Haemochromatosis is an hereditary disorder generally caused by inappropriate absorption of iron by the small intestine which leads to iron deposition in the viscera, endocrine organs, and other sites, causing structural injury and impaired function. The most common form is classical adult haemochromatosis, but juvenile and neonatal forms are recognized, and several other genetic syndromes associated with iron storage have been identified; these may rarely involve specific tissues selectively, such as the lens of the eye or basal ganglia of the brain, or a characteristic range of tissues...
Haemochromatosis is an hereditary disorder generally caused by inappropriate absorption of iron by the small intestine which leads to iron deposition in the viscera, endocrine organs, and other sites, causing structural injury and impaired function. The most common form is classical adult haemochromatosis, but juvenile and neonatal forms are recognized, and several other genetic syndromes associated with iron storage have been identified; these may rarely involve specific tissues selectively, such as the lens of the eye or basal ganglia of the brain, or a characteristic range of tissues including the liver, heart, and endocrine system. Early-onset (juvenile) haemochromatosis has a predilection for the heart, pituitary gonadotrophs and the pancreatic islet—thus myocardial disease (which may be fatal if untreated), hypogonadism and diabetes mellitus are prominent features. Prompt diagnosis and depletion of tissue iron by chelating agents—and venesection where possible—may be life-saving.
Classical adult haemochromatosis
Aetiology and pathogenesis—the condition is inherited as a recessive trait and due to mutations in the MHC class I-related HFE gene that appear to affect the function of key intestinal iron transport proteins such as divalent metal transporter 1 (DMT 1) and ferroportin, also reducing liver production of hepcidin that normally inhibits iron export from enterocytes and macrophages via its interaction with ferroportin (a similar phenotype can be produced by mutation in other genes involved in iron metabolism). The mutant allele, designated C282Y of HFE, is carried by about 1 in 10 individuals of European ancestry, hence about 1 in 400 are homozygotes or compound heterozygotes with biochemical abnormalities of iron storage that may lead to full-blown clinical haemochromatosis.
Clinical features—expression of disease may range from slight abnormality of blood parameters that reflect iron metabolism to the established clinical syndrome of cutaneous pigmentation (generalized slate-grey or localized bronzed coloration), cardiomyopathy, endocrine failure (especially diabetes mellitus and hypogonadism), arthritis (most typically affecting the second and third metacarpophalangeal joints of the hands and feet), and pigment cirrhosis.
Diagnosis—this can be usually established by demonstrating abnormalities of iron metabolism, with fasting serum transferrin iron saturation above 55% and elevated serum ferritin concentration. Molecular analysis of the HFE gene for homozygosity for the C282Y allele may be very useful in patients of European ancestry. Liver biopsy with histochemical determination (and preferably chemical quantification) of tissue iron content is required if there is doubt as to the diagnosis.
Management—since it is the toxicity of iron that is responsible for the manifestations of all forms of haemochromatosis, treatment is directed to the removal of iron at the earliest possible stage by phlebotomy, typically (in an adult) of 500 ml of blood each week until the serum ferritin concentration is reduced to within the low normal range and, if possible, there is a mild iron-deficiency anaemia, after which the frequency of phlebotomy is reduced. Patients with severe clinical manifestations, e.g. life-threatening cardiac arrhythmias, or who are incapable of withstanding frequent phlebotomy, require chelation therapy with the parenteral agent, desferrioxamine. End organ failure, e.g. diabetes mellitus, hypogonadism, may need treatment. Patients with cirrhosis should undergo 6-monthly surveillance by ultrasonography and serum α-fetoprotein (AFP) estimation for early detection of hepatocellular carcinoma.
Prognosis—the main causes of death in untreated patients are hepatocellular failure and carcinoma of the liver, with cardiomyopathy and diabetes also contributing. Life expectancy is probably improved by removing iron and maintaining normal iron homeostasis, and most patients feel better on iron-depletion therapy.
Family members—the diagnosis of haemochromatosis in an individual has immediate implications for first-degree relatives. Those in whom HLA typing or molecular analysis of the HFE or non-HFE iron overload genes indicates a genetic predisposition to the disease require re-evaluation by clinical and biochemical testing at intervals of not more than 5 years.
Identification of mutations in the genes encoding haemojuvelin and hepcidin, which predispose to severe iron loading, also permit genetic testing and presymptomatic diagnosis of juvenile haemochromatosis before irreversible organ injury occurs in first-degree family members at risk. Predictive genetic testing is not available for neonatal haemochromatosis.
Chapter. 14089 words. Illustrated.
Subjects: Clinical Medicine
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