Hereditary Hemochromatosis

GENERAL PRINCIPLES

Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron overload.

• This is the most common inherited form of iron overload affecting Caucasian populations.

• HH is most frequently caused by a missense mutation (C282Y) in the HFE gene located on chromosome 6. Approximately 90% of patients with HH are homozygote for the C282Y mutation. Less frequent mutations that lead to HH include H63D and S65C and the compound heterozygous C282Y/H63D and C282Y/S65C mutations.

• Secondary iron overload states include thalassemia major, sideroblastic anemia, chronic hemolytic anemias, iatrogenic parenteral iron overload, chronic hepatitis B and C, alcohol-induced liver disease, porphyria cutanea tarda, and aceruloplasminemia.

DIAGNOSIS

Clinical Presentation

• Presentation varies from asymptomatic disease to cirrhosis and HCC.

• Clinical findings include increased pigmentation, porphyria cutanea tarda, diabetes, cardiomyopathy, arthritis, hypogonadism, and hepatic dysfunction.

Diagnostic Testing

Diagnosis is based on laboratory testing, imaging, and liver biopsy.

• The diagnosis is suggested by high fasting transferrin saturation (gt;45%) (serum iron divided by the total iron-binding capacity). Other nonspecific laboratory tests include elevated serum iron and ferritin levels. Ferritin level gt;1000 ng/mL is an accurate predictor of the degree of fibrosis in patients with HH.

• If transferrin saturation is gt;45% and ferritin is elevated, check for HFE genotype homozygosity. If patient is a C282Y homozygote, then

î If ferritin lt;1000 ng/mL and liver enzymes are normal, proceed to therapeutic phlebotomy.

î If ferritin gt;1000 ng/mL or liver enzymes are elevated, proceed to liver biopsy for histology and hepatic iron concentration.

• In patients with elevated transferrin saturation and heterozygosity of the C282Y mutation, exclude other liver or hematologic diseases and consider liver biopsy.

• MRI is the modality of choice for noninvasive quantification of iron storage in the liver and for noninvasive surveillance of HCC. It allows for repeated measures and minimizes sampling error.

TREATMENT

• Therapy consists of phlebotomy every 7-14 days (500 mL blood) until iron depletion is confirmed by a ferritin level of 50-100 ng/mL and a transferrin saturation of lt;40%. Maintenance phlebotomy of one or two units of blood three to four times a year is continued for life, unless there are contraindications for rapid mobilization of iron stores (i.e., heart failure).

• Patients with HH should avoid excess alcohol consumption. Vitamin C and iron supplementation should be avoided.

Medications

• Iron chelation with deferoxamine is an alternative to phlebotomy, but it is often more expensive and has side effects such as GI distress, visual and auditory impairments, and muscle cramps. Deferoxamine binds free iron, facilitates urinary excretion, and is recommended only when phlebotomy is contraindicated. Deferoxamine is only given IV IM, or SC.

• Deferasirox is an oral iron chelator that selectively binds iron, forming a complex that is excreted through the feces.

Surgical Management

Liver transplantation may be considered in cases of HH with cirrhosis.

Outcome and Prognosis

• The survival rate in appropriately treated noncirrhotic patients is identical to that of the general population.

• The relative risk for HCC is approximately 20, with an annual incidence of 3%-4%. Patients with HH and advanced fibrosis or cirrhosis should be screened annually for HCC.¹⁹