The HFE gene regulates the body’s iron levels. It provides instructions for producing a protein found on liver and intestinal cells. This protein interacts with other proteins to sense iron levels. When functioning properly, it ensures the body absorbs appropriate iron from dietary sources.
Understanding the HFE Mutation
The HFE gene encodes a protein that regulates iron absorption by influencing hepcidin, a liver hormone controlling iron uptake and release. This protein interacts with transferrin receptor 1 to maintain balanced iron levels.
The most common mutations in the HFE gene are C282Y and H63D. The C282Y mutation involves a change at position 282 where the amino acid cysteine is replaced by tyrosine, which prevents the HFE protein from reaching the cell surface effectively. The H63D mutation, where histidine is replaced by aspartic acid at position 63, alters the protein’s three-dimensional shape, impairing its function. Both mutations disrupt the HFE protein’s interaction with transferrin receptor 1 and other proteins, leading to dysregulated iron absorption. Individuals can inherit one or two copies of these mutations; inheriting two copies of the C282Y mutation or one C282Y and one H63D mutation can lead to iron overload.
The Link to Iron Overload and Hemochromatosis
When the HFE protein’s function is impaired due to mutations, the body absorbs excessive iron from the diet. This leads to a condition called hereditary hemochromatosis, where iron chronically accumulates in various organs. The body lacks an efficient mechanism to excrete excess iron, causing it to build up in tissues and organs, which can lead to dysfunction and damage.
The excess iron can deposit in the liver, potentially leading to scarring (cirrhosis) or liver cancer. It can also accumulate in the heart, causing irregular heartbeats (arrhythmia) or heart failure. The pancreas may also be affected, potentially leading to diabetes mellitus.
Common symptoms of hemochromatosis, which appear between the ages of 30 and 60, arise from this iron buildup. These symptoms include persistent fatigue, joint pain, abdominal pain, and weakness. If left untreated, the progressive iron accumulation can result in long-term organ damage, impacting overall health and potentially reducing life expectancy.
Diagnosis and Management Approaches
Diagnosing hemochromatosis begins with blood tests that indicate iron overload. Key tests include serum ferritin, which measures the amount of iron stored in the liver, and transferrin saturation, which indicates how much iron in the blood is bound to the protein transferrin. A transferrin saturation level greater than 45% and elevated serum ferritin levels are considered high. If these blood tests suggest iron overload, specific genetic testing for HFE gene mutations is performed to confirm a diagnosis of hereditary hemochromatosis.
The primary treatment for hemochromatosis is therapeutic phlebotomy, involving regular blood removal, similar to blood donation. This process aims to reduce iron levels to a healthy range. Initially, a pint of blood may be removed once or twice a week, with the frequency adjusted based on the individual’s iron levels and overall health. The goal is to lower serum ferritin to 50-100 µg/L.
Other management strategies complement phlebotomy. Dietary considerations include avoiding iron supplements and multivitamins containing iron, as these can increase iron levels. Limiting or avoiding alcohol is also advised, especially for individuals with liver damage, because alcohol can exacerbate liver problems in those with hemochromatosis. Additionally, individuals are advised to avoid raw fish and shellfish due to the risk of infections from certain bacteria in people with liver disease.
Genetic Implications for Families
HFE mutations are inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of a mutated HFE gene—one from each parent—to be at risk for developing hemochromatosis. Parents of an affected individual carry one copy of the mutated gene but do not show symptoms. The likelihood of siblings inheriting both mutated copies is about 25%.
Offspring of an individual with hemochromatosis inherit one mutant HFE allele from the affected parent. The risk of their children having hemochromatosis depends on whether the other parent is also a carrier; if the other parent is a carrier, the risk for the offspring is around 5%. However, not everyone with the genetic mutations will develop the disease, as there is incomplete penetrance.
Family screening and genetic counseling are recommended for at-risk relatives, such as parents, siblings, and children of a diagnosed individual. Knowing one’s genetic status allows for early monitoring of iron levels and timely intervention if iron overload begins to develop. Early diagnosis and treatment can prevent or slow organ damage and improve long-term health outcomes.