Hemochromatosis results from a relatively common inherited genetic mutation in European populations. Once thought to be a single disease entity it is now known to be an iron-storage disorder with genetic heterogeneity but with a final common metabolic pathway resulting in inappropriately low production of the hormone hepcidin. This leads to an increase in intestinal iron absorption and the deposition of excessive amounts of iron in parenchymal cells with eventual tissue damage and organ failure. Thus, the term hemochromatosis now refers to a group of genetic diseases that predispose to iron overload, potentially leading to fibrosis and organ failure. Cirrhosis of the liver, diabetes mellitus, arthritis, cardiomyopathy, and hypogonadotropic hypogonadism are the major clinical manifestations.
The following terminology is widely accepted.
Hereditary hemochromatosis is most often caused by a mutant gene, termed HFE, which is tightly linked to the HLA-A locus on chromosome 6p. Persons who are homozygous for the mutation are at increased risk of iron overload and account for 80–90% of clinical hereditary hemochromatosis in persons of northern European descent. In such subjects, the presence of hepatic fibrosis, cirrhosis, arthropathy, or hepatocellular carcinoma constitutes iron overload–related disease. Rarer forms of non-HFE hemochromatosis are caused by mutations in other genes involved in iron metabolism (Table 407-1). The disease can be recognized during its early stages when iron overload and organ damage are minimal. At this stage, the disease is best referred to as early hemochromatosis or precirrhotic hemochromatosis.
Secondary iron overload occurs as a result of an iron-loading anemia, such as thalassemia or sideroblastic anemia, in which erythropoiesis is increased but ineffective. In the acquired iron-loading disorders, massive iron deposits in parenchymal tissues can lead to the same clinical and pathologic features as in hemochromatosis.
TABLE 407-1Classification of Iron Overload States |Favorite Table|Download (.pdf) TABLE 407-1 Classification of Iron Overload States
|Hereditary Hemochromatosis |
|Hemochromatosis, HFE-related (type 1) |
| C282Y homozygosity |
| C282Y/H63D compound heterozygosity |
|Hemochromatosis, non-HFE-related |
| Juvenile hemochromatosis (type 2A) (hemojuvelin mutations) |
| Juvenile hemochromatosis (type 2B) (hepcidin mutation) |
| Mutated transferrin receptor 2, TFR2 (type 3) |
| Mutated ferroportin 1 gene, SLC11A3 (type 4) |
|Acquired Iron Overload |
Chronic hemolytic anemias
Transfusional and parenteral iron overload
Dietary iron overload
Chronic liver disease
Alcoholic cirrhosis, especially when advanced
Porphyria cutanea tarda
Dysmetabolic iron overload syndrome
|Iron overload in sub-Saharan Africa |
|Neonatal iron overload |
|Congenital atransferrinemia |
Although HFE-associated hemochromatosis mutations are common, the prevalence varies in different ethnic groups. It is most common in populations of northern European extraction in whom ~1 in 10 persons are heterozygous carriers and 0.3–0.5% are homozygotes. However, expression of the disease is variable and modified by several factors, especially alcohol consumption, dietary iron intake, blood loss associated with menstruation and pregnancy, ...