HFE- Related Hemochromatosis

Clinical characteristics: HFE-related hemochromatosis (HFE HC) is characterized by increased intestinal iron absorption and increased recycling of iron derived from senescent red blood cells. The phenotypic spectrum of HFE HC includes clinical HFE HC (increased serum ferritin and transferrin saturation and end-organ damage secondary to iron overload), biochemical HFE HC (increased serum ferritin and transferrin saturation without end-organ damage), and non-penetrant HFE HC (neither clinical manifestations of HFE HC nor iron overload are present, although elevated transferrin saturation may occur). Clinical HFE 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 HFE 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 HFE HC is more common in males than females.

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

Management: Targeted therapies: In individuals with clinical HFE 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 HFE HC, phlebotomy is indicated when serum ferritin exceeds 300 µg/L (males) and 200 µg/L (females).

Treatment of manifestations: Management of complications of HFE HC (arthropathy, diabetes mellitus, cirrhosis, hypogonadism, and cardiomyopathy) do not differ from the management of these conditions in persons without HFE 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.

Surveillance: In individuals with clinical HFE 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 HFE 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).

Agents/circumstances to avoid: 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.

Evaluation of relatives at risk: Offer molecular genetic testing to adult sibs of a proband to facilitate early diagnosis and surveillance.

Genetic counseling: HFE HC is inherited in an autosomal recessive manner and has low clinical penetrance. (Note: Pseudodominance has been observed in HFE HC and is attributed to the relatively high prevalence of p.Cys282Tyr heterozygotes in persons of European ancestry.) Most parents of individuals with HFE HC are p.Cys282Tyr heterozygotes (i.e., have one copy of HFE p.Cys282Tyr). On occasion, one parent has p.Cys282Tyr homozygosity and may have clinical, biochemical, or non-penetrant HFE 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 HFE-related iron overload, although the clinical penetrance of HFE HC is low.