Hereditary Haemochromatosis

Haemochromatosis is iron overload of the liver, pancreas, heart, joints and other organs impairing their structure and function. Hereditary Haemochromatosis (HHC) is a common inherited disorder characterised by the genetic predisposition to absorb excess dietary iron. In Northern Europe, 95% of patients with HHC will have mutations in the HFE gene.

HHC is an adult onset disease, children do not need to be tested. We advise that children of affected parents attend their GPs when they are adults themselves to arrange for genetic testing at this stage.
Secondary iron overload is seen in a variety of conditions including alcoholic liver disease, cirrhosis from any cause, haemolytic anaemia and transfusional/parenteral overload.

In Northern Europe 10% of people are carriers of one of the two main alterations (called mutations) in the HFE gene; C282Y and H63D. Carriers (also known as heterozygotes) have one altered HFE gene and one normal HFE gene and are generally not affected by iron overload.

Iron overload can arise when both copies of an individuals’ HFE gene (also known as homozygous affected) are altered/ mutated. A blood-based genetic test can be arranged to screen for the HFE C282Y and H63D mutations. Many large teaching hospitals around Ireland offer this service. Please contact your local unit for details of the nearest hospital that will offer genetic testing.

Currently there is some debate regarding the H63D variant, some centres argue that the effect of this variant is so small that it should not be regarded as a HHC susceptibility finding at all. As this debate is ongoing, we have included H63D in our table but the advice may change as the involvement of H63D in HHC is clarified.

Not everyone who inherits two HFE mutations will develop iron overload and fewer will develop the clinical syndrome. The majority of Irish HHC patients have two copies of the C282Y mutation (homozygous affected) but clinical and biochemical features vary:

• 90% have high plasma iron (raised Transferrin Saturation)
• only 50- 70% have high tissue iron (raised serum ferritin)
• only 35% develop organ damage (with ferritin > 1000ng/ ml)

There are several factors known to influence expression of the disease in those patients that are genetically susceptible. Women tend to have a later and less severe onset because of menstruation and pregnancy. Alcohol, a diet high in iron, obesity and hepatitis B and C increase the chance of clinical symptoms. There are ~54,000 people in the Republic of Ireland with the genetic predisposition to HHC. We don’t diagnose everyone with the genetic predisposition because only some will develop symptoms. Nevertheless, there is also evidence suggesting that many individuals who are clinically affected and are symptomatic are not identified.

Symptomatic organ involvement, when it does occur, tends to begin in middle age. No two people are alike and symptoms will vary from person to person. The most common symptoms noticed by people with HHC are:

fatigue, general weakness and lethargy

• joint pain
• abdominal pain
• sexual dysfunction – loss of sex drive
• discolouration or bronzing of the skin
• mood swings and irritability

The early bio-chemical signs of HHC tend to be:

• hepatomegaly (enlarged liver)
• abnormal liver function tests (LFTs)
• increased ferritin and transferrin saturation

If not treated early, people with HHC can develop diabetes mellitus, cirrhosis, cardiac problems and hepatocellular carcinoma.

Early diagnosis is not easy, since presenting symptoms are relatively common and non-specific. Consider diagnosis, especially if two or more of the following:

• Men aged 40-50 years
• Type 2 diabetes mellitus, especially those diagnosed at an early age, with elevated LFT, hepatomegaly, early-onset sexual dysfunction or abnormal iron markers
• Unexplained liver disease or liver disease with abnormal iron markers
• Chronic unexplained fatigue, weakness and abdominal pain
• Asymptomatic patients with incidental elevated LFT, ferritin or hepatomegaly
• Early onset arthralgia (joint pain), atypical arthropathy
• Early onset male impotency, early menopause and loss of libido in women
• Early onset arrhythmias and cardiomyopathy
• Unexplained increasing skin pigmentation or ‘permanent tan’
• First degree relatives over 18 years of age of a confirmed case of HHC

Transferrin Saturation (TS) and Ferritin

Non-fasting test initially if considering the diagnosis and/or as part of a general screen. Both TS and ferritin are required as patients in the early stages of clinical disease can have normal ferritin, but raised TS. In addition, ferritin is an acute phase protein which can be raised in intercurrent illness. If the TS is >50% a fasting TS and ferritin is needed as it avoids effect of diet and diurnal variation.

If the fasting TS is >55% (in men or post menopausal women) or >50% in premenopausal women, this indicates a need for HFE genetic testing, regardless of the ferritin level. These tests may need to be done on a serial basis if the genetic test reveals someone has two susceptibility mutations.

HFE Genetic Testing

A serum ferritin >300mcg/l in men and postmenopausal women or >200mcg/l in premenopausal women, suggests that the patient may be iron overloaded. This should prompt a fasting TS. If this is abnormal (see above) HFE genetic testing should be done and a referral to the liver centre once the genetic test result is available. If the patient is negative for the HFE mutations, further investigations will be needed.

A ferritin of 1000mcg/l should prompt a fasting TS. If this is abnormal, a referral to gastroenterology should be made at the same time as the blood is sent for genetic testing. Genetic testing for HFE mutations is positive in over 95% of those affected in our population. A genetic test never needs to be repeated.

Liver biopsy

Secondary care will consider the need for liver biopsy and advanced genetic testing.

A liver biopsy will not be needed if the patient:

• is aged <40 yr
• does not have hepatomegaly
• has a normal alanine aminotransferase test (ALT)
• has ferritin <1000mcg/l

Monitoring 

• Asymptomatic C282Y homozygote with normal ferritin level at diagnosis: annual TS and ferritin recommended
• Asymptomatic C282Y/H63D compound heterozygote with normal ferritin level at diagnosis: 3 yearly testing of ferritin and TS
• is satisfactory
• If cirrhosis is present: surveillance for hepatocellular carcinoma with 6 monthly ultrasound scan and alpha feto protein levels

Dietary Advice

• Avoid iron supplements. No other dietary advice. It is important to continue to eat the high iron leafy vegetables as these have health benefits.

Cascade (family) Screening

• Once a person with Haemachromatosis is diagnosed, family screening is recommended for all first-degree relatives.
• If patients with HHC are worried about their children, it is useful to perform genetic testing on the other parent to predict whether the children will need to be considered for genetic testing.
• If your patient tests positive for two HFE mutations, further iron study tests (transferrin saturation and ferritin) will be required.

Once the serum ferritin is above the normal range venesection will be started in secondary care. The aim is to keep ferritin <100mcg/l. Some patients may consider blood donation if they are well and fulfil donation criteria.
If venesection is needed and is started before 35 yr, all major hepatic morbidity can be avoided. Once a person is affected clinically, some signs and symptoms respond more readily to venesection:

• Fatigue, abdominal pain, hepatomegaly and skin pigmentation respond very well
• Joint pain, glucose intolerance, NIDDM and cardiac signs improve in 40%
• Hypogonadism and impotence respond poorly
• Cirrhosis and insulin-dependent diabetes are irreversible, but venesection can reduce portal hypertension and reduce insulin requirements
• Risk of hepatocellular carcinoma is not removed if cirrhosis is already present

• (opens in a new window)European Association for the Study of the Liver. EASL Clinical Practise Guidelines for HFE Hemachromatosis. Journal of Hepatology (2010) doi: 10.1016/j. jhep.2010.03.001 
• (opens in a new window)Irish Haemochromatosis Association 
• (opens in a new window)British Haemotology Society 
• (opens in a new window)The Haemochromatosis Society

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