Q J Med 2004; 97: 315-324
QJM vol. 97 no. 6 © Association of Physicians 2004; all rights reserved.
Review |
Hereditary haemochromatosis
From the Hope Hospital, Salford, Manchester, and 1Wythenshawe Hospital, South Manchester University Hospital, Wythenshawe, Manchester, UK
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Summary |
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 Top Summary HistoryGeneticsPathophysiologyClinical featuresDiagnosisPhenotypeGenotypeThe role of liver...TreatmentThe role of liver...Family and population screeningConclusionReferences |
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Hereditary haemochromatosis is a very common genetic defect in the Caucasian population, with an autosomal recessive inheritance. It is characterized by inappropriately increased iron absorption from the duodenum and upper intestine, with consequent deposition in various parenchymal organs, notably the liver, pancreas, joints, heart, pituitary gland and skin, with resultant end-organ damage. Clinical features may be non-specific and include lethargy and malaise, or reflect target organ damage and present with abnormal liver tests, cirrhosis, diabetes mellitus, arthropathy, cardiomyopathy, skin pigmentation and gonadal failure. Early recognition and treatment (phlebotomy) is essential to prevent irreversible complications such as cirrhosis and hepatocellular carcinoma. The history of this condition dates as far back as 1865, but in the last decade great advances have been made. We discuss the genetics, pathophysiology, clinical features, diagnosis and management of a condition that could easily present to a generalist, and is an important diagnosis not to miss.
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History |
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Hereditary haemochromatosis is a very common autosomal recessive disorder affecting the Caucasian population with a prevalence of between 1 in 200 and 1 in 500,1,2 with an even higher prevalence likely in the Irish population.3–6
It was Trousseau who described the syndrome of portal cirrhosis, diabetes mellitus and bronze skin pigmentation7 in 1865, although Von Recklinghaussen is credited with giving the disorder its name ‘haemochromatosis’ when describing a disorder of iron storage and widespread tissue injury in 1889.8 Sheldon explained the inherited nature of the disease in 1935,9 and several years later Simon and colleagues identified the linkage to the HLA complex on the short arm of chromosome 6.10,11
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Genetics |
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TopSummaryHistoryGeneticsPathophysiologyClinical featuresDiagnosisPhenotypeGenotypeThe role of liver...TreatmentThe role of liver...Family and population screeningConclusionReferences |
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The discovery of the candidate gene in 1996 was a major breakthrough in the understanding of this intriguing disease.12 Initially identified as HLA-H, it was renamed HFE by the WHO Nomenclature Committee for Factors of the HLA system.13 The HFE gene encodes a novel 343-amino-acid complex class-1-type molecule. Two missense mutations were initially identified, one resulting in a change of cysteine at position 282 to tyrosine (known as the C282Y mutation), the second in a change of histidine at position 63 to aspartate (known as the H63D mutation).12 In the original study by Feder et al.,12 83% (148/178) of typical phenotypic HH patients were homozygous for C282Y and 4% (8/178) were compound heterozygotes (C282Y/H63D). A mutation resulting in a substitution of serine to cysteine at amino acid 65 (S65C) has recently been suggested as causing a mild form of the disease.14 Among subjects of North European descent, 80–100% of those with clinical features of hereditary haemochromatosis are C282Y homozygous.2–4 Lower rates of C282Y homozygosity are associated with clinical disease in Mediterranean and Southern European populations.15,16 A minority of compound heterozygotes (C282Y/H63D) actually develop clinical symptoms of haemochromatosis (11%).2,17,18 Further, the H63 D homozygous mutation is not as penetrant as the C282Y mutation, although there are rare reported cases of haemochromatosis with this genotype.19,20
Hereditary haemochromatosis not associated with the characteristic mutations of the HFE gene is termed non-HFE-related haemochromatosis. Juvenile haemochromatosis (HFE2), although a rare disorder, is the commonest in this group, affecting males and females equally. It is a more severe form of disease, often presenting before the age of 30 due to cardiac disease and hypogonadism. The HFE 2 locus maps to chromosome 1q, and until very recently the gene had not been identified.21 Animal models have indicated that hepcidin (HAMP); an antimicrobial peptide is probably a key regulator of iron absorption in mammals. Two mutations (93
G and 
) in HAMP on 19q13 have been identified in two families with a new type of juvenile haemochromatosis.23 A new gene called HFE2, whose protein product has been called haemojuvelin, has been identified recently, with amino acid substitution 
accounting for two-thirds of the mutations found.23
The HFE 3 locus maps to chromosome 7q22 and the gene is transferrin receptor 2 (TfR2).14
An autosomal dominant form has also been described25 linked to a mutation in the SLC11A3 gene.26 Other forms of haemochromatosis are known to have a genetic basis, but have yet to be defined.
The presence of the HFE genotype does not equate to a clinical diagnosis of hereditary haemochromatosis, which is made when iron overload is manifest in these patients. Genotype denotes susceptibility.
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Pathophysiology |
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The intestinal absorption of iron is inappropriately high in patients with HH, and steadily increases from birth. The normal iron content of the body is approximately 3–4 g. It exists as haemoglobin (2.5 g), iron-containing proteins (400 mg), iron bound to transferrin in plasma (3–7 mg) and as ferritin or haemosiderin in the storage form. Dietary iron is mainly in the ferric state, which is poorly soluble and as such poorly absorbed. Dietary iron is therefore reduced from the ferric to the ferrous state by ferric reductase, expressed on the luminal surface of the duodenum. The ferrous iron is taken up by the apical transporter, divalent metal transporter-1 (DMT1).27–30 Iron may be stored within the mucosal cell as ferritin or transported across to the plasma via ferroportin 1.31
The C282Y mutation disrupts the normal biological activity of the HFE protein. The HFE gene is found in the crypt cells of the duodenum in association with ß2-microglobulin and transferrin receptor TfR, which is the receptor by which cells acquire iron-loaded transferrin. HFE forms a complex with TfR.
It is believed that HFE may facilitate transferrin-receptor-dependant uptake of iron into crypt cells, allowing the complex to act as a sensor of body iron stores.2,28,30,32 Increased body iron stores and the accompanying rise in transferrin-bound iron would lead to an enhanced uptake of iron into crypt cells. Consequently, differentiating enterocytes migrating up the villous tip down-regulate the production of the iron transporter DMT1, reducing the absorption of dietary iron. This process is reversed in iron deficiency, with iron transporters in developing villous cells and iron absorption being increased. In hereditary haemochromatosis, the mutant HFE may impair TfR-mediated uptake of transferrin-bound iron into crypt cells, causing a false signal that iron stores are low. A relative iron deficiency in duodenal crypt cells, results in an increased expression of divalent metal ion transporter 1 (DMT-1), which in turn is responsible for iron absorption in villous cells of the small intestine.2,27–30 The reader is referred to an excellent review of the physiology of iron absorption and the HFE gene.32
Hepcidin is a newly described protein in iron transport, which may be the long sought iron regulatory hormone. Park et al.33 identified this peptide from human urine, and named it from its site of synthesis (liver, hep-) and antibacterial properties in vitro (-cidin). Krausse et al.34 identified the same peptide from plasma ultra-filtrate and named it LEAP-1 (liver-expressed antimicrobial peptide). The connection between hepcidin and iron metabolism was first made by Pigeon et al.35 during studies of hepatic responses to iron overload.
Since hepcidin deficiency caused severe iron overload in mice, the search was on for human mutations that would cause or contribute to haemochromatosis.36 Roetto et al. recently identified two families with severe new type of juvenile haemochromatosis with mutations in the coding region of hepcidin.22 It is likely that hepcidin is involved in the pathogenesis of the commoner mutant form of HH.36 Recent studies by Ahmad et al. 37 and Bridle et al.38 show that in HFE knockout mice, unlike in normal mice, hepatic hepcidin mRNA levels do not increase after iron loading.
Further, patients with hereditary haemochromatosis due to HFE mutations have lower than normal hepcidin m RNA in liver biopsies, despite iron overload.38 This suggests that partial hepcidin deficiency may contribute to iron overload in the most common form of haemochromatosis.37,38 If this hypothesis is correct, it may be possible to treat haemochromatosis by hepcidin replacement, either using optimized forms of the peptide or smaller molecular agonists.36 Further studies in the molecular mechanisms of hepcidin activity may improve our understanding of the regulation of iron transport, and potentially lead to new therapies for haemochromatosis and anaemia of inflammation.
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Clinical features |
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TopSummaryHistoryGeneticsPathophysiologyClinical featuresDiagnosisPhenotypeGenotypeThe role of liver...TreatmentThe role of liver...Family and population screeningConclusionReferences |
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Inappropriately increased iron absorption leads to iron loading of parenchymal cells in the liver, pancreas, heart and other organs, with resultant damage to their structure and impairment of their function. Clinical manifestations reflect this damage.39
The classic description is that of cutaneous hyperpigmentation, diabetes mellitus and hepatomegaly.9 Other clinical manifestations include fatigue (the commonest symptom), abdominal pain, abnormal liver tests, hepatocellular carcinoma, cardiomyopathy, cardiac conduction defects, hypogonadism, hypothyroidism, impotence and arthropathy (Table 1).
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Patients with haemochromatosis absorb only a few milligrams of iron in excess of physiological need, and thus clinical manifestations often occur at 40–60 years of age, when 20–40 g of excess iron have accumulated. Symptomatic disease is approximately 10 times more common in males than females,9 with women probably being spared by physiological blood loss during menstruation.
Hepatomegaly is present in 95% of symptomatic patients and abdominal pain of a dull aching character with hepatic tenderness may be noted in 56% of patients.40 Primary hepatocellular carcinoma develops in 30% of cirrhotic patients,40,41 and must be considered in patients with clinical deterioration, rapid liver enlargement, abdominal pain and ascites. Men outnumber women in most case series by a ratio of 3:1, where patients were identified by clinical morbidity.2
Chronic alcoholism and smoking are further risk factors for hepatocellular carcinoma in patients with HH.41
Diabetes mellitus develops in 30–60% of patients, and may result from a hereditary predisposition, cirrhosis or indeed deposition of iron in the pancreas.42 Loss of libido and testicular atrophy are common in symptomatic patients,42 with loss of potency occurring in up to 35% of men and amenorrhoea in 15% of women.40 Hypogonadism may be due to hypothalamic, pituitary or gonadal dysfunction.28
Arthropathy is seen in 20–70% of patients, and may even be the presenting feature.42 In two-thirds it starts in the metacarpophalangeal joints, although wrists and hips may also be affected.44 Radiologically, it is identical to degenerative osteoarthritis, except that chondrocalcinosis (calcium pyrophosphate deposition) is seen in the menisci and articular cartilage.42 Joint lesions improve in 30% with venesection, but 20% will worsen symptomatically despite venesection.40 Nonetheless, a destructive arthropathy is unusual/42 Arthralgia often proves difficult to treat, with resistance to conventional non-steroidal agents.
The classical cardiac abnormalities are congestive cardiac failure and cardiac dysrhythmias. ECG abnormalities are present in up to 35% of symptomatic patients.40 Ventricular ectopics are the commonest dysrhythmia, but supraventricular and ventricular tachycardias, ventricular fibrillation, and varying degrees of heart block also occur. Cardiac complications possibly relate to iron deposition in the myocardium and conducting system.
It is worth mentioning here that despite its myriad manifestations, a large proportion of patients will be asymptomatic and identified by serum iron studies as part of screening studies, screening of family members of an affected individual and or population screening.45
There may be a delay in the time of presentation to diagnosis of 5–8 years,46 emphasizing the need for a high index of suspicion and prompt evaluation before the phenotype becomes manifest.
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Diagnosis |
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TopSummaryHistoryGeneticsPathophysiologyClinical featuresDiagnosisPhenotypeGenotypeThe role of liver...TreatmentThe role of liver...Family and population screeningConclusionReferences |
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The diagnosis must be considered in any patient with unexplained hepatomegaly, abnormal skin pigmentation, idiopathic cardiomyopathy, arthritis, diabetes and/ or loss of libido. A particular emphasis must be placed on oral or intravenous iron administration, blood donations, multiple pregnancies and menstrual blood losses. Due consideration should be given to causes of secondary iron overload, a detailed discussion of which is beyond the scope of this article (Table 2). Haematological assessment is helpful to exclude iron overload from thalassaemia major or sideroblastic anaemia. Often, as pointed out above, liver test abnormalities may be the only clue and a detailed history and full physical examination should be performed to consider other liver diseases.
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Phenotype |
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Having considered the diagnosis serum ferritin and fasting transferrin saturation should be checked. Ferritin estimation is inexpensive, automated and easy to obtain. Unfortunately, ferritin levels may be raised in a host of other conditions, such as alcoholic liver disease, hepatitis C infection and non-alcoholic steatohepatitis.47–49 It is also well known that ferritin, being an acute-phase reactant, may be elevated in inflammatory disorders and neoplastic disease, and as such is not specific. Here transferrin saturation is helpful.
Transferrin saturation is obtained by the following formula:
100 x [serum iron concentration/total iron binding capacity]
A threshold value of 45% has been proposed, using the gold standard based on good sensitivity and acceptable cost.50 A serum ferritin in combination with transferrin saturation has a negative predictive value of 97%, and exceeds the accuracy of any of the indirect tests used in isolation.51 Despite this, reliance on iron studies is not enough to establish a diagnosis of hereditary haemochromatosis. Prior to 1996, if serum ferritin and or fasting transferrin saturation were elevated, a liver biopsy would be considered to establish the diagnosis. Following the discovery of the HFE mutations, that is no longer so.
In addition to the AASLD guidelines outlined in Figure 1, comprehensive guidelines for the diagnosis and management of haemochromatosis are also available from the British Society of Haematology (2000) and from the European Association for the Study of Liver Diseases.39
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Genotype |
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TopSummaryHistoryGeneticsPathophysiologyClinical featuresDiagnosisPhenotypeGenotypeThe role of liver...TreatmentThe role of liver...Family and population screeningConclusionReferences |
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The presence of the C282Y and H63D mutations can now be detected by polymerase chain reaction using whole blood samples.12 The presence of C282Y homozygosity in a patient with evidence of biochemical iron overload is consistent with HH, and these patients should proceed to phlebotomy. Compound heterozygotes (C282Y/H63D), C282Y heterozygotes or non-HFE-mutated individuals with biochemical evidence of iron overload should probably be evaluated with a liver biopsy. Although these individuals account for a small proportion of phenotypic HH, they have a low likelihood of iron overload, and elevated iron tests are often due to other causes of liver disease.2 Genotype non-expression is common in women.17
Genotype expression may be influenced by several factors, which include sex, age, diet, alcohol intake,52 hepatitis C infection, and blood donation. Subjects drinking > 60 g/day of alcohol are nine times more likely to develop cirrhosis than those drinking less than this amount.52 The presence of the HFE genotype does not equate to clinical disease. It merely indicates susceptibility to the development of the phenotype.39
Recent population-based studies have looked at disease expression in people genetically susceptible to hereditary haemochromatosis. Olynyk et al.53 identified C282Y homozygosity in 16 from a sample of 3011 unrelated White adults (1:188) with a median age of 52.7 years (range 20–79). Four had been given a diagnosis of haemochromatosis previously and seven of the other twelve had elevated serum ferritin levels, while four with normal iron studies were premenopausal women. Only half of those who were homozygous had clinical features of the disease. Prevalence of symptoms in non-homozygotes was not given for comparison. In a more recent study by Beutler et al.,54 152 homozygotes were identified from 41 038 individuals (1:270) attending a health appraisal clinic in San Diego. Homozygotes were twice as likely to report liver problems, but there was no evidence for a higher prevalence for any other symptom associated with hereditary haemochromatosis in homozygotes. The authors suggested that the penetrance of haemochromatosis might be < 1%.54 There has been a plethora of letters and opinions in response to this study. Demographic factors, such as the immigration of younger Hispanic and Asian populations with a lower prevalence of C282Y homozygosity, were suggested as major confounding factors.55 Further, Allen et al. suggested that exclusion of people with pre-existing disease might have biased the estimate of true disease penetrance downward.56 It would appear that though the genotype may be common, phenotypic expression probably depends upon multiple factors such as gene penetrance, environmental and genetic modifiers.
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The role of liver biopsy |
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TopSummaryHistoryGeneticsPathophysiologyClinical featuresDiagnosisPhenotypeGenotypeThe role of liver...TreatmentThe role of liver...Family and population screeningConclusionReferences |
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Genetic advances have completely changed the way in which a clinician uses the liver biopsy in the context of haemochromatosis. Liver biopsy has more prognostic significance and thus helps determine the presence or absence of hepatic fibrosis, for which it remains the gold standard.
Recently, non-invasive predictors have been studied predicting cirrhosis in C282Y homozygotes.57–59 In the study by Guyader et al.,57 there were no cases of cirrhosis in 96 C282Y homozygotes who had serum ferritin levels < 1000 µg/l, normal AST values and no evidence of hepatomegaly. In the study by Morrison et al.,59 only 1/93 patients with a ferritin level < 1000 µg/l had cirrhosis, compared with 39/89 patients with serum levels > 1000 µg/l. No C282Y homozygotes or C282Y/H63D compound heterozygotes with serum ferritin levels < 1000 µg/l had cirrhosis.
The AASLD recommends that individuals with serum indicators of iron overload who are homozygous for the C282Y mutation require phlebotomy.60 Individuals who are unlikely to have significant hepatic injury should be offered phlebotomy without the need for a liver biopsy. These are persons aged < 40 years, who have no clinical evidence of liver disease (as reflected by raised transaminases, hepatomegaly) and whose serum ferritin levels are < 1000 µg/l.57–60 Higher values may indicate significant hepatic injury or fibrosis. Liver biopsy may be considered in all homozygotes with clinical evidence of liver disease, serum ferritin > 1000 µg/l, and particularly those aged > 40 years, with other risk factors for liver disease.
The cut of value for age at 40 years should be interpreted with caution. Due consideration should be given to other causes of liver disease that may co-exist,60 and these should be carefully evaluated.
When a liver biopsy is performed, a biopsy core of at least 2.5–3 cm in length should be obtained. A 0.5–1 cm piece should be placed in a dry tube or in 10% formalin, the remainder being processed for histopathological evaluation and a Perls’ Prussian blue stain. This will permit the confirmation of iron overload, the determination of the pattern and degree of hepatic iron overload, the calculation of the hepatic iron concentration and hepatic iron index, and the detection of associated lesions, such as steatosis or hepatitis.61
Liver biopsies in HH classically show grade 2–4+ hepatocellular iron stores on staining, with the greatest density of iron staining in periportal areas62. Kupffer cell iron staining is not usually present unless total iron storage is more severe, with grade 4+ iron stores and fibrosis. The hepatic iron index (HII) is calculated by dividing the hepatic iron concentration (HIC) in µmol/g by the age in years. The normal HIC is < 1800 µg/g dry weight. A HII > 1.9 µmol/g/year is strong evidence for homozygous haemochromatosis.60 However, up to 15% of genotypic homozygotes for HH will have an HII <1.9, so an elevated HII is not considered necessary for the diagnosis.58
Non-invasive methods of detecting fibrosis such as type IV collagen have been studied, but at present cannot be recommended for use in clinical practice.63 Computed tomography may not detect milder degrees of iron overload.64 Magnetic resonance imaging has low sensitivity,65,66 although the paramagnetic properties of haemosiderin and ferritin permit the use of a superconducting quantum interference device (SQUID) to measure the hepatic magnetic susceptibility and correlates with hepatic iron concentration.67
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Treatment |
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The goal of treatment is to remove excess iron from the system. This is done by phlebotomy. There is good evidence now that the institution of phlebotomy before the onset of cirrhosis reduces the morbidity and mortality from HH.40 Some clinical manifestations such as malaise, fatigue, skin pigmentation, insulin requirements in diabetics, and abdominal pain are ameliorated by phlebotomy, but others, such as arthropathy, hypogonadism and cirrhosis, are not affected.60 Hepatocellular carcinoma may continue to be a potential threat, despite phlebotomy accounting for approximately 30% of deaths from HH, with other complications accounting for 20%.40 The observation that HCC is rare in non-cirrhotics further supports the rationale for instating phlebotomy prior to the development of cirrhosis.41
Phlebotomy of 500 ml of whole blood can be carried out in most patients once a week and although some patients may tolerate a twice-weekly regimen, this can be tedious. A venesection of 500 ml of whole blood removes 250 mg of iron. Each venesection should be preceded by measurement of the haematocrit, which should have returned to within 10 points of, or no lower than, 20% of the starting value. The serum ferritin and transferrin saturation should be checked once every 3 months. The aim of phlebotomy is to bring and maintain the ferritin levels down to 50 ng/ml. A secondary goal is to reduce transferrin saturation levels to <50%.60 After the serum ferritin has reached 50 ng/ml, therapeutic phlebotomy should probably be carried out lifelong every 3–4 months to keep ferritin levels <50 ng/ml (Table 3).
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Strict dietary restrictions are not required in patients undergoing phlebotomy. A normal balanced diet is usually sufficient, although reduced intake of iron-containing and iron-fortified foods can avoid excessive dietary iron. While tannin in tea may inhibit iron absorption (blocking agent), it is not a substitute for phlebotomy.68 Patients with hereditary haemochromatosis are susceptible to septicaemia from Vibrio vulnificus infection, and thus are advised to avoid consumption of uncooked seafood.69
Supplemental vitamin C must be avoided in these patients, as pharmacological doses can accelerate iron mobilization to a level that saturates circulating transferrin, resulting in an increase in pro-oxidant and free-radical activity.60
Cardiac dysrhythmias and cardiomyopathy are the commonest cause of death in iron overload states. During rapid mobilization of iron, there is an additional risk of developing these complications. End-organ damage should also be assessed and managed as normally. Thus, diabetes may require insulin and appropriate treatment of macro vascular and micro vascular complications. Arthritis should be managed with simple analgesia as far as possible, and hypogonadotrophic hypogonadism may require hormone replacement therapy.
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The role of liver transplantation |
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Phlebotomy prior to the development of cirrhosis may reduce morbidity and mortality from HCC, but once cirrhosis develops, phlebotomy will not reverse the pathology. The development of decompensation is an indication for consideration of orthotopic liver transplantation. Survival in patients transplanted for haemochromatosis is lower than those transplanted for other liver diseases.70,71 Infections in the first year after transplantation (mainly fungal), and later cardiac complications, were noted to be the commonest cause of post transplant deaths.72
Nonetheless, HCC develops in 30% of cirrhotic HH patients,40,41 and accounts for a third of deaths in HH patients; the risk does not decrease despite adequate iron removal with phlebotomy.71 The AASLD recommends close lifelong HCC surveillance in individuals with HC and significant fibrosis or cirrhosis.60 There are no randomized control studies of screening for HCC in cirrhosis of any aetiology, and it is unlikely that it will ever be ethical to recruit subjects to a control (no screening) arm of such a study. Thus screening practice has been based on non-randomized studies on either at-risk populations or from clinic-based series.73 Common practice is to screen with a six-monthly AFP (alpha fetoprotein) and ultrasound.
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Family and population screening |
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TopSummaryHistoryGeneticsPathophysiologyClinical featuresDiagnosisPhenotypeGenotypeThe role of liver...TreatmentThe role of liver...Family and population screeningConclusionReferences |
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The clinician's responsibility does not end with the diagnosis and management of the proband. Screening is recommended for all first-degree relatives (parents, siblings and children) of the patient.60 Testing for the C282Y mutation is cost-effective for screening relatives of patients with HH.74 C282Y and H63D mutations should be checked. Family members identified as having homozygosity to C282Y or heterozygosity to C282Y/H63D mutation should have their serum ferritin, fasting transferrin saturation and liver enzymes checked. If ferritin levels are raised and transferrin saturation is >45%, therapeutic phlebotomy should be commenced. Due consideration should be given to other aetiologies of abnormal liver chemistry that may co-exist, and they should be investigated appropriately. Liver biopsy is probably also not necessary in these individuals if their ferritin levels are < 1000 µg/ml and transaminase levels are normal, for reasons similar to those for the identified proband who meets these same criteria.57–60
Prior to obtaining the HFE gene test, the individual should be appropriately counselled about the risks, benefits and options by a qualified professional.
HH meets a number of WHO criteria for population screening, such as a latent period, availability of a screening test, and safe, cost-effective treatment, yet this remains a highly contentious issue. There is currently insufficient evidence to recommend universal population screening.39,75
There are obvious concerns regarding employment and insurance implications for the individual concerned. In Australia, unlike in the USA, insurance companies are bound by law to provide health insurance at one rate to all and therefore only life insurance is open to discrimination.76 For life insurance, an agreement has been reached with the insurance industry that considerably reduces the risk of discrimination.76 Those who are not C282Y homozygous will have no insurance loadings on the basis of this test. C282Y homozygotes with normal iron indices obtain insurance at baseline rates, while those with raised iron indices but no evidence of organ damage will be required to show that steps are being taken to normalize iron indices, the policy being issued at baseline rates under these circumstances. Those C282Y homozygotes with raised iron indices and evidence of organ damage would be penalized if obtaining new policies, but insurance companies would comment that testing is desirable, as treatment will keep disease progress to the minimum.76
It is suggested that the optimal time for screening is between the age of 18 and 30 when HH is evident from biochemical tests, but before serious organ damage has occurred.2 Screening is currently not recommended in children.39
Until it can be demonstrated suitably that benefits or savings outweigh any potential harm or costs, population genetic screening programs will remain a contentious issue.77
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Conclusion |
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TopSummaryHistoryGeneticsPathophysiologyClinical featuresDiagnosisPhenotypeGenotypeThe role of liver...TreatmentThe role of liver...Family and population screeningConclusionReferences |
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Hereditary haemochromatosis should be suspected in any individual presenting with abnormal liver chemistry, clinically manifest liver disease, diabetes, arthropathy, hypogonadism, cardiomyopathy, skin pigmentation or non-specific features such as lethargy. Serum ferritin and fasting transferrin saturation should be checked. A high ferritin with transferrin saturation >45% is highly suggestive of the diagnosis of HH. In such individuals, genotyping for C282Y and H63D mutations should be requested. Homozygosity for either mutation or indeed C282Y/H63D heterozygosity in the context of biochemical evidence of iron overload makes the diagnosis highly likely. Liver biopsy is not required to establish the diagnosis of HH, but may need to be considered if cirrhosis, hepatocellular carcinoma, or indeed an additional aetiology, is being considered in the clinical context. Individuals with normal transaminase levels and a ferritin <1000 µg/l are unlikely to have cirrhosis.
Patients diagnosed to have this condition should have regular venesection, usually weekly initially, until their ferritin levels come down to <50 ng/ml, after which phlebotomy may usually be carried out 3–4 monthly. Other complications such as diabetes, arthropathy, etc. should be addressed. Patients need to be closely followed for the development of complications such as cirrhosis and hepatocellular carcinoma, which may develop in a third of patients, and will not respond to phlebotomy. Decompensated liver disease is an indication to consider transplantation, if appropriate in the clinical context.
Screening is recommended for first-degree relatives, particularly for those >18 years of age, after appropriate counselling, and using similar biochemical and genotype tests as in the index case.
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Footnotes |
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Address correspondence to Dr J.K. Limdi, Hope Hospital, Stott Lane, Salford, Manchester M6 8HD. e-mail: jklimdi{at}doctors.org.uk
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References |
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14. Mura C, Raguenes O, Ferec C. HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of haemochromatosis. Blood 1999; 93:2502–5.
15. Pointon JJ, Wallace D, Merryweather-Clarke AT, Robson KJ. Uncommon mutations and polymorphisms in the hemochromatosis gene. Genet Test. 2000; 4:151–61.
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