Elsevier

The Lancet

Volume 388, Issue 10045, 13–19 August 2016, Pages 706-716
The Lancet

Seminar
Haemochromatosis

https://doi.org/10.1016/S0140-6736(15)01315-XGet rights and content

Summary

Haemochromatosis is now known to be an iron-storage disease with genetic heterogeneity but with a final common metabolic pathway resulting in inappropriately low production of the hormone hepcidin. This leads to increase in intestinal absorption and deposition of excessive amounts of iron in parenchymal cells which in turn results in eventual tissue damage and organ failure. A clinical enigma has been the variable clinical expression with some patients presenting with hepatic cirrhosis at a young age and others almost asymptomatic for life. Research is unravelling this puzzle by identifying environmental factors—especially alcohol consumption—and associated modifying genes that modulate phenotypic expression. A high index of suspicion is required for early diagnosis but this can lead to presymptomatic therapy and a normal life expectancy. Venesection (phlebotomy) therapy remains the mainstay of therapy, but alternative therapies are the subject of current research.

Introduction

Haemochromatosis is the most common inherited genetic disease in European populations.1 Although multiple mutations can lead to the clinical syndrome (panel), the most common mutation is that in the HFE gene leading to the p.Cys282Tyr substitution.2 Individuals homozygous for this defect might develop iron overload and its clinical consequences. This mutation is present in roughly one in ten people of northern European descent. Thus, one in 200 people will be homozygous.3 Whether such people develop substantial iron overload depends on environmental and genetic factors, including sex, alcohol consumption, and blood loss. The fact that disease expression is greater in men is only partly explained by physiological blood loss with other probable genetic factors yet to be elucidated. Research is unravelling the relevant genetic factors associated with this disease. This disease is increasingly being recognised in its early stages by greater clinical awareness.4, 5 By contrast with HFE-associated haemochromatosis, the non-HFE-associated forms (panel) are rare, although globally ubiquitous.

Section snippets

Pathophysiology

Genetic iron overload syndromes, such as haemochromatosis, result from either excessive cellular egress of iron or impaired iron recycling. Excessive iron egress might be secondary to either hepcidin deficiency or insensitivity of ferroportin to hepcidin. It results in the classic phenotype of haemochromatosis with increased transferrin saturation and parenchymal iron excess.

Hepcidin synthesis is a multistep process including several genes and proteins (figure 1). Hepcidin deficiency might be

p.Cys282Tyr homozygosity

In the general population, the allelic frequency of p.Cys282Tyr was reported to be as high as 6·2% in a pooled cohort of 127 613 individuals from 36 screening studies with substantial variability across Europe, ranging from 12·5% in Ireland to zero in southern Europe.17 With respect to populations of northern European descent, the HealthIron longitudinal study18 using data from the Melbourne Collaborative Cohort study in Australia reported that in a population of 29 676 individuals, p.Cys282Tyr

Clinical presentation, signs, and symptoms

The classic well known clinical manifestations of haemochromatosis are hepatic cirrhosis, diabetes, and skin pigmentation (figure 3).49 This clinical picture is now not representative of most individuals with haemochromatosis.50 It is rare, nowadays, to encounter advanced symptomatic disease and is usually seen in individuals with a serum ferritin concentration exceeding 1000 μg/L.

Individuals with p.Cys282Tyr homozygosity might present with abnormal iron tests with or without clinical symptoms,

Diagnosis

With the readily available testing for HFE and increased awareness of the disorder, most patients are now diagnosed at an early stage before the development of symptomatic disease18 (figure 3). Patients are often detected at health checks with clinical symptoms compatible with but unrelated to haemochromatosis, especially chronic fatigue and arthralgia or through family screening. The commonest symptom at this stage is lethargy67 and early abnormal tests often indicate raised serum transaminase

Differential diagnosis

In the differential diagnosis of haemochromatosis, transferrin saturation becomes important (figure 3). In haemochromatosis, the percentage of serum transferrin sauration might fluctuate but is frequently increased. If not, an alternative diagnosis should be considered, especially inflammation, cell necrosis, alcohol-related damage, or metabolic syndrome (fatty liver disease). If these are excluded and the serum ferritin concentration is substantially increased, then rarer causes might be

Family screening

Once the diagnosis is established in an individual, it is important to counsel and screen other family members, especially first-degree relatives (parents, siblings, and children).74 Testing for p.Cys282Tyr alone or with the His63Asp substitution is suggested in those with abnormal iron ferritin.75 Because of the frequency of asymptomatic forms, genotyping is now widely proposed as an initial test. For children of an identified proband, testing for HFE substitutions in the other parent is

Management

Once the diagnosis of HFE haemochromatosis has been made, the question is whether additional tests are needed to assess the effects of the disease. If serum ferritin concentrations are less than 1000 μg/L, most clinicans propose to test the patient for diabetes (fasting serum glucose) and not to perform other tests unless there are clinical or biochemical abnormalities. With respect to liver assessment, Guyader and colleagues showed that patients with no hepatomegaly, serum ferritin

Therapeutic venesection

All international guidelines67, 78 agree that excess iron should be treated with venesection and that the usefulness of other therapies is limited. In the absence of randomised controlled trials, recommendations are based upon the clinical evidence that iron removal before the onset of cirrhosis and diabetes is associated with reduced morbidity and mortality96, 97 and that some features including hepatic fibrosis might be improved by venesection therapy.74 Recommendations vary with respect to

Controversies and uncertainties

There is much debate about when treatment should be initiated. The international guidelines published by both the American and European Liver Associations advocate that therapy should be commenced when the serum ferritin concentrations are above the upper limit of normal.67, 78 However, no strong evidence exists to substantiate this, and present research might change this recommendation.107, 108

The optimum concentrations of serum ferritin and transferrin saturation for maintenance therapy are

Search strategy and selection criteria

We searched MEDLINE, PubMed, and the Cochrane Library for published work relevant to this Seminar with the search words: “haemochromatosis”, “hemochromatosis”, “inherited iron overload”, “screening”, and “genetic liver disease”. This search was done from Jan 30, 2005, to June 30, 2015, with no language restrictions. Publications were selected for review based on original research, randomised controlled trials, and meta-analyses and evidence-based reviews of assessment of interventions. We also

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