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 and 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

HFE-related Genetic Haemochromatosis (GH) testing guide

Referral flow chart for first degree relative of patient who has a diagnosis of GH / Patient with suspected GH (291.59kB PDF)

Key facts

GH can lead to iron overload, through excessive absorption through the gut, which results in deposition in tissues.
A significant number of people who inherit GH do not develop iron overload.
Pre-menopausal women are less likely to develop symptoms as they excrete iron through menstruation.
Initial presentation can be non-specific e.g. lethargy, polyarthria or liver disease.
If untreated, iron overload can lead to endocrine disorders (diabetes, hypogonagotrophic hypogonadism), arthritis and cardiac disease (arrhythmias and heart failure) and liver disease (cirrhosis).
Treatment is by venesection. With early treatment, complications can be prevented and life expectancy is normal.
GH is inherited in an autosomal recessive pattern. The population carrier frequency is ~ 1 in 10.
More information can be found at: https://patient.info/doctor/hereditary-haemochromatosis
Diagnosis of a genetic condition may impact on life/critical illness/income protection insurance, and may result in increased premiums or exclusions. See Information for patients. However, due to the treatable nature of this condition this diagnosis is less likely to impact on insurance premiums.

Who to test

People with clinical features suggestive of GH. Please give clinical details on sample referral form). This includes men with serum ferritin (SF) of >300μg/l and transferrin saturation (Tsat) of >50% and women with SF of >200μg/l and Tsat of >40%, with normal FBC
First degree adult relatives (parents, siblings and children) of an affected person or C282Y carrier. Testing of more distant healthy relatives is not generally recommended.
GH is an adult onset condition therefore carrier testing is not recommend in healthy children. To clarify the risk to children partners of an affected or carrier person may be tested

How to test

2 to 5ml blood in EDTA (anticoagulant) tube sent with DNA request card to Northern Molecular Genetic Service via your local hospital pathology department.
Include reasons for testing or name of affected relative on sample referral form where applicable.
Sample referral forms can be found in the ‘downloadable documents’ section at https://www.newcastlelaboratories.com/lab_service/clinical-services/
By completing the form, this indicates that patients have consented to testing, and DNA being stored by the testing laboratory.

Results

Results are usually available within 4 weeks and will be returned to refer given on the request (placing others details in this section will result in a delay to the patient)

Interpretation of results and management:

Result	Interpretation and Management
C282Y Homozygous	Interpretation: Patient has 2 copies of the C282Y variant. At risk of iron overload. Management: In men: SF>300µg/l, TS >50%, in women: >200µg/l, TS >40%. Refer to secondary care (gastroenterology/haematology) for management and treatment. If asymptomaticSF and TS checked annually. Patient could consider blood donation. Dietary advice to limit iron intake may offer some benefit. Relatives: Biological parents and children will be obligate carriers, with a low risk (5%) of being affected. All first-degree relatives (parents, siblings, children over the age of 16*) should be offered genetic testing via their GP.
C282Y Carrier (also known as C282Y heterozygote)	Interpretation: Patient carries a single copy of C282Y variant. Carriers do not usually iron load. Management: No further follow up required. If symptomatic consider other causes of Haemochroamtosis e.g. obesity and alcohol intake. Refer to secondary care for management/treatment. Secondary care may also consider other rarer genetic causes. Relatives: At least one biological parent will be a carrier for GH. Children of patient will be at 50% risk of being a carrier. Risk to carriers’ parents and/or children being affected is small (approximately 3%). Therefore, testing is NOT indicated in healthy individuals.
C282Y/H63D Compound Heterozygous	Interpretation: Patient carries a single C282Y variant, and a single H63D variant. Management: Most patients with this genotype do not iron load. However, 3 yearly checks of TS and ferritin are recommended. If symptomatic consider other causes of Haemochroamtosis e.g. obesity and alcohol intake. Refer to secondary care for management/treatment. Secondary care may also consider other rarer genetic causes. Relatives: Biological parents and children will be obligate carriers for one of the variants, with a low risk (5%) of being affected. All first-degree relatives (parents, siblings, children over the age of 16*) should be offered genetic testing via their GP.
H63D Homozygous	Interpretation: Patient has 2 copies of the milder H63D variant. Most people with this genotype never develop symptoms or iron load. Management: No further follow up or monitoring required. If symptomatic consider other causes of Haemochroamtosis e.g. obesity and alcohol intake. Refer to secondary care for management/treatment. Secondary care may also consider other rarer genetic causes. Relatives: Both biological parents and any children will all be obligate carriers of the milder H63D variant. H63D is a milder variant and very rarely causes patients to iron load even when they have 2 copies of the variant (homozygous). Therefore, no testing is recommended for any of your relatives in the absence of any symptoms.
H63D Carrier	Interpretation: Patient has a single copy of the H63D variant. Carriers of H63D are at a very low risk of iron loading. Management: No further follow up or monitoring required. If symptomatic consider other causes of Haemochroamtosis e.g. obesity and alcohol intake. Refer to secondary care for management/treatment. Secondary care may also consider other rarer genetic causes. Relatives: At least one biological parent’s will be a carrier of the milder variant H63D. Siblings and children are at 50% risk of also being a carrier of the H63D variant. As this is a mild variant, in the absence of any symptoms no testing is recommended.
Not a carrier (C282Y not present)	Interpretation: Patient does not carry either of the most common variants for GH. Management: No further follow up or monitoring required If symptomatic consider other causes of Haemochroamtosis e.g. obesity and alcohol intake. Refer to secondary care for management/treatment. Secondary care may also consider other rarer genetic causes. Relatives: Relatives do not require any genetic testing unless they themselves have an affected relative.

* For children under the age of 16, partners can be tested to help inform their risk. Ensure that affected relatives name is indicated on test referral forms.

Please note; there are rare forms of HFE-related GH caused by other gene alterations. If GH still clinically suspected, patient should be referred to haematology/gastroenterology.

UK Guidelines:

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjh.15164

Useful Websites for further information:

https://patient.info/health/haemochromatosis-leaflet

http://www.haemochromatosis.org.uk/

If you need more advice please contact:

Genetic Counsellor on call (clinical): nuth.GeneticCousnellorEnquires@nhs.net
Molecular Duty Scientist (lab and samples): nuth.dna@nhs.net

Northern Genetics Service
Institute of Genetic Medicine International
Centre for Life Central Parkway
Newcastle upon Tyne
NE1 3BZ
Tel: 0191 241 8600
Fax: 0191 241 8799
8:30am to 5pm Monday to Friday

Teesside Genetics Service
James Cook University Hospital
Marton Road
Middlesbrough
TS4 3BW
Tel: 0164 228 2673
8.30am to 5pm Monday to Friday