Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) is by far the most common inherited cause of iron overload (1). Without diagnosis and therapeutic intervention, there is a risk that iron overload will occur resulting in tissue damage and potentially premature death. Less common forms of iron overload associated with mutations of transferrin receptor 2, (TFR2), hepcidin, hemojuvelin, and a sub-type of ferroportin (1) will not be discussed. 

Hereditary hemochromatosis is associated with a gene known as HFE on the short arm of chromosome 6 (2). Specifically, a mutation in this gene, known as the C282Y mutation, has been identified as the most common mutation in HH (3). The frequency of C282Y homozygosity in the general population is approximately 1:200-300 patients (4-5). Still, there are many patients with C282Y homozygosity who never develop overt hemochromatosis. In most studies, C282Y homozygosity has been found in about 90% of cases of hereditary hemochromatosis. However, in 3-5% of cases, there is a second mutation of H63D with C282Y resulting in compound heterozygosity that accounts for HH. In patients without the classic genetic mutations associated with HH, a secondary cause of iron overload should be considered such as alcohol consumption, chronic viral hepatitis, porphyria cutanea tarda, fatty liver disease, chronic hemolytic anemia (thalassemia/sickle cell anemia/sideroblastic anemia), multiple blood transfusions or other underlying liver disease (2).

Clinical Features

The classic presentation of hemochromatosis includes increased skin pigmentation (bronze color), elevated liver enzymes/cirrhosis, and diabetes mellitus. Also common are fatigue, arthropathy, impotence in males, and cardiomyopathy (enlarged heart) which may include conduction defects. Interestingly, overt clinical hemochromatosis is much more frequent in males than in females since women tend to have iron loss with menstruation and pregnancy. Classically, women who do present with hemochromatosis are post menopausal or have had hysterectomies. The majority of cases of symptomatic hemochromatosis are diagnosed between 40 and 60 yeas of age. In two studies, it was reported that the presentation of hemochromatosis has shifted from the classic manifestations described above to 75% of such patients being asymptomatic at presentation (6,7). Many cases of HH come to clinical attention only secondary to elevated liver enzymes or elevated serum iron levels. Hepatocellular carcinoma (HCC) is a well recognized complication of HH and develops in approximately 15 to 30% of patients with HH who have cirrhosis (8-12) . In patients with cirrhosis and HH, approximately 70% will have clinical diabetes. Cardiac involvement from iron overload has also been reported, and can present with heart failure. Cardiac complications are thought secondary to iron deposits in the myocardium and conductive system predisposing to dysrhythmias. In approximately 50% of patients, they will develop a specific arthropathy classically affecting the second and third metacarpophalangeal joints. 
Genetic testing for HH in the general population is NOT recommended due to low disease penetrance in those homozygous from the C282Y mutation (1). HFE testing should be performed in patients with chronic unexplained liver disease, and chondrocalcinosis (1). Per the American Association for the Study of Liver Disease (AASLD), screening for HH should be considered in those with type II diabetes mellitus, particularly if there is hepatomegaly, atypical cardiac disease or early onset sexual dysfunction (2). The AASLD also recommends screening for HH in first degree relatives of confirmed cases of HH > age 20 (2)


Classically, patients who have hemochromatosis will have an elevated ferritin. In fact, normal serum concentrations of ferritin essentially rule out HH (13). Serum ferritin, however, does suffer from a low specifity as a range of inflammatory, metabolic and neoplastic conditions will elevate the ferritin. The AASLD recommends calculating a transferring saturation (TS) (iron/total iron binding capacity) as a screen for HH. In cases where the TS exceeds 50% for women and 60% for men the sensitivity was 92% the specifity was 93% and the positive predictive vale was 86% for a diagnosis of HH (14-16). Others recommend using a lower threshold of TS, specifically 45% for both genders to increase the sensitivity HFE detection (1). Liver biopsy has traditionally been used to quantitate the amount of iron present in HH and to provide staging of fibrosis using the hematoxylin-eosin and masson trichrome staining. Liver biopsy also allows for evaluation of alternative diagnosis that may explain the patients liver disease. Both the AASLD and European Association for the Study of the Liver (EASL) recommend liver biopsy in C282Y homozygotic patients with serum ferritin > 1000 mcg/L, elevated AST/ALT or age >40 years (1,2). In cases in which the patient with a C282Y homozygous mutation but is < 40 years, has normal AST/ALT and has a ferritin <1000 mcg/L the likelihood that the patient has cirrhosis is low and as such, a liver biopsy would not be required.


The treatment of hemochromatosis is focused on reducing the amount of iron in the body which is best accomplished by phlebotomy. In cases in which the patient is intolerant to phlebotomy or there is a contraindication to phlebotomy iron chelators may be used. Iron chelators include deferoxamine (Desferal®) which is administered as a parenteral (IV) infusion and an oral agent, Deferasirox (Exjade®). When starting phlebotomy it is recommended that one unit of blood should be removed once weekly as tolerated (equal to 250 mg of iron). In those with significant iron overload, it may take up to 2-3 years to reduce the iron stores to the end point (just short of iron deficiency). Serum ferritin should be assessed after every 10-12 phlebotomies with initial therapy. The target of the phlebotomy is a ferritin of 50 mcg/L. In the maintenance phase, most patients require the removal of 3-4 units of blood annually (2). There are no studies proving that dietary restriction of iron has an additional beneficial effect in patients already undergoing phlebotomy (1). The important issue is maintaining a healthy, well balanced diet. Iron containing vitamin preparations and iron fortified foods should be avoided. Based on an association of vitamin C with worsening cardiac function in HH it has been recommended to limit vitamin C supplementation to no more than 500 mg/day (17,18). Similarly, excess alcohol may accelerate hepatic injury and is associated with an increase in serum iron indices and increased iron absorption in those that with alcohol dependence (19-21)

Management of major complications

Given the significant increase in risk for HCC in those with HH, in cases of cirrhosis patients should have ultrasound and alpha fetoprotein measurement every 6 months. In the absence of cirrhosis in HH surveillance for HCC is not recommended (1). In cases of progressive hepatic failure in HH liver transplant has been successfully performed, however, the survival rates are lower than in other transplant populations. Survival for transplant patients is around 64% after one year and falls to 34% after 5 years (22). If possible, iron depletion prior to transplant is ideal. The primary causes of death in liver transplant for HH are heart disease/arrhythmia, infection and malignancy (22).


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