Symptoms usually appear earlier in men than in women since menstrual bleeding limits the accumulation of iron until menopause. This results in a male-to-female ratio of clinically significant iron overload of approximately 5:1 to 7:1. In the most common form caused by HFE mutations, symptoms usually appear in the fifth and sixth decades of life in men and later in women. With population screening, it has become clear that homozygosity for the most common HFE mutation (C282Y) shows variable penetrance; thus disease development is not inevitable, presumably because other genetic and environmental factors influence the rate of iron accumulation.
Fig. 16.20 Hereditaryhemochromatosis.InthisPrussianblue–stainedsection,hepatocellularironappearsblue.Theparenchymalarchitectureisnormalatthisstageofdisease,evenwithsuchabundantiron.
The principal manifestations include hepatomegaly, abdominal pain, skin pigmentation (particularly in sun-exposed areas), deranged glucose homeostasis or frank diabetes mellitus due to destruction of pancreatic islets, cardiac dysfunction (arrhythmias, cardiomyopathy), and atypical arthritis. In some patients, the presenting complaint is hypogonadism (e.g., amenorrhea in the female, impotence and loss of libido in the male). As noted, clinically apparent disease is more common in males and rarely becomes evident before 40 years of age. Death may result from cirrhosis or cardiac disease. In those with untreated disease, the risk for HCC is increased 200-fold, presumably because of ongoing liver damage and the genotoxic effects of oxidants generated by iron in the liver.
Fortunately, hemochromatosis can be diagnosed long before irreversible tissue damage has occurred. Screening of family members of probands is important. Heterozygotes also accumulate excessive iron, but not to a level that causes significant tissue damage. Currently most patients with hemochromatosis are diagnosed in the subclinical, precirrhotic stage due to routine serum iron measurements (as part of another diagnostic workup). Regular phlebotomy results in steady removal of excess tissue iron, and with this simple treatment life expectancy is normal.
Wilson disease is an autosomal recessive disorder caused by mutation of the ATP7B gene, which results in impaired copper excretion into bile and a failure to incorporate copper into ceruloplasmin. This disorder is marked by the accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye. Normally, 40% http://ebooksmedicine.net to 60% of ingested copper (2–5 mg/day) is absorbed in the duodenum and proximal small intestine, from where it is transported complexed with albumin and histidine to the liver. Here, free copper dissociates and is taken up by hepatocytes, where copper is incorporated into enzymes and α2-globulin (apoceruloplasmin) to form ceruloplasmin, which is secreted into the blood. Ceruloplasmin carries 90% to 95% of plasma copper. Circulating ceruloplasmin is eventually desialylated, endocytosed by the liver, and degraded within lysosomes, after which the released copper is excreted into bile. This degradation/excretion pathway is the primary route for copper elimination.