HFE-Related Hemochromatosis

Clinical characteristics.

HFE-related hemochromatosis (HFE HC) is characterized by increased intestinal iron absorption and increased recycling of iron derived from senescent red blood cells. The phenotypic spectrum of HFE HC includes clinical HFE HC (increased serum ferritin and transferrin saturation and end-organ damage secondary to iron overload), biochemical HFE HC (increased serum ferritin and transferrin saturation without end-organ damage), and non-penetrant HFE HC (neither clinical manifestations of HFE HC nor iron overload are present, although elevated transferrin saturation may occur). Clinical HFE HC is characterized by excessive iron in the liver, pancreas, heart, skin, joints, and anterior pituitary gland. In untreated individuals, early manifestations include weakness, chronic fatigue, abdominal pain, weight loss, arthralgias, and diabetes mellitus. Individuals with HFE HC have an increased risk of cirrhosis when their serum ferritin is higher than 1,000 µg/L. Other findings of severe iron overload include hypogonadism, congestive heart failure, arrhythmias, and progressive increase in skin pigmentation. Clinical HFE HC is more common in males than females.

Diagnosis/testing.

The diagnosis of HFE HC is established in most persons with characteristic laboratory and/or clinical features by identification of HFE p.Cys282Tyr homozygosity.

Management.

Targeted therapies: In individuals with clinical HFE HC, a major initial treatment goal is to remove excess iron by phlebotomy to achieve serum ferritin 50-100 µg/L. Erythrocytapheresis is sometimes used to remove excess iron. Iron chelation therapy may be used to treat individuals intolerant of phlebotomy or erythrocytapheresis or those with symptomatic anemia. In individuals with biochemical HFE HC, phlebotomy is indicated when serum ferritin exceeds 300 µg/L (males) and 200 µg/L (females).

Treatment of manifestations: Management of complications of HFE HC (arthropathy, diabetes mellitus, cirrhosis, hypogonadism, and cardiomyopathy) do not differ from the management of these conditions in persons without HFE HC. Treatment of arthropathy includes nonsteroidal anti-inflammatory drugs, physiotherapy, and joint replacement. Standard treatment for diabetes mellitus. Vaccination for hepatitis A and B. Treatment of hepatitis B or C with standard antiviral agents may reduce liver injury. In individuals with cirrhosis, evaluation and treatment of complications is warranted, including endoscopic surveillance of varices; prophylaxis with nonselective beta-blockers; salt restriction and diuretics for ascites, with paracentesis and portosystemic shunts as needed; antibiotics to decrease risk of spontaneous bacterial peritonitis; and low-protein diet for hepatic encephalopathy with lactulose and rifaximin as indicated. Orthotopic liver transplant for end-stage liver disease. Hormone replacement therapy for hypogonadism; gonadotropins for infertility. Standard treatments for heart failure and arrhythmias in individuals with cardiomyopathy.

Surveillance: In individuals with clinical HFE HC, after serum ferritin is ≤100 µg/L, monitor serum ferritin concentration every three to four months, and maintain serum ferritin <300 µg/L (males) and <200 µg/L (females) thereafter; joint radiographs as needed; in those with diabetes mellitus assess for complications every six to 12 months; liver enzyme tests every six to 12 months; standard evaluations for primary liver cancer in those with cirrhosis; assessment for hormonal deficiency in those with hypogonadism; cardiac assessment in those with cardiac siderosis annually or as needed. In individuals with biochemical HFE HC and non-penetrant p.Cys282Tyr homozygotes, monitor serum ferritin concentration every six to 12 months, and begin phlebotomy to achieve iron depletion when serum ferritin exceeds 300 µg/L (males) and 200 µg/L (females).

Agents/circumstances to avoid: Medicinal iron, mineral supplements containing iron, excess alcohol, excess vitamin C, uncooked seafood, and lifestyle behaviors that increase the risk of viral hepatitis infection; alcohol consumption should be avoided in those with hepatic fibrosis or cirrhosis.

Evaluation of relatives at risk: Offer molecular genetic testing to adult sibs of a proband to facilitate early diagnosis and surveillance.

Genetic counseling.

HFE HC is inherited in an autosomal recessive manner and has low clinical penetrance. (Note: Pseudodominance has been observed in HFE HC and is attributed to the relatively high prevalence of p.Cys282Tyr heterozygotes in persons of European ancestry.) Most parents of individuals with HFE HC are p.Cys282Tyr heterozygotes (i.e., have one copy of HFE p.Cys282Tyr). On occasion, one parent has p.Cys282Tyr homozygosity and may have clinical, biochemical, or non-penetrant HFE HC. If both parents are p.Cys282Tyr heterozygotes, each sib of an affected individual has a 25% chance of being homozygous for p.Cys282Tyr, a 50% chance of being heterozygous for p.Cys282Tyr, and a 25% chance of being neither homozygous nor heterozygous for p.Cys282Tyr. Sibs who are homozygous for p.Cys282Tyr are at risk for HFE-related iron overload, although the clinical penetrance of HFE HC is low.

Suggestive Findings

HFE-related hemochromatosis (HFE HC) should be suspected in an individual with laboratory features of hemochromatosis, clinical manifestations of advanced iron overload, and/or a family history of HFE HC.

Laboratory features of hemochromatosis

• Elevated transferrin saturation. Elevated transferrin saturation in persons with HFE HC (≥60% in males, ≥50% in females) is an indicator of increased recycling of iron and increased risk for iron overload. Approximately 80% of individuals with HFE HC have a fasting serum transferrin saturation of ≥60% (in males) or ≥50% (in females) on two or more occasions in the absence of other known causes of elevated transferrin saturation. Transferrin saturation is not age related in adults with HFE HC and is not significantly associated with the presence or absence of clinical findings or increased serum ferritin levels. In some adults with inflammatory conditions, transferrin is a negative acute-phase reactant. Therefore, transferrin saturation may be spuriously elevated due to decreased production of transferrin by the liver.
• Elevated serum ferritin concentration. Normal serum ferritin values from the Hemochromatosis and Iron Overload Screening (HEIRS) Study are <300 µg/L in males and <200 µg/L in females [Adams et al 2005]. Serum ferritin concentration generally increases progressively over time in individuals with untreated clinical HFE HC. An elevated serum ferritin concentration alone is not specific for iron overload because serum ferritin is an acute-phase reactant and elevated serum ferritin levels may be caused by non-iron liver disorders or by inflammatory or neoplastic disorders. In these instances, transferrin saturation is usually not elevated. Serum ferritin values in individuals with HFE HC can range from below normal to much greater than 1,000 µg/L.
• Higher hemoglobin (Hb), mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV). Mean values of Hb, MCH, and MCV are significantly higher in persons with HFE HC than controls, although most persons with HFE HC have neither erythrocytosis (Hb >18.0 g/L) nor macrocytosis (MCV >100 fL) [Barton et al 2000]. Higher values of Hb, MCH, and MCV are due in part to ample quantities of iron for Hb synthesis by erythroid cells due to elevated transferrin saturation [Barton et al 2000, McLaren et al 2007]. Liver disease, alcoholism, deficiencies of vitamin B₁₂ or folate acid, or medications do not account for higher Hb, MCH, and MCV in most individuals with HFE HC. Accordingly, higher Hb, MCH, and MCV in persons with elevated transferrin saturation suggest the diagnosis of HFE HC. In one study, mean pre- and post-phlebotomy MCV and MCH values were always significantly higher than those of other groups and demonstrated excellent diagnostic utility for detection of HFE HC in males and females [Adris et al 2019]. Persons with hemochromatosis related to other HFE genotypes also have higher Hb, MCH, and MCV than controls.

Clinical manifestations of advanced iron overload

• Weakness, chronic fatigue
• Abdominal pain, weight loss
• Arthropathy (especially metacarpophalangeal joints, hips, knees)
• Diabetes
• Hepatomegaly
• Cirrhosis
• Primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma)
• Hypogonadotropic hypogonadism (decreased libido and impotence in males, amenorrhea in females)
• Cardiomyopathy, arrhythmias
• Progressive increase in skin pigmentation

Family history is consistent with autosomal recessive inheritance, although penetrance is low. Absence of a family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of HFE HC is established in most persons with characteristic laboratory and/or clinical features by identification of HFE p.Cys282Tyr homozygosity (see Table 1).

Note: HFE HC is associated predominantly with p.Cys282Tyr homozygosity. The penetrance of other common HFE genotypes (e.g., p.Cys282Tyr/p.His63Asp compound heterozygosity and p.His63Asp homozygosity) is markedly lower than that of p.Cys282Tyr homozygosity. Most individuals with p.Cys282Tyr/p.His63Asp compound heterozygosity or p.His63Asp homozygosity who develop clinical or biochemical HC are believed to have a pathogenic allele in another HC-related gene (digenic inheritance) or a predisposing environmental factor. Approximately 100 other uncommon or rare pathogenic or likely pathogenic HFE alleles, many inherited in association with p.Cys282Tyr heterozygosity or another HFE allele, have been described in persons with and without clinical or biochemical HC. Penetrance of many of these uncommon or rare pathogenic or likely pathogenic HFE genotypes is uncertain. Almost all persons described to have HFE HC report European ancestry, although rarely HFE HC has been described in individuals who report African American or Chinese ancestry.

Molecular genetic testing approaches can include a combination of targeted testing and use of a multigene panel.

• Targeted analysis for HFE p.Cys282Tyr and p.His63Asp should be considered first in individuals of northern European ancestry.
• A hemochromatosis multigene panel that includes HFE and other genes of interest (see Differential Diagnosis) may be considered in individuals without northern European ancestry to identify the genetic cause of the condition while limiting identification of alleles of uncertain significance and pathogenic alleles in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in HFE-Related Hemochromatosis

Clinical Description

HFE-related hemochromatosis (HFE HC) is composed of three phenotypes:

• Clinical HFE HC. Individuals with end-organ damage secondary to iron overload
• Biochemical HFE HC. Individuals with both elevated transferrin saturation and elevated serum ferritin concentration
• Non-penetrant HFE HC. Persons with, e.g., HFE p.Cys282Tyr homozygosity without clinical or laboratory features of iron overload (Transferrin saturation may be elevated in the absence of elevated serum ferritin.)

Genotype-Phenotype Correlations

p.Cys282Tyr. Most HFE p.Cys282Tyr homozygotes do not have clinical HFE HC. A significant proportion of individuals with p.Cys282Tyr homozygosity (especially males) have biochemical HFE HC. Three longitudinal population-based studies showed that 38%-50% of p.Cys282Tyr homozygotes develop elevated serum ferritin concentration and 10%-33% eventually develop clinical HFE HC [Whitlock et al 2006].

p.His63Asp. Some HFE p.Cys282Tyr/p.His63Asp compound heterozygotes and HFE p.His63Asp homozygotes identified in general population testing have elevated transferrin saturation and mild hyperferritinemia [Barton & Parker 2023]. Identification of serum ferritin >500 µg/L in persons with these genotypes should prompt a search for non-iron causes of hyperferritinemia.

In 58 screening program participants without HFE p.Cys282Tyr homozygosity who had both elevated transferrin saturation and elevated serum ferritin on two occasions in the absence of treatment for iron overload, anemia, erythrocyte transfusion >10 units, alcohol intake >30 g/day, hepatitis B or C, or pregnancy, relative risks of HFE genotypes p.Cys282Tyr/His63Asp, p.His63Asp/His63Asp, and p.Cys282Tyr heterozygosity were significantly higher (11.0-, 3.9-, and 1.9-fold, respectively) than those of 42,640 White screening participants with neither elevated transferrin saturation nor elevated serum ferritin. Serum ferritin levels were positively associated with mean corpuscular volume and swelling/tenderness of 2nd/3rd metacarpophalangeal joints. Elevated serum concentrations of hepatic transaminases were significantly associated with mean corpuscular volume and diabetes [Barton et al 2022].

Penetrance

Environmental factors. Some environmental factors modify penetrance of laboratory phenotypes of persons with HFE HC. Increased dietary consumption of heme iron was associated with higher serum ferritin levels in postmenopausal females [Cade et al 2005]. Nonalcoholic fatty liver in referred adults with HFE HC with iron overload was associated with significantly higher median serum ferritin and greater prevalence of diabetes mellitus type 2, after adjustment for other factors, although nonalcoholic fatty liver did not significantly influence the quantity of iron removed by phlebotomy to achieve iron depletion [Barton et al 2023]. Gastric acid suppression reduces phlebotomy requirements [Hutchinson et al 2007]. Nonetheless, effects of these factors on penetrance of HFE HC is probably small.

Consumption of more than two alcoholic drinks per day was associated with increased risk of elevated transferrin saturation and elevated serum ferritin in a general population cohort [Ioannou et al 2004]. This could explain in part observations that HFE HC is often associated with chronic alcoholism. Risk of liver injury or progression of hepatic fibrosis is increased in persons with HFE HC who also have alcoholism, nonalcoholic fatty liver, or viral hepatitis [Wood et al 2008].

Viral hepatitis accelerates liver injury in persons with HFE HC. Prevalence of viral hepatitis differs greatly across geographic regions. In 78 referred individuals with HFE HC in Italy, the prevalence of hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus (HCV) were 5.1% and 20.5%, respectively [Piperno et al 1992]. Chronic hepatitis C infection prevalence in 961 referred individuals with HFE HC in the United States and Canada was 1.0% (10/961) [Barton et al 2019]. The anti-HBsAg antibody response to hepatitis B vaccination in persons with HFE HC is substantial. It is unknown whether hepatitis vaccinations reduce risk of cirrhosis or primary liver cancer or increase longevity.

Sex. The proportion of females with clinical HFE HC is lower than that of males (1% vs 28%, respectively) [Allen et al 2008]. Population studies demonstrate that the greatest sex-related factor that modifies penetrance of clinical HFE HC is the premenopausal state in females. It is plausible although unproven that physiologic blood (iron) loss in premenopausal females accounts for their lower penetrance of clinical HFE HC. Hepatic iron concentrations were higher in females who underwent menopause at age <50 years than in females who underwent menopause at an older age [Moirand et al 1997]. In contrast, the number of pregnancies was not significantly correlated with iron burden in females with HFE HC [Deugnier et al 2002]. Other undefined genetic factors may also contribute to reduced penetrance of clinical HFE HC in females [Wood et al 2008].

Genetic factors. Increased iron burden occurs in persons with HFE HC who are also heterozygous for HAMP or HJV pathogenic alleles. Some BMP alleles have been associated with variability of serum ferritin levels in persons with HFE HC [Wood et al 2008].

Nomenclature

HFE HC has been described as bronze diabetes with cirrhosis, primary hemochromatosis, genetic hemochromatosis, hereditary hemochromatosis, and hemochromatosis type 1. The current term is HFE-related hemochromatosis (HFE HC) [Girelli et al 2022].

Prevalence

Among most populations of European ancestry, the prevalence of individuals homozygous for HFE p.Cys282Tyr is 1:200 to 1:500 [Barton & Parker 2023]. In non-Hispanic Whites in North America, the prevalence of p.Cys282Tyr homozygotes is 1:200 to 1:400 [Adams et al 2005]. Among Hispanics in North America, the prevalence of p.Cys282Tyr homozygotes is 0.027% [Adams et al 2005]. Among Blacks in North America, the prevalence of p.Cys282Tyr homozygotes is 1:6,781 [Barton et al 2005]. Among Asians in North America, the prevalence of p.Cys282Tyr homozygotes is 1:25,000 [Adams et al 2005].

Primary Iron Overload Disorders

Primary iron overload disorders (summarized in Table 2) are characterized by increased absorption of iron from a normal diet in subjects without severe anemia. Juvenile hemochromatosis and TFR2-related hemochromatosis result from hepcidin deficiency and thus the clinical manifestations of these disorders are similar to, but typically more severe than, those of HFE HC.

Table 2.

Primary Iron Overload Disorders in the Differential Diagnosis of HFE-Related Hemochromatosis

African iron overload (OMIM 601195), reported in sub-Saharan African populations, is associated with excessive intake of dietary iron in traditional beer brewed in non-galvanized steel drums. A genetic contribution to the pathogenesis of African iron overload, if any, is unknown.

Secondary Iron Overload Disorders

Liver diseases associated with secondary iron overload include alcoholic liver disease, acute viral hepatitis, chronic viral hepatitis C (uncommon), neoplasms, familial porphyria cutanea tarda, and inflammatory disorders such as rheumatoid arthritis.

Nonalcoholic fatty liver disease in persons with HFE HC does not increase amounts of iron removed by phlebotomy to achieve iron depletion, although serum ferritin levels are typically higher in persons with HFE HC and nonalcoholic fatty liver disease due to hepatic inflammation [Barton et al 2023].

In persons without HFE HC, nonalcoholic fatty liver disease is sometimes associated with elevated transferrin saturation or serum ferritin concentration but infrequently with increased hepatic iron deposition.

Iron overload can result from ingested iron in foods, cooking ware, and medicines, in addition to parenteral iron from iron injections or transfusions for anemia (e.g., beta-thalassemia, sickle cell disease, hereditary sideroblastic anemia [OMIM PS300751], pyruvate kinase deficiency [OMIM 266200], hereditary spherocytosis [see EPB42-Related Hereditary Spherocytosis], myelodysplastic syndrome with refractory anemia).

Erythroferrone is an inhibitor of hepcidin transcription. Due to bone marrow production of erythroferrone (and consequent hepcidin deficiency), iron absorption is increased in some heritable anemias (e.g., non-transfusion-dependent beta-thalassemia, pyruvate kinase deficiency, hereditary sideroblastic anemia).

Neonatal hemochromatosis develops in utero and is characterized by severe hepatic injury (marked loss of hepatocytes, coarsely granular hepatocyte siderosis) and extrahepatic siderosis (epithelia of thyroid, exocrine pancreas, and salivary glands; myocardium). Gestational alloimmune liver disease is the cause of fetal liver injury in most cases [Feldman & Whitington 2013]. Maternal alloimmunity accounts for the occurrence of neonatal hemochromatosis in two or more offspring of the same mother. Antenatal therapy with high-dose intravenous immunoglobulin G prevents poor outcome of pregnancies at risk for neonatal hemochromatosis [Whitington et al 2018]. There is little evidence that neonatal hemochromatosis is a heritable disorder attributed to an as-yet-unidentified gene. Some investigators have suggested that DGUOK pathogenic alleles lead to phenotypes that resemble those of neonatal hemochromatosis (see Deoxyguanosine Kinase Deficiency).

Evaluations Following Initial Diagnosis

To establish the extent of iron overload and optimal management of persons diagnosed with HFE HC, the evaluations summarized in Table 3 are recommended if not performed as part of the evaluation that led to the diagnosis [Kowdley et al 2019, European Association for the Study of the Liver 2022].

Table 3.

HFE-Related Hemochromatosis: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Optimal implementation of these recommendations involves multidisciplinary care (see Table 4).

Table 4.

HFE-Related Hemochromatosis: Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, surveillance is based on guidelines proposed for individuals with HFE HC due to p.Cys282Tyr homozygosity in Europe [European Association for the Study of the Liver 2022] and North America [Kowdley et al 2019].

Table 5.

HFE-Related Hemochromatosis: Recommended Surveillance

Agents/Circumstances to Avoid

Avoid the following:

• Medicinal iron and nutritional supplements containing iron
• Excessive alcohol intake, which increases iron absorption and is toxic to hepatocytes. Individuals with cirrhosis should avoid alcohol consumption.
• Daily ingestion of more than 500 mg of supplemental vitamin C, which may enhance iron absorption
• Consumption of uncooked seafood, which increases the risk of infection from microorganisms that thrive in conditions of excess iron (Vibrio vulnificus and other Vibrio species)
• Lifestyle-related behaviors that increase the risk of viral hepatitis infection

Evaluation of Relatives at Risk

Evaluation of adult sibs and offspring of individuals with HFE HC identifies those who have HFE HC and might benefit from both treatment and preventive measures. The following strategy is recommended:

1.

Inform probands with HFE HC that HFE molecular genetic testing is recommended for their adult sibs (≥18 years)

2.

Measurement of transferrin saturation and serum ferritin concentration in sibs with HFE p.Cys282Tyr homozygosity (HFE HC)

3.

Phlebotomy therapy for sibs with HFE HC and elevated serum ferritin concentrations

Note: HFE molecular genetic testing has a low positive predictive value for clinical HC because few p.Cys282Tyr homozygotes and no p.Cys282Tyr/His63Asp compound heterozygotes develop clinically significant iron overload without other predisposing factors [El-Serag et al 2000, Beutler et al 2002].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Inducing iron depletion during pregnancy or in females who anticipate pregnancy is undesirable. In the absence of severe iron-related liver disease or cardiomyopathy, it is prudent to withhold therapeutic phlebotomy during pregnancy [European Association for the Study of the Liver 2022].

Therapies Under Investigation

The oral iron chelator deferasirox (Exjade^®) has been evaluated in Phase I/II studies of individuals with HFE HC, results of which suggest that deferasirox reduces iron burdens within an acceptable safety profile [Phatak et al 2010, Cançado et al 2015]. Subcutaneous deferoxamine was effective in achieving iron depletion in three individuals with HFE HC in whom phlebotomy therapy was not feasible [Nielsen et al 2003]. Rusfertide, a peptidic mimetic of hepcidin, reduced the mean number of maintenance phlebotomies in 12 individuals with HFE HC during a 24-week trial [Kowdley et al 2023]. Nonetheless, these studies are very limited and to date, the US Food and Drug Administration and the European Medicines Agency have not approved deferasirox, deferoxamine, deferiprone, or rusfertide for treatment of hemochromatosis.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

HFE-related hemochromatosis (HFE HC) is inherited in an autosomal recessive manner with low clinical penetrance.

Pseudodominance (the occurrence of an autosomal recessive disorder in two generations of a family without consanguinity) has been observed in HFE HC and is attributed to the high prevalence of HFE p.Cys282Tyr in persons of European ancestry (see Prevalence).

Risk to Family Members

Parents of a proband

• Most parents of individuals with HFE HC are HFE p.Cys282Tyr heterozygotes (i.e., have a single copy of p.Cys282Tyr). Individuals who are heterozygous for p.Cys282Tyr do not develop HFE-related iron overload, although some have abnormal serum iron measures (see Clinical Description, Heterozygotes).
• Infrequently, one parent of a proband with HFE HC may have HFE p.Cys282Tyr homozygosity and have clinical HFE HC (presence of significant end-organ damage including cirrhosis, cardiac failure, skin hyperpigmentation, diabetes, or hypogonadism). Thus, it is appropriate to recommend to probands that their parents be evaluated for HFE HC by molecular genetic testing or by measuring transferrin saturation and serum ferritin concentration.

Sibs of a proband

• If both parents of a proband with HFE HC are HFE p.Cys282Tyr heterozygotes, each sib of that proband has a 25% probability of being homozygous for p.Cys282Tyr, a 50% probability of being heterozygous for p.Cys282Tyr, and a 25% probability of being neither homozygous nor heterozygous for p.Cys282Tyr.
• If one parent of a proband with HFE HC is homozygous for HFE p.Cys282Tyr and the other parent is heterozygous for p.Cys282Tyr, each sib of that proband has a 50% chance of being homozygous for p.Cys282Tyr and a 50% chance of being heterozygous for p.Cys282Tyr.
• Sibs of probands with HFE HC who inherit biallelic p.Cys282Tyr alleles are at risk for HFE-related iron overload, although the clinical penetrance of HFE HC is low. Several large-scale screening studies of general populations have demonstrated that most individuals who are homozygous for HFE p.Cys282Tyr do not have or eventually develop clinical HFE HC (see Penetrance). Note: It is recommended that the proband's physician suggest that the proband notify their family members to undergo molecular genetic testing or measurement of transferrin saturation and serum ferritin to ascertain whether they also have HFE HC (see Management, Evaluation of Relatives at Risk).
• Sibs of probands with HFE HC who are p.Cys282Tyr heterozygotes are not at risk for HFE-related iron overload, although they may have abnormal serum iron studies (see Clinical Description, Heterozygotes).

Offspring of a proband

• Unless the reproductive partner of a proband with HFE HC also has HFE HC or is a p.Cys282Tyr heterozygote, all offspring will be obligate p.Cys282Tyr heterozygotes.
• It is sometimes recommended that reproductive partners of individuals with HFE HC undergo HFE molecular genetic testing or measurement of transferrin saturation and serum ferritin concentration to determine if their children are at risk for HFE HC.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with HFE HC.

Molecular genetic testing for HFE p.Cys282Tyr can be offered to the reproductive partner of a person with HFE HC to determine if their offspring are at risk for HFE HC. Among most populations of European ancestry, prevalence of p.Cys282Tyr is approximately 1 in 9 persons. Therefore, offspring of an individual with HFE HC and an individual of European ancestry have an approximately 5% risk of inheriting biallelic HFE p.Cys282Tyr alleles.

Population Screening

Population screening has been performed due to the high prevalence of HFE HC, the lack of early clinical findings, the lack of specificity of clinical findings if they appear, the low cost of diagnosis, the availability of relatively simple and effective early treatment, and the high cost and low success rate of treatment when the diagnosis is established late.

• Molecular genetic testing-based population screening for HFE HC is not recommended because penetrance is low and the natural history of untreated individuals cannot be predicted. Some experts opine that available evidence is insufficient to make a decision regarding a recommendation to perform population screening for HFE HC [Schmidtke 2022].
• Biochemical-based screening (using transferrin saturation and serum ferritin) of males of European descent age >30 years may be considered [Phatak et al 2008, European Association for the Study of the Liver 2010, Bacon et al 2011].

Prenatal Testing and Preimplantation Genetic Testing

Prenatal testing is not usually performed because HFE HC is an adult-onset, treatable disorder with low clinical penetrance, although preimplantation genetic testing and prenatal testing for a pregnancy at increased risk are feasible once biallelic HFE p.Cys282Tyr alleles have been identified in a family member.

Differences in perspective exist among medical professionals and within families regarding the use of prenatal testing. Although most centers consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

HFE encodes hereditary hemochromatosis protein (HFE). The largest predicted primary translation product is 348 amino acids, which gives rise to a mature protein of approximately 321 amino acids after cleavage of the signal sequence. HFE is similar to HLA class I molecules at the level of both primary [Feder et al 1996] and tertiary structure [Lebrón et al 1998]. The mature protein is expressed on the cell surface as a heterodimer with beta-2-microglobulin, and this interaction is necessary for normal presentation on the cell surface. HFE binds to transferrin receptor protein 1 on the cell surface and interacts with the trimolecular complex of transferrin receptor protein 2, bone morphogenic protein receptor, and hemojuvelin.

HFE allele c.845G>A (p.Cys282Tyr) disrupts a disulfide bond and alters the conformation of HFE, affecting its interaction with beta-2-microglobulin, transferrin receptor protein 2, bone morphogenic protein receptor, and hemojuvelin on hepatocytes. Consequently, hepatocytes lose the capacity to upregulate hepcidin, the master regulator of iron metabolism. The action of hepcidin is mediated by binding to ferroportin, the only known exporter of intracellular iron. Following binding of hepcidin to ferroportin, the complex is degraded intracellularly. Therefore, the end result of hepcidin binding to ferroportin (which is present primarily on hepatocytes, enterocytes, and reticuloendothelial cells) is reduction of expression of ferroportin. When hepcidin is low (as in HFE HC), ferroportin activity is concomitantly increased, resulting in greater iron absorption by enterocytes and greater iron recycling by reticuloendothelial cells [Olynyk & Ramm 2022].

Mechanism of disease causation. Loss of function

Table 6.

HFE Pathogenic Alleles Referenced in This GeneReview

Author Notes

James C Barton, MD, is a Clinical Professor of Medicine in the Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, and Medical Director of Southern Iron Disorders Center, Birmingham, AL. As a hematologist, his interests include population screening, diagnosis, and management of hemochromatosis, iron deficiency, and other iron-related disorders. Dr Barton received his MD from the University of Tennessee College of Medicine, Memphis, TN. He received training in internal medicine, hematology, and medical oncology at the University of Tennessee College of Medicine, Memphis, TN, and the University of Alabama at Birmingham, Birmingham, AL. Dr Barton has edited two textbooks on hemochromatosis. Email: moc.liamg@633semajnotrab

Charles J Parker, MD, is a Professor of Medicine in the Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, at the University of Utah and the Huntsman Cancer Institute, Salt Lake City, UT. As a hematologist, his clinical interests include paroxysmal nocturnal hemoglobinuria (PNH), hemochromatosis, and porphyria. Dr Parker received his MD from The University of North Carolina, Chapel Hill, NC. He received training in medicine and hematology from the North Carolina Memorial Hospital, Chapel Hill, NC, and Duke University, Durham, NC, respectively. In the past, Dr Parker served as President of the International Paroxysmal Nocturnal Hemoglobinuria Interest Group and Editor-in-Chief of The Hematologist. Web page: medicine.utah.edu/internal-medicine/hematology; email: ude.hatu.csh@rekrap.selrahc

Acknowledgments

Dr Barton acknowledges Drs Marcel E Conrad, William H Crosby, Ernest Beutler, Corwin Q Edwards, and Ronald T Acton for sharing their experience, collaborations, and enthusiasm about studying hemochromatosis and other iron-related disorders.

Author History

James C Barton, MD (2018-present)
Robin L Bennett, MS; University of Washington (2000-2015)
Corwin Q Edwards, MD; University of Utah School of Medicine (2018-2024)
Kris V Kowdley, MD; Virginia Mason Medical Center (2000-2015)
Arno G Motulsky, MD; University of Washington (2000-2015)
Charles J Parker, MD (2024-present)
Lawrie Powell, AC, MD, PhD; Royal Brisbane & Women's Hospital (2015-2018)
Rebecca Seckington; University of Queensland (2015-2018)
Jonathan F Tait, MD, PhD; University of Washington School of Medicine (2000-2011)

Revision History

• 11 April 2024 (sw) Comprehensive update posted live
• 6 December 2018 (sw) Comprehensive update posted live
• 17 September 2015 (me) Comprehensive update posted live
• 19 April 2012 (me) Comprehensive update posted live
• 4 December 2006 (me) Comprehensive update posted live
• 7 October 2003 (me) Comprehensive update posted live
• 3 April 2000 (me) Review posted live
• October 1998 (kk) Original submission

Published Guidelines / Consensus Statements

• Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:328–43. [PubMed]
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 4-2-24.
• European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53:3–22. [PubMed]
• European Association for the Study of the Liver. EASL clinical practice guidelines on haemochromatosis. J Hepatol. 2022;77:479-502. [PubMed]
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 4-2-24.

Literature Cited

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