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33 Disorders of Copper, Zinc, and Iron Metabolism Eve A

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33 Disorders of Copper, Zinc, and Iron Metabolism Eve A 33 Disorders of Copper, Zinc, and Iron Metabolism 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 liver 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, heart, and synovia. Wilson disease can present as liver disease, 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 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 Occipital Horn syndrome 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; diarrhea, 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 mutations in the ZIP4 gene 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 cholestasis 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 biliary atresia 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 anemia requiring chronic transfusion or to dietary excess in a genetically sus- ceptible individual (Bantu siderosis). 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 chromosome 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 diabetes mellitus tend to be later features. Liver disease is common and may lead to cir- rhosis and hepatocellular carcinoma. Early diagnosis (based on elevated fasting transferrin saturation and serum ferritin, abnormal serum aminotransferases, and positive genetic testing) permits reduction of total body iron load by phle- botomy (Tavill 2001). Treatment is indicated even if cirrhosis has developed, and symptoms relating to extrahepatic disease may improve on treatment. Vitamin C supplements should be avoided. G 33.6.2 Juvenile hemochromatosis 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 hypogonadism 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, hemojuvelin, may affect hepcidin expression. A clinically indistinguishable disease has recently been described in two kindred with mutations in hepcidin, a protein 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 transferrin receptor-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 Ferroportin deficiency This is an important cause of hereditary hemochromatosis not related to the HFE locus. The disorder is inherited in an autosomal dominant pattern (Mon- tosi et al. 2001; Njajou et al. 2001). Patients present with anemia, diabetes, and arthritis. 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 liver failure accompanied by iron overload in the liver, pancreas, 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 biopsy 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.
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