Northern Genetics Service

Hereditary Haemochromatosis

Hereditary Haemochromatosis (HHC) or Genetic Haemochromatosis (GH) Information for Primary Care in the Northern Region.
Based on consensus documents by EASL, BCSH, Regional Guideline 2001 & in conjunction with Dr Steven Masson, Hepatology, Freeman Hospital, Newcastle upon Tyne.


Definition

Haemochromatosis is iron overload of the liver, pancreas, heart, joints and other organs, impairing their structure and function.

Hereditary Haemochromatosis 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.

Secondary iron overload is seen in a variety of conditions including alcoholic liver disease, cirrhosis from any cause, haemolytic anaemia, and transfusional/parenteral iron overload.

Genetics 

In Northern Europe, 10% of people are carriers of one of the two significant mutations: C282Y and H63D, with 1 in 200 being homozygous (having two copies) for the C282Y mutation.

Clinical signs of iron overload can be seen in C282Y homozygosity, or when there is one copy of each of the mutations C282Y and H63D (so called compound heterozygotes). C282Y heterozygosity and H63D homozygosity do not lead to clinically significant iron overload.

Not everyone who inherits two mutations will develop iron overload, and even fewer will develop the clinical syndrome.

90% of C282Y homozygotes have high plasma iron (raised transferrin saturation), but only 50-70% have high tissue iron (raised serum ferritin), and only 35% develop organ damage (with ferritin greater than 1000ng/ml).

Given that there are 250,000 people in the UK with the genetic predisposition, but only 5000 people currently diagnosed, there is also evidence suggesting that many who are clinically affected are not identified.

There are several factors known to influence expression of the disease in those patients who are genetically susceptible. Women tend to have a later and less severe onset, because of menstruation and pregnancy. Alcohol, a diet rich in iron, obesity and Hepatitis B & C increase the chance of clinical expression.

Clinical Features and Natural History

Symptomatic organ involvement, when it does occur, tends to begin in middle age. The early bio-clinical signs of HHC tend to be tiredness/general weakness, arthralgia, hepatomegaly and abnormal LFTs with increased ferritin and transferrin saturation. If not treated early, people with HHC can develop diabetes mellitus, cirrhosis, cardiac problems, and hepatocellular carcinoma.

Diagnosis

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

  • Men age 40-50 yr
  • 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, 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 age 18 yr of age) of a confirmed case of HHC.

Testing

Transferrin Saturation (TS) and Ferritin
Non-fasting test initially if considering the diagnosis and as part of general screen. Both TS & ferritin are required as patients in the early stages of clinical disease can have a normal ferritin, but raised TS. In addition, ferritin is an acute phase protein which can be raised in intercurrent illness.
If the TS comes back at >50%, a Fasting TS & Ferritin is needed (avoids effect of diet & diurnal variation).
If the fasting TS is >55% (in men or postmenopausal women) or > 50% in premenopausal women, this indicates a need for genotyping, regardless of the ferritin level.
In patients with raised Fasting TS and a serum ferritin >300mcg/l in men & postmenopausal women, or >200mcg/l in premenopausal women, this suggests that the patient may be iron overloaded. This should prompt a referral to gastroenterology once the genotype is available. Even if the genotype is negative for the HFE genes, further investigations will be necessary.

A ferritin of 1000mcg/l   should prompt a Fasting TS, if not already done and, if the TS is abnormal, a referral to gastroenterology at the same time as the blood is sent to genetics.

Genotyping
Send 5-10 ml blood in EDTA bottles to Molecular Genetics Laboratory, Northern Region Genetics Service, Institute of Human Genetics, Newcastle upon Tyne.

Genotyping for HFE mutations is positive in over 95% of those affected in our population.
Genotyping should be undertaken:

  • in patients (>18 years of age) who are First Degree relatives of someone with Hereditary Haemochromatosis.
  • in those with a Fasting TS > 55% in men and postmenopausal women, and > 50% in premenopausal women.

Liver biopsy
Secondary care will consider the need for liver biopsy and advanced genotyping.
No liver biopsy will be needed if the patient is a C282Y homozygote, aged <40 yr, no hepatomegaly, normal ALT and ferritin <1000mcg/l.

Management considerations

See following page.
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