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Contains fulltext : 80568.pdf (Publisher’s version ) (Closed access) Haemochromatosis should currently refer to hereditary iron overload disorders presenting with a definite and common phenotype characterised by normal erythropoiesis, increased transferrin saturation and ferritin and primarily parenchymal iron deposition related to innate low (but normally regulated) production of the hepatic peptide hormone hepcidin. Since the discovery of the haemochromatosis gene (HFE) in 1996, several novel gene defects have been detected, explaining the mechanism and diversity of iron overload diseases. Overall, at least four main types of hereditary haemochromatosis (HH) have been identified. This review describes the systematic diagnostic and therapeutic strategy and pitfalls for patients suspected for HH and their relatives.

HFE-related hereditary haemochromatosis (HH) is an iron overload disease attributed to the highly prevalent homozygosity for the C282Y mutation in the HFE gene. The pathophysiology of this error in iron metabolism is not completely elucidated yet, although deficiency of the iron regulatory hormone hepcidin appears to play a role. Ways of diagnosing iron overload include measurement of the serum iron parameters, i.e. serum transferrin saturation and serum ferritin, by a liver biopsy or by calculating the amount of mobilisable body iron withdrawn by phlebotomies. Clinical signs attributed to HFE-related HH include liver failure, arthralgia, chronic fatigue, diabetes mellitus and congestive heart failure. organ failure can be prevented by phlebotomies starting before irreversible damage has occurred. Therefore, screening to facilitate early diagnosis is desirable in individuals at risk of developing HFE-related iron overload. over time it appeared that the clinical penetrance of the HFE mutations was much lower than had previously been thought. This changed the opinion about a suitable screening modality from case detection, via population screening, to family screening as the most appropriate method to prevent HFE-related disease. However, before the implementation of family screening it is vital to have thorough information on the relevance of the specific health problem involved, on the clinical penetrance of C282Y homozygosity and on the effectiveness of the screening approach.

Family screening has been suggested as a sophisticated model for the early detection of HFE-related hereditary haemochromatosis (HH). However, until now, controlled studies on the morbidity and mortality in families with HH are lacking.Data on iron parameters, morbidity and mortality were collected from 224 dutch C282Y-homozygous probands with clinically overt HH and 735 of their first-degree family members, all participating in the HEmochromatosis fAmily study (HEfAs). These data were compared with results obtained from an age- and gender-matched normal population. HEfAs and controls filled in similar questionnaires on demographics, lifestyle factors, health, morbidity and mortality.A significantly higher proportion of the HEfAs first-degree family members reported to be diagnosed with haemochromatosis-related diseases: 45.7 vs 19.4% of the matched normal population (McNemar p0.001). Mortality among siblings, children and parents in the HEFAS population was similar to that in the relatives of matched control.In this study we show that, morbidity among first-degree family members of C282Y-homozygous probands previously diagnosed with clinically proven HH is higher than that in an age- and gender-matched normal population. Further studies are needed to definitely connect these increase morbidity figures to increase prevalenc of the C282Y mutated HFE-gene and elevated serum iron indices.

Hereditary haemochromatosis (HH) is a disease related to mutations in the HFE gene and can lead to progressive iron accumulation, especially in the liver, eventually resulting in organ damage. We have developed guidelines for the diagnosis and treatment of this disease according to CBO methodology (dutch institute for Healthcare Quality). The prevalence of clinical symptoms such as fatigue, arthropathies, impotence and diabetes mellitus among homozygotes was similar to that in a control population. Nevertheless, we recommend the assessment of serum iron indices when these symptoms remain unexplained. When transferrin saturation is45% and ferritin exceeds local reference ranges, HFE mutations should be investigated. Homozygosity for the C282Y mutation or combined C282Y/H63d mutation confirms the diagnosis of HFE-related HH. Liver biopsy is recommended when ferritin exceeds 1000 microg/l to establish the presence or absence of cirrhosis, which will affect prognosis and management. iron accumulation confirmed by magnetic resonance imaging (MRI) in the absence of the homozygous C282Y mutation or the combined C282Y/H63d genotype may justify a search for rare hereditary forms of non-HFE HH in a specialised centre. The literature supports the benefits of adequate phlebotomy and the screening of first-degree relatives of index patients with clinically overt HH. overall, the guidelines presented here are to a great extent based on the expert opinion of the working party, as the quantity of evidence that met predefined criteria posed by the evidence-based approach was small. We therefore recommend world-wide efforts to collaboratively address these remaining issues.

Primary haemochromatosis is an autosomal recessive disorder with a high prevalence (1 in 200-400) among North-Europeans. Approximately 64-100% of patients with primary haemochromatosis are homozygous for a missense mutation that alters a major-histocompatibility-complex class I-like protein designated HFE (from 'haemochromatosis'). This predominant mutation is a substitution of cysteine to tyrosine at amino acid residue 282 (Cys282Tyr) in the alpha 3-domain of the HFE protein. This mutation in the HFE protein in the intestinal crypt cells is supposed to lead to up-regulation of iron transporters for dietary iron in the mucosal cells at the tip of the duodenal villi. As a consequence, an excess of absorbed iron accumulates in the major organs of the HFE-mutated patients, leading to multi-organ dysfunction. A second mutation, His63Asp, in the HFE-gene is enriched in primary haemochromatosis patients who are concomitantly heterozygous for the Cys282Tyr-mutation. However, its role in the pathophysiology of primary haemochromatosis is not yet clear. A small subgroup of patients with primary haemochromatosis do not have mutations in HFE; for some of them the genetic basis has been determined. Homozygosity for the Cys282Tyr-mutation plus biochemical and clinical evidence of iron overload renders the diagnosis of HFE-related primary haemochromatosis indisputable. In other cases, liver biopsy remains the gold standard for the diagnosis of primary haemochromatosis. First-degree relatives of index patients should be screened for the disease.

In a 49-year-old man and a 28-year-old woman, both of whom complained of fatigue, HFE-gen related respectively non-HFE-gen related primary haemochromatosis was diagnosed, based on the elevated serum transferrin saturation, the elevated serum ferritin levels, DNA studies and liver biopsy with qualitative respectively quantitative iron measurements. Their complaints diminished after bloodletting. Three women respectively 64, 61 and 46 years of age, were also suspected of primary haemochromatosis. The latter two presented with complaints of fatigue and malaise and chronic hepatitis C respectively. All three showed an elevated serum transferrin saturation and serum ferritin concentration. Further investigation showed the presence of secundary iron overload. Causes for it being excessive alcohol consumption, overweight and a poorly regulated diabetes mellitus type 2, and chronic hepatitis C respectively. These patients received specific therapy. Primary haemochromatosis is a common disorder of iron metabolism in individuals of Northern European descent. Diagnosis is based on an elevated serum transferrin saturation in combination with both elevated serum ferritin levels and homozygosity for the Cys282Tyr-mutation in the HFE-gen. The presence of an elevated serum transferrin saturation in combination with an elevated serum ferritin level is not always sufficient for the diagnosis, since these may be affected by other disorders. Moreover, iron overload may be caused by a form of haemochromatosis that is not HFE-related. In case of doubt as to the diagnosis, histological examination of the liver with a qualitative or quantitative iron determination is the golden standard.

To determine whether patients previously diagnosed as chronic fatigue syndrome (CFS) actually have primary haemochomatosis (PH).The setting was a Dutch referral centre. Transferrin saturation (TS) was retrospectively evaluated in banked blood samples of 88 patients diagnosed as CFS. Patients with elevated TS values were asked to provide a new overnight fasting blood sample for a second determination of TS and measurement of serum ferritin. The DNA was investigated for mutations in the HFE gene when one of these iron parameters was elevated.For 19 out of 88 patients with CFS an elevated TS was found. A new blood sample was obtained from 11 of these 19: six had increased TS and two had elevated serum ferritin values. These eight patients were neither C282Y homozygotes nor compound C282Y-H63D heterozygotes. In the eight cases where no new blood samples could be obtained, the TS was50% for two of the five men and45% for the three female patients.In a group of 88 CFS patients we could exclude PH in all but two of them (prevalence 2.3%; 95% confidence interval 0-5.5%). In our population of CFS patients PH is not more common than in a control population of northern European descent (prevalence 0.25-0.50%).