Gene test interpretation: HFE (hereditary hemochromatosis gene)

INTRODUCTION — This monograph summarizes the interpretation of genetic testing for HFE, the main gene associated with hereditary iron overload. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the care of the tested person. These subjects are discussed separately [1]. (See 'UpToDate topics' below.)

OVERVIEW

How to read the report — The checklist provides important caveats for genetic testing (table 1). Any result obtained for research or by direct-to-consumer testing that has clinical implications for the tested individual or their relatives should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or other nationally certified laboratory with verified patient identification.

Two variants in HFE have been associated with most cases of hereditary hemochromatosis (HH). Both are point mutations. Testing for C282Y, the most common variant, is standard; many laboratories test for H63D.

●C282Y – Substitution of tyrosine (Y) for cysteine (C) at amino acid 282 (also written p.Cys282Tyr) [2]. In the DNA, guanine (G) is replaced by adenine (A) at nucleotide 845 (written c.G845A or c.845G>A).

●H63D – Substitution of aspartic acid (D) for histidine (H) at amino acid 63 (also written p.His63Asp). In the DNA, cytosine (C) is replaced by G at nucleotide 187 (written c.C187G or c.187C>G).

Some cases of iron overload are associated with rare variants such as HFE gene deletions or variants affecting other iron regulatory genes (table 2). Testing for these may be indicated in suspected or known juvenile hemochromatosis. (See "HFE and other hemochromatosis genes", section on 'Rare HFE variants' and "HFE and other hemochromatosis genes", section on 'Non-HFE hemochromatosis'.)

Disease associations

Iron overload — The diagnosis of iron overload is made using iron studies and other evaluations to quantify organ iron deposition. Genetic testing is an adjunct that provides additional information about the cause of iron overload and facilitates identification of potentially affected relatives, but genetic testing alone cannot determine if an individual has iron overload or requires treatment.

Conversely, individuals with iron overload should receive appropriate treatment regardless of genetic test results, and first-degree relatives of an individual with iron overload not due to transfusions generally should be screened with iron studies regardless of their genetic test results. (See 'Further evaluation and management' below.)

HFE-related hemochromatosis is an autosomal recessive disorder with low penetrance (terms are defined in the glossary (table 3)). A pathogenic (disease-causing) variant affecting both HFE alleles (one from each parent) is generally required for iron overload to develop (table 4). However, the majority of individuals with biallelic HFE variants will not develop iron overload.

●Homozygosity for the C282Y variant (C282Y/C282Y) accounts for 80 to 100 percent of hemochromatosis cases. Compound heterozygosity with H63D (C282Y/H63D) accounts for most of the remainder; however, most experts do not consider C282Y/H63D to be causal, since other risk factors are generally required for iron overload to occur [2,3].

•The likelihood of iron overload in C282Y/C282Y homozygotes has been cited at 1 percent in females to 28 percent in males [4]. Most C282Y homozygotes will have abnormal iron studies (increased iron, transferrin saturation [TSAT], and ferritin) but will not develop a clinically relevant iron overload. Development of iron overload is age-related (generally after menopause in females; after age 40 in males). (See "HFE and other hemochromatosis genes", section on 'Likelihood of developing iron overload'.)

•C282Y/H63D confers an even lower risk of iron overload than C282Y/C282Y. Indeed iron overload is typically mild and develops only if other risk factors are present.

•Less common forms of hemochromatosis with higher penetrance and usually a younger age of onset may be caused by variants in other iron regulatory genes (table 2). (See "HFE and other hemochromatosis genes", section on 'Non-HFE hemochromatosis'.)

•Iron overload may also be caused or exacerbated by liver disease (alcoholic or other), thalassemia or other disorder of ineffective erythropoiesis, or blood transfusions (typically more than 10 to 20 units of red blood cells [RBCs]). (See "Approach to the patient with suspected iron overload", section on 'Causes of iron overload'.)

●Homozygosity for H63D (H63D/H63D) does not confer an increased risk of iron overload unless other risk factors are present.

●Heterozygosity (C282Y/wild-type or H63D/wild-type) is not associated with an increased risk of iron overload relative to the general population.

Organ damage — For those with iron overload, the magnitude of iron burden may progress over time. Other factors can influence the rate of iron accumulation. As examples, iron burden is reduced by regular menstrual periods and pregnancy; iron uptake is accelerated by liver disease or consumption of excess alcohol (generally, >10 drinks per week in females or >15 drinks per week in males).

Organ injury is generally of greatest concern as the total body iron burden increases over decades. However, organ injury can occur with lower iron burden. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Clinical manifestations'.)

The following may be seen:

●Liver injury and cirrhosis

●Cardiac toxicity

●Diabetes

●Other endocrinopathies including hypopituitarism, hypogonadism, and hypothyroidism

●Arthropathy

●Skin pigmentation (bronze skin)

●Increased susceptibility to infection

If untreated, severe or even fatal complications such as cirrhosis, hepatocellular cancer, heart failure, or arrhythmias may develop. Removal of iron with regular phlebotomy can prevent (and in some cases reverse) these complications. (See 'Further evaluation and management' below.)

FURTHER EVALUATION AND MANAGEMENT

People not previously diagnosed with iron overload — Iron studies (serum iron, ferritin, transferrin or total iron binding capacity [TIBC], and transferrin saturation [TSAT]) are the first step for determining whether iron overload is present.

●We obtain iron studies for individuals with homozygosity for HFE C282Y (C282Y/C282Y) or compound heterozygosity with H63D (C282Y/H63D) (algorithm 1).

●For individuals with negative testing for HFE C282Y or another genotype such as homozygosity for H63D or heterozygosity for C282Y or H63D, we only obtain iron studies if there are other reasons to do so, such as a family history of hereditary hemochromatosis (HH) or unexplained liver disease, heart failure, endocrine disorders, or arthropathy (algorithm 1). (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Genotype-phenotype correlations' and "Management and prognosis of hereditary hemochromatosis", section on 'Heterozygous individuals'.)

For children and adolescents, testing is usually deferred until adulthood unless there is a positive family history of early-onset iron overload or another cause of iron overload such as multiple transfusions or thalassemia. (See 'Iron overload' above.)

Typically, individuals being evaluated for iron overload also have a complete blood count (CBC) and liver function tests. Discussion of alcohol intake and other causes of liver disease may be indicated.

Increased iron stores are indicated by a high serum ferritin (>300 ng/mL in males or postmenopausal females; >200 ng/mL in premenopausal females) and high TSAT (>45 percent in males; >55 percent in females); the thresholds vary in different guidelines [5-7]. Increased hepatic transaminases may be seen but are nonspecific.

Subsequent testing is individualized (algorithm 1):

●Repeat iron studies (annually or less frequently) may be reasonable for younger individuals (premenopausal females or males <40 years) or those with normal or borderline values who remain at risk based on family history or genotype.

●Liver and/or cardiac magnetic resonance imaging (MRI) is often appropriate for those with a ferritin >1000 ng/mL.

●Liver biopsy is generally used when other diagnoses are being considered that require histologic evaluation.

●For patients with advanced fibrosis, screening for hepatocellular cancer (HCC) is indicated. (See "Surveillance for hepatocellular carcinoma in adults", section on 'Our approach to surveillance'.)

This testing may be performed by the individual's primary clinician or by a specialist such as a hematologist, hepatologist, or genetics expert. (See 'Locating a genetics expert' below.)

The rationale for testing and interpretation of the results are discussed separately. (See "Approach to the patient with suspected iron overload", section on 'Sequence and interpretation of testing' and "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Diagnostic evaluation'.)

People known to have iron overload — Individuals with known iron overload require treatment regardless of their HFE genotype. The goal is to prevent organ injury or reverse it if possible.

Phlebotomy is the mainstay of treatment. Regular phlebotomies over time can completely deplete the excess iron and can prevent, or in some cases reverse, organ damage and other complications. The indications for phlebotomy, timing of initiation, pace, and number of phlebotomies depend on the degree of iron excess. Following removal of excess iron, maintenance phlebotomies are generally continued throughout adulthood. (See "Management and prognosis of hereditary hemochromatosis", section on 'Phlebotomy'.)

HFE testing may be helpful in identifying a genetic contribution to iron overload, with the following potential implications for those who test positive:

●Lifelong need to monitor iron burden and to perform phlebotomies when indicated

●Testing of at-risk relatives

●Motivation to avoid excess alcohol or other hepatotoxins

Phlebotomy and monitoring is often done by a hematologist, but the primary clinician can also manage therapy if they have the appropriate expertise and resources. Details of the procedure and other subjects such as dietary modifications and blood donation by people with hemochromatosis are discussed separately. (See "Management and prognosis of hereditary hemochromatosis".)

For those with documented HFE C282Y homozygosity or C282Y/H63D compound heterozygosity, their first-degree relatives should be informed and, in many cases, tested either by the relative's primary clinician or a genetics expert. (See 'At-risk relatives' below and 'Locating a genetics expert' below.)

For individuals with unexplained iron overload (not due to thalassemia or transfusions) who test negative for HFE C282Y or H63D or who are found to be heterozygous, it may be appropriate to refer to a genetics expert for more advanced testing of other HFE and/or non-HFE variants. This is especially useful in rare cases of hemochromatosis in a child, adolescent, or young adult. (See "HFE and other hemochromatosis genes", section on 'Juvenile hemochromatosis'.)

At-risk relatives — First-degree relatives of an individual with HFE C282Y are at risk for inheriting the variant. This includes relatives of a tested individual who is C282Y/C282Y homozygous, C282Y/H63D compound heterozygous, or C282Y heterozygous.

●First-degree relatives of a heterozygote have a 50 percent chance of carrying (or inheriting) the variant. Because C282Y is relatively common in certain populations, it is also possible for the other parent to carry the variant and for some of these relatives to be homozygous or compound heterozygous [8].

●Offspring of a C282Y homozygote or compound heterozygote (C282Y/H63D) will inherit at least one of the variants. Full siblings of a homozygote or compound heterozygote have a 25 percent chance (or higher, depending on the genotype of both parents) of themselves also being a homozygote or compound heterozygote.

Based on these probabilities, genetic testing of any first-degree relative is reasonable if the tested individual carries the C282Y variant. Testing may be omitted or deferred if the results would not alter management, such as for older individuals or those with acute medical problems. If indicated, testing should generally be deferred until the tested individual's results have been reviewed and caveats are addressed, and until the relative is 18 or older, to allow for proper informed consent. (See 'How to read the report' above and "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)

At-risk relatives of an individual with documented iron overload not explained by an acquired condition should generally have iron studies testing, regardless of the tested individual's genotype. (See "Management and prognosis of hereditary hemochromatosis", section on 'Testing and counseling first-degree relatives'.)

Discussions of risk and initial testing can be performed by the relative's primary clinician. If the relative requires counseling, additional information, or testing that cannot be provided by the primary clinician, referral to a genetics expert is reasonable. (See 'Resources' below.)

RESOURCES

UpToDate topics

●Genetics – (See "HFE and other hemochromatosis genes".)

●Diagnosis of hereditary hemochromatosis (HH) – (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

●Treatment of HH – (See "Management and prognosis of hereditary hemochromatosis".)

●Differential diagnosis – (See "Approach to the patient with suspected iron overload".)

Locating a genetics expert

●Genetic counselors – The National Society of Genetic Counselors (NSGC)

●Clinical geneticists – The American College of Medical Genetics and Genomics (ACMG)