Hereditary haemochromatosis - liver disease

Hereditary haemochromatosis

Definition

Inherited disorder resulting in abnormal accumulation of iron in the body.

Incidence/prevalence

Homozygous mutation 1 in 350, clinical disease rare.

Age

Clinical disease; most common in middle age.

Sex

Clinical disease, M > F.

Aetiology

Hereditary haemochromatosis is inherited in an autosomal recessive manner. The carrier frequency is 1 in 10. The gene (HFE) is located on the short arm of chromosome 6, closely linked to HLA A3. The commonest mutation is a cysteine-to-tyrosine substitution at amino acid 282 (C282Y). Although 80–90% of patients with hereditary haemochromatosis are homozygous for the C282Y mutation, 75–99% of homozygotes are clinically disease free.

Pathophysiology

The mechanism by which HFE mutation causes disease is unclear. It is thought that there is a gradual accumulation of iron over decades. Women accumulate less iron due to menstrual losses and therefore present later. Iron accumulates in the tissues as haemosiderin particularly within the liver, pancreas, pituitary, heart and skin.

·        Hepatocyte necrosis leading to cirrhosis.

·        Islet cell death, leading to diabetes mellitus.

·        Cardiomyopathy and heart failure.

·        Pituitary and gonadal abnormalities.

Clinical features

Pigmentation of the skin (due to increased melanin), diabetes and hepatomegaly is the classical description of the disease. Arthritis due to calcium pyrophosphate deposition may occur, usually affecting the knees and meta-carpophalangeal joints. Other presenting features include pituitary dysfunction, cardiac enlargement and/or failure.

Macroscopy/microscopy

The tissues appear rusty brown. The iron is mainly around the portal tracts. Portal fibrosis is seen, prior to cirrhosis.

Complications

There is a high risk of hepatocellular carcinoma if cirrhosis develops.

Investigations

Diagnosed on liver biopsy.

1.     Liver function tests may be normal.

2.     Serum iron is high, with >90% saturation of total iron binding capacity.

3.     Serum ferritin is a measure of the total body iron content and is useful for followup.

Management

Regular venesection reduces the iron load and the risk of cirrhosis and hepatocellular carcinoma. Other manifestations are treated symptomatically, e.g. insulin for diabetes, testosterone for gonadal failure. First degree relatives should undergo screening with serum ferritin levels.

Prognosis

The earlier the diagnosis and treatment, the better the prognosis. With treatment, symptoms tend to improve, including diabetes. However, cirrhosis is not reversible.