EASL Clinical Practice Guidelines


This Clinical Practice Guideline (CPG) has been developed to assist physicians and other healthcare providers as well as patients and interested individuals in the clinical decision making process for HFE-HC. The goal is to describe a number of generally accepted approaches for the diagnosis, prevention, and treatment of HFE-HC. To do so, four clinically relevant questions were developed and addressed:

  1. What is the prevalence of C282Y homozygosity?
  2. What is the penetrance of C282Y homozygosity?
  3. How should HFE-HC be diagnosed?
  4. How should HFE-HC be managed?

Each question has guided a systematic literature review in the Medline (PubMed version), Embase (Dialog version), and the Cochrane Library databases from 1966 to March 2009. The study selection was based on specific inclusion and exclusion criteria (Table 1). The quality of reported evidence has been graded according to the Grades of Recommendation, Assessment, Development, and Evaluation system (GRADE) [[2], [3], [4], [5], [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 confidence in 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], [3], [4], [5], [6]]. Every recommendation in this CPG is followed by its GRADE classification in parentheses.

Table 1
Inclusion and exclusion criteria for the literature search.

Inclusion and exclusion criteria for searching references
Inclusion criteria
1. Populations: adults age >18 years, population applicable to Europe, North America, Australia, New Zealand, screening population with elevated iron measures, asymptomatic iron overload, or HFE C282Y homozygosity (all ages were included for questions on C282Y prevalence)
2. Disease: symptomatic (liver fibrosis, cirrhosis, hepatic failure, hepatocellular carcinoma, diabetes mellitus, cardiomyopathy, or arthropathy hypogonadism, attributable to iron overload) or asymptomatic with or without C282Y homozygosity
3. Design:
 a. Questions on prevalence: cohort or cross-sectional studies (also studies in newborns)
 b. Questions on burden, natural history, penetrance: cross-sectional and longitudinal cohort studies
 c. Questions on therapeutics: RCTs and large case series
4. Outcomes: incidence, severity, or progression of clinical hemochromatosis or iron measures, nonspecific symptoms (for questions on therapy)
Exclusion criteria
1. Non-human study
2. Non-English-language
3. Age: <18 years unless adult data are analyzed separately
4. Design: case-series with <15 patients, editorial, review, letter, congress abstract (except research letters)
5. For questions on epidemiology and diagnosis: does not include HFE genotyping
6. Does not report relevant prevalence or risk factors (for questions on prevalence–penetrance), does not report relevant outcomes (for questions on therapy)
7. Not phlebotomy treatment (for questions on therapy)

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, or observational studies with very large treatment effects Further research is very unlikely to change our confidence in the estimate of effect A
Moderate Randomized trials with methodological limitations, or observational studies with large effect Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate B
Low and very Low Observational studies without exceptional strengths, or randomized trials with very serious limitations; unsystematic clinical observations (e.g. case reports and case series; expert opinions) as evidence of very-low-quality evidence Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any estimate of effect is very uncertain C
Strength of recommendations
Strong Defined as being 'confident that adherence to the recommendation will do more good than harm or that the net benefits are worth the costs' 1
Weak Defined as being 'uncertain that adherence to the recommendation will do more good than harm OR that the net benefits are worth the costs' The uncertainty associated with weak recommendations follows either from poor-quality evidence, or from closely balanced benefits versus downsides 2

∗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], [3], [4], [5], [6]]).