Cholangiopathy in critically ill patients surviving beyond the intensive care period: a multicentre survey in liver units.

BACKGROUND: The outcome of cholangiopathy developing in intensive care unit (ICU) is not known in patients surviving their ICU stay. AIM: To perform a survey in liver units, in order to clarify the course of cholangiopathy after surviving ICU stay. METHODS: The files of the liver units affiliated to the French network for vascular liver disease were screened for cases of ICU cholangiopathy developing in patients with normal liver function tests on ICU admission, and no prior history of liver disease. RESULTS: Between 2005 and 2015, 16 cases were retrieved. Extensive burns were the cause for admission to ICU in 11 patients. Serum alkaline phosphatase levels increased from day 11 (2-46) to a peak of 15 (4-32) × ULN on day 81 (12-511). Magnetic resonance cholangiography showed irregularities or frank stenosis of the intrahepatic ducts, and proximal extrahepatic ducts contrasting with a normal aspect of the distal common bile duct. Follow-up duration was 20.6 (4.7-71.8) months. Three patients were lost to follow-up; 2 patients died from liver failure and no patient was transplanted. One patient had worsening strictures of the intrahepatic bile ducts with jaundice. Nine patients had persistent but minor strictures of the intrahepatic bile ducts on MR cholangiography, and persistent cholestasis without jaundice. One patient had normal liver function tests. CONCLUSIONS: In patients surviving their ICU stay, ICU cholangiopathy is not uniformly fatal in the short term or clinically symptomatic in the medium term. Preservation of the distal common bile duct appears to be a finding differentiating ICU cholangiopathy from other diffuse cholangiopathies.

Idarubicin-loaded beads for chemoembolisation of hepatocellular carcinoma: results of the IDASPHERE phase I trial.

BACKGROUND: A phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads was performed in cirrhotic patients with hepatocellular carcinoma (HCC). AIM: To estimate the maximum-tolerated dose (MTD) and to assess safety, efficacy, pharmacokinetics and quality of life. METHODS: Patients received a single TACE session with injection of 2 mL drug-eluting beads (DEBs; DC Bead 300-500 µm) loaded with idarubicin. The idarubicin dose was escalated according to a modified continuous reassessment method. MTD was defined as the dose level closest to that causing dose-limiting toxicity (DLT) in 20% of patients. RESULTS: Twenty-one patients were enrolled, including nine patients at 5 mg, six patients at 10 mg, and six patients at 15 mg. One patient at each dose level experienced DLT (acute myocardial infarction, hyperbilirubinaemia and elevated aspartate aminotransferase (AST) at 5-, 10- and 15-mg, respectively). The calculated MTD of idarubicin was 10 mg. The most frequent grade ≥3 adverse events were pain, elevated AST, elevated γ-glutamyltranspeptidase and thrombocytopenia. At 2 months, the objective response rate was 52% (complete response, 28%, and partial response, 24%) by modified Response Evaluation Criteria in Solid Tumours. The median time to progression was 12.1 months (95% CI 7.4 months--not reached); the median overall survival was 24.5 months (95% CI 14.7 months--not reached). Pharmacokinetic analysis demonstrated the ability of DEBs to release idarubicin slowly. CONCLUSIONS: Using drug-eluting beads, the maximum-tolerated dose of idarubicin was 10 mg per TACE session. Encouraging responses and median time to progression were observed. Further clinical investigations are warranted (NCT01040559).

Long-term outcome of chronic hepatitis C in a population-based cohort and impact of antiviral therapy: a propensity-adjusted analysis.

This population-based study aimed to assess the determinants of the outcome of chronic hepatitis C with analysis of the impact of antiviral therapy with or without sustained virological response (SVR) on cirrhosis decompensation, hepatocellular carcinoma, liver-related and non-liver-related mortality. A total of 1159 HCV-positive patients newly detected between 1994 and 2001 were included. For each outcome, the prognostic effect of patients' baseline characteristics was estimated by time-dependent Cox models using age as the time-scale and adjusting for treatment received during follow-up. The impact of antiviral therapy was assessed by using a propensity score in a sample including 184 patients treated in the first 24 months following diagnosis who were matched to 184 untreated patients. At the end of a 59-month median follow-up, 100 cases of compensated disease, 58 liver cancer and 163 deaths (55 liver related) were recorded. The 5-year rates of decompensated cirrhosis, hepatocellular carcinoma, liver-related and non-liver-related death were 4.4%, 2.7%, 5.0% and 8.9%, respectively. Multivariate analyses identified two variables with pejorative influence: alcohol consumption (RR = 4.29 for CD; RR = 5.76 for HCC; RR = 6.69 for liver-related death; P < 0.0001); HCV diagnosis unrelated to systematic screening (RR = 2.25 for CD; RR = 3.05 for HCC; RR = 4.31 for liver-related death, P < 0.03). In the matched subset, no significant benefit of antiviral therapy was observed. Nevertheless, among the 144 patients who achieved SVR, no death was observed. This population-based study showed substantial rates of decompensated cirrhosis, hepatocellular carcinoma and non-liver-related mortality. Alcohol consumption and absence of systematic screening were significant determinants of poor outcome, whereas treatment did not have significant influence.

The Treviso Longeva (Trelong) study: a biomedical, demographic, economic and social investigation on people 70 years and over in a typical town of North-East of Italy.

Longevity is a complex process resulting from genetic and environmental factors, as well as their interaction. These factors are poorly understood, and the comparison among health status, socio-economics, demographic and other characteristics of the elderly people can help in understanding these complex interactions. Such an interdisciplinary approach is necessary to allow an appropriate evaluation of longevity. Here we report the methodology and the first results of a representative study performed in 2003-2004 on people of 70 years and over, living in a typical town of North-East of Italy. In the research we collected biomedical, demographic, socio-economic and quality of life (QoL) data.

Is the management of hepatitis C patients appropriate? A population-based study.

BACKGROUND: In order for hepatitis C patients to receive antiviral treatment, they must reach medical care. AIM: To assess the proportion of patients reaching medical care after hepatitis C diagnosis in a general population (1 006 171 inhabitants) in France. METHODS: Between 1994 and 1999, 1508 cases were diagnosed, of which 1251 were eligible for the study. RESULTS: Two-hundred and two patients did not have any medical care; among them, 55.4% had normal alanine transferase, 58.4% had risk factors related to lifestyle and 22.8% were alcoholics. Amongst the 1049 other patients, 41.6% had a liver biopsy, 25.0% were treated. Treatment was more often carried out in males than in females (OR: 1.59; P = 0.001), and in patients under 65 than in older patients (OR: 2.22; P < 0.008). Among non-treatment reasons, alcoholism (P = 0.001), drug-addiction (P = 0.04) and escaping monitoring (P = 0.04) were more frequent in males than in females, whereas normal alanine transferase was more frequent in females than in males (P = 0.004). Amongst 278 patients with a Metavir score >A1F1, 71 (25.5%) did not undergo treatment. CONCLUSION: In a general population, one patient in six did not receive on-going health care; a quarter of patients with a Metavir score >A1F1 did not receive any treatment. These results showed insufficient clinical management, which could compromise the effectiveness of treatment in general population.

Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C.

BACKGROUND/AIMS: Our aims were to investigate the host and viral specific factors associated with diabetes mellitus (DM) and insulin resistance in chronic hepatitis C patients. METHODS: One hundred and three hepatitis C virus (HCV)-infected were studied to assess the effects of HCV genotype, hepatic iron content, steatosis, hepatic fibrosis, body mass index (BMI) and family history of DM on the occurrence of DM. Insulin resistance (HOMA IR) was studied in 81 non-diabetic patients to determine the mechanism associated with insulin resistance in this subgroup. RESULTS: Sixteen of the 123 were diabetic (13.0%). The variables predictive of DM were METAVIR fibrosis score 4 (OR, 13.16; P = 0.012), family history of diabetes (OR, 16.2; P = 0.0023), BMI (OR, 1.37; P = 0.017) and age (OR, 1.09; P = 0.002). In non-diabetic HCV-infected patients, HOMA-IR of METAVIR fibrosis score 0 and 1 patients were significantly different than score 2 and score 3/4 patients. CONCLUSIONS: Our findings indicate that older age, obesity, severe liver fibrosis and family history of diabetes help identify those HCV patients who might have potential risk factors for development of DM. We observed that insulin resistance in non-diabetic HCV-infected patients was related to grading of liver fibrosis, and occurs already at an early stage in the course of HCV infection.

[Febrile cytolysis disclosing hemorrhagic fever with renal syndrome]. / Cytolyse fébrile révélatrice d'une fièvre hémorragique avec syndrome rénal.

We report the case of a 40-year-old-man who developed febrile cytolysis as the presenting sign of hemorragic fever with renal syndrome (HFRS). On admission, he had fever (40 degrees C) and epigastric pain. The AST level was at 2N, the ALT at 3N. There was a thrombocytopenia (61 000/mm(3)) without anemia or hyperleukocytosis. Three days after admission, the platelet count decreased to 40 000/mm(3), serum urea and creatinine increased from normal rate to 10.8mmol/l, 204.0 micromol/l, respectively. The HIV, HBV, HCV, leptospirosis antibodies were negative. The Hantavirus serology was positive (Ig G: 1/512). This case suggests that HFRS should be entertained as a possible cause of cytolysis with thrombocytopenia in patients with fever and no initial sign of renal involvement in North-Eastern France.

[The characteristics of patients with hepatitis C virus antibodies followed in specialized university hospital units are different from those of patients in the general population. The Research Group of the REBOHC]. / Les caractéristiques des malades ayant des anticorps dirigés contre le virus de l'hépatite C sont différentes en service spécialisé hospitalo-universitaire et dans la population générale. Groupe de Recherche du REBOHC.

OBJECTIVES: To compare the characteristics of patients with anti-hepatitis C virus antibodies followed in a University Hospital Department of Hepatogastroenterology with those in patients who received medical care elsewhere. METHODS: Since 1994, a specialized viral hepatitis register has recorded since 1994 all new cases of anti-hepatitis C virus antibodies diagnosed in inhabitants of the French department of Côte-d'Or (493931). The factors correlated with the type of medical care in patients followed in the University Department were studied by logistical regression. RESULTS: One hundred of the 498 new patients with anti-hepatitis C virus antibodies diagnosed in the Côte-d'Or between 1994 and 1996 were followed in a University Hospital Department. Multivariate analysis showed that age (<60), contamination due to transfusion, elevated ALT levels and no excessive alcohol consumption were factors significantly correlated with follow-up at the University Department. Liver biopsy was more often performed (66%) and a treatment was more often prescribed (34%) in patients followed in a University Department of Hepatogastroenterology patients than in other patients (20.4%; P <0.0001 et 7.5%; P <0.0001 respectively). CONCLUSIONS: This study shows that patients with anti-hepatitis C virus antibodies who are followed by a specialised University Department are a selected group; these patients are more likely to be treated than others. This study emphasizes that the greatest care must be taken when extending the extension of results of hospital series to a non-selected population.

Primary disease recurrence after liver transplantation for alveolar echinococcosis: long-term evaluation in 15 patients.

Between 1986 and 1991, 21 patients received liver grafts in our center for incurable alveolar echinococcosis (AE). The aim of this study was to analyze the long-term results in 15 of these 21 patients who survived more than 1 year after undergoing a liver transplantation (LT). The follow-up, mainly aimed at the diagnosis of recurrence, consisted of repeated radiological and specific immunological investigations. The role of pre- and post-LT benzimidazole (BZM) therapy was also evaluated. Among the 15 patients, 8 patients had a palliative LT related to previously known pulmonary AE metastases and/or inextirpable abdominal parasitic foci. In the 7 remaining patients, LT was considered curative. In June 1998, the mean follow-up duration was 96 months (range: 28-138 months). Five late deaths occurred, 2 of them were directly related to residual AE. A reinfection of the graft was observed in 4 patients. Preoperative BZM therapy seemed useful in preventing or delaying the parasitic recurrence. Post-LT BZM was able to stabilize and even to reduce residual AE. The anti-Em2 enzyme-linked immunosorbent assay (ELISA), which is the standard test used in patient follow-up after partial liver resection for AE, did not appear useful in detecting recurrence here; however, an ELISA, using a crude heterologous antigen (Echinococcus granulosus) allowed early diagnosis of residual AE. In conclusion, primary disease recurrence is not rare after LT for AE. Immunosuppressive therapy may favor larval growth in extrahepatic sites; therefore, an extensive extrahepatic radiological check-up has to be performed before LT. BZM therapy seems to stabilize residual foci. Anti-Eg immunoglobulin G (IgG) follow-up is the most useful test for early diagnosis of parasite recurrence.

Time trends and age-period-cohort effects on the incidence of primary liver cancer in a well-defined French population: 1976-1995.

BACKGROUND/AIMS: There is growing interest worldwide in primary liver cancer. The aim of this study was to describe the incidence of this cancer over a 20-year period in a well-defined French population. METHODS: Time trends by 4-year period were studied by sex, age group, place of residence, histological type and associated cirrhosis. Trends were also analysed using the age-period-cohort model. RESULTS: Primary liver cancer incidence in men increased from 7.5/100000 for the period 1976-79 to 10.2/100000 for the period 1992-95. The mean annual variation was +2.2%, (p<0.05). The increase in incidence was seen mainly in the 55-64 and 65-74 age groups and concerned hepatocellular carcinomas. In men, the increase in incidence rates with time was observed mainly in rural areas, whereas incidence rates in urban areas remained stable. The rise in incidence was due mostly to an increase in primary liver cancer with cirrhosis, in relation to a progressive increase in post-hepatitic cirrhosis and a recent increase in alcoholic cirrhosis. The estimated cumulative risk for the life span 30-74 years increased from 0.8% for the 1904-1908 cohort to 2.1% for the 1934-1938 cohort. There was no significant trend in female rates. CONCLUSIONS: In France, incidence rates for primary liver cancer are increasing in men, whilst they are remaining stable in women. Our data confirm the primary importance of alcohol in the aetiology of this cancer. Further studies are necessary to unravel the respective roles of alcohol and hepatitis C virus in the increasing incidence of primary liver cancer.

[Creation of a viral hepatitis B and C in the Côte-d'Or department. Methodology and initial results]. / Mise en place d'un registre des hépatites virales B et C dans le département de la Côte-d'Or. Méthodologie, premiers résultats. Réseau Bourguignon des Hépatites C.

OBJECTIVES: The epidemiological status of viral B and C hepatitis remains unknown in the general French population. This is why a specialized registry was created in the French Côte-d'Or administrative area (493,931 inhabitants) on 1994 January 1st. METHODS: The three sources of information were: a) biological and virological analysis laboratories, which report all new HBs Ag and HCV Ab cases, b) specialists in gastroenterology, hepatology, infectious diseases and internal medicine, c) pathologists. Additional information was obtained from the medical practitioner who prescribed the serology. RESULTS: Between January and December 1994, 241 new cases of HBs Ag and HCV Ab were reported: 168 cases of HCV Ab (96 males, 72 females) and 73 cases of HBs Ag (37 males, 36 females) including 10 mixed cases (HBs Ag and HCV Ab). The annual standardized rate of detection of patients with HCV Ab was 26.4 +/- 4.6/100,000 inhabitants. Contamination was a result of intravenous drug addiction in 54 cases (32%), blood transfusion in 39 cases (23%) and remained unknown in 56 cases (33%). A liver biopsy was performed in 42 patients, 17 were treated with interferon during the two years following diagnosis. The standardized detection rate of patients with HBs Ag was 12.9 +/- 2.6/100,000 inhabitants. Contamination resulted from sexual transmission in 17 cases (23%), was related to a lengthy stay in endemic countries in 10 cases (14%) or to intravenous drug addiction in 6 cases (8%), and remained unknown in 37 cases (51%). A liver biopsy was performed in 6 cases and 2 patients were treated. CONCLUSION: These preliminary French population based data show that the annual frequency of detection of HBs Ag and HCV Ab is high and that care of these patients must be improved.

Tenoxicam, a non-steroid anti-inflammatory drug, is unable to increase the response rate in patients with chronic hepatitis C treated by alpha interferon.

The purpose of this study is to compare a combination of interferon (IFN)-alpha2a (Roferon) + Tenoxicam with IFN-alpha2a alone in the treatment of chronic hepatitis C. This prospective, randomized double-blind study included 149 patients, all of whom were diagnosed with active chronic hepatitis C but non-cirrhotic (ALT > or = 1.5 upper limit of normal, anti-hepatitis C virus (HCV) positive by enzyme-linked immunosorbant assay2 and RIBA3). The patients were randomized in two groups, as follows: G1 (n = 76): IFNalpha2a 3 million units times per week during 6 months + placebo; and G2 (n = 73): IFNalpha2a 3 million units three times per week + Tenoxicam (20 mg/day) during 6 months. Alanine aminotransferase (ALT) and HCV RNA were determined before and at months 6 and 12 of treatment. 2'5' oligoadenylate synthetase activity (2'5' AS) was dosed in mononuclear cells before and at 3-month treatment intervals in 28 patients. Liver biopsy was performed before and 6 months after the end of therapy. Parameters were similar before therapy for both groups. Biochemical and virological responses were similar for both groups at month 6 (49.3% vs. 42.9% and 43.3% vs. 38.3%, respectively) and month 12 (28.3% vs. 23.8% and 17.2% vs. 17.5%, respectively). HCV RNA level significantly decreased in both groups at month 6, with no difference whatever the therapy; however, the HCV RNA level returned to initial values at month 12 and was the only significant prognostic factor of a sustained response. No peak of 2'5' AS activity was observed during treatment in patients with dual therapy. A histological improvement was also noted in both groups without difference, regardless of therapy. The percentage of adverse events was identical for both groups. Paracetamol intake, assessed in 80 patients, was 49.1 g per 6 months in the G1 group and 22.5 g per 6 months in the G2 group (not significant). In conclusion, the non-steroid anti-inflammatory drug, Tenoxicam, does not increase IFNalpha efficacy in the treatment of chronic hepatitis C. This combination is well tolerated and partially lowers Paracetamol intake, but not preexisting alpha-IFN adverse events.