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May 2007: Detecting genetic haemochromatosis

How common is this condition?

How can it be recognised?

What measures are used to remove excess iron?

How common is this condition?

How can it be recognised?

What measures are used to remove excess iron?

?Genetic haemochromatosis (GH) is an autosomal recessive condition in which iron absorption from the upper small intestine continues despite normal body stores. In healthy individuals iron absorption stops once iron stores are replete.

The continued absorption in GH is subtle and it takes many years for the symptoms and then signs of iron overload to develop. Men typically present in the third and fourth decade. Women usually, but not always, present later in life as iron loss during menstruation delays the iron overload.

Recognising GH is a challenge for all clinicians. Although around 1 in 200 people in the UK are genetically susceptible, clinical expression with the classic features (bronze diabetes – slate-grey skin, cirrhosis and diabetes) is infrequent. In an American study of death certification, GH was recorded in one in 6,000 deaths.1

However, iron accumulation (biochemical expression or penetrance) to levels that do not give these classic features occurs in 50-80% of those genetically susceptible. This group may have symptoms, but they are non-specific and common in other conditions.

Early symptoms of iron overload are:

• fatigue

• abdominal discomfort

• loss of libido

• arthralgia.

Thus spotting the patient with GH at an early stage is very difficult. However, it is important to bear this diagnosis in mind in patients with symptoms that cannot otherwise be explained. Iron studies are worthwhile and may detect other conditions such as iron deficiency.

In some individuals, iron accumulation progresses and eventually damages: the joints, resulting in arthritis; the liver, causing cirrhosis with a risk of hepatocellular carcinoma; the pancreas, causing diabetes; and the pituitary. Excess cardiac iron may lead to arrhythmias and, rarely, cardiac failure.

The goal of GH management is its detection and treatment before irreversible tissue and organ damage has occurred.

Genetics

The HFE (‘High Fe') gene carrying the mutation causing GH was cloned in 1996. It is located on chromosome six. The mutation found in GH is C282Y, a cysteine to tyrosine substitution at position 282 of the amino acid sequence. More than 90% of individuals with GH in the UK are homozygous for the C282Y mutation in the HFE gene.2

When this mutation is present on both chromosomes the fine control of iron absorption is lost. The cellular mechanism for this defect is not absolutely certain but involves a peptide called hepcidin, which is thought to control iron transport across the upper intestinal mucosa.

About one in 200 individuals of Northern European extraction in the UK are homozygous for the C282Y mutation. In Ireland the prevalence is around 1 in 85. This mutation is very rare in ethnic groups from the Middle East, Far East and Asia. The explanation for the geographical distribution is thought to be that the ancestor in whom this mutation first occurred was Celtic or Viking. The high frequency in particular areas could also be the result of breeding within isolated communities.

The vast majority of carriers (heterozygotes) for the C282Y mutation do not develop iron overload. Rarely, another genetic or environmental influence can contribute to iron excess in these patients. However, the excess is usually mild.

Other mutations in HFE have been reported, including the H63D mutation. Around 20% of the UK population are carriers of this mutation. They do not have any increase in iron. The importance of H63D is that a small percentage of individuals with the C282Y mutation on one chromosome and the H63D mutation on the other (compound heterozygotes for the C282Y and H63D mutations) develop mild iron overload.

Clinical expression

The percentage of genetically susceptible individuals that develop severe disease with tissue damage, such as cirrhosis, is uncertain and controversial. An early report suggested that only 1% of patients do so,3 but data from liver biopsies indicate that at least 4% of C282Y homozygotes have advanced fibrosis. Further research is needed.

It has also been found that tiredness is significantly more frequent in C282Y homozygotes than in those without any C282Y mutation (50% v 33% in men; 65% v 50% in women).4

Although an argument for population screening with HFE analysis has been made,5 this has not yet been accepted by public health professionals because of the difficulty in predicting which individuals will go on to accumulate high levels of iron and develop clinical disease.

GPs are sometimes requested to perform genetic analysis in relatives of individuals with GH. Many molecular genetics laboratories perform this analysis, and are quality controlled centrally. The request form should ask for analysis of both C282Y and H63D mutations. If only C282Y is requested and the result shows a carrier state, there is still a need to know the patient's H63D status to rule out compound heterozygosity.

Diagnosis

GPs should suspect GH in any patient of Northern European extraction who appears with bronzed or slate-grey skin, diabetes and/or evidence of liver disease. This is a classic presentation of late-stage GH.

Detecting patients earlier so that treatment can prevent irreversible tissue damage is a problem. Iron studies are worthwhile in any patient of Northern European extraction who has one or more of the following:

• unexplained fatigue

• arthralgia

• abdominal discomfort

• loss of libido

• early menopause.

In a Canadian study, the delay between presentation with such symptoms and diagnosis of GH was five to eight years.6

Serum iron and total iron binding capacity (from which transferrin saturation is calculated) and serum ferritin should be measured. Full blood count, liver function tests and blood sugar should be carried out.

If iron studies are abnormal referral to a gastroenterologist, hepatologist or haematologist (depending on the local interest in GH) is appropriate.

Measuring serum ferritin may show an elevated level that is not caused by iron. It is often raised because of inflammation, alcoholic liver disease or non-alcoholic fatty liver disease. The latter is worth detecting because it is a marker for insulin resistance/ metabolic syndrome, which has other important implications, such as hypertriglyceridaemia and cardiovascular risk. These causes should be considered. Inherited iron overload unrelated to HFE mutations does occur, but is rare and requires input from a specialist unit with an interest in iron disorders.

Whether GPs should request HFE genotyping in an individual they suspect of having GH without referral to a specialist is a difficult issue. It is reasonable if the GP is confident of their knowledge and understanding of haemochromatosis. However, most GPs are probably not, and the discussion of genetic results is best done by someone with experience in GH.

Management

All cases with GH should be referred to secondary care. This is to establish the need for further investigation and whether treatment is necessary. The instigation and completion of family screening is equally important.

Liver biopsy

Published evidence recommends liver biopsy if the ferritin is greater than 1000µg/l, the ALT or AST are abnormal, or the liver is palpable.7

A C282Y homozygote with a ferritin less than 1000µg/l, normal liver function tests and an impalpable liver generally does not need a liver biopsy.

The reason for liver biopsy in those fitting the criteria is to detect cirrhosis. Cirrhotic patients need lifelong follow-up for the complications of chronic liver disease, in particular the development of hepatocellular carcinoma.

Venesection

The management of iron overload is by venesection. This is instituted if the serum ferritin is greater than normal. Therapeutic venesection (usually one unit of blood per week) is done until the serum ferritin and transferrin saturation are below normal, assuming that the patient can tolerate this without becoming anaemic, which most can. Thus the aim of venesection is to attain mild iron deficiency.

After mild iron deficiency has been achieved the rate of venesection is reduced to one unit every three to six months, depending on the serum ferritin and transferrin saturation. The aim of treatment is to keep these levels at around 50µg/l and 50% respectively.8

Venesection is usually done in hospital in an outpatient/day setting by nurse specialist/practitioners. Whether general practice units can participate in this is a local issue. Some patients on maintenance venesection have this done by the Blood Transfusion Service.

Other treatments

Decreasing iron levels is only one facet of management.9 Control of diabetes and monitoring of hepatic parameters are important. Arthralgia and arthritis are managed conventionally and are often the most difficult problem for both the patient and physician; anti-inflammatory agents and analgesics are not always effective. Once tissue damage has occurred the removal of iron does not necessarily reverse symptoms.

Screening

Family screening is essential. Siblings should be offered screening with iron studies and, ideally, HFE genotyping. Children are not screened until they are of an age to understand the issues; this age will vary from child to child, and parents should not simply have their children screened genetically at a young age. Assessment of the chance of children being at risk can be done by genotyping the spouse of the affected individual. Some specialists screen parents, depending on the clinical circumstances.

Conclusion

• Susceptibility to GH is not rare, although the percentage of those genetically susceptible who have symptoms or disease (clinical expression) appears low but has not been clearly established.

• Early detection of GH is the key to prevention of irreversible tissue damage and disease.

• Early symptoms are non-specific, and GPs should think of iron overload in the absence of other explanations. Tests for iron status are worthwhile and may detect other important conditions.

• Screening family members of an individual with GH is essential.

Authors

Dr James S Dooley
MD FRCP
reader in medicine and consultant hepatologist, Centre for Hepatology at Royal Free/Hampstead Campus, Royal Free and University College Medical School, University College London

Dr Ann P Walker
PhD
senior lecturer in molecular genetics, Centre for Hepatology at Royal Free/ Hampstead Campus, Royal Free
and University College Medical School, University College London

Useful information

The Haemochromatosis Society provides useful information and support for GPs and patients, and enables patients and their families to contact other individuals with GH.
www.ghsoc.org

Genetic haemochromatosis key points Key points

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