Hereditary Hemochromatosis and HFE

Updated: Apr 13, 2022
Author: Nilesh L Vora, MD; Chief Editor: Keith K Vaux, MD 

Practice Essentials

Hereditary hemochromatosis (HH) is an autosomal recessive genetic disease characterized by excessively increased absorption of dietary iron. Excess iron can be accumulated because of lack of an effective excretory mechanism, leading to toxic effects.[1]  Hereditary hemochromatosis is clinically characterized by excessive iron deposition in parenchymal organs such as liver, heart, pancreas, and joints. Superfluous iron can aggravate pathogenesis in combination with other diseases and risk factors, such as inflammation, cancer, and hepatopathy; this possibility should not be neglected by clinicians.[2]

HFE hemochromatosis, the most common type, is characterized by increased iron absorption and iron overload due to variants of the iron-regulating HFE gene. Non–HFE-related cases are rare.[3]  The most penetrant of these mutations is the C282Y defect; C282Y homozygotes account for up to 90% of clinical cases of HH. By contrast, H63D and S65C homozygosity typically cause only mild disease or no clinical consequences.[2, 4]

It is unclear exactly how the mutated form of HFE produces an iron overload state. One theory is that mutated HFE undergoes a conformational change in its structure that prevents the transferrin receptor from entering the hepatocyte. The receptor therefore stays active and continues to bind to diferric transferrin while releasing iron, leading to iron overload.[5]

Studies have classified HFE-associated HH as a liver disease with failed production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals the start of excessive iron absorption from the diet and iron deposition in tissues, causing multiple organ damage and failure.[6]

Clinical onset of HH symptoms occurs more frequently in adult men than women, as monthly loss of iron due to menstruation in women slows down accumulation and symptoms usually start to appear after menopause.[1]

Therapeutic phlebotomy is the primary treatment for this disease, combined with use of chelating agents.[1]  Phlebotomy has been provided for more than 60 years and is effective in reducing morbidity and mortality in patients with HH. Iron overload leads to tissue injury mainly through the production of reactive oxygen species, which damage cell membranes and organelles, ending in cellular death. Thus, it is important to start treatment.[7]

Orthotopic liver transplantation (OLT) is performed in patients with advanced cirrhosis to correct reduced hepatic hepcidin secretion. To prevent progression of iron accumulation, early detection may be achieved by performing a genotypic check for frequent mutations of the HFE gene.[1] Liver carcinoma and mortality risks are increased in individuals with clinically diagnosed HH.[8]  In a study of 18 patients who underwent OLT, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; P< 0.05) and was low in 1 patient with iron deficiency anemia. Survival was 83% and 67% at 1 and 5 years, respectively, and was similar to that of patients who underwent OLT for other reasons.[9]

Hemochromatosis is the clinical expression of iron-induced end-organ injury; in HH, the clinical disorder is linked to a genetic cause. Three mutations in the HFE gene have been implicated. The first involves a G→A mutation at nucleoside 845, leading to a cysteine-to-tyrosine substitution at amino acid position 282 (C282Y). The second mutation involves a G→C substitution at nucleotide 197, leading to a histidine-to-aspartic acid substitution at amino acid position 63 (H63D). The third mutation involves an A→T mutation at nucleotide 193, leading to a serine-to-cysteine substitution at amino acid position 65 (S65C).


Clinical Implications of the Genetic Mutation

Although data from multiple studies suggest that HFE genetic mutations are common, the frequency of phenotypic expression and therefore clinical consequences of the mutation remain unclear. 

The environment and the human genome are closely entangled, and many genetic variations that occur in human populations are the result of adaptive selection to ancestral environmental (mainly dietary) conditions. However, selected mutations may become maladaptive when environmental conditions change, thus becoming candidates for disease. Hereditary hemochromatosis is a potentially lethal disease leading to iron accumulation most often as the result of mutations in the HFE gene. Indeed, homozygosity for the C282Y HFE mutation is associated with the primary iron overload phenotype.[10]

Both penetrance of the C282Y variant and clinical manifestations of the disease are extremely variable, suggesting that other genetic, epigenetic, and environmental factors play a role in the development of HH, as well as in its progression to end-stage liver disease. Alcohol consumption and dietary habits may impact the phenotypic expression of HFE-related hemochromatosis. Indeed, dietary components and bioactive molecules can affect iron status both directly by modulating absorption of iron during digestion and indirectly through epigenetic modification of genes involved in its uptake, storage, and recycling.[10]

In a study by the European Association for the Study of the Liver (EASL) on the prevalence of C282Y homozygosity in clinically recognized individuals with iron overload (meta-analysis of 32 studies, with a total of 2802 patients of European ancestry with HH), analysis of pooled data shows that 80.6% (2260 of 2802) of patients were homozygous for the C282Y polymorphism in the HFE gene. Compound heterozygosity for C282Y and H63D was found in 5.3% of patients with HH (114 of 2117). In control groups, which were reported in 21 of the 32 studies, the frequency of C282Y homozygosity was 0.6% (30 of 4913 control individuals) and compound heterozygosity was present in 1.3% (43 of 3190 controls).[11]

According to the EASL, disease penetrance based on symptoms (eg, fatigue, arthralgia) is difficult to assess due to the nonspecific nature and the high frequency of such symptoms in control populations. Researchers note that C282Y homozygotes identified during family screening are at greater risk of expressing the disease (32-35%) when compared with C282Y homozygotes identified during population-based studies (27-29%). They cite data suggesting that up to 38-50% of C282Y homozygotes may develop iron overload, with 10-33% eventually developing hemochromatosis-associated morbidity. The proportion of C282Y homozygotes with iron overload–related disease was found to be substantially higher for men than for women (28% vs 1%).[11]


The Hemochromatosis International Taskforce provided therapeutic recommendations for treatment of patients with HFE HH with the C282Y defect. These recommendations were approved at the Hemochromatosis International Meeting in Los Angeles, California, on May 12, 2017. The intent of the Taskforce was to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE HH with the C282Y phenotype based on published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training.[7]  Following are highlights of these recommendations.

  • Treatment should begin when patients show biochemical evidence of iron overload: increased serum ferritin (>300 μg/L in males and postmenopausal females; >200 μg/L in premenopausal females); increased fasting transferrin saturation (≥45%).
  • A judgment must be made for each individual patient, taking into account ferritin level (according to local reference value), age, gender, and comorbidities.
  • Magnetic resonance imaging, when available, may be used to quantify iron overload in the liver (or in other organs).
  • Phlebotomy (venesection therapy), the standard treatment for patients with HH, is effective in reducing morbidity and mortality. Iron overload leads to tissue injury. Starting treatment is important.
  • The frequency of maintenance phlebotomy varies among individuals, ranging from 1 per month to 1 per year.
  • Hemoglobin levels should not be < 11 g/dL.
  • Hemoglobin values should be assessed before phlebotomy is performed, especially for older patients, who are more susceptible to anemia and chronic blood loss.
  • Serum ferritin should be checked at every other phlebotomy (at the same time as hemoglobin), at least yearly.
  • Fasting transferrin saturation should also be checked at least once a year.
  • A healthy varied diet should be eaten, avoiding foods with iron fortification such as breakfast cereals. Iron and vitamin C supplementation and high alcohol consumption should also be avoided. Dietary restriction should not replace phlebotomy therapy.
  • Iron chelation is usually indicated for iron overload related to chronic anemias that require repeated transfusions. Iron chelators are an alternative treatment to be used only in rare and special cases of HH, as follows: when efficacy is not achieved with phlebotomies, when phlebotomies are impossible to perform because of poor vein conditions, and when phlebotomies are medically contraindicated.
  • Patients who have had iron overload should never stop having their iron status monitored and their treatment planned based on iron status, general condition, and age.
  • Hepcidin-based therapies might become a potential adjunct treatment to phlebotomy in the induction phase or as replacement for phlebotomy maintenance. [7]

Since its discovery, the hemochromatosis protein HFE has been primarily defined by its role in iron metabolism and homeostasis and by its involvement in HH. Although patients with HH are typically afflicted by dysregulated iron levels, many are also affected by several immune defects and by an increased incidence of autoimmune disease, implicating HFE in the immune response. Growing evidence supports an immunologic role for HFE, and studies have described HFE specifically as it relates to major histocompatibility complex class I (MHC I) antigen presentation. Overall, this improved understanding of the role of HFE in the immune response sets the stage for better treatment and management of HH and other iron-related diseases, as well as of immune defects related to this condition.[12]


Testing for the Genetic Mutation

Genetic testing for hereditary hemochromatosis detects C282Y, H63D, and S65C HFE mutations. However, the frequency of genotypic expression seems to be greater than the frequency of phenotypic expression, and a positive genetic test does not necessarily imply the presence of disease. Testing can be done as a follow-up evaluation in patients with elevated transferrin saturation levels or to assess risk for disease in at-risk patients.

Controversy regarding the true penetrance of hemochromatosis has implications regarding population-based screening for this disease. If the incidence of mutations and the penetrance of the disease in mutated patients are low, as suggested by Buetler et al, large-scale screening programs might not be justified.[13] However, if incidence and penetrance are as high as others have postulated, population screening would be imperative, as early disease is effectively treated by phlebotomy, and untreated homozygotes can develop serious consequences. Unfortunately, until future research elucidates the true penetrance of the disease, this matter remains largely unresolved.

In patients with clinical hemochromatosis, transferrin saturation is higher than in normal individuals and remains the most sensitive and cost-effective initial screening test. A level above 60% in males or above 45-50% in females should be repeated and, if still abnormal, should prompt further investigation.

Molecular genotyping of the HFE locus should be considered if the diagnosis remains in question after secondary causes of iron overload have been ruled out, or if at-risk family members have been identified. Historically, liver biopsy was the gold standard for confirming the diagnosis of hemochromatosis, but it is performed less frequently now that genotyping is readily available.

Despite the controversy regarding penetrance, it is imperative that at-risk patients are diagnosed early so as to avoid end-organ complications. For these patients, prompt and aggressive treatment is crucial, and life expectancy can be normal if phlebotomy is initiated early in the course of disease.[14, 15]  Phlebotomy directly reduces serum iron by depleting hemoglobin levels and replacing depleted circulating serum iron by mobilizing iron stores from tissues.[16]

Screening of adults for iron overload or associated genotypes is controversial, largely because of a belief that severe phenotypes are uncommon, although cascade testing of first-degree relatives of patients is widely endorsed. Severe liver disease (cirrhosis or hepatocellular cancer) is not at all uncommon among older males with HH. A review of published data from a variety of empirical sources reveals that roughly 1 in 10 male HFE C282Y homozygotes are likely to develop severe liver disease during their lifetime unless iron overload is detected early and treated.[17]

Evidence from randomized, controlled trials supports treatment of presymptomatic patients. Although population screening for HFE C282Y homozygosity faces multiple barriers, a potentially effective strategy for enhancing early detection and prevention of clinical iron overload and severe disease is to include HFE C282Y homozygosity in lists of medically actionable gene variants when results of genome or exome sequencing are reported.[17]