Intended for healthcare professionals

Practice Easily Missed

Hereditary haemochromatosis

BMJ 2016; 353 doi: https://doi.org/10.1136/bmj.i3128 (Published 30 June 2016) Cite this as: BMJ 2016;353:i3128
  1. Muhajir Mohamed, consultant haematologist and associate professor of medicine1 2,
  2. Jehan Phillips, general practitioner3
  1. 1Department of Medicine, Launceston General Hospital, Tasmania, Australia
  2. 2University of Tasmania, Launceston Clinical School, Launceston, Tasmania, Australia
  3. 3First point Healthcare, Launceston, Tasmania, Australia
  1. Correspondence to: M Mohamed muhajirbm{at}yahoo.com

What you need to know

  • The diagnosis may be missed because symptoms are non-specific, broad, or emerge after the menopause

  • Around one in five cases occur in people who do not fit the northern European stereotype

  • Consider ferritin and transferrin tests to detect to detect iron overload, followed by referral for HFE genetic tests in those with elevated levels

A 38 year old white man presents because of increasing lethargy, excessive sleepiness, and generalised joint pains over the past year, which he attributes to the physical work in his new job. History and examination provide little to suggest a diagnosis. Table 1 shows his basic blood test results.

Table 1

Patient’s blood test results

View this table:

Iron studies showed high values of serum ferritin (1240 μg/L; reference range 30-300) and transferrin saturation (84%; 15-45%). Genetic testing identified a homozygous mutation for C282Y. He was referred to a haematology clinic.

What is hereditary haemochromatosis?

Although hereditary haemochromatosis is thought to be an autosomal recessive disorder in people of northern European ancestry, about a fifth of cases are atypical, and various mutations are described outside the northern European stereotype. Mutations in the HFE gene on chromosome 6 and non-HFE mutations predispose to increased intestinal iron absorption and iron overload. Clinical manifestations are related to iron deposition in organs such as the liver, pancreas, joints, skin, and heart, with the production of free radicals, which have toxic effects at the cellular level.1

Symptoms usually start during the fourth or fifth decade of life.2 Iron overload is uncommon in women of childbearing age because of blood loss during menstruation, so women usually present after menopause. Regular blood donation reduces the likelihood of developing symptoms.

The genetics of haemochromatosis are complex (box 1). The most common mutation associated with iron overload is C282Y homozygous (p.Cys282Tyr). The homozygous H63D mutation and compound heterozygosity (C282Y/H63D) are less common.9 Serum ferritin may be higher in heterozygous carriers than in the general population, but symptoms caused by iron overload are rare.10

Box 1: How common is hereditary haemochromatosis?34567

• Hereditary haemochromatosis is the most common single gene disorder in people of northern European ancestry

• Homozygous C282Y mutation of the HFE gene on chromosome 6 is the most common cause (~80%), affecting nearly one in 250 white people8

• The estimated prevalence of C282Y homozygotes among non-white populations is low at 0.00004-0.1%

• In population screening studies, 25-50% of homozygotes are found to be asymptomatic

• 4-7% of patients are compound heterozygous for C282Y/H63D and about 1% are homozygous for H63D

• About 5% of patients have non-HFE mutations

Why is haemochromatosis easily missed?

The symptoms of iron overload are mostly non-specific at the time of diagnosis. In a cohort study of 251 patients with haemochromatosis, about 75% of patients had lethargy and weakness. Other symptoms were somnolence, memory disturbances, generalised arthralgia, and reduced libido or impotence in men.11 These symptoms can also be caused by other medical conditions or attributed to stress and ageing. Data on the predictive value of these symptoms to identify haemochromatosis in the general population are lacking. An observational study found a similar prevalence of these non-specific symptoms in people with and without iron overload, which delays diagnosis.12

The clinical penetrance of C282Y homozygosity is variable. Iron overload is seen in 38-50% of patients, and haemochromatosis associated morbidity develops in 10-33% of C282Y homozygotes.13 Haemochromatosis is sometimes detected during routine blood tests or screening in people with a family history of haemochromatosis.

Why does it matter?

In untreated patients, progressive iron deposition is most evident in the liver, heart, joints, pancreas, and skin leading to liver cirrhosis, arthropathy, cardiomyopathy, diabetes mellitus, and skin hyperpigmentation. Serum ferritin values >1000 μg/L are independently associated with cirrhosis and symptomatic hereditary haemochromatosis.14 15

Bronze diabetes—a triad of cirrhosis, diabetes, and skin pigmentation—is a complication of iron overload.7

Iron deposition in the pituitary gland may lead to secondary hypogonadism, which is characterised by decreased libido and impotence in men.16 Hypothyroidism is a rare manifestation.17 An increased incidence of hepatocellular and extrahepatic cancers such as colorectal cancer and breast cancer has been observed.18 19

People with untreated haemochromatosis who express the clinical phenotype have a higher risk of mortality than the general population. A longitudinal cohort study of 179 patients with haemochromatosis showed reduced survival compared with a matched normal population (P<0.0001).20 Patients are likely to die of liver cancer, cirrhosis, cardiomyopathy, and diabetes, which are more common than in the general population.11 21 Longitudinal cohort studies show that early detection and adequate treatment in the pre-diabetic and pre-cirrhotic stages result in normal survival, although the benefit has not been quantified.16 22

How is haemochromatosis diagnosed?

Clinical diagnosis

Box 2 outlines clinical features of haemochromatosis.

Box 2: Common clinical manifestations of haemochromatosis8

Symptoms
  • Lethargy

  • Abdominal pain

  • Somnolence

  • Arthralgia

  • Impotence in men

  • Weight loss

Physical findings
  • Hepatomegaly

  • Splenomegaly

  • Skin hyperpigmentation

  • Joint swelling

  • Stigmata of chronic liver disease

  • Testicular atrophy

  • Gynaecomastia

  • Porphyria cutanea tarda

Investigation results
  • Abnormal liver function tests (raised aminotransferase)

  • Diabetes mellitus

  • Cardiac (electrocardiographic) abnormalities; mostly non-specific

Asymptomatic people
  • Haemochromatosis associated morbidity is not seen in 67-90% of C28Y homozygotes.13

Investigations

Blood tests

Request serum ferritin and transferrin saturation assays to detect iron overload. Raised ferritin has a 1.6-17.6% positive predictive value for the detection of C282Y homozygosity.5 Ferritin can also be raised in the absence of iron overload in acute or chronic inflammation, liver disease, renal failure, and cancer.

Genetic testing

On the basis of the American Association for the Study of Liver Diseases guidelines, genetic testing for haemochromatosis (HFE gene mutations) is indicated in the following scenarios:

  • High ferritin values (>300 μg/L in men or >200 μg/L in women)

  • High transferrin saturation (>45%)

  • First degree relative with haemochromatosis.

The C282Y and H63D HFE mutations are commonly tested. Patients who are negative for these genotypes may have rare non-HFE genetic mutations, but because treatment does not differ, screening for these mutations is not recommended.8

Investigations for end organ damage

Liver function tests and imaging studies, fasting blood glucose, electrocardiography, and echocardiography help detect end organ damage. Liver biopsy is recommended with ferritin concentration >1000 μg/L or raised liver enzymes (aminotransferases) to measure hepatic iron content and to detect liver fibrosis or cirrhosis.8 T2 weighted magnetic resonance imaging scan is increasingly preferred as a non-invasive alternative. Similarly, hepatic elastography is gaining popularity as a non-invasive procedure to detect liver fibrosis and cirrhosis.7 Measure serum testosterone, follicle stimulating hormone, and luteinising hormone, and request thyroid function tests if endocrine organ dysfunction is suspected.8

Screening

Screen first degree relatives with tests for serum ferritin, transferrin saturation, and HFE mutation analysis.7

How is haemochromatosis managed?

Phlebotomy is the mainstay of treatment and the goal is to achieve blood ferritin values <50-100 μg/L. Phlebotomy is indicated in all patients with ferritin values >1000 μg/L and is initially performed once a week or fortnightly. In patients with moderately raised serum ferritin (200-1000 μg/L), the decision to initiate phlebotomy should be based on patient preference and clinical judgment. The usual volume of phlebotomy is 400-500 mL, which depletes 200-250 g of iron.23 Volume and frequency may be modified according to the degree of iron overload and baseline haemoglobin values. Haemoglobin and ferritin values must be monitored regularly. High quality evidence to guide the frequency of monitoring and of phlebotomy needed to deplete iron stores is lacking. Once ferritin drops to 50-100 μg/L, maintenance phlebotomy may be scheduled, with most patients requiring phlebotomy every two to four months.8 In some countries, patients with haemochromatosis who are on maintenance phlebotomy and who meet other safety criteria for blood donation are eligible to donate blood regularly at blood transfusion services.5 23

A cohort study of 251 patients with haemochromatosis showed that phlebotomy prevented further tissue damage and that the subgroup of treated patients without cirrhosis and diabetes had normal survival.11 Qualitative data suggest that patients on phlebotomy have decreased fatigue, improved skin hyperpigmentation, and reduced early hepatic fibrosis and left ventricular dysfunction.8 23 An observational study found no improvement in arthropathy and testicular atrophy.24 The risk of hepatocellular carcinoma is not mitigated in patients with cirrhosis even after adequate phlebotomy, and screening for hepatocellular carcinoma must continue.

Dietary restriction is not needed in patients undergoing phlebotomy, but iron and vitamin C supplementation should be avoided because vitamin C increases iron mobilisation.8 Alcohol restriction is advised. Uncooked seafood should be avoided owing to the increased risk of infection with Vibrio vulnificus in these patients.23

Phlebotomy may be difficult or risky in patients with poor venous access, intolerance to phlebotomy, or coexisting haematological disorders. Iron chelation with deferoxamine or deferasirox may be an option in these patients but clinical data on their use in hereditary haemochromatosis are limited.23

How patients were involved in the creation of this article

A patient with hereditary haemochromatosis accepted an invitation to review this manuscript. She shared her long and challenging pathway to diagnosis and attests that the condition is difficult to diagnose because classic symptoms are not always present and general practitioners and other specialists have a low level of suspicion. On the basis of her input we expanded the section on symptoms to cover wide ranging presentations of iron overload.

Footnotes

  • This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at first presentation. The series adviser is Anthony Harnden, professor of primary care, Department of Primary Care Health Sciences, University of Oxford. To suggest a topic for this series, please email us at practice@bmj.com.

  • Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: None.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent: Not required (patient anonymised, dead or hypothetical).

References

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