Hereditary Haemochromatosis

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

Haemochromatosis is the clinical condition of iron overload. Hereditary haemochromatosis (HHC) refers predominantly to iron accumulation due to the genetic mutations in the HFE gene. This leads to excessive absorption of iron from food.¹

HHC is probably under-recognised. Early diagnosis and treatment is important to preserve life expectancy.

HHC is a relatively common genetic disorder in Northern European populations.

It 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.

The commonest cause of HHC is mutation in the HFE gene on chromosome 6:

• The known mutations of the HFE gene are C282Y and H63D; the latter is considered a 'minor mutation'.
• In the UK, over 90% of patients with HHC are homozygous for the C282Y mutation of the HFE gene. Another 4% are compound heterozygotes (C282Y/H63D).
• In the general (white) population, about 1 in 200 people are homozygous for the C282Y mutation. Of these, most accumulate iron but only a minority will go on to develop clinical symptoms.

Other types of inherited haemochromatosis:

• 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 in neonates of unknown cause.

Pathogenesis¹

Normal iron balance is maintained mainly by regulating the amount of dietary iron that is absorbed. In HHC, there is continued intestinal absorption of iron, despite normal and then increased total body iron. The body cannot excrete excess iron, so it accumulates in tissues. The exact mechanism of dysregulation in HHC is not known.

Presentation and complications^1,2

• Early diagnosis is difficult, because HHC is often asymptomatic until the late stages of disease.
• Symptoms usually start between ages 30-50, but may begin earlier.³
• Symptoms can be vague and non-specific.
• HHC may be diagnosed incidentally, e.g. following abnormal serum ferritin or liver function tests.
• Possible presenting features are:
  • Fatigue or weakness.
  • 'Bronze' skin pigmentation - 'like a permanent suntan'.
  • Arthralgia - may affect any joint but commonly in the MCP and PIP joints of the index and middle fingers. Arthritis found only in the first two finger joints is highly suggestive of HHC.²
  • Impotence, amenorrhoea or hypogonadism - due to pituitary gland involvement.
  • Hepatomegaly, cirrhosis, abnormal LFTs or upper abdominal pain.
  • Diabetes mellitus.
  • Cardiac disease - arrythmias or cardiomyopathy.
  • Neurological or psychiatric symptoms - impaired memory, mood swings, irritability, depression.

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

Initial investigations

• Transferrin saturation (calculated from serum iron and serum total iron-binding capacity):
  • If transferrin saturation is > 50%, repeat the measurement on a fasting sample.
  • A fasting transferrin saturation > 55% (men and post-menopausal women) or > 50% (pre-menopausal women) indicates iron accumulation.
• Serum ferritin.
• Liver function tests.
• Assess for hepatomegaly.
• Endocrine investigations may be indicated - depending on the clinical scenario.
• Investigations for other causes of abnormal liver function (e.g. hepatitis serology) may be relevant.

Further investigations

• If transferrin saturation shows iron overload, arrange genetic testing for C282Y and H63D (if not already done).
• Liver biopsy:
  • Is indicated if there is evidence of liver damage (raised AST or hepatomegaly) AND iron overload (serum ferritin >300 μg/l or > 200 μg/l in pre-menopausal women).
  • With liver biopsy, do histological grading of iron concentration (Pearl's stain).
• If there is evidence of iron overload, but the patient is negative for known HHC genes, the following tests may help in diagnosing HHC:
  • The hepatic iron index (calculated from liver biopsy results).
  • Quantitative phlebotomy (a retrospective calculation of iron overload using weekly phlebotomy).
  • Further investigations or specialist referral may be needed to look for other causes of raised transferrin or raised ferritin, e.g. fatty liver, alcoholic liver disease or haematological disease.

Followup

Patients with only a raised transferrin saturation (and normal liver function and serum ferritin) require annual monitoring for iron overload.

Interpretation of tests¹

Iron studies interpretation:

• Transferrin saturation, if raised, is an early indication of iron accumulation.
• Transferrin saturation is calculated as (100 x serum iron / total iron-binding capacity)%.
• Serum ferritin correlates well with total iron stores, but does not exceed normal limits until liver iron concentrations are raised. Ferritin levels may also be raised in other conditions e.g. inflammation and hepatic steatosis.
• During treatment of HHC by venesection, serum ferritin decreases steadily; transferrin saturation remains high until iron deficiency occurs, then falls sharply.²

• Other causes of iron overload - a detailed list is given in the review by Harrison.⁴
• Other types of skin pigmentation e.g. Addison's disease.
• Other forms of liver disease - which may co-exist or contribute.

Treatment is with venesection. This removes iron and reverses some of the symptoms and complications (see prognosis).

Initial management

• Venesection once a week (450–500 ml) until the serum ferritin concentration is < 20μg/l and transferrin saturation is < 16%.
  • Calculate the amount of iron removed, by weighing the blood bag before and after venesection (density of blood is 1.05g/ml ) and assuming that 450 ml blood (Hb concentration = 13.5g/dl) contains 200 mg Fe. Allow for iron absorption at a rate of 3 mg/day (20 mg/week). With these assumptions 25 weekly venesections will remove 4.5g Fe.
• Monitor Hb levels weekly; reduce rate of venesection if anaemia develops.
• Monitor serum ferritin monthly.
• Measure transferrin saturation as the ferritin concentration drops below 50 μg/l.

Maintaining normal iron levels

• The transferrin saturation should be kept < 50% and the serum ferritin concentration < 50 μg/l.
• This may require up to 6 venesections per year.

Management of complications

• Cirrhosis: see separate article. Regular screening is needed because of the risk of hepatocellular carcinoma.
• Cardiac complications: chelation therapy may be needed to reverse cardiac damage. Physicians treating patients with iron overload from thalassaemia have expertise in this area.
• Treatment of endocrine dysfunction may be needed, e.g. for diabetes or hypogonadism.

Diet

Elaborate dietary restrictions are not necessary. The Haemochromatosis Society suggests: avoid iron supplements; reducing intake of liver/kidney/red meat; avoid foods which increase iron absorption e.g. alcohol with meals, large doses of vitamin C.²

• If treatment is started early enough, before cirrhosis and diabetes occur, then life expectancy is normal.
• Cirrhosis is the main prognostic factor.⁴
• There is no clear relationship between the degree of iron overload and the tissue/organ damage produced. Severe fibrosis or cirrhosis are probably unlikely in patients with serum ferritin < 1000 μg/l. Other influences, e.g. alcohol intake, may have a role.

Which clinical features are reversed by treatment?

• Usually reversible: fatigue, transaminase elevation, early cardiac changes.
• Improve in some patients: diabetes mellitus, hypogonadism, arthralgia, skin pigmentation, severe cardiac failure and arrhythmias
• Irreversible: cirrhosis, arthritis.

Family members

• Counselling and testing should be offered to siblings and parents of the HHC patients. Siblings have a 1 in 4 chance of having HHC.
• Partners may be offered genetic testing, to help assess the risk of HHC in their children. This is relevant because HHC genes are common in the general (white) population.
• The necessary tests are:
  • Transferrin saturation
  • Serum ferritin
  • HFE genotype (for C282Y and H63D mutations).
• Test results may affect life insurance and medical insurance, however some companies take the view that properly managed HHC need not affect insurance.
• Note that not all those with genes for HHC will develop clinical problems (as above).

Population screening

Population screening is feasible, using genetic and/or transferrin saturation tests. However, the benefits and drawbacks are still debated.⁵