Clinical Practice Guidelines
EASL clinical practice guidelines for HFE hemochromatosis

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Iron overload in humans is associated with a variety of genetic and acquired conditions. Of these, HFE hemochromatosis (HFE-HC) is by far the most frequent and most well-defined inherited cause when considering epidemiological aspects and risks for iron-related morbidity and mortality. The majority of patients with HFE-HC are homozygotes for the C282Y polymorphism [1]. 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 phenotypic penetrance 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 sub-type of ferroportin (FPN) mutations, on which limited and sparse clinical and epidemiologic data are available, will not be discussed. We have developed recommendations for the screening, diagnosis, and management of HFE-HC.

Introduction

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.

Section snippets

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 36 studies (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

What is the penetrance of C282Y homozygosity?

Differences in inclusion criteria and in the definition of biochemical and disease penetrance have produced a range of estimates for the penetrance of C282Y homozygosity. The disease penetrance of C282Y homozygosity was 13.5% (95% confidence interval 13.4–13.6%) when 19 studies were included in the meta-analysis and the results of individual studies weighted on the inverse variance of the results of the individual study (Fig. 2) [134], [135].

Recommendations for genetic testing:

General population:

  • Genetic screening for HFE-HC is not recommended, because disease penetrance is low and only in few C282Y homozygotes will iron overload progress (1B).

    Patient populations:

  • HFE testing should be considered in patients with unexplained chronic liver disease pre-selected for increased transferrin saturation (1C).

  • HFE testing could be considered in patients with:

    • Porphyria cutanea tarda (1B).

    • Well-defined chondrocalcinosis (2C).

    • Hepatocellular carcinoma (2C).

    • Type 1 diabetes (2C).

  • HFE

How should HFE-HC be diagnosed?

The EASL CPG panel agreed on the following case definition for diagnosis of HFE-HC:

C282Y homozygosity and increased body iron stores with or without clinical symptoms.

The following section will address the genetic tests and tools for assessing body iron stores.

Recommendations for the diagnosis of HFE-HC:

  • Patients with suspected iron overload should first receive measurement of fasting transferrin saturation and serum ferritin (1B), and HFE testing should be performed only in those with increased transferrin saturation (1A).

  • Patients from liver clinics should be screened for fasting transferrin saturation and serum ferritin (1C) and offered genetic HFE testing if transferrin saturation is increased (1B).

  • HFE testing for the C282Y and H63D polymorphism should be carried out in all patients with

Which strategy should be used to diagnose HFE-HC?

To outline a diagnostic strategy in patients with suspected HC, several clinical scenarios for patients who should be investigated for HFE-HC have been selected. The following section will discuss a practical diagnostic approach to patients with suspected iron overload.

In contrast to the previous sections, where evidence based recommendations were made, this section is based on the expert opinion of the EASL CPG panelists (Y.D., J.D., A.E., A.P., R.S., H.Z.).

How should HFE-HC be managed?

There are very few data on the threshold of tissue iron excess at which tissue damage is seen. A study of the degree of lipid peroxidation has been done in treated and untreated HC patients, as well as in heterozygotes, suggesting changes at low levels of iron loading [207]; however, this study has not been confirmed. The relationship between liver iron concentration [208], serum ferritin (>1000 μg/L) [202], and hepatic damage do not help define when the treatment of iron overload should begin.

Recommendations for the management of HFE-HC:

  • Patients with HFE-HC and evidence of excess iron should be treated with phlebotomy (1C).

  • C282Y homozygotes without evidence for iron overload could be monitored annually and treatment instituted when the ferritin rises above normal (2C).

  • Phlebotomy should be carried out by removing 400–500 ml of blood (200–250 mg iron) weekly or every two weeks. Adequate hydration before and after treatment, and avoidance of vigorous physical activity for 24 h after phlebotomy is recommended (1C).

  • Phlebotomy can be

Patient organizations

The European Federation of Associations of Patients with Hemochromatosis (EFAPH) federates national European patient organizations. Its mission is to provide information for HC patients and their relatives, to raise public awareness, and to improve the quality of care for HC patients through the support of basic and clinical research (http://www.european-haemochromatosis.eu/index2.html).

Genetic testing

Measures must be put in place to avoid discrimination of HC patients. In accordance with legal regulations in

Contributors

Clinical Practice Guidelines Panel: Antonello Pietrangelo, Yves Deugnier, James Dooley, Andreas Erhardt, Heinz Zoller, Rifaat Safadi.

Reviewers: Bruce Bacon, John Crowe, Claus Niederau.

Financial disclosures

Heinz Zoller has received lecture fees from Novartis. Claus Niederau has received research funding and consultancy fees from Novartis. All other contributors and reviewers declare they have nothing to disclose.

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