Assessment of the functional impact of germline BRCA1/2 variants located in non-coding regions in families with breast and/or ovarian cancer predisposition.

PURPOSE: The molecular mechanism of breast and/or ovarian cancer susceptibility remains unclear in the majority of patients. While germline mutations in the regulatory non-coding regions of BRCA1 and BRCA2 genes have been described, screening has generally been limited to coding regions. The aim of this study was to evaluate the contribution of BRCA1/2 non-coding variants. METHODS: Four BRCA1/2 non-coding regions were screened using high-resolution melting analysis/Sanger sequencing or next-generation sequencing on DNA extracted from index cases with breast and ovarian cancer predisposition (3926 for BRCA1 and 3910 for BRCA2). The impact of a set of variants on BRCA1/2 gene regulation was evaluated by site-directed mutagenesis, transfection, followed by Luciferase gene reporter assay. RESULTS: We identified a total of 117 variants and tested twelve BRCA1 and 8 BRCA2 variants mapping to promoter and intronic regions. We highlighted two neighboring BRCA1 promoter variants (c.-130del; c.-125C > T) and one BRCA2 promoter variants (c.-296C > T) inhibiting significantly the promoter activity. In the functional assays, a regulating region within the intron 12 was found with the same enhancing impact as within the intron 2. Furthermore, the variants c.81-3980A > G and c.4186-2022C > T suppress the positive effect of the introns 2 and 12, respectively, on the BRCA1 promoter activity. We also found some variants inducing the promoter activities. CONCLUSION: In this study, we highlighted some variants among many, modulating negatively the promoter activity of BRCA1 or 2 and thus having a potential impact on the risk of developing cancer. This selection makes it possible to conduct future validation studies on a limited number of variants.

Comparison of transient elastography (FibroScan), FibroTest, APRI and two algorithms combining these non-invasive tests for liver fibrosis staging in HIV/HCV coinfected patients: ANRS CO13 HEPAVIH and FIBROSTIC collaboration.

OBJECTIVES: Combining noninvasive tests increases diagnostic accuracy for staging liver fibrosis in hepatitis C virus (HCV)-infected patients, but this strategy remains to be validated in HIV/HCV coinfection. We compared the performances of transient elastography (TE), Fibrotest (FT), the aspartate aminotransferase-to-platelet ratio index (APRI) and two algorithms combining TE and FT (Castera) or APRI and FT (SAFE) in HIV/HCV coinfection. METHODS: One hundred and sixteen HIV/HCV-coinfected patients (64% male; median age 44 years) enrolled in two French multicentre studies (the HEPAVIH cohort and FIBROSTIC) for whom TE, FT and APRI data were available were included in the study. Diagnostic accuracies for significant fibrosis (METAVIR F ≥ 2) and cirrhosis (F4) were evaluated by measuring the area under the receiver-operating characteristic curve (AUROC) and calculating percentages of correctly classified (CC) patients, taking liver biopsy as a reference. RESULTS: For F ≥ 2, both TE and FT (AUROC = 0.87 and 0.85, respectively) had a better diagnostic performance than APRI (AUROC = 0.71; P < 0.005). Although the percentage of CC patients was significantly higher with Castera's algorithm than with SAFE (61.2% vs. 31.9%, respectively; P < 0.0001), this percentage was lower than that for TE (80.2%; P < 0.0001) or FT (73.3%; P < 0.0001) taken separately. For F4, TE (AUROC = 0.92) had a better performance than FT (AUROC = 0.78; P = 0.005) or APRI (AUROC = 0.73; P = 0.025). Although the percentage of CC patients was significantly higher with the SAFE algorithm than with Castera's (76.7% vs. 68.1%, respectively; P < 0.050), it was still lower than that for TE (85.3%; P < 0.033). CONCLUSIONS: In HIV/HCV-coinfected patients, TE and FT have a similar diagnostic accuracy for significant fibrosis, whereas for cirrhosis TE has the best accuracy. The use of the SAFE and Castera algorithms does not seem to improve diagnostic performance.

The new paradigm of hepatitis C therapy: integration of oral therapies into best practices.

Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945-1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels.

Surgical treatment of hepatocellular carcinoma associated with the metabolic syndrome.

BACKGROUND: The incidence of metabolic syndrome-associated hepatocellular carcinoma (MS-HCC) is increasing. However, the results following liver resection in this context have not been described in detail. METHODS: Data for all patients with metabolic syndrome as a unique risk factor for HCC who underwent liver resection between 2000 and 2011 were retrieved retrospectively from an institutional database. Pathological analysis of the underlying parenchyma included fibrosis and non-alcoholic fatty liver disease activity score. Patients were classified as having normal or abnormal underlying parenchyma. Their characteristics and outcomes were compared. RESULTS: A total of 560 resections for HCC were performed in the study interval. Sixty-two patients with metabolic syndrome, of median age 70 (range 50-84) years, underwent curative hepatectomy for HCC, including 32 major resections (52 per cent). Normal underlying parenchyma was present in 24 patients (39 per cent). The proportion of resected HCCs labelled as MS-HCC accounted for more than 15 per cent of the entire HCC population in more recent years. Mortality and major morbidity rates were 11 and 58 per cent respectively. Compared with patients with normal underlying liver, patients with abnormal liver had increased rates of mortality (0 versus 18 per cent; P = 0·026) and major complications (13 versus 42 per cent; P = 0·010). In multivariable analysis, a non-severely fibrotic yet abnormal underlying parenchyma was a risk factor for major complications (hazard ratio 5·66, 95 per cent confidence interval 1·21 to 26·52; P = 0·028). The 3-year overall and disease-free survival rates were 75 and 70 per cent respectively, and were not influenced by the underlying parenchyma. CONCLUSION: HCC in patients with metabolic syndrome is becoming more common. Liver resection is appropriate but carries a high risk, even in the absence of severe fibrosis. Favourable long-term outcomes justify refinements in the perioperative management of these patients.

Rare germline large rearrangements in the BRCA1/2 genes and eight candidate genes in 472 patients with breast cancer predisposition.

Hereditary breast cancers account for up to 5-10 % of breast cancers and a majority are related to the BRCA1 and BRCA2 genes. However, many families with breast cancer predisposition do not carry any known mutations for BRCA1 and BRCA2 genes. We explored the incidence of rare large rearrangements in the coding, noncoding and flanking regions of BRCA1/2 and in eight other candidate genes--CHEK2, BARD1, ATM, RAD50, RAD51, BRIP1, RAP80 and PALB2. A dedicated zoom-in CGH-array was applied to screen for rearrangements in 472 unrelated French individuals from breast-ovarian cancer families that were being followed in eight French oncogenetic laboratories. No new rearrangement was found neither in the genomic regions of BRCA1/2 nor in candidate genes, except for the CHEK2 and BARD1 genes. Three heterozygous deletions were detected in the 5' and 3' flanking regions of BRCA1. One large deletion introducing a frameshift was identified in the CHEK2 gene in two families and one heterozygous deletion was detected within an intron of BARD1. The study demonstrates the usefulness of CGH-array in routine genetic analysis and, aside from the CHEK2 rearrangements, indicates there is a very low incidence of large rearrangements in BRCA1/2 and in the other eight candidate genes in families already explored for BRCA1/2 mutations. Finally, next-generation sequencing should bring new information about point mutations in intronic and flanking regions and also medium size rearrangements.

ActiTest accuracy for the assessment of histological activity grades in patients with chronic hepatitis C, an overview using Obuchowski measure.

BACKGROUND: ActiTest (AT) is a biomarker of liver necro-inflammatory histological activity validated in patients with chronic hepatitis C (HCV). AIM: The aim was to assess the accuracy of AT in comparison with alanine aminotransferase (ALT) the standard of care. METHODS: Methods used an integrated database of individual data and the new recommended Obuchowski measures. An updated "classical" meta-analysis of AT validation studies was also performed. The main end points were the area under the ROC curves (AUROCs) for the diagnosis of each histological activity grade defined using METAVIR scoring system. To avoid repeated tests and the spectrum effect of activity grades prevalence, the comparison of AT and ALT accuracies used the Obuchowski method. RESULTS: For the individual analysis, a total of 1250 patients were included and for the meta-analysis six studies (2017 patients) were included. The overall accuracy of AT for the diagnosis of any activity grade (Obuchowski measure=0.850) was significantly higher than the accuracy of ALT (Obuchowski measure=0.837; P=0.009). The updated standard meta-analysis confirmed the accuracy of AT (p<0.0001) both in independent AUROC=0.79 (95% CI, 0.73-0.85) and in non independent studies AUROC=0.74 (95% CI, 0.67-0.81). CONCLUSIONS: The accuracy of AT for grading the necro-inflammatory activity of patients with HCV was significantly higher than ALT serum activity alone, the standard biomarker.

Changes of non-invasive markers and FibroScan values during HCV treatment.

The recent advent of non-invasive methods for assessment of fibrosis allows serial assessments in all patients with hepatitis C. The aim of this prospective study was to evaluate changes in liver fibrosis, as measured with non-invasive methods, in a large cohort of HCV-infected patients with and without treatment. From May 2003 through March 2006, all previously untreated HCV-infected patients were enrolled in this study. Liver fibrosis was staged with FibroScan and Fibrotest at inclusion, then every year in untreated patients, and at the end of treatment and 6 months later in treated patients. The study population consisted of 416 patients, of whom 112 started treatment after enrolment. In the treatment group, FibroScan and Fibrotest values were significantly higher before and after treatment than in untreated patients at baseline and after 1 year. However, there was no significant difference between treated and untreated patients at the end of follow-up. FibroScan and Fibrotest values fell in all treated patients, whatever their virological response. In multivariate analysis, treatment was the only factor independently associated with a fall in the FibroScan value. In conclusion, whatever the virological response, treatment for HCV infection is associated with an improvement of FibroScan and Fibrotest values. Further studies are needed to compare these non-invasive methods with liver biopsy. These non-invasive methods, and especially FibroScan, should be useful for assessing treatment efficacy in clinical trials of new drugs.

Liver fibrosis staging with contrast-enhanced ultrasonography: prospective multicenter study compared with METAVIR scoring.

We prospectively assessed contrast-enhanced sonography for evaluating the degree of liver fibrosis as diagnosed via biopsy in 99 patients. The transit time of microbubbles between the portal and hepatic veins was calculated from the difference between the arrival time of the microbubbles in each vein. Liver biopsy was obtained for each patient within 6 months of the contrast-enhanced sonography. Histological fibrosis was categorized into two classes: (1) no or moderate fibrosis (F0, F1, and F2 according to the METAVIR staging) or (2) severe fibrosis (F3 and F4). At a cutoff of 13 s for the transit time, the diagnosis of severe fibrosis was made with a specificity of 78.57%, a sensitivity of 78.95%, a positive predictive value of 78.33%, a negative predictive value of 83.33%, and a performance accuracy of 78.79%. Therefore, contrast-enhanced ultrasound can help with differentiation between moderate and severe fibrosis.

Liver fibrosis on account of chronic hepatitis C is more severe in HIV-positive than HIV-negative patients despite antiretroviral therapy.

The recent availability of non-invasive tools to measure liver fibrosis has allowed examination of its extent and determination of predictors in all patients with chronic hepatitis C virus (HCV) infection. On the other hand, most information on hepatic fibrosis in HCV/human immunodeficiency virus (HIV)-coinfected patients has been derived from liver biopsies taken before highly active antiretroviral therapy (HAART) was widely available. All consecutive HCV patients with elevated aminotransferases seen during the last 3 years were evaluated and liver fibrosis measured using transient elastography (FibroScan) and biochemical indexes. Patients were split according to their HIV serostatus. A total of 656 (69.6%) HCV-monoinfected and 287 (30.4%) HIV/HCV-coinfected patients were assessed. Mean CD4 count of coinfected patients was 493 cells/muL and 88% were under HAART (mean time, 4.2 +/- 2.4 years). Advanced liver fibrosis or cirrhosis was recognized in 39% of the coinfected and 18% of the monoinfected patients (P < 0.005). A good correlation was found between FibroScan) and biochemical indexes [AST to platelet ratio index (r = 0.405, P < 0.0001), FIB-4 (r = 0.393, P < 0.0001) and Forns (r = 0.407, P < 0.0001)], regardless of the HIV status. In the multivariate analysis, age >45 years, body mass index (BMI) >25 kg/m(2), and HIV infection were independently associated with advanced liver fibrosis or cirrhosis. HIV/HCV-coinfected patients have more advanced liver fibrosis than HCV-monoinfected patients despite the immunologic benefit of HAART.

Non-invasive diagnosis of steatosis and fibrosis.

The prognosis and management of liver disease greatly depends on the amount of liver fibrosis. Non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), is emerging as a major cause of liver disease in Western countries because of the increasing prevalence of obesity and type 2 diabetes. A key issue in patients with NAFLD is the differentiation of NASH from simple steatosis. It is particularly important to identify NASH patients as they are at greatest risk of developing complications such as cirrhosis, liver failure and hepatocellular carcinoma. The limitations of liver biopsy (invasive procedure, sampling errors, interobserver variability and non-dynamic fibrosis evaluation) have stimulated the search for non-invasive approaches for the assessment of steatosis and liver fibrosis in patients with NAFLD. A variety of methods, including serum markers, imaging techniques such as ultrasound, CT, MRI and measurement of liver stiffness by transient elastography, have been proposed for the non-invasive assessment of steatosis and hepatic fibrosis. This review discusses the advantages and limitations of these different methods in clinical practice.

Diagnosis of liver fibrosis using FibroScan and other noninvasive methods in patients with hemochromatosis: a prospective study.

BACKGROUND: The role of hepatic iron overload in the development of hepatic fibrosis in patients with hemochromatosis is well-established. Transient elastography (FibroScan) is a new noninvasive, rapid, reproducible bedside method, allowing assessment of liver fibrosis by measuring liver rigidity. OBJECTIVES: The aim of this prospective study was to evaluate liver fibrosis with FibroScan and other noninvasive biochemical methods in patients with hemochromatosis (C282Y homozygosity) compared with control patients. PATIENTS AND METHODS: From January 2004 through October 2006, all consecutive patients with hemochromatosis were evaluated for liver fibrosis using noninvasive methods (FibroScan and biochemical markers). These patients were compared with patients who had chronic cytolysis and no fibrosis on liver biopsy. RESULTS: One hundred and three consecutive patients (57 cases and 46 controls) were fully investigated. Median FibroScan values were similar in both groups, 5.20 kPa versus 4.9 kPa, respectively. No differences were observed between cases and controls for all biochemical markers. A strong correlation was observed between FibroScan and many biochemical markers, although ferritin levels did not correlate with FibroScan values. The prevalence of patients with FibroScan values greater than 7.1 kPa (cut-off level for significant fibrosis) was 22.8% in patients with hemochromatosis and 0% in the controls (P<0.0001). CONCLUSION: FibroScan and biochemical markers could be reliable noninvasive methods for detecting liver fibrosis in patients with hemochromatosis. Such patients have high FibroScan values more often than do control patients. Further longitudinal and prospective studies are necessary to confirm these preliminary data.

Non-invasive evaluation of portal hypertension using shear-wave elastography: analysis of two algorithms combining liver and spleen stiffness in 191 patients with cirrhosis.

BACKGROUND: Two algorithms based on sequential measurements of liver and spleen stiffness using two-dimensional shearwave elastography (2D-SWE) have been recently proposed to estimate clinically significant portal hypertension (hepatic venous pressure gradient [HVPG] ≥10 mm Hg) in patients with cirrhosis, with excellent diagnostic accuracy. AIM: To validate externally these algorithms in a large cohort of patients with cirrhosis. METHODS: One hundred and ninety-one patients with stable cirrhosis (Child-Pugh class A 39%, B 29% and C 31%) who underwent liver and spleen stiffness measurements using 2D-SWE at the time of HVPG measurement were included. Diagnostic accuracy of the 2 algorithms was assessed by calculating sensitivity, specificity, positive and negative predictive values. RESULTS: The first algorithm, using liver stiffness <16.0 kilopascals (kPa) and then spleen stiffness <26.6 kPa, was used to rule-out HVPG ≥10 mm Hg. In our population, its sensitivity and negative predictive value were 95% and 63% respectively. The second algorithm, using liver stiffness >38.0 kPa, or liver stiffness ≤38.0 kPa but spleen stiffness >27.9 kPa, was used to rule-in HVPG ≥10 mm Hg. In our population, its specificity and positive predictive value were 52% and 83% respectively. Restricting the analyses to the 74 patients without any history of decompensation of cirrhosis or to the 65 patients with highly reliable liver stiffness measurement did not improve the results. CONCLUSION: In our population, diagnostic accuracies of non-invasive algorithms based on sequential measurements of liver and spleen stiffness using 2D-SWE were acceptable, but not good enough to replace HVPG measurement or to base clinical decisions.

Variability of the area under the receiver operating characteristic curves in the diagnostic evaluation of liver fibrosis markers: impact of biopsy length and fragmentation.

BACKGROUND: The area under the receiver operating characteristic (ROC) curve is widely used as an estimate of the diagnostic value for fibrosis markers. Biopsy length and fragmentation are known as risk factors of false positive or false negative of biopsy but their quantitative impact on area under the receiver operating characteristic curve variability has not been assessed. AIM: To assess these relationships to better compare the fibrosis markers. METHODS: The area under the ROC curves of FibroTest for the diagnosis of fibrosis was estimated in patients with chronic hepatitis C using an integrated database including 1312 patients with FibroTest and biopsy. To take into account the biopsy length, we used two adjustment factors: one in which an observed area under the ROC curve could be adjusted according to the relative area under the receiver operating characteristic curve of a biopsy of a given length vs. the entire liver and one taking into account the prevalence of each fibrosis stage defining advanced and non-advanced fibrosis. RESULTS: The mean biopsy length was smaller for cirrhosis (F4, 16 mm) vs. F3, (18 mm, P=0.01) and F0 (19 mm, P=0.01). The mean number of fragments was higher for cirrhosis (F4=4.1 fragments) vs. all the other stages (F0=1.9, F1=1.9, F2=1.9, F3=2.3; P<0.001 vs. F4). The FibroTest area under the ROC curves for the diagnosis of advanced fibrosis, adjusted for stages' prevalence, ranged from 0.80 to 0.98 depending on biopsy length and fragmentation, respectively. CONCLUSION: The comparison of the area under the ROC curves of fibrosis markers should take into account the biopsy length and fragmentation.

Impact on adherence and sustained virological response of psychiatric side effects during peginterferon and ribavirin therapy for chronic hepatitis C.

BACKGROUND: The psychiatric side effects of interferon, often responsible for dose reduction or treatment discontinuation, represent a major limitation in the treatment of chronic hepatitis C (CHC). AIM: To prospectively assess the impact on adherence and sustained virological response (SVR) of the occurrence of psychiatric side effects during peginterferon and ribavirin therapy for CHC. METHODS: Ninety-eight consecutive treatment-naïve CHC patients receiving a standard course of peginterferon plus ribavirin were systematically screened for psychiatric side effects, using DSM-IV, at baseline and both during and after treatment. RESULTS: Psychiatric side effects occurred in 38 patients (39%), mostly within the first 12 weeks (87%), and always consisted of mood disorders. Overall, 68% of patients achieved an SVR (71% of patients with mood disorders and 68% of those without; P = N.S.). Peginterferon and ribavirin dose reductions did not differ between patients with mood disorders and those without (46% vs. 37%, respectively; P = N.S. and 13% vs. 22%, respectively; P = N.S.). Anti-viral therapy had to be discontinued in four patients (nonresponse: two, hyperthyroidism: one, psychiatric event: one). CONCLUSION: Early detection and appropriate management of psychiatric side effects during peginterferon and ribavirin therapy for CHC allow optimizing adherence and virological efficacy.

Diagnosis of liver fibrosis by transient elastography (FibroScan) and non-invasive methods in Crohn's disease patients treated with methotrexate.

BACKGROUND: Methotrexate is an effective treatment in Crohn's disease, which may induce liver fibrosis with high cumulative doses. Transient elastography (FibroScan, Echosens, Paris, France) is a new non-invasive rapid, allowing assessment of liver fibrosis by measurement of liver stiffness. AIM: A prospective study to evaluate liver fibrosis with FibroScan and non-invasive biochemical methods in Crohn's disease patients treated with methotrexate. METHODS: Consecutive Crohn's disease patients had evaluation of liver fibrosis with non-invasive methods. Two subgroups of patients were compared: cumulative dose of methotrexate of more than 1500 mg (group 1) and naive for methotrexate (group 2). Liver biopsy was performed in patients with persistent liver enzyme abnormalities or FibroScan value >8.7 kPa. RESULTS: Fifty-four consecutive Crohn's disease patients were fully investigated (45 females, mean age 41 +/- 14 years). Median FibroScan values were similar in group 1 (n = 21) and in group 2 (n = 33), 5.5 and 4.5 kPa, respectively. FibroScan values were not correlated with the cumulative dose of methotrexate. CONCLUSION: In Crohn's disease patients treated with a high dose of methotrexate, significant liver fibrosis is rare and not accurately detected with liver enzymes abnormalities. FibroScan could be recommended and liver biopsy could be performed only with patients with high values and/or with chronic liver enzymes abnormalities.

Steatosis, insulin resistance and fibrosis progression in chronic hepatitis C.

Steatosis is a common histological feature of chronic hepatitis C. Two distinct mechanisms seem to be involved in the pathogenesis of hepatic steatosis in chronic hepatitis C virus (HCV) infection. In HCV genotype 3-infected patients, steatosis is likely viral-induced, and represents a direct cytopathic effect of HCV, whereas in patients infected with other genotypes, host metabolic risk factors for insulin resistance such as obesity, type 2 diabetes and hyperlipidemia play a major role in intracellular lipids accumulation. Interestingly, the outcome of steatosis matches the virological response to treatment in HCV genotype 3-infected patients who have purely virus-induced steatosis but not in patients with metabolic causes of steatosis. Suspected molecular underlying mechanisms include interactions between the HCV core protein and intracellular lipid metabolism pathways as well as induction of insulin resistance. Steatosis is of clinical importance as it appears to be associated with more rapid liver fibrosis progression and impaired response to antiviral therapy. However, whether metabolic and host factors associated with steatosis, steatosis per se or both, may be responsible for this association remains to be clarified. This review is aimed at describing the current knowledge of steatosis, insulin resistance and fibrosis progression in chronic hepatitis C.

[Prognostic indicators in patients with liver cirrhosis admitted to an intensive care unit]. / Indicateurs pronostiques chez les malades atteints de cirrhose admis en service de Réanimation.

OBJECTIVES: Assessment of prognosis in patients with cirrhosis admitted to an Intensive Care Unit remains unsatisfactory. The aims of this retrospective study were to determine the survival rates of patients admitted to an Intensive Care Unit, and to identify and validate prognostic indicators associated with a high mortality rate. METHODS: Two hundred and forty three patients with cirrhosis consecutively admitted to the Intensive Care Unit were studied. The main reasons for admission were upper gastrointestinal bleeding (n = 163), coma (n = 43), sepsis (n = 18), and liver failure (n = 13). Patients were divided into two groups: group 1 (n = 121) to identify prognostic indicators associated with a high mortality rate, and group 2 (n = 122) to validate these indicators. RESULTS: Intensive Care Unit and one year survival rates of patients with cirrhosis admitted for upper gastrointestinal hemorrhage were 76 and 50% respectively. These rates were 40 and 8% respectively for patients admitted for other reasons. In group 1, 4 predictive factors found at admission were identified to have independent significance by stepwise logistic regression: grade III or IV encephalopathy, prothrombin index, serum creatinine, and hypoxemia. On the other hand, the presence of shock on admission was associated with a 100% mortality rate. Two prognostic indicators were defined: shock requiring the administration of vasoactive drugs, and the presence of 3 out of the 4 following predictive factors: grade III or IV encephalopathy, mechanical ventilation, prothrombin index < 30%, and serum creatinine > 130 mumol/L. In group 2, the presence of at least one prognostic indicator at admission or during intensive care was associated with a 96% mortality rate. These indicators were present in 69% of patients who died. In 17 patients who died, but survived more than 24 hours in the Intensive Care Unit, indicators were present an average of 6.0 +/- 5.3 days before death. CONCLUSION: Common prognostic indicators may accurately predict death in patients with cirrhosis admitted to an Intensive Care Unit. These indicators could be helpful in identifying patients who will not benefit from intensive care.

[Autoimmune hepatitis induced by fibrates]. / Hépatites d'allure auto-immune induites par les fibrates.

AIM: Long term treatment by fibrates could induce chronic hepatitis associated with auto-antibodies. The aim of this study was to assess the features of this hepatitis. METHODS: Baseline clinical and biological features, and liver biopsy in 5 patients with fibrate-induced chronic hepatitis were studied, as well as their outcome. RESULTS: At enrollment, patients (4 men, mean age 65 years) had highly (n = 3) or mildly (n = 2) increased serum aminotransferase activity, hypergammaglobulinemia and high titers of anti-nuclear antibodies (with homogenous fluorescence in 3 cases). Liver biopsies demonstrated a lympho-plasmocytic infiltrate in all cases. Hepatocellular necrosis was multilobular in 2 cases, and mild to moderate, located in lobular and periportal areas in 3 cases. Cirrhosis was found at presentation in 3 cases and developed within a few months in the 2 other patients. After discontinuation of fibrates, aminotransferase activity normalized within 6 weeks either spontaneously (n = 3) or under immunosuppressive treatment (n = 2). Immunosuppression was rapidly withdrawn in 2 patients (< 18 months) without relapse, while one patient was treated for 4 years because of relapse after early withdrawal. A second liver biopsy performed 6 months after discontinuation of fibrates in an untreated-patient showed no inflammation or necrosis. CONCLUSION: These observations suggest that fibrates could trigger chronic liver disease resembling type I auto-immune chronic hepatitis, which resolves after drug withdrawal.