The different types of hemochromatosis – primary, secondary, juvenile, and neonatal – have different causes and risk factors. First up, primary hemochromatosis is caused by genetic factors, specifically a defect in the HFE gene that dictates how much iron the body absorbs from the diet. Individuals who inherit one faulty HFE gene from each parent, for a total of two copies, are at risk for hemochromatosis. Children with two parents who carry the faulty HFE gene have a one in four chance of inheriting both of those genes, while children who inherit only one faulty HFE gene become a carrier of hemochromatosis but will most likely not develop the disease themselves. It follows that having two faulty HFE genes is the greatest risk factor of primary hemochromatosis.
In addition to having two copies of faulty HFE genes, there are a number of additional factors that increase an individual’s risk of hereditary hemochromatosis. These include sex, ethnicity, age, and family history. Men are more likely to develop primary hemochromatosis than women and tend to notice signs and symptoms at a younger age. Generally speaking, men experience symptoms between the ages of 30 and 50, while women only experience symptoms between the ages of 50 and 60. This age difference between genders is due to the fact that women experience blood loss from menstruation and childbirth prior to menopause, so the excess iron is flushed out from the body through vaginal bleeding.
In terms of ethnicity, white people of northern European descent are most likely to develop hereditary hemochromatosis, while African Americans, Asians, American Indians, and Hispanics are at a lower risk. As for age, the elderly population is at a higher risk than the younger generation. Lastly, family history plays an important role in hemochromatosis in that individuals who have first-degree relatives with hemochromatosis are far more likely to develop the disease themselves. In this context, first-degree relatives refer to parents and siblings.
While primary hemochromatosis involves mutations of the HFE gene, specifically C282Y and H63D, juvenile hemochromatosis involves mutations of the HJV or HAMP genes. As for neonatal hemochromatosis, the cause of this subtype is largely unknown, though it is believed to be related to a severe form of fetal liver disease. In addition to type I and type II, which refers to primary hemochromatosis and juvenile hemochromatosis respectively, there’s also type III and type IV. Type III involves mutations of the TFR2 gene, while type IV involves mutations of the SLC40A1 gene and is sometimes referred to as ferroportin disease. Each of these various types of hereditary hemochromatosis is classified as non-HFE hemochromatosis since mutations of the HFE gene do not explain most cases.
Secondary hemochromatosis is not caused by genetic factors but rather by other conditions, namely chronic liver diseases, atransferrinemia and aceruloplasminemia, certain types of anemia, long-term kidney dialysis, iron injections or oral iron pills, and blood transfusions. Chronic liver diseases may include chronic hepatitis C infection, alcoholic liver disease, and nonalcoholic steatohepatitis, while certain types of anemia may include thalassemias and sideroblastic anemia. Risk factors that are specific to secondary hemochromatosis include alcoholism, taking dietary supplements with iron or vitamin C, and having a family history of heart disease, diabetes, erectile dysfunction, arthritis, or liver disease.