Hereditary haemochromatosis

What is hereditary haemochromatosis?

Synonyms: genetic haemochromatosis, HLA-linked haemochromatosis, bronze diabetes

Hereditary haemochromatosis (HHC) is an autosomal recessive genetic disease in which increased intestinal absorption of iron causes accumulation in tissues which may lead to organ damage. Organs that may be affected by the amount of iron deposits include the liver, pancreas, joints, heart and skin

Liver fibrosis, cirrhosis and hepatocellular carcinoma are the most serious complications of iron overload. Early diagnosis and treatment are therefore essential.

Epidemiology¹²

• Hereditary haemochromatosis is the most common autosomal recessive disorder in White populations, with a prevalence of 1 in 300 to 1 in 500.

• HHC type 1 is primarily seen in people of Northern European descent but types 2-4 are seen throughout the world.

• HHC is 6 times more common in White people than Black.

• Men are affected 2-3 times more commonly than women.

Hereditary haemochromatosis causes (aetiology)¹

Defects of the HFE gene (located on the short arm of chromosome 6) cause the majority of cases of inherited haemochromatosis, which is often referred to as HFE haemochromatosis (HFE-HC). HFE was the only known gene associated with haemochromatosis but it is now known that there are other genetic associations.³

Type 1 hereditary hemochromatosis occurs in patients who are typically homozygous for loss-of-function mutations in HFE. While more than 100 HFE mutations can cause Type 1 hereditary hemochromatosis, the most common mutation is the p.Cys282Tyr or C282Y variant; the second most common mutation is the p.His63Asp or H63D mutation.

Type 2 hereditary hemochromatosis is also inherited in an autosomal recessive pattern and the typical age of onset is in adolescence or early adulthood (15 to 20 years). Historically, this disease was referred to as "juvenile" hemochromatosis. Type 2a is due to a mutation in the gene HFE2. Type 2b is due to mutations in the hepcidin antimicrobial peptide (HAMP) gene on chromosome 19.

Type 3 hereditary hemochromatosis, also inherited in an autosomal recessive fashion, is due to mutations in the transferrin-receptor gene (TFR2) on chromosome 7.

Type 4 hereditary hemochromatosis is the only known type to be inherited in an autosomal dominant fashion. The mutations occur in the ferroportin transport protein known as ferroportin/solute carrier family 40 member 1, encoded by SCL40A1 on chromosome 2.

Hereditary haemochromatosis symptoms and signs¹⁴

• Early diagnosis can be difficult because HHC is often asymptomatic until the late stages of disease. Diagnosis of type 1 HHC is usually made between the ages of 40 and 50 in males and after the menopause in females (due to blood - and therefore iron - loss in menstruation.

• Initial symptoms are usually vague and nonspecific. Almost all patients complain of fatigue and lethargy; arthralgia is also common.

• It is common for people to have symptoms for up to 10 years before the diagnosis is made.

• HHC may be diagnosed incidentally - eg, following abnormal serum ferritin or LFTs.

• Type 2 HHC is usually diagnosed before the age of 20, type 3 between the ages of 30 and 40, and type 4 at any age between 10 and 80.¹

• Symptoms of advanced disease include:

  • Diabetes.

  • Koilonychia - koilonychia affecting the thumb and forefinger is seen in 50% of people with HHC.

  • Diffuse hyperpigmentation - this is seen in 90% of people with HHC. It was historically described as "bronzing of the skin",

  • Hepatic involvement. Liver dysfunction is seen in 75% of patients; jaundice may or may not be present. Liver involvement can cause abdominal pain, hepatomegaly, cirrhosis, portal hypertension, ascites, and splenomegaly.

  • Arthropathy, especially of the second and third metacarpophalangeal joints but also the knees, wrists, hip, back, neck, and feet.

  • Cardiac involvement. This can lead to arrhythmias, restrictive or dilated cardiomyopathy, and cardiac failure.

  • Pituitary hypogonadism. This can be seen in decreased libido or erectile dysfunction. Amenorrhoea may occur in women.

  • Hypopituitarism, thyroid dysfunction, adrenal dysfunction and parathyroid defects.

  • Osteoporosis.

  • Parkinsonism, chorea, and tremors. This is thought to be due to iron deposition in the basal ganglia, dentate, red nuclei, and the substantia nigra.

  • Infections. There is an increased risk of infection with Yersinia enterocolitica, Listeria monocytogenes, and V vulnificus.

  • Cancer. The risk of hepatocellular carcinoma is 20 times higher in people with HCC than the general population.

Screening⁵

Recommendations for genetic testing:

• General population: genetic screening for HFE-HC is not recommended, as disease penetrance is low and only in few C282Y homozygotes will iron overload progress.

• HFE testing is not recommended in patients with unexplained arthritis or arthralgia or with type 2 diabetes.

Investigations and diagnosis of hereditary haemochromatosis

This involves assessment of iron overload, genetics and organ damage. These tests need careful interpretation.

Initial investigations⁵

• The first step in testing for haemochromatosis is the assessment of serum iron parameters, which should include transferrin saturation and serum ferritin.

  • Serum ferritin is the most widely used biochemical test for iron overload. Serum ferritin is a very sensitive test for iron overload in haemochromatosis and normal serum concentrations essentially rule out iron overload.

  • However, ferritin has low specificity, as elevated values can be the result of a range of inflammatory, metabolic and neoplastic conditions such as diabetes mellitus, alcohol consumption and hepatocellular or other cell necrosis.

  • Serum iron concentration and transferrin saturation do not quantitatively reflect body iron stores and should therefore not be used alone as markers of tissue iron overload.

• Tests to exclude other common causes of hyperferritinaemia: inflammation (check CRP), chronic alcohol consumption, liver cell necrosis (alanine aminotransferase), metabolic syndrome (blood pressure, BMI, triglycerides, glucose), anaemia (haemoglobin, mean cellular volume and further tests depending on ethnic background - eg, testing for sickle cell disease).

• LFTs.

• Other tests, including endocrine investigations, may be indicated, depending on the clinical situation.

• Investigations for other causes of abnormal liver function (eg, hepatitis serology) may be relevant.

Further investigations⁵

• Genetic testing:

  • Individuals with clinical and biochemical signs of haemochromatosis, elevated transferrin saturation and high serum ferritin concentrations, or otherwise unexplained persistently elevated transferrin saturation should be genetically tested for haemochromatosis after informed consent for genetic testing has been obtained.

  • Patients with increased liver iron evident on liver biopsy or MRI should be clinically assessed and biochemically tested for haemochromatosis (serum ferritin and transferrin saturation).

  • Adult individuals with a positive family history of first-degree relatives with haemochromatosis should be genetically tested for haemochromatosis after informed consent for genetic testing has been obtained.

• Liver biopsy:

  • In C282Y homozygote patients with increased iron stores, liver biopsy is no longer necessary to diagnose haemochromatosis.

  • Liver biopsy may still be indicated - eg, to show whether iron stores are increased or not and in assessing liver fibrosis. It may also be indicated where liver enzymes are elevated in a diagnosed case of haemochromatosis or where serum ferritin levels are more than 1000 µg/L.⁶
    One large American study found that hepatic fibrosis and cirrhosis can exist without symptoms.⁷

• MRI may be useful to detect and quantify hepatic iron excess and may also help to identify heterogeneous distribution of iron within the liver, differentiate parenchymal from mesenchymal iron overload and to detect small iron-free neoplastic lesions.

Differential diagnosis

Differential diagnosis of HHC:

• Other hereditary forms of haemochromatosis: hereditary H ferritin cataract syndrome, haem oxygenase deficiency, neonatal iron overload, aceruloplasminaemia, congenital atransferrinaemia or hypotransferrinaemia, divalent metal transporter 1 gene defect.

• Secondary iron overload:

  • Iron loading anaemias.

  • Ineffective erythropoiesis.

  • Thalassaemic syndromes.

  • Sideroblastic anaemia.

  • Myelodysplastic syndrome.

  • Congenital dyserythropoietic anaemia.

  • Parenteral iron overload (including multiple blood transfusions).

• Other diagnoses: metabolic syndrome, obesity, hypertension, insulin resistance.

• Drug toxicity.

• Chronic haemodialysis.

• Chronic liver disease, hepatitis, alcohol misuse, non-alcoholic steatohepatitis, liver cirrhosis.

• Porphyria cutanea tarda.

• Other types of skin pigmentation - eg, Addison's disease.

• Other forms of liver disease - which may co-exist or contribute.

Hereditary haemochromatosis treatment and management¹⁸

• Patients with HFE-HC and evidence of excess iron should be treated with phlebotomy. Phlebotomy is usually carried out by removing 500 ml of blood (250 mg iron) once or twice a week. Adequate hydration before and after treatment and avoidance of vigorous physical activity for 24 hours after phlebotomy are recommended.

• Once iron levels are stabilised, lifelong, but less frequent, phlebotomy (typically 3-4 times a year) is required. The aim to obtain a ferritin level of less than 50 µg/L. Some people with hereditary haemochromatosis may achieve this by donating blood.

• Phlebotomy may improve iron removal and may improve insulin sensitivity, skin pigmentation, and fatigue but will have no effect on cirrhosis, hypogonadism or arthropathy.

• Alcohol should be avoided in HHC.

• To minimise the risk of additional complications, patients with HFE-HC could be immunised against hepatitis A and B while iron-overloaded.

• Liver transplantation:

  • End-stage liver disease may be an indication for liver transplantation.

  • Patients with iron overload conditions have a lower survival rate after transplantation than those who do not.

Monitoring

• Serum ferritin is the main investigation used because it correlates with symptoms and the risk of complications.

• When serum ferritin is less than 1000 μg/L the risk of serious liver damage is below 1%. Serum ferritin levels above 1000 μg/L are an indication for liver biopsy because of the risk of cirrhosis.

• When a liver biopsy shows cirrhosis, periodic screening for hepatocellular carcinoma, using echography or magnetic resonance imaging, is essential.

Prognosis

• C282Y homozygous patients with clinically ascertained HC have an increased risk of developing liver disease and hepatocellular carcinoma.

• Observational studies of patients who received adequate and timely treatment show that overall mortality is not higher than in the general population.