Genetic Haemochromatosis

Genetic testing

Genetic haemochromatosis (GH) is an autosomal recessive condition of incomplete penetrance which may be associated with pathological iron overload and consequent organ damage e.g. liver, pancreas and joints, but pituitary gland and heart damage is not unusual. Over 90% of cases of GH are associated with homozygous alteration (C282Y) in the HFE gene which can be detected by genetic testing. However, the majority (i.e. 75-85%) of people with homozygosity for HFE C282Y do not develop iron overload, although this may develop in later life, so monitoring is required. Heterozygotes for HFE C282Y rarely develop iron overload. Although there is weak evidence that HFE C282Y/H63D genotype may associate with iron loading - in this genotype thorough assessment for other causes of abnormal ferritin /iron studis results is required.

Who to test

Testing for C282Y alteration in the HFE gene may be offered to 2 groups of people:

1. Patients who have symptoms and findings suggesting of GH (see section below for symptoms/signs and associated conditions)

2. First degree relatives of a patient with GH or homozygosity for HFE C282Y. Please state that there is a family history in clinical details when requesting the HFE testing.

Family members of individuals who are heterozygous for HFE C282Y ('carriers') or that have HFE H63D do not need to be routinely screened.

Genetic testing in primary care

Initial baseline FBC, LFTs, ferritin and fasting transferrin saturation should be requested. The GP may then request HFE gene testing (available via ICE) for patients in groups 1 and 2. Unaffected individuals with a family history of GH (group 2) can be managed in primary care and do not require specialist genetic counselling. 

The  Genetic Haemochromatosis (GH) Care Pathway for GPs  also gives advice on monitoring of asymptomatic individuals who are found to be homozygous for HFE C282Y, testing of other family members and when to consider referral. 

When to refer

If patients are symptomatic and/or have abnormal results then please review the section below and consider referral to haematology via eRS or request haematology advice and guidance.

Red Flags

As well as a routine referral to haematology, patients with suspected/confirmed HH who have other concerning findings should also be referred urgently to the relevant specialist. Criteria for urgent parallel specialist referral are as follows:

Urgent hepatology service criteria fulfilled if any of the following (patients offered appointment within 4 weeks):

• decompensated cirrhosis (cirrhosis with ascites +/- encephalopathy +/- coagulopathy)
• ALT > 300 U/L
• Bilirubin  > 100 umol/L

(For moderate derangement in LFTs, consider referral to hepatology routinely or request hepatology advice and guidance. However, please note that haematology will refer on to hepatology if they feel this is clinically indicated.)

Upper GI - USC (2WW) referral if imaging suggestive of hepato-pancreatic-biliary malignancy

Urgent cardiology referral if heart failure (although this is unlikely to be caused by GH) and previous MI or BNP > 2000 in the absence of AF (patients should be offered appointment within 2 weeks)

Monitoring in primary care

Individuals who are homozygous (HFE C282Y/C282Y) and asymptomatic and do not have raised fasting ferritin and transferrin saturations can be monitored in primary care.

Referral is NOT indicated for asymptomatic individuals with​ homozygosity for HFE C282Y with no evidence of iron build up in the body or "end organ damage". 

The local pathway advises that instead these patients should have annual ferritin and FASTING transferrin saturation, with advice from, or referral to, haematology if these become abnormal. Local Haematologists advise that monitoring is particularly important in males and post-menopausal women. If stable, frequency may be reduced (minimum 5 yearly).

Patients should be encouraged to:

• avoid excess alcohol
• maintain healthy diet and body weight
• avoid iron or vitamin C supplements
• Patients may choose to become blood donors, but this does not remove the need to monitor for iron loading

Patients who have a raised ferritin only

Elevated ferritin can be detected in GH but more commonly the cause also is several other conditions, e.g. liver disease, alcohol excess, metabolic syndrome, infection, inflammation or neoplastic disease. 

The local haematology guidelines for primary care suggest appropriate investigation in primary care for patients not meeting criteria for urgent referral:

• Address any acute illness, consider repeat ferritin measurement in 4-6 weeks
• Check liver biochemistry, fasting glucose, transferrin saturation from a FASTING sample
• Look for other causes of raised ferritin - take careful alcohol history, consider 'reactive' cause: liver disease, metabolic syndrome, infection, inflammation, neoplasia
• Consider genetic testing for GH (as above) if not already done.

If patients have raised ferritin (but normal fasting transferrin saturation and negative HFE gene testing), it is unlikely that iron load is causing their abnormal LFTs and they should be investigated as per the chronic liver pathway and referred to hepatology (rather than haematology) for investigation, if indicated.

Referral

See red flag section above for advice on indications for urgent referral.

All patients with raised ferritin AND raised fasting transferrin should be referred to haematology for further investigation even if HFE gene testing is negative as they may still have iron overload or unusual/rare genetics.

Haematology referral is NOT indicated for asymptomatic individuals with​ HFE C282Y homozygosity but no evidence of iron build up in the body or "end organ damage".  These patients can be followed up in primary care as per the Genetic Haemochromatosis (GH) Care Pathway for GPs.

If HFE gene testing is negative, please consider other potential cause of abnormal LFTs and investigate as per the chronic liver pathway  If you have referred to haematology anyway (due to positive HFE gene testing or iron overload), haematology will refer on to hepatology if they feel this is clinically indicated.

Referrals should be sent routinely via eRS to Haematology or request Haematology advice and guidance as appropriate.

Parallel referral to the relevant specialist should also be made where there is evidence of otherwise-unexplained ‘end organ damage’:

• Hepatology referral if significant derangement of LFTs or ferritin>1000, but for mild abnormalities, haematology will monitor and refer on to hepatology if they feel this is clinically indicated.
• Endocrinology referral if hypogonadism identified
• Diabetic medicine referral if also found to be diabetic

Symptoms and Signs

Symptoms and Signs 

• Hepatomegaly and/or splenomegaly
• Signs of chronic liver disease
• Skin hyperpigmentation
• Joint swelling
• Testicular atrophy
• Gynaecomastia

Associated Diseases (in advanced untreated iron overload)

• Liver cirrhosis
• Hepatocellular carcinoma
• Diabetes mellitus
• Cardiomyopathy
• Hypopituitarism
• Hypothyroidism
• Arthropathy (metacarpophalangeal joints)

Efforts are made to ensure the accuracy and agreement of these guidelines, including any content uploaded, referred to or linked to from the system. However, BNSSG ICB cannot guarantee this. This guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer, in accordance with the mental capacity act, and informed by the summary of product characteristics of any drugs they are considering. Practitioners are required to perform their duties in accordance with the law and their regulators and nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.

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