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Haemochromatosis: a genetic disorder easily missed by GPs



Jane Brown is 46, tired and complaining

of aching joints. Her periods have become almost non-existent. You run some tests; her blood glucose

and thyroid function are normal and, as you suspect,

her LH and FSH levels suggest she is perimenopausal. Surprisingly she is not anaemic, but her ferritin level is sky-high. Dr Melanie Wynne-Jones discusses.

What are the causes of a high ferritin level?

Serum ferritin concentrations reflect total body iron stores, so a high level is usually a sign of iron overload.

Very occasionally it may be raised as an acute-phase marker in hepatitis and some malignancies (including acute leukemia, Hodgkin's disease, and gastrointestinal tumours). Alcoholic liver damage, NASH (non-alcoholic steatorrhoeic hepatitis) and chronic hepatitis C infection can also increase iron storage.

However, the commonest cause of high ferritin levels is haemochromatosis, a genetic disorder that increases iron absorption from the gut. Suspect the diagnosis where ferritin levels exceed 200µg/l in women and 300µg/l in men.

The transferrin saturation (serum iron divided by total iron binding capacity) which also indicates iron overload may become elevated even before ferritin levels rise.

How is haemochromatosis inherited?

Haemochromatosis is autosomal recessive, and one of the commonest genetic disorders. It affects between one in 200 to 500 northern Europeans; people of Celtic origin are at greater risk.

GPs with an average list can expect to have three or four affected patients, but they may well be undiagnosed1.

Most cases are the result of a single defective gene on chromosome 6; this gene codes for a protein called HFE which binds to the transferrin receptor.

Abnormal mutations increase absorption of dietary iron which is normally regulated according to the amount of iron currently stored in the body.

What are the symptoms of haemochromatosis?

Normal body iron stores range from around 2-6 grams, but iron overload leads to increased focal or generalised deposition of iron in body tissues.

In haemochromatosis, iron steadily accumulates through life, although symptoms are rare before middle-age by which time total body iron stores may be 10g to 20g and tissue damage may be extensive.

Women may present later than men because of regular blood loss during menstruation and the iron requirements of childbearing.

The classic picture of 'bronzed diabetes' may be present, but symptoms are often vague and non-specific at first. Symptoms/diagnoses associated with haemochromatosis include:



·Liver abnormalities including cirrhosis (alcohol consumption may accelerate the effects of iron overload) and an increased risk of hepatocellular carcinoma

·Cardiomyopathy ­ cardiomegaly, heart failure, arrhythmias and conduction disturbances

·Diabetes (type 2)

·Pituitary failure ­ scanty periods, premature menopause, testicular atrophy, reduced body hair, low libido

·Non-specific abdominal pain

·Skin pigmentation due to deposited iron

·Neuro/psychiatric effects ­ mood and memory problems, depression.

The commonest causes of death are hepatocellular carcinoma/cirrhosis, hepatic failure and cardiac failure.

What are the diagnostic pitfalls?

The main one is remembering that haemochromatosis may co-exist with or mimic other diagnoses:

·'menopausal symptoms' ­ tiredness, aches and pains, low mood


·abnormal liver function tests in people with low/moderate alcohol consumption

·cardiac problems

·sexual disorders


·irritable bowel syndrome.

This is clearly a big list and you will see some or all of these in an average surgery; unless you ask yourself 'could this be haemochromatosis?', you may well miss the diagnosis (as may your colleagues!).

What tests should Jane Brown have now?

·Liver function tests

·Repeat glucose if borderline

·Fasting transferrin saturation (serum iron divided by total iron binding capacity) ­ in haemochromatosis this will be greater than 50 per cent (55 per cent for men)

·Genetic testing for the HFE gene ­ positive in more than 90 per cent of affected people

·Liver biopsy if the ferritin level is >1000µg/l, liver function tests are markedly abnormal or HFE testing is negative

·Tests to confirm or refute other diagnoses as indicated.

What is the treatment?

Regular venesection will remove iron from the tissues, and life expectancy can return to normal. Jane will need to avoid iron supplements and vitamin C which increases iron absorption, as well as limiting her consumption of red meat and alcohol.

Iron stores return to normal with venesection, but diabetes, arthritis, sexual dysfunction and cirrhosis usually persist. However, fatigue and cardiac function may improve.

Should you tell Jane's relatives who are also your patients?

Haemochromatosis is a genetic disease with the capacity to produce extensive disability and shorten life expectancy; however, there is treatment available which may significantly improve individuals' outcomes.

Ethically, Jane's relatives have a right to know information that may affect their own health ­ but if you tell them without her consent, you are breaching confidentiality.

Jane will probably agree to tell them, but she may find it difficult to accept the bad news herself, or to break it to others. She may accept your offer to tell them for her, with or without her being present. The Haemochromatosis Society will also provide support and advice to Jane and her relatives.

Key points

·Haemochromatosis is one of the commonest UK genetic disorders affecting as many as 1 in 200 people

·The defective HFE gene is autosomal recessive

·Damage from iron overload accumulates, although symptoms may be delayed until middle-age

·Symptoms are often vague and non-specific; haemochromatosis may mimic or co-exist with other medical problems

·Early diagnosis

and regular venesection improve symptoms and life expectancy, although not diabetes or



1 Hereditary haemochromatosis: never seen a case? Emery & Rose BJGP Vol 51 pp347-8 (May 2001)

2 The Haemochromatosis Society, Hollybush House, Hadley Green Road, Barnet, Herts EN5 5PR. Tel: 020 8449 1363

Melanie Wynne-Jones is a GP in Marple, Cheshire

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