EASL clinical practice guidelines for HFE hemochromatosis
European Association for the Study of the Liver*
Iron overload in humans is associated with a variety of genetic and acquired conditions. Of these, HFE hemochromatosis (HFEHC) is by far the most frequent and most well-deﬁned inherited cause when considering epidemiological aspects and risks foriron-related morbidity and mortality. The majority of patients with HFE-HC are homozygotes for the C282Y polymorphism . Without therapeutic intervention, there is a risk that iron overload will occur, with the potential for tissue damage and disease. While a speciﬁc genetic test now allows for the diagnosis of HFE-HC, the uncertainty in deﬁning cases and disease burden, as well as the low phenotypicpenetrance of C282Y homozygosity poses a number of clinical problems in the management of patients with HC. This Clinical Practice Guideline will therefore, focus on HFE-HC, while rarer forms of genetic iron overload recently attributed to pathogenic mutations of transferrin receptor 2, (TFR2), hepcidin (HAMP), hemojuvelin (HJV), or to a subtype of ferroportin (FPN) mutations, on which limited andsparse clinical and epidemiologic data are available, will not be discussed. We have developed recommendations for the screening, diagnosis, and management of HFE-HC. Ó 2010 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.
Cochrane Library databases from 1966 to March 2009. The study selection was based on speciﬁc inclusion and exclusion criteria (Table1). The quality of reported evidence has been graded according to the Grades of Recommendation, Assessment, Development, and Evaluation system (GRADE) [2–6]. The GRADE system classiﬁes recommendations as strong or weak, according to the balance of the beneﬁts and downsides (harms, burden, and cost) after considering the quality of evidence (Table 2). The quality of evidence reﬂects the conﬁdencein estimates of the true effects of an intervention, and the system classiﬁes quality of evidence as high, moderate, low, or very low according to factors that include the study methodology, the consistency and precision of the results, and the directness of the evidence [2–6]. Every recommendation in this CPG is followed by its GRADE classiﬁcation in parentheses.
What is the prevalence ofC282Y homozygosity? The prevalence of HFE gene polymorphisms in the general population The frequency of HC-associated HFE gene polymorphisms in the general population was determined in 36 screening studies, which fulﬁlled the inclusion criteria (Table 3). The allelic frequency of C282Y was 6.2% in a pooled cohort of 127,613 individuals included in the individual patient meta-analysis from these 36studies (Table 3). From this allelic frequency for C282Y, a genotype frequency of 0.38% or 1 in 260 for C282Y homozygosity can be calculated from the Hardy–Weinberg equation. The reported frequency of C282Y homozygosity is 0.41%, which is signiﬁcantly higher than the expected frequency. This probably reﬂects a publication or ascertainment bias. Signiﬁcant variations in frequencies of the C282Y allelebetween different geographic regions across Europe have been reported with frequencies ranging from 12.5% in Ireland to 0% in Southern Europe (Fig. 1). In addition to C282Y, which is also known as the ‘major’ HFEassociated polymorphism, H63D, considered to be the ‘minor’ HFE polymorphism, has been found more frequently in HC patients than in the control population. The frequency of the H63Dpolymorphism shows less geographic variation, with an average allelic frequency of 14.0% from pooled data (23,733 of 170,066 alleles). An additional HFE polymorphism is S65C, which can be associated with excess iron when inherited in trans with C282Y on the other parental allele. The allelic frequency of this polymorphism is $0.5% and appears to be higher in Brittany, France.