Hereditary haemochromatosis (HH)

What is Hereditary haemochromatosis (HFE-HC)?

HFE-HC is an autosomal recessive iron-overload disorder caused by pathophysiological predisposition to increased and inappropriate absorption of dietary iron. It is associated with mutation of the HFE gene, located on chromosome 6. In most cases the mutation is a single-base change that results in the substitution of tyrosine for cysteine at position 282 of the HFE protein (C282Y). Other mutations in HFE, less common than C282Y, have also been described. The clinical effects of a mutation in which aspartic acid replaces histidine at position 63 (H63D), for example, appear to be limited, although 1-2% of persons with compound heterozygosity for C282Y and H63D seem predisposed to disease expression. In most studies C282Y/C282Y homozygosity has been found in 80% of patients with HFEHC, while compound heterozygosity (C282Y/H63D) accounts for 3% to 5% of such cases in published series. Rarer forms of genetic iron overload recently attributed to pathogenic mutations of transferrin receptor 2, (TFR2), hepcidin (HAMP), hemojuvelin (HJV), or to a sub-type of ferroportin (FPN) mutations may account for the rest of the cases.

The penetrance and progression of C282Y mutation is variable. Available data suggest that up to 38% to 50% of C282Y homozygotes may develop iron overload, with 10% to 33% eventually developing haemochromatosis-associated morbidity.

Discuss the clinical manifestations of HFE-HC ?

The iron deposition in HFE-HC primarily occurs in parenchymal cells, with reticuloendothelial (RE) cell accumulation occurring very late in the disease. This is in contrast to transfusional iron overload in which iron deposition occurs first in the RE cells and then in parenchymal cells. The clinical condition of HFE-HC evolves in a series of stages beginning with clinically insignificant iron accumulation (0-20 years of age, 0-5g parenchymal iron storage). This evolves to a stage of iron overload without disease (approximately 20-40 years of age, 10-20g parenchymal iron storage), which if left untreated, may progress to a stage of iron overload with organ damage (usually more than 40 years of age and more than 20g parenchymal iron storage).

Fatigue (75%) and arthralgia (45%) are the most common presenting symptoms.

Skin — A combination of primarily melanin and iron deposition causes skin bronzing, slate grey appearance or hyperpigmentation, Porphyria cutanea tarda may be associated with HFE-HC.

Liver disease — Hepatomegaly, elevated liver enzymes, and cirrhosis. HCC is associated with cirrhosis and the amount of mobilisable iron.

Diabetes mellitus — This complication is due to progressive iron accumulation in the pancreas.

Arthropathy — Second and third MCP joints are characteristically affected. HFE-HC can be associated with an arthropathy that displays the full spectrum of calcium pyrophosphate crystal deposition disease (i.e. pseudogout, chondrocalcinosis, and chronic arthropathy).

Heart disease — Dilated cardiomyopathy and conduction disturbances such as the sick sinus syndrome, due to excess deposition of iron within the myocardium. Treatment with phlebotomy or chelation therapy has been associated with reversal of the left ventricular dysfunction.

Hypogonadism — Due to excess iron deposition in pituitary cells, leading to reduced serum levels of a number of trophic hormones. Secondary hypogonadism causes decreased libido and impotence in men. Other pituitary deficiencies may occur, but are much less frequent. Primary hypogonadism, presumably due to testicular iron deposition, also can occur, but is much less common. Repeated phlebotomy to remove excess tissue iron deposits may reverse the hypogonadism. Amenorrhea can occur in women but appears to be much less common than hypogonadism in men. Hypothyroidism occurs in approximately 10% of males.

Osteoporosis — Patients are at risk of osteoporosis, and should undergo a DEXA scan.

Susceptibility to specific infections — Iron overload states appear to be risk factors for infection with Listeria and Yersinia enterocolitica. Iron overload of macrophages can diminish phagocytosis, while high serum iron levels may increase bacterial virulence. Septicemia from Vibrio vulnificus, another iron-requiring bacterium, is also common in patients with HFEHC who ingest uncooked seafoods. Accordingly, it has been recommended that patients with HFEHC avoid consumption of uncooked seafood.

Discuss the diagnosis of HFE-HC ?


A search for common causes of hyperferritinaemia should be made initially. Ferritin has low specifity as elevated levels are found in a range conditions including; inflammation (check CRP), neoplastic conditions (ESR, CT scan), chronic alcohol consumption, and hepatocellular or other cell necrosis (check AST/ALT/CK). Of note one third of patients with NAFLD and the metabolic syndrome (check BP, cholesterol, serum glucose, triglycerides), have what is called the dysmetabolic iron overload syndrome.

Transferrin saturation (TS: 100X SI/TIBC) and serum ferritin are used as initial tests. If TS <45% and serum ferritin is normal, a diagnosis of HFE-HC is excluded. A TS >45% in females and >50% in males with a raised serum ferritin will need genetic testing to confirm the diagnosis. If the genotype is homozygous C282Y/C282Y, a diagnosis of HFE-HC is confirmed. Of note, compound heterozygotes for C282Y/H63D usually present with mild iron overload, which is associated with comorbid factors such as obesity, NAFLD, chronic alcohol consumption, and end-stage cirrhosis.

For all other genotypes, then confounding cofactors, non-HFE iron overload disease (ferroportin disease, aceruloplasminemia), hepatic or other haematological diseases will need to be excluded and this may need a liver biopsy/MRI imaging. L-ferritin gene mutations cause hyperferritinaemia-cataract syndrome with an elevated serum ferritin, TS <45% and normal liver iron content.

Discuss the role of genetic testing?

  • HFE testing should be considered in patients with unexplained chronic liver disease pre-selected for increased TS.
  • HFE testing could be considered in patients with:
    • Porphyria cutanea tarda
    • Well-defined chondrocalcinosis
    • Hepatocellular carcinoma
    • Type 1 Diabetes

Discuss family screening

  • Siblings of patients with HFE-related HC must undergo screening, since they have a 25% chance of being susceptible.
  • HFE genotyping of the unaffected spouse is valuable to establish the need for genetic testing in children later on in life, once above the age of consent.

Discuss the role of liver biopsy?

  • Liver biopsy and hepatic iron evaluation are also recommended in compound heterozygotes (C282Y/H63D), C282Y heterozygotes, or non-HFE mutated individuals who have indirect markers of iron overload, particularly if they also have abnormal liver enzymes or clinical evidence of liver disease.
  • Liver biopsy could be offered to document the degree of fibrosis in C282Y homozygotes that are over the age of 40 years, or have an elevated AST level, hepatomegaly, or have a serum ferritin >1,000µg/L
  • Patients less than 40 years of age who have no clinical evidence of liver disease (raised AST, hepatomegaly, etc.) and whose serum ferritin <1,000µg/L are unlikely to have significant hepatic injury and thus may be offered therapeutic phlebotomy without the necessity for a liver biopsy.
  • Serum ferritin is an extremely useful diagnostic threshold test. If the ferritin is <1000µg/L, the patient has essentially no risk of having cirrhosis and thus liver biopsy is optional. By contrast, if the ferritin is >1000µg/L, there is a fairly high risk that the patient will have cirrhosis and thus liver biopsy is indicated. Documentation of extensive bridging fibrosis or cirrhosis by liver biopsy has a profound impact on the prognosis in HFE-HC patients. HFE-HC patients have a normal life span in the absence of cirrhosis and diabetes.  .
  • A hepatic iron index or HII (hepatic iron conc. or HIC/age in years) of >1.9 µmol/g/y is diagnostic of HFE-HC.

Future tests for assessing fibrosis

  • Serum hyaluronic acid is reported to correlate with the degree of hepatic fibrosis in HFE-HC, and may provide an alternative approach to liver biopsy for the diagnosis of advanced fibrosis .
  • Transient elastography can also be helpful for determination of advanced fibrosis and cirrhosis.

Discuss the management of HFE-HC (C282Y homozygosity)?

  • If ferritin is normal then once yearly follow up is advised.
  • If ferritin is elevated then initial evaluation should include AST, ALT, fasting serum glucose with further investigations according to clinical features (ECG/ECHO/gonadotropic hormones/liver scanning).
  • Liver biopsy should be considered as discussed above.
  • Those with cirrhosis should have 6-monthly HCC screening with (Alpha)&-FP and US liver as they have a 100-fold greater chance of developing HCC compared with the normal population.

Therapeutic phlebotomy

Is the most effective way to remove iron. There is no data from which to base the optimal treatment regimen and target serum iron indices. Generally, the indication for initiating phlebotomy is ferritin >200µg/L in females and >300µg/L in males.

  • One phlebotomy (removal of 500ml of blood) weekly or biweekly.
  • Check haematocrit prior to each phlebotomy; allow haematocrit to fall by no more than 20% of prior level.
  • Check ferritin level after 10-12 phlebotomies.
  • Stop frequent phlebotomy when ferritin falls below 50µg/L (usually takes 3 to 6 months)
  • Continue phlebotomy at intervals to keep serum ferritin between 50-100µg/L. The frequency of maintenance phlebotomy varies from monthly to 3-4 times a year.

The blood withdrawn from a patient with HFE-HC can be used for direct transfusion. Each 500ml of whole blood removed contains 200 to 250mg of iron. The marrow, in providing replacement for the lost Hb, mobilises iron from tissue stores, thereby reducing the degree of iron overload.


A normal balance diet is sufficient. However, dietary supplements containing iron, iron fortified cereals should be avoided and limit vitamin C intake to 500mg/day.

Discuss quantitative phlebotomy?

This is a way of confirming iron overload when iron overload is suspected and a liver biopsy cannot be performed. Iron overload can be confirmed or refuted by determining the number of weekly 500 mL phlebotomies which is required to produce iron deficient erythropoiesis. Normal men have approximately 1 g of iron stores. As a result, 4-5 phlebotomies will produce an iron deficient state (microcytosis or hypochromia with anaemia). In contrast, patients with significant iron loading usually have at least 5-20g of iron stores, requiring at least 20 units of phlebotomy to induce iron deficiency.

Discuss the prognosis?

The major causes of death are decompensated cirrhosis, hepatocellular carcinoma (HCC), diabetes mellitus, and cardiomyopathy. HCC accounts for about 30% of all deaths in HFE-HC, whereas other complications of cirrhosis account for an additional 20%. HCC is exceedingly rare in noncirrhotic HFE-HC. There is overwhelming evidence that institution of phlebotomy therapy before cirrhosis and/or diabetes develop will significantly reduce the morbidity and mortality of HFE-HC. Certain clinical features may be ameliorated by phlebotomy (malaise, fatigue, skin pigmentation, insulin requirements in diabetes, abdominal pain), whereas other features are either less responsive to iron removal or do not respond at all (arthropathy, hypogonadism, cirrhosis). Cirrhosis does not reverse with iron removal and the development of decompensated liver disease is an indication to consider OLT.

Discuss secondary causes of iron overload?

Secondary iron overload occurs in ineffective erythopoiesis like thalassaemia major, sideroblastic anaemia, chronic haemolytic anaemia’s etc and chronic liver diseases like hepatitis C and B, alcohol-induced liver disease, porphyria cutanea tarda, fatty liver disease etc. Phlebotomy is useful only in certain forms of secondary iron overload. It has been used in African iron overload and porphyria cutanea tarda with reduction in morbidity and mortality.
 In secondary iron overload associated with ineffective erythropoiesis, iron chelation therapy with parenteral deferoxamine is the treatment of choice.


  1. AASLD Practice Guidelines. Diagnosis and Management of Hemochromatosis.
  2. EASL Clinical Practice Guidelines for HFE Hemochromatosis. J Hepatol (2010).
  3. Iron in fatty liver and in the metabolic syndrome: A promising therapeutic target. Dongiovanni P, Fracanzani AL, Fargion S, Valent L. J Hepatol. 2011 Oct;55(4):920–932.

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