Michèle Perrin

Unité Inserm U1077, Caen, Lower Normandy, France

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Publications (15)103.85 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Backround Mortality studies in patients with hemochromatosis gave conflicting results especially with respect to extrahepatic causes of death. Our objective was to assess mortality and causes of death in a cohort of HFE C282Y homozygotes diagnosed since the availability of HFE testing. Methods We studied 1085 C282Y homozygotes consecutively diagnosed from 1996 to 2009 and treated according to current recommendations. Mortality and causes of death were obtained from death certificates and compared to those of the general population. Standardized mortality ratios (SMR) were used to assess specific causes of death and Cox’s model to identify prognostic factors for death. Results Patients were followed for 8.3±3.9 years. Overall SMR was the same as in the general population (0.94 - CI:0.71-1.22). Patients with serum ferritin ⩾2000 μg/L had increased liver-related deaths (SMR: 23.9-CI:13.9-38.2), especially due to hepatic cancer (SMR: 49.1-CI:24.5-87.9). Patients with serum ferritin between normal and 1000μg/L had lower mortality than the general population (SMR: 0.27-CI:0.1-0.5) due to decreased mortality related to cardiovascular events and extrahepatic cancers in the absence of increased liver-related mortality. Age, diabetes, alcohol consumption, and hepatic fibrosis were independent prognostic factors of death. Conclusion In treated HFE hemochromatosis, only patients with serum ferritin higher than 2000μg/L have increased mortality, mainly related to liver diseases. Those with mild iron burden have decreased overall mortality in relation to reduced cardiovascular and extrahepatic cancer-related mortality. These results support a beneficial effect of early and sustained management of patients with iron excess, even when mild.
    Journal of Hepatology 10/2014; 62(3). DOI:10.1016/j.jhep.2014.10.025 · 10.40 Impact Factor
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    ABSTRACT: Initial venesection therapy in dysmetabolic iron overload syndrome (DIOS) was shown to improve insulin resistance. However, no data are available on the long-term outcome of iron store, thus questioning the relevance of maintenance therapy. The aim of the study was to describe the long-term evolution of iron overload after successful iron removal in patients with DIOS. Patients diagnosed with DIOS from 1998 to 2003 and having completed venesection therapy were proposed an outpatient visit in 2009. Inclusion criteria were as follows: confirmation of the DIOS diagnosis, absence of iron-related treatment or bloodletting since the end of the initial venesection treatment, at least 2 years of follow-up since last phlebotomy. Clinical and biological data were recorded at diagnosis and at inclusion. A total of 58 patients were included. The mean liver iron content at diagnosis was 80±43 µmol/g and the mean amount of iron removed was 2.2±1.2 g. The mean follow-up time was 71±23 months since end of treatment. At inclusion, 64% of patients had recurrence of iron overload. Serum ferritin at diagnosis was the only parameter associated with recurrence of iron overload. In patients with DIOS, the course of iron loading after initial iron removal supports periodical follow-up to detect those patients with recurrence of iron overload who could benefit from maintenance therapy.
    European journal of gastroenterology & hepatology 02/2014; 26(4). DOI:10.1097/MEG.0000000000000058 · 2.15 Impact Factor
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    ABSTRACT: Background The current phenotypic descriptors of high Fe gene hemochromatosis are hardly specific and time dependent in a context of highly variable expressivity. We hypothesized that the rate of iron removed during maintenance therapy and corresponding to the iron reabsorption index (IRI) could be patient specific and may then represent a new useful phenotypic marker.AimThe present study aimed to describe IRI with respect to its phenotypic specificity and to its potential usefulness.Methods We studied a cohort of 316 p.Cys282Tyr homozygous patients with stable low serum ferritin levels on maintenance therapy for at least 12 months. Characteristics at diagnosis, date and volume of phlebotomies, and parameters of iron metabolism throughout maintenance therapy were determined.ResultsIRI ranged from 1.3 to 6.1 mg/day (median: 2.44). It was lower in women (difference: 1.26 mg/day), mainly explained by physiological blood loss, weight, and alcohol consumption. IRI was correlated to iron burden and fibrosis stage at diagnosis, was stable over time (variation: 11.5%), and depended on serum ferritin level during therapy.Conclusion Its independence from disease duration, its stability, its wide distribution, and its significant correlation with iron burden markers make IRI a valuable potential phenotypic indicator of the daily iron overabsorption in hemochromatosis. Moreover, IRI provides a conceptual frame for empiric adaptation of maintenance therapy. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
    European journal of gastroenterology & hepatology 05/2013; 25(11). DOI:10.1097/MEG.0b013e328361e129 · 2.15 Impact Factor
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    ABSTRACT: Background and rationale: Excess of visceral adipose tissue could be involved as a modulator of the penetrance of HFE hemochromatosis since fat mass is associated with over-expression of hepcidin and low transferrin saturation was found to be associated with overweight in women. The present study was aimed at assessing the relationship between Body Mass Index (BMI), a surrogate marker of insulin-resistance, and iron burden in HFE hemochromatosis. Patients and methods: 877 patients from a cohort of C282Y homozygous were included in the study when BMI at diagnosis and amount of iron removed (AIR) by phlebotomy were available. Main results: No relationship between AIR and BMI was found in men whilst 15.1% (52/345) of women with AIR <6 g had BMI ≥ 28 versus 3.9% (2/51) of women with AIR ≥ 6 g (p=0.03). At multivariate analysis, BMI was an independent factor negatively associated with AIR (Odds ratio: 0.13 - 95% CI: 0.03-0.71) together with serum ferritin, serum transferrin, transferrin saturation, hemoglobin and alanine amino transferase. In a control group of 30 C282Y homozygous women, serum hepcidin was significantly higher in overweight (14.3 mmoL/L ± 7.1) than in lean (7.9 mmoL/L ± 4.3) women (p = 0.0005). Conclusion:In C282Y homozygous women, BMI ≥ 28 Kg/m(2) is independently associated with lower amount of iron removed by phlebotomy. BMI is likely a modulator factor of the phenotypic expression of C282Y homozygosity, likely through an increase of circulating levels of hepcidin. (HEPATOLOGY 2013.).
    Hepatology 05/2013; 57(5). DOI:10.1002/hep.26261 · 11.19 Impact Factor
  • Science & Sports 02/2012; DOI:10.1016/j.scispo.2011.05.001 · 0.54 Impact Factor
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    ABSTRACT: Hepcidin and hemojuvelin (HJV) are two critical regulators of iron metabolism as indicated by the development of major iron overload associated to mutations in hepcidin and HJV genes. Hepcidin and HJV are highly expressed in liver and muscles, respectively. Intensive muscular exercise has been reported to modify serum iron parameters and to increase hepcidinuria. The present study aimed at evaluating the potential impact of low intensity muscle exercise on iron metabolism and on hepcidin, its key regulator. Fourteen normal volunteers underwent submaximal cycling-based exercise in a crossover design and various iron parameters, including serum and urinary hepcidin, were serially studied. The results demonstrated that submaximal ergocycle endurance exercise did not modulate hepcidin. This study also indicated that hepcidinuria did not show any daily variation whereas serum hepcidin did. The findings, by demonstrating that hepcidin concentrations are not influenced by submaximal cycling exercise, may have implications for hepcidin sampling in medical practice.
    Arbeitsphysiologie 04/2009; 106(3):435-43. DOI:10.1007/s00421-009-1031-8 · 2.30 Impact Factor
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    ABSTRACT: Most cases of genetic hemochromatosis (GH) are associated with the HFE C282Y/C282Y (p.Cys282Tyr/p.Cys282Tyr) genotype in white populations. The symptoms expressed by C282Y homozygotes are extremely variable. Only a few suffer from an overt disease. Several studies have suggested that, in addition to environmental factors, a genetic component could explain a substantial part of this phenotypic variation, although very few genetic factors have been identified so far. In the present study, we tested the association between common variants in candidate genes and hemochromatosis penetrance, in a large sample of C282Y homozygotes, using pretherapeutic serum ferritin level as marker of hemochromatosis penetrance. We focused on two biologically relevant gene categories: genes involved in non-HFE GH (TFR2, HAMP, and SLC40A1) and genes involved in the regulation of hepcidin expression, including genes from the bone morphogenetic protein (BMP) regulatory pathway (BMP2, BMP4, HJV, SMAD1, SMAD4, and SMAD5) and the IL6 gene from the inflammation-mediated regulation pathway. A significant association was detected between serum ferritin level and rs235756, a common single-nucleotide polymorphism (SNP) in the BMP2 genic region (P=4.42x10-5). Mean ferritin level, adjusted for age and sex, is 655 ng/ml among TT genotypes, 516 ng/ml in TC genotypes, and 349 ng/ml in CC genotypes. Our results further suggest an interactive effect on serum ferritin level of rs235756 in BMP2 and a SNP in HJV, with a small additive effect of a SNP in BMP4. This first reported association between common variants in the BMP pathway and iron burden suggests that full expression of HFE hemochromatosis is linked to abnormal liver expression of hepcidin, not only through impairment in the HFE function but also through functional modulation in the BMP pathway. Our results also highlight the BMP regulation pathway as a good candidate for identification of new modifier genes.
    The American Journal of Human Genetics 11/2007; 81(4):799-807. DOI:10.1086/520001 · 10.99 Impact Factor
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    ABSTRACT: Patients with chronic hepatitis C have frequently mild to moderate liver iron overload which increases with fibrosis stage. Thus, it has been postulated that iron could enhance the progression of fibrosis. However, the real impact of iron is still controversial. The study was undertaken to determine the effect of confounding variables. All factors known to influence both iron overload and fibrosis were taken into account. Five hundred and eighty-six patients, who had liver biopsy performed prior to antiviral treatment, were included. Serum ferritin and liver iron were correlated with clinical, biological and histological variables in univariate and multivariate analysis. The impact of iron on fibrosis was evaluated in multivariate analysis in the whole group and in the subgroup of 380 patients with available date of infection. Hyperferritinemia, encountered in 27%, was associated with liver iron deposits in only 46% of cases. Liver iron was elevated in 17%, and correlated with age, male sex, and alcohol intake. The univariate strong link which existed between liver iron and fibrosis disappeared after adjustment for confounding variables. According to the results of this study, liver iron should be considered more as a surrogate marker for disease severity than as a fibrogenic factor per se.
    Journal of Hepatology 05/2007; 46(4):587-95. DOI:10.1016/j.jhep.2006.09.021 · 10.40 Impact Factor
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    ABSTRACT: To assess the effects of iron removal on cytochrome P450 2E1 activity and oxidative stress in dysmetabolic iron overload syndrome. Forty-eight patients were randomized to phlebotomy therapy consisting of removal of 300-500 mL of blood every 14 days until serum ferritin levels dropped under 100 microg/L or to follow-up without phlebotomy therapy. Cytochrome P450 2E1 activity was measured at baseline and at the end of treatment by using the 6-hydroxychlorzoxazone/chlorzoxazone blood metabolic ratio, 2 h after the intake of 500 mg of chlorzoxazone. In the treatment group, a mean of 3.9 +/- 1.3 L of blood was removed and serum ferritin levels dropped from 715 +/- 397 to 74 +/- 34 microg/L. Variation of cytochrome P450 2E1 activity was not significantly different between the 2 groups (0.07 +/- 0.26 vs. 0.03 +/- 0.19, P = 0.36). In the treatment group, low-density lipoprotein cholesterol and vitamin E were lowered after treatment compared with control group (-0.15 +/- 0.51 vs. 0.24 +/- 0.58, P = 0.002 and -1.3 +/- 4.4 vs. 2.3 +/- 5.2, P = 0.03, respectively). Inversely, vitamin C was increased (0.5 +/- 3.5 vs. -1.8 +/- 3.9, P = 0.03). In dysmetabolic iron overload syndrome, reduction of iron stores does not significantly influence cytochrome P450 2E1 activity but is associated with a significant decrease of low-density lipoprotein cholesterol, suggesting that venesection therapy may be a suitable option in these patients.
    Alimentary Pharmacology & Therapeutics 11/2006; 24(8):1207-13. DOI:10.1111/j.1365-2036.2006.03116.x · 5.48 Impact Factor
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    ABSTRACT: The current study was undertaken to assess whether fibrosis could regress under venesection therapy in patients with C282Y homozygous genetic hemochromatosis. The 36 patients studied were recruited from a subfile of our database consisting of 125 C282Y homozygotes with either severe fibrosis or cirrhosis (F3 or F4 fibrosis stage, respectively, according to the METAVIR grading system). The second liver biopsy was performed for management of liver cancer, extrahepatic surgery, or assessment of liver fibrosis. All paired biopsies were reviewed by two pathologists without knowledge of clinical data. Among the 13 patients who had F3 fibrosis on their initial liver biopsy, 3 had F0, 6 had F1, and 2 had F2 on their second liver biopsy. Among the 23 patients with cirrhosis on their initial liver biopsy, 1 had F0, 4 had F1, 3 had F2, and 2 had F3 on their second liver biopsy. When defining regression of fibrosis as a decrease of at least 2 METAVIR units, fibrosis regressed in 9 of 13 (69%) F3 and in 8 of 23 (35%) F4. When the ratio of gammaglobulins (g/L) to (platelets [n/mm(3)] x prothrombin activity [%]) was greater than 7.5, fibrosis never regressed. In conclusion, these data extend the concept of regression of fibrosis to patients with treated genetic hemochromatosis and suggest that some simple biochemical tests would be predictive of further regression of fibrosis as a result of venesection therapy. If confirmed on larger series, this could modify the ultrasound screening policy of hepatocellular carcinoma in genetic hemochromatosis.
    Hepatology 08/2006; 44(2):472-7. DOI:10.1002/hep.21260 · 11.19 Impact Factor
  • Hepatology 02/2006; 43(2):377-8. DOI:10.1002/hep.21038 · 11.19 Impact Factor
  • Clinical Chemistry and Laboratory Medicine 02/2006; 44(4):505-7. DOI:10.1515/CCLM.2006.076 · 2.96 Impact Factor
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    ABSTRACT: Aims. – To study mortality and body iron stores in former elite road cyclists.Synthesis of facts. – Mortality and body iron stores were studied in 514 former elite cyclists. Mortality. Twenty-seven deaths (5%) were recorded compared to 38 (7,4%) in a control group. Iron stores. Hyperferritinemia was found in 13% of cyclists and associated with both the metabolic syndrome and previous iron supplementation, especially through parenteral route and in the youngest subjects.Conclusion. – Middle-term mortality of former elite cyclists is unmodified. Previous iron supplementation may be responsible of persisting and long-term damaging iron excess.
    Science & Sports 08/2005; 20(4):202-204. DOI:10.1016/j.scispo.2005.01.012 · 0.54 Impact Factor
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    ABSTRACT: The aim of this study was to determine noninvasive predictive factors of significant liver fibrosis in patients with increased serum aminotransferases associated with features of metabolic syndrome (abdominal obesity, systemic hypertension, fasting hyperglycemia, and dyslipidemia). One hundred seventy-three patients were prospectively examined, regardless of alcohol consumption. Biometric, metabolic, and hepatic biochemical variables were tested for association with fibrosis assessed on liver biopsy according to the Metavir score system. Significant fibrosis, defined as Metavir scores F2, F3, or F4, was observed in 42 of 173 patients (24%). A logistic regression model and receiver operating characteristic curve were used to construct a simple index predictive of significant fibrosis. None of the patients with serum hyaluronate levels of 35 microg/L or less had significant fibrosis. In patients with serum hyaluronate levels >35 microg/L, no case of fibrosis stage F3 or F4 was found when serum carbohydrate-deficient transferrin/transferrin ratio was less than 0.9. In conclusion, in patients with increased serum aminotransferases associated with features of metabolic syndrome, a simple algorithm, including serum hyaluronate and serum carbohydrate-deficient transferrin/transferrin ratio, allows the exclusion of clinically relevant hepatic fibrosis, regardless of current or past alcohol consumption.
    Hepatology 06/2004; 39(6):1639-46. DOI:10.1002/hep.20219 · 11.19 Impact Factor
  • Hepatology 01/2003; 38:441-441. DOI:10.1016/S0270-9139(03)80622-5 · 11.19 Impact Factor