Department of Medicine
Gastroenterology and Hepatology
Medical University of Innsbruck,
Chronic fatigue, darkening of the skin, progressive liver disease – including cirrhosis – diabetes, heart failure and arrhythmias, impotence and arthralgias can indicate the iron storage disease hemochromatosis. The disease is caused by iron overload in affected organs, primarily the liver. Early diagnosis and therapeutic phlebotomy reduces the disease burden, but if the diagnosis is delayed, liver disease can advance to cirrhosis, hepatocellular carcinoma, and diabetic complications can develop.1
Epidemiology and genetics of hemochromatosis
Hemochromatosis is regarded as the commonest genetic disease in adults of northern European ancestry, where the disease has a prevalence of 1:200 to 1:500.2
The genetic causes of hemochromatosis are heterogenous, where homozygosity for the C282Y polymorphism of the HFE gene is found in more than 80% of patients with clinically diagnosed hemochromatosis.3 The allele frequency of the C282Y polymorphism varies across Europe (Figure 1). H63D is another common allele that occurs with a constant frequency of about 15% in populations of different ethnic origins.3
Modifiers of disease expression
In screening studies, homozygosity for C282Y was about four to ten-fold more prevalent than hemochromatosis. Follow-up studies have shown that long-term progression of iron overload occurs in few C282Y homozygous individuals. Hence, the penetrance of hemochromatosis is 10%–25%, which illustrates that modifiers of disease expression exist.
Genetic hemochromatosis modifiers are male sex and heterozygosity for other hemochromatosis genes (see below). Environmental factors that affect disease expression are increased alcohol consumption, hepatitis C virus infection, consumption of non-citrus fruit and red meat.3
The strongest risk factor for hemochromatosis is homozygosity for C282Y. Although the compound heterozygous C282Y/H63D genotype is present in 5% of patients with hemochromatosis, the penetrance of this genotype is so low that it is no longer considered a sufficient cause of hemochromatosis.4
In patients with hemochromatosis and genotypes other than homozygosity for C282Y, other causes of iron overload are typically found. Genetic causes of iron overload in non-HFE hemochromatosis patients are mutations in genes encoding ferroportin, transferrin receptor 2 hemojuvelin or hepcidin.5 The commonest iron overload syndrome in adults after HFE-associated hemochromatosis is ferroportin disease, which is associated with mutations of the gene encoding the iron export pump ferroportin (SLC40A1). In contrast to HFE-associated hemochromatosis, ferroportin disease rarely progresses to liver cirrhosis and iron overload can affect liver and spleen.6
Clinical signs of iron overload in children and adolescents more frequently include heart failure and endocrine abnormalities than in adult patients. Hemochromatosis presenting before the third decade of life is regarded as juvenile hemochromatosis, which is associated with mutations in the genes encoding hepcidin or hemojuvelin.7
How to assess for iron overload
Hemochromatosis is a complex genetic disease with incomplete penetrance and strong environmental modifiers of disease expression. The diagnosis requires evidence of increased total-body iron stores, as indicated by hepatic iron overload. The gold standard method to assess the iron concentration in the liver is chemical quantification of tissue iron in a liver biopsy specimen.8 Liver biopsy also shows the degree of liver fibrosis and therefore has prognostic relevance.
Magnetic resonance imaging and T2* relaxation times have evolved as a non-invasive alternative to liver biopsy to quantify tissue iron. MRI is more accurate for the assessment of hepatic iron concentrations in patients with inhomogeneously distributed iron. Furthermore, MRI theoretically allows measurement of iron concentrations in other organs that are inaccessible to biopsy, such as the spleen, pancreas and possibly the heart. However, the specificity of MRI-based hepatic iron quantification in patients with hepatic steatosis or inflammation is unknown.9
The initial screening test in patients with suspected disorders of iron status are serum iron parameters, which include serum iron, transferrin, serum ferritin and iron saturation of transferrin (transferrin saturation). Increased transferrin saturation is a sensitive and specific surrogate of iron overload. However, this parameter has a low specificity and repeated testing has been advocated to reduce unnecessary genetic testing and unnecessary assessment of hepatic iron overload.
In patients with hypotransferrinemia as it occurs during inflammation or in patients with advanced cirrhosis, elevated transferrin saturation does not necessarily indicate hepatic iron overload.
The serum concentration of the iron-storage protein ferritin is an indicator of body iron status and hyperferritinemia is frequently found in patients with hemochromatosis. Serum ferritin also increases during acute or chronic inflammation, malignancies or metabolic syndrome, where it is not an indicator of increased iron stores.
Clinical problem: hyperferritnemia
Hyperferritinaemia is a common clinical problem, whose differential diagnostic workup thus requires careful exclusion of malignant diseases, inflammatory conditions and cell necrosis. In patients with hyperferritinemia and increased transferrin saturation, HFE testing is recommended, where the identification of C282Y homozygosity confirms the diagnosis hemochromatosis.
In patients with elevated transferrin saturation and other HFE genotypes, further investigation is required. Differential diagnoses include genetic iron overload caused by other genetic defects. But before complex of genetic testing beyond HFE genotyping is performed, assessment of hepatic iron concentrations by MRI or liver biopsy is recommended.
Few patients with hyperferritinemia and normal-to-low transferrin saturation will have iron overload and inflammation, metabolic syndrome, cell necrosis or malignancies. In patients with hyperferritinemia and normal-to-low transferrin saturation and evidence for iron overload, ferroportin disease and aceruloplasminemia are rare differentials.
Dysmetabolic iron overload syndrome
Increased serum ferritin concentrations are frequently present in patients with metabolic syndrome, where the cause of hyperferritinemia is multifactorial. Subclinical inflammation and true iron overload can both contribute to a variable extend to the hyperferritinemia. Regardless of whether iron overload is present or not, iron reduction by phlebotomy has been found to have beneficial effects on metabolic parameters and can reduce cancer mortality in these patients.10
Management of hemochromatosis
In individuals homozygous for the C282Y polymorphism, with hyperferritinemia and increased transferrin saturation, the diagnosis hemochromatosis can be made. In these patients, liver biopsy is only recommended if fibrosis or cirrhosis is suspected.
Patients without hepatomegaly, normal transaminases and ferritin <1,000µg/L have low pretest likelihood for significant fibrosis, which makes a liver biopsy dispensable in such cases.11 An increased prevalence of hepatocellular carcinoma has been reported in patients with hemochromatosis even in the absence of cirrhosis. Liver imaging studies by CT or MRI at the time of diagnosis is therefore advisable in all patients with hemochromatosis.
Regardless of the degree of iron overload and of the absolute ferritin concentration, hemochromatosis patients should be evaluated for extrahepatic complication of the disease by determination of fasting glucose and HbA1c concentrations. In addition, cardiac evaluation by echocardiography, clinical assessment of joints and evaluation of sexual function as well as osteodensitometry could be recommended.
Treatment of hemochromatosis
The preferred treatment option is iron reduction treatment with therapeutic phlebotomy, which was found to reduce the progression to cirrhosis, prevent hepatocellular carcinoma and extrahepatic complications of the disease in case-controlled studies. Even in patients with liver cirrhosis, therapeutic phlebotomy can reduce the severity of liver disease and prevent complications of liver cirrhosis.12
For therapeutic phlebotomy, patients should have 450-500ml of blood removed weekly to fortnightly as long as haemoglobin concentrations are >120g/L in females and >130g/L in males. Another treatment endpoint is serum ferritin, which should be determined every three months or once patients have become anaemic.
Maintenance phlebotomy is usually required two to four times per year, aiming at maintaining serum ferritin below 50µg/L. Investigative treatment alternatives are erythrocyteapharesis or iron chelation therapy.
In patients with end-stage liver disease, liver transplantation cures the underlying defect, which is deficiency of the iron hormone hepcidin. Extrahepatic manifestations of hemochromatosis should be managed regardless of the underlying cause.
Iron reduction by therapeutic phlebotomy can prevent complications of the disease and normalise life expectancy. Although genetic testing allows early diagnosis before disease manifestation, the low penetrance of the disease complicates genetic counselling. Nevertheless, recent guidelines clearly recommend family screening of first-degree relatives, because the penetrance in C282Y homozygous family members of hemochromatosis patients is higher than in C282Y homozygotes identified by family screening.
The high prevalence, the availability of a presymptomatc test – be it genetic testing or phenotypic testing with transferrin saturation – and a preventive treatment make hemochromatosis an ideal candidate for population screening. The recommendation of the US Preventive Services Task Force is against screening of primary care populations, because the potential benefits do not outweigh the risks and cost of such a screening programme.2,13
Hemochromatosis testing is reserved for patients with clinical signs of symptoms suggestive of hemochromatosis, a suggestive serum iron parameter profile or evidence of iron overload in a liver biopsy specimen or by MRI.
Summary and conclusions
In summary, hemochromatosis is a frequent genetic disease associated with homozygosity for the common C282Y polymorphism of the HFE gene. Its clinical presentation is variable and often includes unspecific symptoms such as arthralgias, impotence and fatigue.
In patients with advanced stages of the disease or comorbidities, complications of the severe disease may develop that include liver cirrhosis, hepatocellular carcinoma heart failure and diabetes. Early diagnosis and preventive phlebotomy are therefore mandatory.
In patients with suspected hemochromatosis, serum iron parameters should be determined and, if serum ferritin and transferrin saturation is increased, genetic testing should be carried out.
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- Mayr R, Janecke AR, Schranz M, et al. Ferroportin Disease: A systematic meta-analysis of clinical and molecular findings. J Hepatol 2010;in press.
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