, albumin

References

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