Thompson & Thompson Genetics in Medicine, 8th Edition

Case 20. Hereditary Hemochromatosis (HFE Mutation, MIM 235200)

Autosomal Recessive


• Incomplete penetrance and variable expressivity

• Sex differences in penetrance

• Population screening versus at-risk testing

• Molecular versus biochemical testing

Major Phenotypic Features

• Age at onset: 40 to 60 years in males; after menopause in females

• Fatigue, impotence, hyperpigmentation (bronzing), diabetes, cirrhosis, cardiomyopathy

• Elevated serum transferrin iron saturation

• Elevated serum ferritin level

History and Physical Findings

S.F. was a 30-year-old healthy white man referred to the genetics clinic for counseling because his 55-year-old father had just been diagnosed with cirrhosis due to hereditary hemochromatosis. History and physical examination findings were normal. His transferrin iron saturation was 48% (normal, 20% to 50%). His serum ferritin level was normal (<300 ng/mL), and liver transaminase activities were normal. Given that S.F. was an obligate carrier for the condition and his mother had an 11% population risk for being a carrier of mutations in the hereditary hemochromatosis gene (HFE), his prior risk for having inherited two mutant HFE alleles was 5.5%. S.F. chose to have his HFE gene examined for the two common hemochromatosis variants. Molecular testing revealed that he was homozygous for the Cys282Tyr mutation, putting him at risk for development of hemochromatosis. He was referred to his primary care provider to follow serum ferritin levels every 3 months and to institute therapy as needed.


Disease Etiology and Incidence

Hereditary hemochromatosis (MIM 235200) is a disease of iron overload that occurs in some individuals with homozygous or compound heterozygous mutations in the HFE gene. Most patients (90% to 95%) with hereditary hemochromatosis are homozygous for a Cys282Tyr mutation; the remaining 5% to 10% of affected individuals are compound heterozygotes for the Cys282Tyr and another mutation, His63Asp. Homozygosity for His63Asp does not lead to clinical hemochromatosis unless there is an additional cause of iron overload. The carrier rate in the white population of North America is approximately 11% for Cys282Tyr and approximately 27% for His63Asp, which means that approximately 1 in 330 individuals will be Cys282Tyr homozygotes and an additional 1 in 135 will be compound heterozygotes for HFEdisease-causing mutations. The frequency of these mutations is far lower in Asians, Africans, and Native Americans.

The penetrance of clinical hereditary hemochromatosis has been difficult to determine; estimates vary from 10% to 70%, depending on whether hereditary hemochromatosis is defined as organ damage due to pathological iron overload or by biochemical evidence of an elevation of ferritin and transferrin saturation. In a family-based study, for example, between 75% and 90% of homozygous relatives of affected individuals were asymptomatic. Population-based studies have provided estimates of penetrance based on biochemical evidence of hereditary hemochromatosis of 25% to 50%, but penetrance may be higher if liver biopsies are performed to find occult cirrhosis. Whatever the penetrance, it is clear that males are affected more frequently than females and that Cys282Tyr/His63Asp compound heterozygotes are at much lower risk for hereditary hemochromatosis than Cys282Tyr homozygotes. Although the exact value of the penetrance in Cys282Tyr homozygotes remains to be definitively determined, penetrance is clearly incomplete.

At least four additional iron overload disorders labeled hemochromatosis have been identified on the basis of clinical, biochemical, and genetic characteristics. Juvenile hemochromatosis, or hemochromatosis type 2 (HFE2), is autosomal recessive and is divided into two forms: HFE2A, caused by mutation in HJV, and HFE2B, caused by mutation in HAMP. Hemochromatosis type 3, an autosomal recessive disorder, is caused by mutation in TFR2. Hemochromatosis type 4, an autosomal dominant disorder, is caused by mutation in SLC40A1.


Hereditary hemochromatosis is a disorder of iron overload. Body stores of iron are determined largely by dietary iron absorption from enterocytes of the small intestine and release of endogenous iron from macrophages that phagocytose red blood cells. Iron release from enterocytes and macrophages is regulated by a circulating iron response hormone, hepcidin, which is synthesized in the liver and released to block further iron absorption when iron supplies are adequate. Mutant HFE interferes with hepcidin signaling, which results in the stimulation of enterocytes and macrophages to release iron. The body therefore continues to absorb and recycle iron, despite an iron-overloaded condition.

Ultimately, a small proportion of individuals with two mutations in the HFE gene will develop symptomatic iron overload. Early symptoms include fatigue, arthralgia, decreased libido, and abdominal pain. An additional presentation is the finding of elevated transferrin iron saturation or ferritin on routine screening. Late findings of iron overload include hepatomegaly, cirrhosis (Fig. C-20), hepatocellular carcinoma, diabetes mellitus, cardiomyopathy, hypogonadism, arthritis, and increased skin pigmentation (bronzing). Males develop symptoms between the ages of 40 and 60 years. Women, who are reported to develop symptoms at 10% to 50% the rate of men, do not develop symptoms until after menopause. Prognosis is excellent in patients diagnosed and treated before the development of cirrhosis. Patients diagnosed with cirrhosis and treated effectively with phlebotomy still have a 10% to 30% risk for liver cancer years later.


FIGURE C-20 Liver of patient with hereditary hemochromatosis showing iron deposition and cirrhosis. A, Low-power view showing area of fibrosis (arrow; hematoxylin and eosin stain). B, Higher power view showing iron deposition (brown pigment seen within hepatocytes) next to an area of fibrosis (hematoxylin and eosin stain). C, Perl's stain in which iron stains dark blue. Heavy staining in hepatocytes flanks an area of fibrosis with much less iron deposition. See Sources & Acknowledgments.


The diagnosis of clinical HFE-associated hereditary hemochromatosis in individuals with clinical findings consistent with HFE-associated hereditary hemochromatosis and the diagnosis of biochemical HFE-associated hereditary hemochromatosis is typically based on finding elevated transferrin-iron saturation of 45% or higher and serum ferritin concentration above the upper limit of normal (i.e., >300 ng/mL in men and >200 ng/mL in women), as well as two HFE-associated hereditary hemochromatosis–causing mutations on confirmatory HFE gene testing. Although serum ferritin concentration may increase progressively over time in untreated individuals with HFE-associated hereditary hemochromatosis, it is not specific for HFE-associated hereditary hemochromatosis and therefore cannot be used alone for identification of individuals with HFE-associated hereditary hemochromatosis.

Individuals with an at-risk genotype are monitored with serum ferritin levels annually. If the level is higher than 50 ng/mL, phlebotomy to remove a unit of blood is recommended to maintain normal levels. Phlebotomy is repeated until a normal ferritin concentration is achieved. Failure to achieve a normal ferritin concentration within 3 months of starting phlebotomy is a poor prognostic sign. Once the ferritin concentration is below 50 ng/mL, maintenance phlebotomy is performed every 3 to 4 months for men and every 6 to 12 months for women. Symptomatic patients with initial ferritin concentrations of more than 1000 ng/mL should undergo liver biopsy to determine if cirrhosis is present. Patients found to have biochemical abnormalities should undergo phlebotomy weekly until the hematocrit is 75% of the baseline and the ferritin concentration is below 50 ng/mL.

Inheritance Risk

Hereditary hemochromatosis is an autosomal recessive disorder with reduced penetrance. The sibs of an affected individual have a 25% chance of having two mutations. The child of an affected individual will be a carrier and has a 5% risk for having two mutations if both parents are white. Because of the apparently low penetrance of this disease, universal population screening for HFE mutations is not indicated. However, because of the prevalence of the disorder, the uncertainty as to the true penetrance, and the availability of easy and effective treatment, one-time screening of serum transferrin iron saturation and ferritin concentrations in adult white, non-Hispanic men of northern European descent may be justified.

Questions for Small Group Discussion

1. Why do women have a much lower incidence of clinical hemochromatosis?

2. Besides phlebotomy, what dietary interventions would be indicated to prevent iron overload?

3. Discuss the possible reasons for the high prevalence of the Cys282Tyr mutation among whites.


Barton JC. Hemochromatosis and iron overload: from bench to clinic. Am J Med Sci. 2013;346:403–412.

Kanwar P, Kowdley KV. Diagnosis and treatment of hereditary hemochromatosis: an update. Expert Rev Gastroenterol Hepatol. 2013;7:517–530.

Kowdley KV, Bennett RL, Motulsky AG. HFE-associated hereditary hemochromatosis. [Available from]