B-HFE genotype

Analysis for suspected hereditary hemochromatosis (B-HFE genotype)

Hereditary hemochromatosis (HH) is an inherited genetic disorder characterized by increased intestinal iron absorption and excessive iron accumulation in the body. Excess iron is primarily deposited in the liver but may also accumulate in organs such as the pancreas, heart, joints, skin, and pituitary gland. Without treatment, the condition may over time lead to serious complications including liver fibrosis, liver cirrhosis, hepatocellular carcinoma, diabetes mellitus, and cardiac involvement.

B-HFE genotype is a genetic analysis used to determine whether an individual carries mutations in the HFE gene associated with hereditary hemochromatosis. The test is commonly performed in cases of suspected iron overload or elevated iron-related laboratory markers such as ferritin or transferrin saturation.

Hereditary hemochromatosis is most common among individuals of Northern European ancestry and is one of the most common inherited genetic disorders in Sweden. Early detection is important, as treatment may prevent organ damage and reduce the risk of long-term complications.

What is analyzed in the B-HFE genotype test?

The analysis investigates two common HFE gene mutations associated with hereditary hemochromatosis:

• HFE c.845 G>A (C282Y/H282Y mutation)
• HFE c.187 C>G (H63D mutation)

These mutations affect the body's regulation of iron absorption by disrupting the function of the HFE protein and hepcidin-mediated hormonal regulation. This may result in increased intestinal iron absorption and progressive iron accumulation in various organs.

Inheritance and genetics

Hereditary hemochromatosis is inherited in an autosomal recessive manner, meaning that an individual generally needs to inherit a mutated gene variant from both parents to develop the disease.

The HFE gene is located on chromosome 6 and encodes a protein involved in iron homeostasis. The HFE protein influences the production of hepcidin, a hormone that regulates intestinal iron absorption and the release of iron from the body's iron stores. Mutations in the HFE gene may lead to reduced hepcidin regulation and consequently increased iron absorption.

Common mutations associated with hereditary hemochromatosis

The most common genetic alteration associated with hereditary hemochromatosis is the C282Y mutation in the HFE gene. Approximately 90% of individuals with classic hereditary hemochromatosis are homozygous for the C282Y mutation, meaning that the mutation is present on both alleles.

Compound heterozygosity, where an individual carries one C282Y mutation and one H63D mutation, also occurs and may be associated with a milder form of iron overload.

Homozygosity for the H63D mutation may in some cases confer a mildly increased risk of iron accumulation but is generally associated with a lower clinical risk than C282Y homozygosity.

Why is B-HFE genotype analyzed?

The analysis is primarily used in the evaluation of suspected hereditary hemochromatosis or iron overload. Genetic testing may help explain elevated iron-related laboratory values and support further clinical investigation.

B-HFE genotype analysis may be relevant in cases of:

• elevated ferritin
• high transferrin saturation
• suspected iron overload
• unexplained liver abnormalities
• evaluation of hereditary hemochromatosis
• screening of close relatives in confirmed hereditary hemochromatosis
• symptoms such as fatigue, joint pain, or skin hyperpigmentation in combination with elevated iron parameters.

In confirmed hereditary hemochromatosis, screening of close relatives is often recommended due to the hereditary nature of the condition. Siblings of affected individuals are at particularly increased risk of carrying disease-associated variants.

Interpretation of test results

The analysis identifies whether mutations are present in heterozygous or homozygous form and may provide information regarding the genetic risk of hereditary hemochromatosis.

• HFE 845 A/A (homozygous for C282Y/H282Y)
  Consistent with an increased risk of developing hereditary hemochromatosis and clinically significant iron overload.
• HFE 845 G/A and HFE 187 C/G (compound heterozygosity)
  Consistent with an increased risk of developing a milder form of iron overload disorder.
• HFE 187 G/G (homozygous for H63D)
  Consistent with a mildly increased risk of developing hereditary hemochromatosis.

A genetic finding does not necessarily mean that disease will develop. The risk of iron overload is also influenced by factors such as sex, age, alcohol consumption, diet, menstruation, and coexisting medical conditions. Test results should therefore always be interpreted together with iron-related laboratory markers and the overall clinical context.

Symptoms of hereditary hemochromatosis

Symptoms of hereditary hemochromatosis often develop gradually and vary between individuals. Many people remain asymptomatic for years despite elevated iron levels.

Common symptoms may include:

• fatigue and reduced energy levels
• joint pain
• abdominal pain
• liver involvement
• skin hyperpigmentation
• diabetes mellitus
• cardiac involvement
• hormonal disturbances and reduced libido.

Early diagnosis and treatment may reduce the risk of permanent organ damage.

Sample collection for B-HFE genotype

B-HFE genotype is analyzed using a blood sample. Fasting is generally not required prior to genetic testing. Since the analysis evaluates genetic variants, the results are not affected by diet, circadian variation, or temporary fluctuations in iron levels. The sample may therefore be collected at any time of the day.