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Hereditary hemochromatosis (HHC) is a hereditary multisystem disorder that results in iron overload and subsequent deposition into various tissues.
- HHC 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 early clinical features often include fatigue, malaise, arthralgia, and decreased libido.
- Late effects may include diabetes, liver cirrhosis, hypermelanotic pigmentation of the skin, porphyria cutanea tarda, cardiomyopathy, and cardiac arrhythmias.
- Cirrhosis may ultimately result in hepatocellular carcinoma.
- Synonym(s): bronze diabetes; Troisier-Hanot-Chauffard syndrome
- Predominant age: Metabolic abnormality is congenital, but symptoms typically present between the 3rd and 5th decades for HHC types 1, 3, and 4; type 2 juvenile hemochromatosis 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 in the United States for carrying an HFE gene mutation (type 1 HHC) 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 accounts for >90% of HHC 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 (1,2).
Juvenile (type 2) HHC is rare but can present in young patients (between 1st and 3rd decades of life) with hypogonadism and cardiomyopathy.
Etiology and Pathophysiology
- HHC type 1 is caused by mutations in the HFE gene (most commonly C282Y and/or H63D), type 2 by mutations in either the HJV or HAMP gene, type 3 by mutations in the TFR2 gene, and type 4 by mutations in the SLC11A3 gene.
- Types 1 to 3 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 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 HHC exist as a result of different gene mutations.
- Increased plasma iron and transferrin saturation leads to elevated levels of unbound iron which are then absorbed into various tissue, eventually causing organ dysfunction.
- Genetically heterogeneous disorder of iron overload; types 1, 2, and 3 are autosomal recessive; type 4 is autosomal dominant.
- Penetrance is incomplete; expressivity is variable; ~13.5% disease penetrance of C282Y homozygosity (CI 13.5%) (3)
- Factors contributing to variable expressivity include different mutations in the same gene, mitigating or exacerbating genes, and environmental factors.
- Family history
- White men between the ages of 30 and 50 years (particularly for HFE-related HHC)
- Alcohol consumption, as it increases the absorption of iron and synergistically damages the liver along with the oxidative effects of iron.
- Loss of blood, such as that which occurs during menstruation and pregnancy, delays the onset of symptoms in women.
First degree relatives of those with HHC should be screened; typically, with fasting transferrin saturation and ferritin levels
Commonly Associated Conditions