The prevalence of homozygosity for C282Y in the HFE gene inclinically recognized hemochromatosis
The prevalence of C282Y homozygosity in clinically recognizedindividuals with iron overload was assessed in a meta-analysisincluding 32 studies with a total of 2802 hemochromatosispatients of European ancestry (Table 4). This analysis of pooleddata shows that 80.6% (2260 of 2802) of HC patients are homozy-gous for the C282Y polymorphism in the HFE gene. Compoundheterozygosity for C282Y and H63D was found in 5.3% of HCpatients (114 of 2117,Table 4). In the control groups, which werereported in 21 of the 32 studies, the frequency of C282Y homozy-gosity was 0.6% (30 of 4913 control individuals) and compoundheterozygosity was present in 1.3% (43 of 3190 of the controlpopulation).Hence, 19.4% of clinically characterized HC patients have thedisease in the absence of C282Y homozygosity. Although com-pound heterozygosity (H63D/C282Y) appears to be disease asso-ciated, in such individuals with suspected iron overload, cofactorsshould be considered as a cause[72–74].
The prevalence of HFE genotypes in selected patient groupsFatigue
To date, there are only cross-sectional or case-control studiesinvestigating the prevalence of C282Y homozygosity in patientswith fatigue or chronic fatigue syndrome[75–77]. None of thethree studies found the prevalence of C282Y homozygosity tobe increased.
Most available studies investigated the prevalence of C282Y mutations in patients with inﬂammatory arthritis[78–80]; thereare few studies in patients with non-inﬂammatory arthralgia orchondrocalcinosis[75,81].In the majority of studies of patients
with undifferentiated osteoarthritis the prevalence of C282Y homozygosity did not exceed that of the control population[3,80]. In patients with osteoarthritis in the 2nd and 3rd metacar-pophalangeal joints, higher allele frequencies of the HFE-poly-morphisms (C282Y and H63D) were found, although this wasnot accompanied by an increased frequency of C282Y homozy-gotes[82,83]. A higher prevalence of C282Y homozygosity wasonly found in patients with well-characterized chondrocalcinosis.
Association of the C282Y polymorphism with diabetes mellitushas been mainly evaluated in patients with type 2 diabetes mel-litus in cross-sectional and case-control studies[84–95]. Apartfrom one exception, no association between type 2 diabetes
Table 2. Quality of evidence and strength of recommendations according to GRADE.
Example Note Symbol
Quality of evidence
High Randomized trials that show consistent results, orobservational studies with very large treatment effectsFurther research is very unlikely to change our conﬁdencein the estimate of effectAModerate Randomized trials with methodological limitations, orobservational studies with large effectFurther research is likely to have an important impact onour conﬁdence in the estimate of effect and may changethe estimateBLow and very Low Observational studies without exceptional strengths, orrandomized trials with very serious limitations;unsystematic clinical observations (e.g. case reports andcase series; expert opinions) as evidence of very-low-quality evidenceFurther research is very likely to have an importantimpact on our conﬁdence in the estimate of effect and islikely to change the estimate. Any estimate of effect isvery uncertainC
Strength of recommendations
Strong Deﬁned as being ‘conﬁdent that adherence to therecommendation will do more good than harm or that thenet beneﬁts are worth the costs’1Weak Deﬁned as being ‘uncertain that adherence to therecommendation will do more good than harm OR thatthe net beneﬁts are worth the costs’The uncertainty associated with weak recommendationsfollows either from poor-quality evidence, or from closelybalanced beneﬁts versus downsides2
Factors that affect the strength of a recommendation are: (a) quality of evidence; (b) uncertainty about the balance between desirable and undesirable effect; (c)uncertainty or variability in values and preferences; (d) uncertainty about whether the intervention represents a wise use of resources (see Refs.[2–6]).
Table 1. Inclusion and exclusion criteria for the literature search.
Inclusion and exclusion criteria for searching references
1. Populations: adults age >18 years, population applicable to Europe, NorthAmerica, Australia, New Zealand, screening population with elevated ironmeasures, asymptomatic iron overload, or HFE C282Y homozygosity (all ageswere included for questions on C282Y prevalence)2. Disease: symptomatic (liver ﬁbrosis, cirrhosis, hepatic failure, hepatocellularcarcinoma, diabetes mellitus, cardiomyopathy, or arthropathy hypogonadism,attributable to iron overload) or asymptomatic with or without C282Y homozygosity3. Design:a. Questions on prevalence: cohort or cross-sectional studies (also studies innewborns)b. Questions on burden, natural history, penetrance: cross-sectional andlongitudinal cohort studiesc. Questions on therapeutics: RCTs and large case series4. Outcomes: incidence, severity, or progression of clinical hemochromatosis oriron measures, nonspeciﬁc symptoms (for questions on therapy)
1. Non-human study2. Non-English-language3. Age: <18 years unless adult data are analyzed separately4. Design: case-series with <15 patients, editorial, review, letter, congressabstract (except research letters)5. For questions on epidemiology and diagnosis: does not include HFEgenotyping6. Does not report relevant prevalence or risk factors (for questions onprevalence–penetrance), does not report relevant outcomes (for questions ontherapy)7. Not phlebotomy treatment (for questions on therapy)
Clinical Practice Guidelines
4 Journal of Hepatology