Biomedical subjects
R Moirand
Publications and source records attributed to R Moirand.
[The diagnosis of hemochromatosis in the era of the gene].
The discovery of the hemochromatosis gene has deeply changed and simplified the diagnosis of the disease. In a given individual, establishing the diagnosis relies, from now on, on a simple blood sample showing the couple: elevated transferrin saturation and homozygous C282Y mutation (= C282Y +/+). Liver biopsy should only be performed when iron overload is massive in order to detect cirrhosis (or bridging fibrosis), i.e. in a prognostic view. Practically, liver biopsy is confined to the following two situations: when the C282Y +/+ patient exhibits hepatomegaly and/or an increase in serum transaminases and/or a serum ferritin level above 1,000 micrograms/L; whenever, despite a strong bio-clinical suspicion of iron overload, genetic testing does not show the expected homozygosity for C282Y. At the family level, evaluating the risk for hemochromatosis is now "instantaneous" thanks to genetic testing. One must, however, keep in mind in interpreting the data of the family members that: clinical expression of the homozygous status is not constant; heterozygosity for C282Y does not per se lead to significant iron overload, but may constitute a co-factor exacerbating (or increasing the risk of) other hepatic or non hepatic diseases. Heterozygosity exposes also to the risk of homozygosity among the offspring; this knowledge of C282Y status must be balanced by the negative impact from the standpoint of possible societal genetic discrimination.
[Iron in the era of molecular biology].
Identification of the HFE gene and its C282Y and H63D mutations has improved the classification of iron overload disorders. Inherited hemochromatosis is due mainly, or perhaps only, to C282Y homozygosity, whereas nonhemochromatosis forms of iron overload are due to other HFE mutations and are usually responsible for mild overload precipitated by another factor such as cirrhosis or insulin-resistance. In practice, the diagnosis of inherited hemochromatosis rests on demonstration of homozygosity for the C282Y mutation; in this setting, the role of liver biopsy is to evaluate the prognosis by looking for fibrosis. In patients who are not homozygous for the C282Y mutation but have severe iron overload, causes other than hemochromatosis should be looked for before the extremely remote possibility of nonC282Y-related hemochromatosis is considered; here, liver biopsy remains of considerable diagnostic usefulness.
Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis.
BACKGROUND & AIMS: The diagnosis of hemochromatosis is now possible for C282Y homozygous patients using noninvasive molecular genetic tests. The aim of this study was to define noninvasive factors predictive of severe fibrosis (bridging fibrosis or cirrhosis) to avoid unnecessary liver biopsies in such patients. METHODS: Clinical and biological data were recorded at the time of diagnosis in 197 French C282Y homozygous patients, 52 (26%) of whom had severe fibrosis. Variables significantly linked to severe fibrosis using univariate analysis were entered into a multivariate stepwise analysis. These variables were combined to obtain a simple index allowing for prediction of severe fibrosis. RESULTS: Serum ferritin, hepatomegaly, and serum aspartate aminotransferase were selected using multivariate analysis. Their combination applied to the 96 patients with ferritin level of </=1000 microgram/L, normal aspartate aminotransferase values, and absence of hepatomegaly showed that no severe fibrosis was encountered in this subgroup of patients. The results were validated in 113 C282Y homozygous patients in Canada with a good reproducibility of negative prediction but a poor reproducibility of the positive prediction of severe fibrosis. CONCLUSIONS: In C282Y homozygous patients, the diagnosis of severe fibrosis relies on liver biopsy, but absence of severe fibrosis can be accurately predicted in most patients on the basis of simple clinical and biochemical variables.
Hemochromatosis after the gene discovery: revisiting the diagnostic strategy.
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[Epidemiology of hepatitis C virus infection in 1,304 HCV positive patients: variations according to the origin of transmission and year of diagnosis].
UNLABELLED: The evolution of epidemiological data on hepatitis C virus infection is poorly documented and thus the impact of screening is difficult to evaluate. AIM: To study epidemiological variations based on the origin of transmission and the year of diagnosis of hepatitis C virus infection. METHODS: The files of all 1304 patients seen in the hepatology unit of the Rennes University Hospital were analyzed (retrospectively before and prospectively after October 1995) in relation to epidemiological features. RESULTS: Despite widespread screening which is the source of 60% of the diagnoses, the total number of new cases of hepatitis C infection per year has not increased. Compared to patients diagnosed in the first years following the discovery of the virus, patients recently identified were younger (42 +/- 14 years) and frequently drug addicts (40%). Aminotransaminases were normal in 20% of cases. The frequency of cirrhosis has declined (17%). There has been a decrease in the proportion of patients who undergo liver biopsy (50%) and treatment with interferon (one third of patients). CONCLUSIONS: The impact of screening on the number of newly treated patients seems to be lower than previously predicted.
[Iron metabolism and its exploration in clinical biology].
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[Diagnosis of hyperferritinemia].
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Clinical features of genetic hemochromatosis in women compared with men.
BACKGROUND: The clinical expression of hemochromatosis is presumed to be less frequent and less severe in women than in men because of the iron loss associated with menses and pregnancy, but this hypothesis has not been validated. OBJECTIVE: To compare the clinical features of women who have genetic hemochromatosis with those of men who have the disease. DESIGN: Cross-sectional study. SETTING: Tertiary referral centers for hemochromatosis in France and Canada. PATIENTS: 176 women and 176 men with hemochromatosis, matched for year of birth. MEASUREMENTS: Age at presentation, clinical symptoms, transferrin saturation, serum ferritin level, hepatic iron concentration, and hepatic iron index. RESULTS: Hepatic iron concentration and hepatic iron index were similar in men and women. Women had lower serum ferritin levels than men did (911 micrograms/L compared with 1911 micrograms/L; mean difference, 1000 micrograms/L [95% CI, 669 micrograms/L to 1331 micrograms/L]) and less iron removed by venesections (5.5 g and 8.6 g; mean difference, 3.1 g [CI, 1.5 g to 4.8 g]). Compared with women, men had a higher incidence of cirrhosis (25.6% and 13.8%; mean difference, 11.8 percentage points [CI, 3.2 to 20.4 percentage points]) and diabetes (15.9% and 7.4%; mean difference, 8.5 percentage points [CI, 1.9 to 5.2 percentage points]). Compared with men, women had a higher incidence of fatigue (64.8% and 42%; mean difference, -22.8 percentage points [CI, -32.9 to -12.5 percentage points]) and pigmentation (48% and 44.9%; mean difference, -13.1 percentage points [CI, -23.4 to 2.7 percentage points]). Hepatic iron concentration and hepatic iron index were greater in women in whom menstruation had stopped before 50 years of age. Serum ferritin levels and transferrin saturation were normal in 6.2% of women and 0% of men. CONCLUSIONS: Women with genetic hemochromatosis can have full phenotypic expression of the disease, including cirrhosis. Recognizing the nonspecific nature of presenting symptoms in women is essential for early diagnosis and treatment.
A new syndrome of liver iron overload with normal transferrin saturation.
BACKGROUND: We investigated patients who had unexplained hepatic iron overload and normal transferrin saturation. METHODS: 65 patients with a median liver iron concentration of 65 mumol/g dry weight of liver (normal < 36 mumol/g), hyperferritinaemia (566 micrograms/L; normal < 400 micrograms/L), and normal transferrin saturations (32%) were compared with genetic haemochromatosis (GH) controls including homozygous (matched for sex and serum ferritin concentration) and heterozygous individuals. Relatives of patients who had ratios of liver iron concentration to age greater than 1.9 were also studied. FINDINGS: The 65 patients were significantly older and had significantly less hepatic iron overload than individuals with genetic haemochromatosis. The frequency of HLA-A3 antigen was significantly lower in these patients than in individuals with homozygous (p < 0.0001) or heterozygous (p < 0.0002) GH. Five HLA-identical siblings of the patients had normal serum ferritin concentrations. Most of the patients (95%) had one or more of the following conditions; obesity, hyperlipidaemia, abnormal glucose metabolism, or hypertension. INTERPRETATION: We have found a new non-HLA-linked iron-overload syndrome which suggests a link between iron excess and metabolic disorders. The current diagnostic criteria for genetic haemochromatosis should be reviewed.
The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis.
The aim of this study was to investigate the relationship between iron overload, age, and clinical symptoms in genetic hemochromatosis. The relationship was studied between clinical symptoms and liver iron concentration, serum ferritin, and iron removed in a retrospective study of 410 homozygotes diagnosed using strict criteria. No significant relationship was found between liver iron concentration, iron removed by venesection, and serum ferritin level with age. The prevalence of cirrhosis, diabetes, cardiac disease, pigmentation, and fatigue increased as liver iron concentration increased. The most common presentations at diagnosis were fatigue or as an incidental finding in all age groups. Twenty-seven percent of patients (110 of 410) had no clinical symptoms of hemochromatosis. Iron accumulation is highly variable in patients with genetic hemochromatosis. The significant relationship between liver iron concentration and cirrhosis, diabetes, cardiac disease, pigmentation, and fatigue confirms the importance of iron toxicity in the pathogenesis of hepatic and extrahepatic disease. The nonspecific nature of the presenting features in patients and the presence of significant clinical symptoms in patients discovered through family investigations underscore the importance of family and population screening for hemochromatosis.
A reappraisal of hepatic siderosis in patients with end-stage cirrhosis: practical implications for the diagnosis of hemochromatosis.
The aim of this study was to describe the histologic pattern of iron distribution in end-stage cirrhosis due to various causes and to test the reliability of the hepatic iron index (equal to hepatic iron concentration divided by age) in excluding or confirming associated hemochromatosis in such a condition. Large slices of the resected livers of 30 patients transplanted for alcoholic and/or viral end-stage cirrhosis were assessed histologically for iron distribution and biochemically for hepatic iron concentration in the least and the most iron-overloaded nodules of each case. HLA-A3 was used as the marker for the hemochromatosis gene in the population studied. Intranodular parenchymal siderosis was found in 23 cases (12 spotty, 11 diffuse) with diffuse intrabiliary iron deposits apparent in only two cases. Although in 14 patients the hepatic iron index was significantly high (> 1.9) so as to suggest hemochromatosis, these cases did not correspond to homozygous hemochromatosis with respect to the prevalence of HLA-A3 antigen. End-stage cirrhosis arising from different causes is frequently complicated by parenchymal siderosis that may mimic hemochromatosis, including a hepatic iron index greater than 1.9. The diagnosis of hemochromatosis in patients with end-stage cirrhosis, even those with a hepatic iron index greater than 1.9, should rely mainly on clinical and histologic data.
[Management of a family with genetic hemochromatosis].
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[Hyper-ferritinemia and Gaucher disease].
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Congenital right hepatico-diaphragmatic venous anastomosis discovered during a liver transplant resulting in a fatal outcome.
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Regulation of ferritin expression by alcohol in a human hepatoblastoma cell line and in rat hepatocyte cultures.
Serum ferritin increases in chronic alcoholism, without clear explanation. We have previously shown that alcohol increases ferritin levels in a human hepatoblastoma cell line (HepG2). The aims of the present work were: 1) To extend our results in normal rat hepatocyte cultures, and 2) To determine the mechanism by which alcohol enhances ferritin levels. In HepG2 cells, high alcohol concentrations (300 mM) during long exposure (4 days) increased the synthesis of H and L ferritin subunits, in association with increased levels of ferritin mRNAs. In rat hepatocyte cultures, the synthesis of L ferritin increased after 24 h of exposure to lower alcohol concentrations (10 mM); alcohol had no effect on ferritin mRNAs levels. In both cell types, the alcohol effect was not related to an increase in iron intracellular incorporation. In HepG2 cells, desferrioxamine (Df), a potent iron chelator, abolished ferritin synthesis in the presence or absence of alcohol, and abolished the alcohol induction of ferritin mRNAs. In rat hepatocytes, Df decreased ferritin synthesis to a similar level in the presence or absence of alcohol. Alcohol increased ferritin synthesis differently in HepG2 cells and in normal rat hepatocyte cultures. In the latter case, the alcohol effect was observed at low concentration. Despite a striking inhibiting effect of Df on ferritin synthesis, in both cellular models a mechanism accounting for increased ferritin synthesis independently of iron is suggested. Globally, these data strongly suggest that hyperferritinemia in chronic alcoholism could be related to the induction of ferritin by alcohol.
Increased liver iron stores in patients with hepatocellular carcinoma developed on a noncirrhotic liver.
Iron was systematically studied in the nontumorous liver of 24 patients with hepatocellular carcinoma (HCC) developed on a noncirrhotic liver compared with 4 control groups (cirrhosis with and without HCC, liver metastasis, and normal liver) matched according to age, sex, and presence of chronic alcoholism. Assessment of liver iron was made by (1) histology according to iron distribution and quantification (total iron score: 0 to 60), and (2) biochemistry (liver iron concentration-N < 36 mumol/g) with calculation of the hepatic iron index (liver iron concentration/age). Patients with hepatocellular carcinoma developed on a noncirrhotic liver presented with (1) histological iron in 83%; (2) parenchymal iron excess significantly more frequent (90%) than in controls; (3) total iron score (15 +/- 12) and liver iron concentration (81 +/- 96) significantly greater than in controls; and (4) hepatic iron index significantly increased (1.4 +/- 1.5) when compared with control groups, except for the hepatocellular carcinoma complicating cirrhosis group (0.9 +/- 1.1). This study (1) shows a mild but unquestionable parenchymal iron excess in the nontumorous liver of most patients presenting with hepatocellular carcinoma developed on a noncirrhotic liver and, at a lesser extent, on cirrhosis, (2) should incite others to study the putative role of iron in the development of liver cancer both in patients with cirrhosis and those without it, whatever the cause of the underlying liver disease, and (3) add argument to take into account and to treat any liver iron excess, even when mild.
[Liver abscess caused by Yersinia enterocolitica with spontaneously favourable course].
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