Related Hemochromatosis

CLINICAL CHARACTERISTICS

related hemochromatosis ( HC) is characterized by increased intestinal iron absorption and increased recycling of iron derived from senescent red blood cells. The phenotypic spectrum of HC includes clinical HC (increased serum ferritin and transferrin saturation and end-organ damage secondary to iron overload), biochemical HC (increased serum ferritin and transferrin saturation without end-organ damage), and non-penetrant HC (neither clinical manifestations of HC nor iron overload are present, although elevated transferrin saturation may occur). Clinical HC is characterized by excessive iron in the liver, pancreas, heart, skin, joints, and anterior pituitary gland. In untreated individuals, early manifestations include weakness, chronic fatigue, abdominal pain, weight loss, arthralgias, and diabetes mellitus. Individuals with HC have an increased risk of cirrhosis when their serum ferritin is higher than 1,000 µg/L. Other findings of severe iron overload include hypogonadism, congestive heart failure, arrhythmias, and progressive increase in skin pigmentation. Clinical HC is more common in males than females.

DIAGNOSIS/TESTING: The diagnosis of HC is established in most persons with characteristic laboratory and/or clinical features by identification of p.Cys282Tyr homozygosity.

MANAGEMENT

In individuals with clinical HC, a major initial treatment goal is to remove excess iron by phlebotomy to achieve serum ferritin 50-100 µg/L. Erythrocytapheresis is sometimes used to remove excess iron. Iron chelation therapy may be used to treat individuals intolerant of phlebotomy or erythrocytapheresis or those with symptomatic anemia. In individuals with biochemical HC, phlebotomy is indicated when serum ferritin exceeds 300 µg/L (males) and 200 µg/L (females). Management of complications of HC (arthropathy, diabetes mellitus, cirrhosis, hypogonadism, and cardiomyopathy) do not differ from the management of these conditions in persons without HC. Treatment of arthropathy includes nonsteroidal anti-inflammatory drugs, physiotherapy, and joint replacement. Standard treatment for diabetes mellitus. Vaccination for hepatitis A and B. Treatment of hepatitis B or C with standard antiviral agents may reduce liver injury. In individuals with cirrhosis, evaluation and treatment of complications is warranted, including endoscopic surveillance of varices; prophylaxis with nonselective beta-blockers; salt restriction and diuretics for ascites, with paracentesis and portosystemic shunts as needed; antibiotics to decrease risk of spontaneous bacterial peritonitis; and low-protein diet for hepatic encephalopathy with lactulose and rifaximin as indicated. Orthotopic liver transplant for end-stage liver disease. Hormone replacement therapy for hypogonadism; gonadotropins for infertility. Standard treatments for heart failure and arrhythmias in individuals with cardiomyopathy. In individuals with clinical HC, after serum ferritin is ≤100 µg/L, monitor serum ferritin concentration every three to four months, and maintain serum ferritin <300 µg/L (males) and <200 µg/L (females) thereafter; joint radiographs as needed; in those with diabetes mellitus assess for complications every six to 12 months; liver enzyme tests every six to 12 months; standard evaluations for primary liver cancer in those with cirrhosis; assessment for hormonal deficiency in those with hypogonadism; cardiac assessment in those with cardiac siderosis annually or as needed. In individuals with biochemical HC and non-penetrant p.Cys282Tyr homozygotes, monitor serum ferritin concentration every six to 12 months, and begin phlebotomy to achieve iron depletion when serum ferritin exceeds 300 µg/L (males) and 200 µg/L (females). Medicinal iron, mineral supplements containing iron, excess alcohol, excess vitamin C, uncooked seafood, and lifestyle behaviors that increase the risk of viral hepatitis infection; alcohol consumption should be avoided in those with hepatic fibrosis or cirrhosis. Offer molecular genetic testing to adult sibs of a proband to facilitate early diagnosis and surveillance.

GENETIC COUNSELING

HC is inherited in an autosomal recessive manner and has low clinical penetrance. (Note: Pseudodominance has been observed in HC and is attributed to the relatively high prevalence of p.Cys282Tyr heterozygotes in persons of European ancestry.) Most parents of individuals with HC are p.Cys282Tyr heterozygotes (i.e., have one copy of p.Cys282Tyr). On occasion, one parent has p.Cys282Tyr homozygosity and may have clinical, biochemical, or non-penetrant HC. If both parents are p.Cys282Tyr heterozygotes, each sib of an affected individual has a 25% chance of being homozygous for p.Cys282Tyr, a 50% chance of being heterozygous for p.Cys282Tyr, and a 25% chance of being neither homozygous nor heterozygous for p.Cys282Tyr. Sibs who are homozygous for p.Cys282Tyr are at risk for -related iron overload, although the clinical penetrance of HC is low.