Description

Hereditary hemochromatosis (HH) is a common genetic disease with autosomal recessive inheritance that results in iron overload and subsequent deposition into various tissues.

• HH includes at least four types of iron overload conditions, which involve gene mutations that alter iron metabolism.
• There is no mechanism to excrete excess iron, so the surplus is stored in tissue, including the liver, pancreas, and heart, eventually resulting in severe damage to the affected organ(s).
• Patients are often asymptomatic, but late effects may include diabetes, liver cirrhosis, hypermelanotic pigmentation of the skin, cardiac issues, and other complications.
• Synonym(s): bronze diabetes; Troisier-Hanot-Chauffard syndrome

Epidemiology

Incidence

• Predominant age: Metabolic abnormality is congenital, but symptoms typically present between the 3rd and 5th decades for types 1, 3, and 4 HH; juvenile type 2 HH typically presents between the 1st and 3rd decades of life, and neonatal presentation is exceedingly rare.
• Predominant sex: Gene frequency is equal between male and female, although clinical signs are more frequent in men.

Prevalence

• Prevalence in the United States for carrying an HFE gene mutation (type 1 HH) is 5.4% for the C282Y gene and 13.5% for the H63D gene; prevalence for homozygosity is 0.3% for C282Y and 1.9% for H63D (1).
• Type 1 HH accounts for >90% of HH cases in the United States and primarily occurs in people of northern European descent; ~1 in 200 white adults in the United States are C282Y homozygous (1).

Pediatric Considerations
Juvenile (type 2 HH) is rare but can present in young patients (between 1st and 3rd decades of life) with hypogonadism and cardiomyopathy.

Etiology and Pathophysiology

• Type 1 HH is caused by mutations in the HFE gene (most frequently C282Y and/or H63D), and it is the most common form of HH overall. Other variations include type 2 HH which is caused by mutations in either the HJV or HAMP gene, type 3 HH by mutations in the TFR2 gene, and type 4 HH by mutations in the SLC11A3 gene.
• Types 1 to 3 HH involve a deficiency in an iron-regulating hormone named hepcidin, which causes increased intestinal absorption of iron through excessive expression of ferroportin (a transmembrane protein that transports iron out of the cell and into the bloodstream).
• Type 4 HH is caused by an insensitivity of ferroportin to hepcidin (4a) or an inactivity of ferroportin itself (4b); the latter leads to iron accumulation within mesenchymal tissue.
• Other rare types of HH exist as a result of different gene mutations.
• Increased plasma iron and transferrin saturation (TS) leads to elevated levels of unbound iron, which are then absorbed into various tissue, eventually causing organ dysfunction.

Genetics

• Genetically, heterogeneous disorder of iron overload; types 1, 2, and 3 HH are autosomal recessive; type 4 HH is autosomal dominant.
• Biochemical penetrance is incomplete and expressivity is variable; in type 1 HH the penetrance for developing clinically significant iron overload is rare but approximately 75% of men with type 1 HH and 50% of women will have an increase in TS (with or without elevated serum ferritin [SF]) (2).
• Factors contributing to variable expressivity include different mutations in the same gene, mitigating or exacerbating genes, and environmental factors.

Risk Factors

• Family history
• White men between the ages of 30 and 50 years (particularly for HFE-related HH)
• Loss of blood, such as that which occurs during menstruation and pregnancy, delays the onset of symptoms in women.
• Alcohol consumption, because it increases the absorption of iron and synergistically damages the liver along with the oxidative effects of iron.

General Prevention

• First-degree relatives of those with HH should be screened; typically, with fasting TS and ferritin levels.
• Children of a diagnosed parent, HFE testing of the other parent is recommended with no further testing required if the results are normal.

Commonly Associated Conditions

See “Complications.”