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Biomedical subjects

R Moirand

Publications and source records attributed to R Moirand.

53 records · Page 3Linked to original sources
PubMed1995

Interferon and ursodeoxycholic acid combined therapy in the treatment of chronic viral C hepatitis: results from a controlled randomized trial in 80 patients.

Because 70% to 75% of patients with chronic hepatitis C either do not respond to or relapse after interferon (IFN) therapy, and because ursodeoxycholic acid (UDCA) has been shown to reduce aminotransferase levels in patients with chronic hepatitis, we undertook a prospective controlled randomized trial of IFN (group I) versus IFN plus UDCA (group II) in 80 patients with chronic hepatitis C. IFN was administered in both groups for 6 months (3 to 5 million units [MU] three times a week), and in group II UDCA (10 mg/kg/d) was administered with IFN and then alone for 3 additional months. Response to therapy was defined as the normalization of alanine transaminase (ALT) levels. The results showed that 6 months after cessation of IFN, 59% of responders had relapsed in group I but only 27% had relapsed in group II (P = .03). There was no difference between the two groups for the initial (month 6) and the late (months 15 and 18) response rates to IFN. There was no virological effect or significant histological improvement attributable to the addition of UDCA to IFN treatment. In conclusion, the results of this study show that the addition of UDCA to IFN therapy significantly prolongs the period for which serum ALT remain, within the normal range after discontinuation of IFN. Further studies would be required to determine whether UDCA has any potential for long-term amelioration of the histological severity of liver disease caused by hepatitis C virus (HCV) infection, and, therefore, whether it could be advocated as an adjunct to antiviral therapy.

Adult↗
PubMed1994

Serum increase and liver overexpression of carbohydrate 19.9 antigen in patients with genetic haemochromatosis.

CA 19.9 antigen is mainly secreted by biliary and pancreatic duct cells. Its metabolism could be modified in genetic haemochromatosis by iron accumulation within these cells. Therefore, CA 19.9 was assayed in the serum samples of 84 patients with genetic haemochromatosis before and after iron depletion and immunolocalised in the liver of 24 untreated genetic haemochromatosis cases. The study showed that serum CA 19.9 (N < 37 IU/l) was increased (SD) before treatment (41.2 (34)) when compared with after the venesection period (16 (12)), and correlated, before treatment, with the amount of iron excess, transaminases, fibrosis, and biliary iron deposits. Hepatic CA 19.9 was located within the cytoplasm of bile duct and cholangiolar cells. In conclusion, this study shows that a mild, reversible, and non-specific increase in serum CA 19.9 is common in genetic haemochromatosis patients and shows that this increase is related to iron excess, directly or through associated liver damage. The unexplained finding of a mild increase in serum CA 19.9 should lead, in a patient with no diagnosis, to the search for liver iron overload, and, in a patient with untreated genetic haemochromatosis, not to further diagnostic procedures unless this finding persists after completion of the venesection treatment.

Alkaline Phosphatase↗
PubMed1993

Regulation of ferritin and transferrin receptor expression by iron in human hepatocyte cultures.

HepG2 cell cultures and human hepatocyte primary cultures were used to develop appropriate hepatocytic in vitro models of iron load in order to further understand the pathophysiological mechanisms occurring in the liver of patients with hemochromatosis. The first step of this study was to obtain an efficient iron supply in conditions of minimal toxicity. It was demonstrated that iron complexed to citrate entered efficiently into HepG2 cells and human hepatocytes. This iron load was obtained with minimal toxicity in both culture models as evaluated by the intracellular LDH activity and the total protein content. The second step was to study the effect of iron on ferritin and transferrin receptor expression. In HepG2 cell cultures, intracellular and extracellular ferritin concentrations were strikingly increased by iron in dose- and time-dependent manners. However, the relative amounts of H and L ferritin mRNAs were not significantly affected by iron, suggesting that ferritin regulation occurred at a translational level. On the other hand, in human hepatocyte cultures, the increase of intracellular and extracellular ferritin concentrations was accompanied by an increase in the amounts of H and L ferritin mRNAs. In this model, iron-induced ferritin biosynthesis seemed to be more complex than in HepG2 cells and to be governed by transcriptional and/or post-transcriptional regulatory mechanisms. However, an additional translational level of regulation could not be excluded. In contrast, transferrin receptor expression was decreased by iron in HepG2 cells as well as in human hepatocyte cultures. This decrease was associated with a decrease in the mRNA steady-state level. In both culture models, transferrin receptor regulation seemed to occur at a transcriptional or post-transcriptional level. These results demonstrate that normal human hepatocytes in primary culture respond to iron in a manner close to that observed in vivo and thereby provide a promising experimental model for further understanding pathophysiological mechanisms involved in human hemochromatotic liver.

Blotting, Northern↗
PubMed1993

Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: a study of 192 cases.

The biochemical hepatic iron index, defined as the ratio of hepatic iron concentration (expressed as micromoles per gram dry weight) to age permits accurate prediction of genetic status in patients with genetic hemochromatosis. However, the hepatic iron concentration is not always available. Therefore a histological hepatic iron index, defined as the ratio of total histological iron score (range = 0 to 60) to age, was evaluated in a total of 192 Australian and French patients with genetic hemochromatosis. These subjects had been classified previously as heterozygotes (n = 18) or homozygotes (n = 174) according to clinical and familial data only. Biochemical hepatic iron index and histological hepatic iron index were well correlated (Spearman's test: rho = 0.75, p < 0.0001). Both were significantly (p < 0.0001) increased in homozygotes (respectively, 6.7 +/- 3.8 [range = 1.2 to 22.6] and 0.62 +/- 0.28 [range = 0.14 to 1.5]) compared with heterozygotes (respectively, 1 +/- 0.4 [range = 0.45 to 1.6] and 0.08 +/- 0.05 [range = 0 to 0.14]). The histological hepatic iron index was less than 0.15 in all heterozygotes and greater than 0.15 in all but two homozygotes. These data show that the age-dependent nature of iron accumulation can also be accommodated by calculating the histological hepatic iron index and that histological study is an accurate means of predicting the genetic status of hemochromatosis patients when hepatic iron concentration is not available.

Adult↗
PubMed1992

Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations.

Liver pathology was assessed in 135 patients with well-defined genetic hemochromatosis ranging from mild disease to severe overload. Three lesions were clearly linked to iron-overload intensity--scarce sidero-necrosis, mild inflammation, and progressive fibrosis. Iron-free foci made of typical or dysplastic hepatocytes were found in 7.4% of the cases. An original grading allowed a reliable quantification of iron and the study of cellular and lobular distribution of iron, which permitted (a) the accurate identification of a decreasing iron gradient in hepatocytes from zone 1 to zone 3 in all cases, (b) the definition of a threshold hepatocytic/mesenchymal iron ratio related to the appearance of sidero-necrosis and to the development of fibrosis, and (c) demonstration that non-iron-related factors (mainly alcoholism) could shift iron from hepatocytes to sinusoidal cells without an increase in the total liver iron amount. This study provides a dynamic view of the iron overload process and suggests that sidero-necrosis and progressive sinusoidal iron overload play a role in the development of fibrosis in human genetic hemochromatosis.

Adolescent↗
PubMed1992

Liver fibrosis in genetic hemochromatosis. Respective roles of iron and non-iron-related factors in 127 homozygous patients.

A retrospective study of 127 patients with untreated homozygous genetic hemochromatosis (HGH) was conducted to evaluate the respective roles of iron overload and non-iron-related factors in the development of hepatic fibrosis in HGH. Twenty-seven percent of the patients had cirrhosis, 21% had liver fibrosis and 52% had no fibrosis (prefibrotic group). The mean value of liver iron concentration was increased significantly (p < 0.001) in cirrhotic (378 +/- 144 mumol/g dry wt.) and in fibrotic (331 +/- 168) subjects compared to prefibrotic (237 +/- 108) patients. Of 13 patients with liver iron concentration > or = 500, 12 had liver fibrosis or cirrhosis, versus 48/134 with liver iron concentration < 500. Chronic alcoholic men exhibited hepatic fibrosis or cirrhosis more frequently than non-alcoholic men (p < 0.001). Non-alcoholic men had hepatic fibrosis or cirrhosis more often than non-alcoholic women (p < 0.05). Cirrhotic and fibrotic patients were significantly older than prefibrotic patients whilst a significant correlation between age and liver iron concentration was found in younger patients only. These results suggest that the iron overload threshold necessary to induce fibrosis is modulated by non-iron-related factors such as alcoholism, sex and age. The development of fibrosis in HGH with liver iron concentration < 500 mumol/g is frequent and must lead to a search for associated non-iron-related fibrogenic factors.

Adult↗
PubMed1992

[Histochemical detection of hepatic iron. A comparative study of four stains].

Due to its specificity and easiness, Perls' stain is widely used in the histochemical assessment of liver iron content. However, it can underestimate slight iron overload, which can hamper screening for genetic hemochromatosis, especially in young people. The aim for the present study was to compare Perls' stain to three other specific iron stains (Tirmann-Schmeltzer (TRM); Hukill and Putt (HPT); Perls with Diaminobenzidine (DAB)), biochemical liver iron concentration (LIC) being used as the reference. 1) There is a significant difference between number of stained cells with TRM or DAB, compare with Perls' stain (p < 0.05). 2) Correlation (r) between histological assessment (T) and LIC was 0.39 for Perls' stain, 0.64 for TRM 0.53 for HPT and 0.64 for DAB. These data suggest that Perls' stain is not the most sensitive method for the assessment of slight iron overload. Tirmann-Schmeltzer's stain and Perls plus dAB should be preferred, especially in the screening of early liver siderosis.

Histocytochemistry↗
PubMed1991

Increase in glycosylated and nonglycosylated serum ferritin in chronic alcoholism and their evolution during alcohol withdrawal.

Increase in serum ferritin, which occurs in 40 to 70% of chronic alcoholics, remains poorly understood. We tested the hypothesis which links hyperferritinemia in chronic alcoholism not only to ferritin release from damaged liver cells, but also to increased ferritin secretion. Fifty-eight chronic alcoholic patients hospitalized for alcohol withdrawal were subdivided into three groups according to liver damage. Their serum levels of ferritin and ferritin bound to concanavalin A (ferritin Con A, which represents glycosylated, i.e., secreted ferritin) were measured serially on days 1, 7, and 11 of withdrawal and compared with a control group. The results were: (1) Total serum ferritin increased in alcoholics. Both free and Con A ferritins increased in equal proportions, the ferritin Con A to total ferritin ratio remaining unchanged. The increase was dependent on liver disease, as both free and Con A ferritins increased significantly with the severity of liver illness. Serum ferritin levels were related to iron status: it correlated with hepatic iron concentration (obtained in 19 patients); however, high ferritin values were not related to the degree of iron overload, which remained low. Finally, there was no correlation between serum ferritin and the average of alcohol consumption. (2) Both free and Con A ferritin decreased by about 40% during alcohol withdrawal. In conclusion, we have demonstrated that (1) total serum ferritin is increased in chronic alcoholism and (2) that this ferritin increase is due in part to an increase in ferritin Con A, proof of the induction of ferritin secretion by alcohol in humans.

Adult↗
PubMed1991

Iron load increases ferritin synthesis and secretion in adult human hepatocyte cultures.

In order to determine if iron load was able to stimulate specifically ferritin synthesis and secretion in adult human hepatocytes, primary cultures were submitted to increasing concentrations of ferric iron. The following results were obtained: 1. iron incorporation within the hepatocytes increased as a function of culture time and reached a high level after 48 h of treatment; 2. a dose-dependent significant stimulation of ferritin synthesis and secretion was observed when the medium iron concentration increased from 1 to 40 mumols.1(-1); 3. transferrin and albumin secretions were unaffected. The present data demonstrate that, in adult human primary cultures, iron load increases ferritin synthesis and secretion in a specific manner.

Cells, Cultured↗
PubMed1990

Alcohol induction of ferritin expression in a human hepatoblastoma cell line (HEP G2).

Hyperferritinemia, an unclear mechanism, is frequently observed in chronic alcoholics. The aim of this work was to study the effect of alcohol on ferritin expression in a human hepatoblastoma cell line, HepG2. This cell line proved to be sensitive to alcohol, since alcohol increased gamma-GT activity both in cells and media. The most striking result was the increase of ferritin in cells and media by alcohol. Moreover, this effect was specific, since it contrasted with a decrease in total protein synthesis and secretion, a decrease in transferrin excretion and a lack of effect on orosomucoid. In our model, alcohol was able to induce, in a specific manner, ferritin expression.

Carcinoma, Hepatocellular↗
PubMed1989

Iron induction of ferritin synthesis and secretion in human hepatoma cell (Hep G2) cultures.

In order to determine if iron was able to stimulate specifically ferritin synthesis and secretion in transformed human hepatocytes in culture, human hepatoma cell (HepG2) cultures were submitted to increasing doses of ferric nitrilotriacetate. Iron uptake by the cells was demonstrated by incorporation of 59 Fe and the staining method of Perls. The following results were obtained: 1. iron incorporation within the hepatocytes increased as a function of culture time; 2. during the first 24 h of treatment, ferritin synthesis increased progressively, in parallel to the iron uptake; 3. a dose-dependent significant stimulation of ferritin synthesis and secretion were observed when the medium iron concentration increased from 5 to 20 mumol/l; 4. albumin, transthyretin and transferrin secretions were unaffected. These data demonstrated that, in our hepatocyte culture model, iron load increased the expression of ferritin in a highly specific manner.

Albumins↗
PubMedDate not supplied

Low penetrant hemochromatosis phenotype in eight families: no evidence of modifiers in the MHC region.

The gene responsible for hemochromatosis (HFE) has been identified on the short arm of chromosome 6, 4.5 Mb telomeric to HLA-A. A major mutation C282Y is closely correlated with the disease, as it accounts for 68 to 100\% of the cases of hemochromatosis. Nevertheless, some C282Y homozygotes subjects have no clinical or biological expression of the disease. Moreover, in Northern European populations a large discrepancy is observed between the number of C282Y homozygotes and the number of diagnosed hemochromatosis patients, suggesting incomplete penetrance of the mutation. To localize and identify the modifying genes, we investigated eight families including C282Y homozygous relatives showing no clinical signs of the disease, in addition to the hemochromatosis patients. Genomic DNA from 20 C282Y homozygotes (10 patients and 10 siblings presenting no or minor biological abnormalities) were studied. Five polymorphisms from the HFE gene were determined by PCR restriction. Extended haplotypes of the 6p21.3 region were constructed with 10 microsatellite markers. All the C282Y homozygotes shared the same HFE polymorphism. The haplotypes presented no significant difference between the probands and their unaffected relatives. These studies suggest that neither HFE polymorphism nor genes surrounding HFE are able to modulate HFE expression.

Adult↗
PubMedDate not supplied

Haemochromatosis and HFE gene.

The discovery of the HFE gene has improved classification and diagnosis of iron overload. Most patients with a phenotypic diagnosis of haemochromatosis are homozygote for the C282Y mutation. Among those with other genotypes, only compound heterozygotes, who present the C282Y mutation on one chromosome and the H63D on the other, may present with haemochromatosis, but with a low penetrance and a mild expression. Other patients usually present with another cause of iron overload, such as insulin resistance, alcoholic liver disease or liver cirrhosis. The practical management of haemochromatosis has been greatly modified, since liver biopsy is no more necessary for diagnosis in C282Y homozygotes, and is only needed for exclusion of cirrhosis. Family screening has also greatly benefited from genotyping.

Chromosome Mapping↗
PubMedDate not supplied

[Interactions of alcohol and iron proteins].

The known relationship between ethanol and the two main proteins of iron metabolism, transferrin and ferritin, are reviewed. Transferrin synthesis decreases in alcoholic cirrhosis, and increases in alcoholic fatty liver. In the latter case, its turnover is accelerated. Serum desialylated transferrin increases in chronic alcoholism and could be the best marker of heavy drinking. The increased uptake of desialylated transferrin by the liver could explain the development of hepatic siderosis in some alcoholics. Serum ferritin increases in chronic alcoholism, much more because of liver damage than in relation to iron stores. It is clear in this review that few experimental studies have been interested in the investigation of these relationships.

Alcoholism↗