The C282Y mutation resulting in hereditary hemochromatosis causes both positive and negative effects on the human body.
Hemochromatosis affects the neurological, musculoskeletal, cardiovascular, immune, gastrointestinal, endocrine, and dermatological systems of the body (Hollerer et. al., 2017). The negative effects on these systems manifest as the symptoms of the disease. However, positive effects can also be seen in individuals who are affected. As seen in Figure 1, these positive effects can include a decrease in the proliferation of pathogens, risk of developing ALS, and intramacrophage iron (Hollerer et. al., 2017). The negative effects range from depression to heart diseases to diabetes.
Detection of Hemochromatosis
The manifestation of hemochromatosis occurs more in men in their 40s or 50s than in women. Additionally, individuals with family members who have the disease are more prone to acquire it themselves. A number of clinical tests can be used to detect the presence of hemochromatosis.
Serum Transferrin Saturation
Serum ferritin is the most useful biomarker for estimating systemic iron storage within the body (Kawabata et. al., 2018). Ferritin is a cytoplasmic blood protein that stores iron. Systemic iron overload is suspected if serum ferritin levels exceed 300 ng/mL (Kawabata et. al., 2018). Iron is not the only control of ferritin expression, as inflammatory cytokines, hormones, and oxidative stress at transcriptional and post-transcriptional levels can also control the expression (Watt, 2011). Therefore, serum ferritin levels are typically evaluated with C-reactive proteins as an inflammatory marker (Watt, 2011).
Transferrin saturation (TSAT) is another biomarker used for systemic iron status. TSAT is calculated by dividing the serum iron level by the total iron binding capacity (Kawabata et. al., 2018). Organ damage can result if TSAT exceeds 50%, indicative of iron overload (Kawabata et. al., 2018).
Hemochromatosis can be detected from imaging tests. When the liver accumulates excess iron, the density increases and can be imaged on a computed tomography image. Magnetic resonance imaging (MRI) can be used to detect iron accumulation in organs. The direct iron deposition in the liver can be demonstrated through a liver biopsy, but the procedure is invasive (Kawabata et. al., 2018).
Serum hepcidin levels are directly proportional to iron and inflammation levels. In other words, an increase in serum ferritin levels leads to an increase in serum hepcidin levels (Kawabata et. al., 2018). Increased serum hepcidin levels can be a marker for those suspected of having hemochromatosis.
If hemochromatosis is suspected based on the clinical features, family history, blood test results, and imaging results of a patient, a genetic test can be used to diagnose hemochromatosis. The HFE gene is observed for the presence of the C282Y and H63D mutations.
Treatments of Hemochromatosis
The goal of all of the following treatments is to lower the iron content within the body down to normal levels.
Phlebotomy and Erythrocytapheresis
Early treatment of hemochromatosis can prevent permanent organ damage. Hepatic function, glucose tolerance, cardiac function, thyroid function, and gonadal function are the primary targets of the disease and should be carefully evaluated after diagnosis (Kawabata et. al., 2018). Secondary issues, such as diabetes, cardiomyopathy, hypothyroidism, and hypogonadism can arise as a consequence of this disease. Targeting these issues (highlighted in Figure 2) is essential for treating hemochromatosis.
The standard and most effective treatment for hemochromatosis is phlebotomy, which is the removal of blood using a needle. The standard volume of phlebotomy is 400-500 mL and is modified according to the age, body weight, hemoglobin levels, and comorbidities of a patient (Kawabata et. al., 2018). This treatment should be utilized at appropriate intervals for at least 1 week.
Before each phlebotomy, the hemoglobin levels should be monitored in order to avoid inducing anemia (Kawabata et. al., 2018). In targeting hepatic dysfunction, mild liver disease can occur but is reversible, whereas liver cirrhosis will be permanent. Improvement of diabetes can be difficult because damage to the islet cells results in impaired insulin secretion, which requires insulin therapy as an additional treatment (Kawabata et. al., 2018). Phlebotomy treatments remove other factors and nutrients along with iron, but the use of erythrocytapheresis and erythropoiesis-stimulating agents can counter the loss of other nutrients due to the time period of both treatments (Kawabata et. al., 2018). Similar to phlebotomy, erythrocytapheresis removes iron predominantly as hemoglobin (Adams et. al., 2010). The treatment period is shorter with erythrocytapheresis compared to phlebotomy, although usually resulting in similar depletion of iron.
Iron Chelation Drugs
For patients who are unable to undergo phlebotomy or erythrocytapheresis treatments, iron chelation drugs are used. Although the side effects are toxic, deferoxamine (DFO) and deferasirox (DFX) have been successful in depleting high levels of iron (Adams et. al., 2010). Weekly doses of parenterally administered DFO was as effective as phlebotomy, removing 500 mL of iron from the liver. Orally administered DFX provided similar results after a 24-week dose period (Adams et. al., 2010). DFO and DFX result in the elimination of iron deposits, but additional liver damage also results from the usage.
Proton Pump Inhibitors
Iron absorption can also be regulated through the use of proton pump inhibitors (PPIs). The iron uptake that is mediated by DMT1 requires proton cotransport, which is inhibited by PPIs (Adams et. al., 2010).
Changes in diet can alleviate effects of iron overload. Consumption of red meat, limitation of vitamin C, and no consumption of raw shellfish are examples of dietary recommendations that hemochromatosis patients can follow in order to diminish the rate of iron deposit formation (Adams et. al., 2010).
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Adams, P. C.; Barton, J. C. How I Treat Hemochromatosis. Blood 2010, 116 (3), 317–325.
Hollerer, I.; Bachmann, A.; Muckenthaler, M. U. Pathophysiological Consequences and Benefits of HFE Mutations: 20 Years of Research. Haematologica 2017, 102 (5), 809–817.
Kawabata, H. The Mechanisms of Systemic Iron Homeostasis and Etiology, Diagnosis, and Treatment of Hereditary Hemochromatosis. International Journal of Hematology 2018, 107 (1), 31–43.
Watt, R. K. The Many Faces of the Octahedral Ferritin Protein. Biometals 2011, 24 (3), 489–500.