What is Hereditary Hemochromatosis?
Hereditary hemochromatosis is a disorder characterized by the dysfunction of iron absorption and an accumulation of iron stores in the body. It can be broken down into subtypes based on the mutation causing the disease; some like type II have an acute symptomatic juvenile onset while others have milder effects and occur later in life (Bacon 2011)
How common is it?
The most prevalent subtype of hereditary hemochromatosis is type I, accounting for more than 80% of all documented cases (Bacon, 2011). In the United States it is estimated that between 1 in 200 to 1 in 500 people have hereditary hemochromatosis (Steinberg 2001). While the prevalence of mutation is high, it is not fully penetrant, meaning only a small percentage of these people, less then 5% will develop severe symptoms due to the disease (Beutler 2003).
What are the symptoms?
The most common symptoms of disease are joint pain/arthritis, fatigue, diabetes, impotence, cirrhosis or hepatomegaly (Allen 2010). Interestingly, symptoms of hereditary hemochromatosis do not typically manifest until adulthood, around the age of 50 as iron progressively builds up in the body until iron overload, or toxic amounts of iron occur (Allen 2010). Additionally, men are more likely to develop symptoms due to hereditary hemochromatosis then women as women prior to menopause lose iron stores through their monthly menses (Steinberg 2001).
How is it diagnosed?
Since symptoms of hereditary hemochromatosis are non-specific, diagnosis typically begins based on high serum levels of two iron storage proteins, transferrin which holds iron in the blood, and ferritin, which stores iron in the body (Trieβ 2012). Subsequent genetic screening then can confirm hereditary hemochromatosis and the subtype and liver biopsies can be used to determine the level of iron stores and liver damage in a patient (Trieβ 2012).
What causes it?
The homozygous mutation Cys282Tyr of the hemochromatosis protein (HFE) is the cause of hereditary hemochromatosis in the majority of type one patients (Bacon 2011). HFE serves as a signaling molecule that stabilizes the ALK3 receptor which when bound by BMP promotes expression of hepcidin, a crucial iron sensing molecule (Wu 2014). In mutated HFE this signaling pathway does not occur and hepcidin levels are very low (Rishi 2015). Hepcidin is responsible for controlling the amount of ferroportin receptors on the lining of the stomach, macrophages and hepatic cells by inducing the internalization and degradation of the receptor (Nemeth 2014) So, when HFE is mutated, iron is continuously being absorbed into cells even if it is not needed. This is what leads to iron overload and the deposition of iron stores that causes symptoms (Nemeth 2014). Additionally hepcidin binds to the transferrin receptor to transport transferrin (iron carrying molecule) into the cells (Rishi 2015).
How is it treated?
Early diagnosis is the best way to prevent iron stores from becoming too high. However, when iron overload occurs the treatment is periodic therapeutic phlebotomy, this reduces iron levels which when done consistently, typically twice a week over two to three years until iron levels are normalized (Bacon 2011)