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Am Fam Physician. 2021;104(2):263-270

Patient information: A handout on this topic is available at https://familydoctor.org/condition/hereditary-hemochromatosis.

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Hereditary hemochromatosis is an autosomal recessive disorder that disrupts iron homeostasis, resulting in systemic iron overload. It is the most common inherited disorder among people of northern European ancestry. Despite the high prevalence of the gene mutation, there is a low and variable clinical penetrance. The deposition of excess iron into parenchymal cells leads to cellular dysfunction and the clinical manifestations of the disease. The liver, pancreas, joints, heart, skin, and pituitary gland are the most commonly involved organs. Hereditary hemochromatosis is usually diagnosed in the 40s or 50s. Women are often diagnosed later than men, likely because of menstrual blood loss. There is no typical presentation or pathognomonic signs and symptoms of hereditary hemochromatosis. Because of increased awareness and earlier diagnosis, the end-organ damage secondary to iron overload is not often seen in clinical practice. A common initial presentation is an asymptomatic patient with mildly elevated liver enzymes who is subsequently found to have elevated serum ferritin and transferrin saturation. Ferritin levels greater than 300 ng per mL for men and 200 ng per mL for women and transferrin saturations greater than 45% are highly suggestive of hereditary hemochromatosis. Phlebotomy is the mainstay of treatment and can help improve heart function, reduce abnormal skin pigmentation, and lessen the risk of liver complications. Liver transplantation may be considered in select patients. Individuals with hereditary hemochromatosis have an increased risk of hepatocellular carcinoma and colorectal and breast cancers. Genetic testing for the hereditary hemochromatosis genes should be offered after 18 years of age to first-degree relatives of patients with the condition.

Hereditary hemochromatosis is an autosomal recessive condition that results in systemic iron overload due to a deficiency in hepcidin, an iron regulatory protein.1,2 The body's iron stores are primarily regulated by controlling intestinal absorption. Other than menses and shedding of senescent cells, there are no physiologic mechanisms of iron excretion. Deposition of excess iron into parenchymal cells leads to tissue damage and ultimately organ failure. The liver, pancreas, joints, heart, skin, and pituitary glands are the most commonly involved organs.3,4 This article summarizes the best available patient-oriented evidence regarding hereditary hemochromatosis.

RecommendationSponsoring organization
Do not order HFE genetic testing for a patient without iron overload or a family history of HFE-associated hereditary hemochromatosis.American College of Medical Genetics and Genomics

Epidemiology

  • There are four types of hereditary hemochromatosis, which are categorized by the specific gene mutation involved (Table 1).1,5,6

  • Homozygous C282Y and heterozygous C282Y/H63D mutations of the HFE gene (iron regulatory protein) on chromosome 6 are responsible for up to 95% of hereditary hemochromatosis cases (type 1).1,3

  • Hereditary hemochromatosis types 2 to 4 comprise the small percentage of remaining cases and are caused by non- HFE mutations.1,5

  • Hereditary hemochromatosis is the most common inherited disorder among people of northern European ancestry.1,3 The United States, Europe, and Australia have a similar disease prevalence of one case per 200 to 400 people, with the highest prevalence in those of Irish and Scandinavian ancestry.1,3,5

  • The hereditary hemochromatosis mutation is rare in people of Asian, African, Hispanic, and Pacific Islander ancestry.7

  • Despite the high prevalence of the gene mutation, there is a low and variable clinical penetrance, with up to 25% of people with C282Y homozygosity being clinically asymptomatic.4,8

  • The clinical manifestations of iron overload typically develop in the 40s or 50s.1

  • The disease is equally prevalent in men and women. Women typically present later in life when they are postmenopausal, likely because of menstrual blood loss delaying the development of symptomatic iron overload.1,3

ClassificationGenes involved/inheritanceClinical manifestationsPrevalence
Type 1A hereditary hemochromatosis (homozygote)HFE gene C282Y, autosomal recessiveArthropathy, skin pigmentation, diabetes mellitus, endocrine dysfunction, cardiomyopathy, hypogonadismMost common worldwide
Type 1B (compound heterozygote)HFE gene H63D, autosomal recessiveArthropathy, skin pigmentation, diabetes, endocrine dysfunction, cardiomyopathy, hypogonadism
Type 1CHFE gene S65C, autosomal recessivePossible elevations of serum iron/ferritin, no evidence of tissue iron deposition
Type 2 (juvenile hereditary hemochromatosis)HJV and HAMP gene mutation, autosomal recessiveEarly onset (< 30 years of age), hypogonadism, cardiomyopathyRare
Type 3TFR2 gene mutation, autosomal recessiveArthropathy, skin pigmentation, diabetes, endocrine dysfunction, cardiomyopathy, hypogonadismRare, most common in Japan and Brazil
Type 4SLC40A1 gene mutation, autosomal dominantIron deposition in the spleen, anemia, fatigue, joint painRare

Screening and Prevention

  • Genetic testing for the C282Y and H63D mutations of the HFE gene is recommended for first-degree relatives of people with hereditary hemochromatosis; screening does not need to begin until 18 years of age because clinical manifestations are rare before this age.1,3

  • Population-level genetic testing or laboratory screening for hereditary hemochromatosis is not recommended because of the cost and the variable prevalence and incomplete penetrance of the C282Y mutation.1,35,9

Diagnosis

  • The presentation of hereditary hemochromatosis varies, with biochemical expression occurring first and clinical expression occurring in later stages of disease.3,8 Table 2 summarizes the stages of hereditary hemochromatosis.1,2,4,5

  • The differential diagnosis includes other causes of secondary iron overload via excess absorption and organ deposition of iron (Table 3).15,10

  • Hereditary hemochromatosis should be considered in the differential diagnosis of patients with elevated liver enzymes and abnormal iron study results.24,11

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