Hereditary Hemochromatosis and HFE

Updated: Apr 21, 2016
  • Author: Nilesh L Vora, MD; Chief Editor: Keith K Vaux, MD  more...
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Hereditary hemochromatosis is an autosomal recessive disorder that results from a mutated hemochromatosis (HFE [human factors engineering]) protein. [1] In the bloodstream, iron binds to transferrin, forming diferric transferrin. Iron is released from transferrin when the compound binds with the transferrin receptor on the basolateral surface of hepatocytes. It is at this location where the HFE protein normally binds to the transferrin receptor, and the iron is brought into the cell along with the deactivated transferrin receptor. The association between the HFE protein and the transferrin receptor reduces the affinity of the transferrin receptor for diferric transferrin, resulting in a decreased release of iron from the iron-transferrin complex. [2, 3]

It is unclear exactly how the mutated form of HFE leads to an iron overload state. One theory is that mutated HFE has a conformation 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 and release iron, leading to iron overload. [2]

Studies have classified HFE-associated hereditary hemochromatosis as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues, causing multiple organ damage and failure. [4]

Liver transplantation (LT) has been determined to be a key treatment for HFE-related hereditary hemochromatosis to correct reduced hepatic hepcidin secretion. In a study of 18 patients who underwent LT, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; P < 0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at 1 and 5 years, respectively, and was was similar to that of patients who received LT for other causes. [5]

Hemochromatosis is the clinical expression of iron-induced end-organ injury; in hereditary hemochromatosis, 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).

The most penetrant of these mutations is the C282Y defect; C282Y homozygotes account for up to 90% of clinical cases of hereditary hemochromatosis. By contrast, H63D and S65C homozygosity typically cause only mild disease or no clinical consequences. [2, 6]


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 the clinical consequences of the mutation remain unclear. Olynyk et al studied 3011 unrelated individuals in Australia and showed that 16 were homozygous for the C282Y mutation. Of the 16 homozygotes, 8 had clinical signs or symptoms associated with hemochromatosis, suggesting a penetrance of 50%. [7]

In a meta-analysis of data from 7 studies, clinical manifestations were present in 50% of males and 44% of female patients who were homozygous for the HFE mutation. [8] This high frequency rate was supported by Bulaj et al who published reports indicating that 52% of males older than 52 years and 16% of females older than 50 years with the homozygous genotype had at least one “disease-related condition.” [9] Based on these and other data, Neiderau and Strohmeyer concluded that genetic hemochromatosis is one of the most frequent inborn errors of metabolism. [10]

However, Beutler et al refute the claim that hemochromatosis is a common disease, noting that “all of the investigations of the penetrance of hemochromatosis had one flaw in common; the prevalence of the findings attributed to hemochromatosis was not reported in matched controls.” [11] Beutler reports a study in which 41,038 individuals attending a health appraisal clinic operated by the Kaiser-Permanente San Diego health plan underwent genotyping at the HFE locus. Comparisons were made between 152 C282Y homozygotes and ethnically matched subjects with wild-type HFE.

Assessment of the homozygotes via laboratory tests as well as a history and physical led to the conclusion that subjective symptoms of hemochromatosis occurred no more frequently in homozygous HFE mutants than in age- and sex-matched controls who were homozygous for wild-type HFE alleles. Only 1 of the 152 subjects had multiple stigmata of classically clinical hemochromatosis.Thisstudyestimatesthepenetrance of the mutation, even for homozygotes, to be less than 1%. [11]

The conclusion drawn by Buetler et al has been the basis for considerable debate; discussants point to the lack of liver biopsies confirming the diagnosis, varied definitions of penetrance, and the high frequency of symptoms in the control population. Perhaps most notably, the health plan had previously initiated a hemochromatosis screening program, thereby excluding a quarter of the C282Y homozygotes because they had a previous diagnosis of hereditary hemochromatosis.

Allen et al followed, for 12 years, 31,192 Australian subjects enrolled in the Melbourne Collaborative Cohort Study. From this sample, 203 were homozygous for the C282Y HFE mutation, or 1 case per 146 subjects. A total of 28% of men and 1.2% of women satisfied the criteria for iron overload, based on serum laboratory results or other clinical manifestations. Seventeen of the 40 patients who had indications for liver biopsies proceeded with biopsy; all 17 showed evidence of iron overload, with 12 showing liver cirrhosis or fibrosis. The authors concluded that disease related to iron overload develops commonly in men who are homozygous for the C282Y mutation, especially when laboratory evidence of iron overload is present. [12]

In a study by the European Association for the Study of the Liver (EASL) of the prevalence of C282Y homozygosity in clinically recognized individuals with iron overload (meta-analysis of 32 studies with a total of 2802 hemochromatosis patients of European ancestry), an analysis of pooled data showed that 80.6% (2260 of 2802) of hemochromatosis patients were homozygous for the C282Y polymorphism in the HFE gene. Compound heterozygosity for C282Y and H63D was found in 5.3% of hemochromatosis patients (114 of 2117). In the 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 of the control population). [13]

According to the EASL, disease penetrance based on symptoms (eg, fatigue, arthralgia) is difficult to assess due to the nonspecific nature and high frequency of such symptoms in control populations.  They note that C282Y homozygotes identified during family screening have a higher 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%). [13]

The 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, then large-scale screening programs might not be justified. However, if the 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, the matter remains largely unresolved.


In patients with clinical hemochromatosis, the 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% to 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. In 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 the depleted circulating serum iron by mobilizing iron stores from tissues. [16]


Testing for the Genetic Mutation

Genetic testing for hereditary hemochromatosis detects the C282Y, H63D, or S65C HFE mutations. However, as discussed above, 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 the risk for disease in at-risk patients.