Hereditary haemochromatosis

What is hereditary haemochromatosis?

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

Hereditary haemochromatosis (HHC) is a heterogeneous group of disorders related to deficiency of the iron regulatory hormone hepcidin. HHC is an autosomal recessive genetic disease in which increased intestinal absorption of iron causes accumulation in tissues, especially the liver, which may lead to organ damage. Other organs that may be affected by the amount of iron deposits include the pancreas, joints, heart, skin and gonads.

Liver fibrosis, cirrhosis and hepatocellular carcinoma are the most serious complications of iron overload. Early diagnosis and treatment are therefore essential¹ .

Hereditary haemochromatosis causes (aetiology)²

Defects of the HFE gene (located on the short arm of chromosome 6) cause the majority of cases of inherited haemochromatosis, which is therefore 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.

A systematic review has shown that about 0.4% of people of northern European descent have the genetic mutation that increases the risk of developing haemochromatosis but the clinical penetrance of the mutation is much lower than the genetic prevalence³ .

The known mutations of the HFE gene are C282Y and H63D. The C282Y mutation is most common in white populations⁴ . The prevalence of C282Y homozygosity in a meta-analysis of 2,802 haemochromatosis patients of European ancestry was 80.6%. HHC is a relatively common genetic disorder in northern European populations and is probably under-diagnosed³ .

Haemochromatosis is inherited in an autosomal recessive pattern but the clinical picture is more complex because the expression (penetrance) of the gene varies. This means that not everyone who is homozygous for HHC genes will develop clinical disease. The variation in gene expression may be due to other factors affecting iron accumulation.

Other types of inherited haemochromatosis⁵ :

• There are rarer forms of inherited haemochromatosis, where patients have 'classical' clinical features of haemochromatosis but lack mutations in the HFE gene.

• Juvenile haemochromatosis is an inherited condition in which there is clinical onset in the second or third decade. The gene responsible is probably located on chromosome 1.

• African iron overload is a syndrome originally ascribed to drinking beer brewed in iron containers; however, a genetic influence has been detected.

• Neonatal haemochromatosis is a condition of acute liver damage with iron accumulation. This includes severe iron overload of unknown cause in neonates.

Hereditary haemochromatosis symptoms

• Early diagnosis is difficult because HHC is often asymptomatic until the late stages of disease. Signs and symptoms usually start between ages 40-60 in males and after the menopause in females⁶ :

  • Initial symptoms are usually vague and nonspecific - eg, fatigue, weakness, arthropathy affecting various joints, nonspecific abdominal problems, erectile dysfunction and heart problems³ .

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

• Symptoms of advanced disease include diabetes, bronzing of the skin, hepatomegaly and arthropathy, especially of the second and third metacarpophalangeal joints³ . Other presenting features of advanced disease include:
  

  • Impotence, amenorrhoea or hypogonadism.

  • Cirrhosis.

  • Diabetes mellitus.

  • Cardiac disease - arrhythmias or cardiomyopathy.

  • Neurological or psychiatric symptoms - impaired memory, mood swings, irritability, depression.

Screening

Recommendations for genetic testing⁷ :

• 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 should be considered in patients with unexplained chronic liver disease pre-selected for increased transferrin saturation.

• HFE testing could be considered in patients with:
  

  • Porphyria cutanea tarda

  • Well-defined chondrocalcinosis

  • Hepatocellular carcinoma

  • Type 1 diabetes

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

Siblings of patients with HFE-related HHC should undergo screening, since they have a 25% chance of being susceptible. Serum ferritin and transferrin saturation should be assessed. Ideally HFE mutation analysis should be encouraged after appropriate genetic counselling.

Investigations and diagnosis of hereditary haemochromatosis

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

Initial investigations

• Assessment of iron stores⁷ :
  

  • Patients with suspected iron overload should first receive measurement of fasting transferrin saturation and serum ferritin, and HFE genetic testing should be performed only in those with increased transferrin saturation.

  • 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 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)³ .

• 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 investigations

• Genetic testing⁷ :
  

  • HFE testing for the C282Y and H63D polymorphism should be carried out in all patients with otherwise unexplained increased serum ferritin and increased transferrin saturation.

  • C282Y homozygosity is required for the diagnosis of HFE-HC, when iron stores are increased.

  • Diagnosis of HFE haemochromatosis should not be based on C282Y homozygosity alone but requires evidence of increased iron stores.

• Liver biopsy:
  

  • In C282Y homozygote patients with increased iron stores, liver biopsy is no longer necessary to diagnose haemochromatosis⁷ .

  • It is now rarely required because genetic testing for HFE mutations is very reliable in the diagnosis of haemochromatosis in Caucasians and the majority of patients with haemochromatosis are now diagnosed at an early stage, well before permanent tissue damage occurs⁸ .

  • Liver biopsy may still be indicated - eg, to show whether iron stores are increased or not and in assessing liver fibrosis⁷ . 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/L⁹ .
    One large American study found that hepatic fibrosis and cirrhosis can exist without symptoms¹⁰ .

• 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 lesions⁷ .
  

Genetic tests interpretation^{6 11}

Differential diagnosis

Differential diagnosis of HHC³ :

• HHC: HFE-associated HHC (type 1), C282Y homozygosity, C282Y/H63D compound heterozygosity.

• Other HFE gene defects: non-HFE-associated HHC, haemojuvelin gene defect, hepcidin gene defect, transferrin receptor 2 gene defect, ferroportin gene defect.

• 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 management⁹

• Patients with HFE-HC and evidence of excess iron should be treated with phlebotomy. Phlebotomy should be 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

• Before the initiation of phlebotomy, patients with HFE-HC should be assessed for complications (including diabetes mellitus, joint disease, endocrine deficiency (hypothyroidism), heart failure, porphyria cutanea tarda and osteoporosis), which should be managed regardless of whether or not HC is the underlying cause and whether there is symptomatic relief or improvement during phlebotomy.

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

• 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.

Monitoring³

• 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.

Pregnancy

• Iron supplements should not be given routinely to pregnant women with HFE-related HC.

• Serum ferritin should be monitored.

• Iron deficiency should be treated according to the usual guidelines applied to pregnancy.

• If the ferritin is high, therapeutic phlebotomy should be deferred until the end of pregnancy unless there are cardiac or hepatic issues, in which case the appropriate specialist should be involved in the discussion of the positive and negative effects of treatment.

Diet

• Compliance with phlebotomy will prevent iron overload.

• Iron-containing vitamin preparations and iron-supplemented foods such as breakfast cereals should be avoided. Compliance with phlebotomy will prevent iron overload.

• Tea drinking has been reported as possibly reducing the increase in iron stores in HC patients but this finding has not been confirmed.

• Vitamin C has been reported to be potentially toxic in patients with iron overload. This was from a single case report of a patient in whom vitamin C could have had a negative effect on cardiac function but has led to the recommendation that it is prudent to limit ingestion of vitamin C supplements to 500 mg/day⁷ .

• Excess alcohol ingestion leads to increased hepatic damage in HFE-HC. There is a linear correlation between alcohol intake and serum iron indices and increased iron absorption in alcoholics.

Prognosis³

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

• A population screening survey showed that the absolute risk of liver damage is about 5% in homozygous men and less than 1% in women. Patients with either of these complications have a reduced life expectancy.

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