A genetic test for hereditary hemochromatosis (HH) is used to diagnose or determine the risk for this common inherited disorder. Hemochromatosis is an iron overload condition that, if left unmanaged, can lead to serious health complications. The genetic test looks for changes in a person’s DNA that interfere with the body’s ability to regulate iron absorption from the diet. This test provides information about a person’s genetic predisposition, which is then paired with blood iron level measurements to establish a diagnosis.
Understanding Hemochromatosis
Hereditary hemochromatosis is a genetic disorder where the body absorbs an excessive amount of iron from food, resulting in a progressive buildup of iron stores in tissues and organs. Humans lack an efficient mechanism to excrete excess iron, so this continuous over-absorption leads to iron overload. This excess iron can become toxic and disrupt the normal function of several organs over time.
Iron typically accumulates in organs like the liver, heart, and pancreas, potentially causing tissue damage. Untreated iron overload can lead to severe conditions such as liver cirrhosis, heart failure, arthritis, and diabetes. The most common form, Type 1 or HFE-related hemochromatosis, is an autosomal recessive disorder. This means an individual must inherit a mutated gene copy from each parent to be at risk for developing the condition.
Genetic Markers Identified by the Test
The genetic test primarily focuses on mutations within the HFE gene, which is responsible for the majority of hemochromatosis cases. The HFE gene provides instructions for making a protein that helps regulate the amount of iron absorbed. A mutation impairs this regulatory function, leading to excessive iron uptake.
The test specifically looks for two main mutations: C282Y and H63D, which are the most common variants in people of Northern European descent. The C282Y mutation is the most significant because it prevents the HFE protein from properly reaching the cell surface. This loss of function leads to the highest risk of iron overload.
The H63D mutation is less severe in its effect on iron regulation, and rarely leads to significant iron overload alone. However, the combination of one copy of C282Y and one copy of H63D can also increase the risk for iron accumulation.
When Testing is Recommended and How It Is Performed
Genetic testing is recommended after initial blood work suggests a potential problem with iron levels. The test is ordered for individuals who show abnormal iron indices, specifically an elevated serum ferritin level (stored iron) and a high transferrin saturation percentage (iron carried in the blood). A transferrin saturation level greater than 45% can trigger further investigation.
Testing is also indicated when a person presents with unexplained symptoms associated with early iron overload, such as chronic fatigue, joint pain, or liver issues. Additionally, if a first-degree relative (parent or sibling) has been diagnosed with HFE-related hemochromatosis, the test is recommended to screen for the genetic variants.
The procedure is straightforward, requiring only a blood draw or, in some cases, a cheek swab. The sample is sent to a lab where the DNA is analyzed for the C282Y and H63D mutations in the HFE gene. Since the test analyzes DNA, it only needs to be performed once.
Interpreting the Genotype Results
The results of the genetic test are reported as a genotype, which indicates the combination of HFE gene variants an individual carries. The most significant result is C282Y/C282Y, known as homozygous, where two copies of the C282Y mutation are present. This genotype carries the highest risk for developing clinical iron overload, although a significant number of people with this result never develop symptoms or organ damage.
A person with one copy of the C282Y variant and one normal copy, known as heterozygous, is considered a carrier and usually has a very low risk of developing iron overload. Another important result is compound heterozygous, C282Y/H63D, where an individual has one copy of each of the two main mutations. This combination presents a moderate risk, but it is rare for these individuals to accumulate enough iron to cause organ damage.
A positive genetic test result, or a high-risk genotype, does not automatically mean a person has the disease. The diagnosis of clinical hemochromatosis requires confirmation through iron panel blood tests, which show actual iron accumulation or evidence of iron overload in the organs. The genotype only indicates the genetic predisposition, and follow-up iron studies are necessary to determine the actual disease status.
Management Following a Positive Diagnosis
Once a diagnosis of clinical iron overload is confirmed, the primary management strategy is therapeutic phlebotomy, which involves removing blood. This process effectively removes excess iron from the body, as iron is stored primarily in red blood cells. Initially, phlebotomies may be performed frequently, such as once or twice a week, until iron stores are depleted.
The goal of this phase is to reduce serum ferritin levels to a target range, often below 50 micrograms per liter. After the excess iron is removed, a maintenance phase begins, where phlebotomies are performed less often, typically four to eight times a year, to keep iron levels within the healthy range. Regular monitoring of serum ferritin levels determines the necessary frequency of maintenance phlebotomies.
Patients are also advised on lifestyle adjustments to prevent further iron accumulation. This includes avoiding iron supplements and multivitamins that contain iron. While a strict low-iron diet is not required, it is recommended to moderate red meat consumption and avoid raw seafood due to an increased infection risk associated with high iron levels.