Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan(®): validation in chronic hepatitis C.

A novel controlled attenuation parameter (CAP) has been developed for Fibroscan(®) to assess liver steatosis, simultaneously with liver stiffness measurement (LSM). We assessed CAP diagnostic accuracy in a large cohort of patients with chronic hepatitis C (CHC) virus. A total of 615 patients with CHC, who underwent both Fibroscan(®) and liver biopsy, were analysed. Fibrosis was graded using METAVIR score. Steatosis was categorized by visual assessment as S(0) : steatosis in <10% of hepatocytes, S(1) : 11-33%, S(2) : 34-66% and S(3) : 67-100%. Performances of CAP and liver stiffness were determined using receiver operating characteristic (ROC) curve analysis and cross-validated using the bootstrap method. The Obuchowski measure was used to assess overall accuracy of CAP and to differentiate between steatosis grades. In multivariate analysis, CAP was related to steatosis (P < 10(-15) ) independently of fibrosis stage (which was related to LSM). The areas under ROC curves using CAP to detect steatosis were 0.80 (95% CI, 0.75-0.84) for S ≥ S(1) , 0.86 (0.81-0.92) for S ≥ S(2) and 0.88 (0.73-1) S = S(3) . CAP exhibited a good ability to differentiate steatosis grades (Obuchowski measure = 0.92). Performance of LSM for fibrosis assessment confirmed results from previous studies. CAP is a novel tool to assess the degree of steatosis and both fibrosis and steatosis can be evaluated noninvasively during the same procedure using Fibroscan(®) , in patients with CHC.

HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis.

Liver steatosis is a main histopathological feature of Hepatitis C (HCV) infection because of genotype 3. Steatosis and/or mechanisms underlying steatogenesis can contribute to hepatocarcinogenesis. The aim of this retrospective study was to assess the impact of infection with HCV genotype 3 on hepatocellular carcinoma (HCC) occurrence in patients with ongoing HCV cirrhosis. Three hundred and fifty-three consecutive patients (193 men, mean age 58 ± 13 years), with histologically proven HCV cirrhosis and persistent viral replication prospectively followed and screened for HCC between 1994 and 2007. Log-rank test and Cox model were used to compare the actuarial incidence of HCC between genotype subgroups. The patients infected with a genotype 3 (n = 25) as compared with those infected with other genotypes (n = 328) had a lower prothrombin activity [78 (interquartile range 60-85) vs 84 (71-195) %, P = 0.03] and higher rate of alcohol abuse (48%vs 29%, P = 0.046). During a median follow-up of 5.54 years [2.9-8.6], 11/25 patients (44%) and 87/328 patients (26%) with a genotype 3 and non-3 genotype, respectively, develop a HCC. HCC incidences were significantly different among the genotype subgroups (P = 0.001). The 5-year occurrence rate of HCC was 34% (95% CI, 1.3-6.3) and 17% (95% CI, 5.7-9.2) in genotype 3 and non-3 genotype groups, respectively (P = 0.002). In multivariate analysis, infection with a genotype 3 was independently associated with an increased risk of HCC occurrence [hazard ratio 3.54 (95% CI, 1.84-6.81), P = 0.0002], even after adjustment for prothrombin activity and alcohol abuse [3.58 (1.80-7.13); P = 0.003]. For patients with HCV cirrhosis and ongoing infection, infection with genotype 3 is independently associated with an increased risk of HCC development.

Hepatic iron overload and risk of hepatocellular carcinoma in cirrhosis.

Iron accumulation in the liver is considered to be a co-factor for progression of liver disease. Iron overload can enhance the effects of oxidative stress and influence the natural history of patients with cirrhosis, exposing them to a higher risk of hepatocellular carcinoma. The results of clinical studies designed to assess the impact of liver iron content on the risk of tumor development have remained controversial for some time. It is known that common factors can affect both liver iron overload and the risk of cancer, necessitating multivariate analyses of these features in large cohorts of cirrhotic patients. Furthermore, the causes and consequences of hepatic iron overload appear to depend on the cause of the underlying liver disease. Thus, the only solid evidence of a relationship between liver iron overload and event occurrence has come from longitudinal studies conducted in homogeneous cohorts of patients with cirrhosis. So far, the available data suggest that iron accumulation in the liver is an independent risk factor for hepatocellular carcinoma in patients with alcoholic cirrhosis and/or nonalcoholic hepatosteatosis, but not in those with viral hepatitis C cirrhosis.

[Hepatocellular carcinoma: increasing incidence and optimized management]. / Carcinome hépatocellulaire: une incidence croissante, une prise en charge << optimisée >>.

Hepatocellular carcinoma is the main type of primary liver cancer. It is a major complication of chronic liver diseases, mainly cirrhosis. High increase in incidence and mortality has been observed in industrialized countries for about 30 years, as well as major improvement in the understanding of carcinogenesis and diagnostic and therapeutic management of patients: ultrasonographic screening of patients with cirrhosis, noninvasive (probabilistic) diagnosis mainly based on imaging procedures, improvement of liver transplantation results, development of tumor destruction using percutaneous radiofrequency, and more recently slight but significant increase in survival in patients treated with sorafenib. Nevertheless, some progress is still needed in order to improve significantly the incidence and the mortality of patients with hepatocellular carcinoma: widespread and improvement of ultrasonographic screening in patients with cirrhosis, effective chemoprevention, expanded indications of liver transplantation, prevention and treatment of cancer recurrences after surgical resection or radiofrequency, and methodological improvement in assessment of new treatments.

Fibrosis progression occurs in a subgroup of heavy drinkers with typical histological features.

BACKGROUND: Studies using consecutive liver biopsies constitute an attractive approach to gaining insight into the pathogenesis of alcoholic liver disease. AIM: To analyse histological factors at baseline, which are predictive of fibrosis progression and recurrence of alcoholic hepatitis. RESULTS: A total of 193 drinkers underwent consecutive biopsies at an interval of 4 years. At baseline, 20 had normal livers, 135 steatosis, five fibrosis and 33 alcoholic hepatitis. The fibrosis score increased from 1.07 +/- 0.07 to 1.7 +/- 0.94 (P < 0.001). In multivariate analysis, only steatosis (P = 0.04), alcoholic hepatitis (P = 0.0004) and stage of fibrosis (P < 0.0001) were independent predictive factors of the fibrosis score at the second biopsy. Cirrhosis developed more frequently in patients with steatosis (11%) and alcoholic hepatitis (39%) than in others (0%, P < 0.0001). Alcoholic hepatitis recurred more frequently in patients with alcoholic hepatitis at baseline: 58% vs. 15%, P < 0.0001. In multivariate analysis, alcoholic hepatitis at the first biopsy was the only predictive factor of its recurrence (P < 0.0001). CONCLUSIONS: In a large cohort of drinkers with consecutive biopsies, steatosis, fibrosis stage and alcoholic hepatitis at baseline were independent predictive factors of fibrosis progression. In terms of mechanisms, we propose a novel concept of multiple hits of alcoholic hepatitis occurring in the same patient.

UDP-glucuronosyltransferase UGT1A7 genetic polymorphisms in hepatocellular carcinoma: a differential impact according to seropositivity of HBV or HCV markers?

BACKGROUND: We conducted a case-control study to evaluate the role of UDP-glucuronosyltransferase 1A7 (UGT1A7) polymorphisms in the onset of hepatocellular carcinoma (HCC). METHODS: The study included 165 patients with HCC, 134 with cirrhosis and 142 controls without liver disease, matched for age and hospital. All were men younger than 75 years. HCC and cirrhosis patients were stratified according to time since cirrhosis diagnosis. RESULTS: We found a positive association between the UGT1A7*3/*3 genotype and HCC when the comparison was restricted to patients whose disease was of viral origin [OR = 3.4 (0.3-45)] but a negative association when it included only alcoholic patients [OR = 0.1 (0.02-0.6), p = 0.01]. CONCLUSION: Our study shows that UGT1A7 may play a role in hepatocellular carcinogenesis and that this role may differ according to the primary cause of the cirrhosis.

[The impact of large vessel proximity on effectiveness of radiofrequency ablation of hepatocellular carcinoma: a controlled study]. / Influence de la proximité des gros vaisseaux sur les résultats du traitement des carcinomes hépato-cellulaires par radiofréquence: une étude contrôlée.

PURPOSE: To evaluate the risk of radiofrequency ablation treatment failure for hepatocellular carcinomas (HCC) next to large vessels. MATERIALS AND METHODS: Between May 2000 and October 2002, from a total of 83 patients treated by radiofrequency ablation for HCC in a single center, 13 patients with tumoror=3 mm in diameter (Group A) were matched with 13 patients with similar size tumors located away from large vessels (Group B). Immediate response and recurrence rate were evaluated on CT. RESULTS: After mean follow-up interval of 39+/-16.5 months for Group A and 39+/-14 months for Group B, local recurrence rates were 7/12 versus 1/12 respectively (p=0.03). For Group A, 6/7 local recurrences clearly contacted a large vessel. CONCLUSION: The cooling effect from flowing blood in large vessels markedly increases the rate of local failure of radiofrequency ablation for small HCC located near large vessels.

Review article: intra-arterial treatments in patients with hepatocellular carcinoma.

In Western countries, most of the patients with hepatocellular carcinoma (HCC) are not eligible for curative treatments. Intra-arterial treatments have a palliative effect that could lead to extensive tumour necrosis and therefore have been widely used. Arterial embolization, Lipiodol-targeted chemoembolization and intra-arterial injection of radioactive iodine mixed with Lipiodol provided promising results in terms of tumoral growth, but were also responsible for severe side-effects, particularly in patients with cirrhosis. Their influence on survival has been assessed by randomized trials with contradictory results. In patients with advanced cases, embolization alone has limited or no influence on survival, and chemoembolization provided a beneficial effect mostly in patients with viral liver diseases, without liver failure, and with an adequate portal flux. The effects of radioactive iodine either in the treatment of advanced cases or the prevention of recurrences after a curative treatment must be investigated further.

Severe necroziting vasculitis in a patient with hepatitis C virus infection treated by interferon.

We report a case of polyarteritis nodosa occurring in a patient with hepatitis C, ten days after the beginning of alpha-IFN therapy. There was no cryoglobulinemia. Serum HCV-RNA was detectable before INF therapy and disappeared during the vasculites. The patient received boli of methylprednisolone and the neurological and skin lesions regressed after 5 months. This observation could suggest a precocious response to alpha-INF and a relationship between INF and the occurrence of vasculites.

Intra-arterial chemoembolization in patients with hepatocellular carcinoma.

Hepatocellular carcinoma occurs almost exclusively in patients with cirrhosis, at least in the West. In most of these patients, potential curative treatments, such as resection or percutaneous alcohol injection, are usually contra-indicated. Transarterial chemoembolization may induce tumor necrosis. In order to avoid massive necrosis of the non tumoral liver, two major contra-indications have been identified: inadequate portal flow and liver failure. The influence of chemoembolization on survival was thought to be high on the basis of non randomized trials. However, no beneficial effects on survival were observed in three randomized trials. In these trials, the beneficial effect on tumor necrosis was counterbalanced by frequent deleterious effects on liver function. Moreover, progressive liver atrophy may follow repeated procedures. As there is no alternative treatment for most of these patients and chemoembolization can still be beneficial in selected cases, efforts have been made to improve patient selection and method to improve the results. Good liver function, a normal portal flow, and a well limited hypervascularized tumor are necessary conditions for treatment, which may even be curative when used in association with percutaneous alcohol injection. Moreover, arterial embolization can be performed without chemotherapy, and the procedure should not be repeated in the short term.

[Does oral zinc improve the cellular immunity of patients with alcoholic cirrhosis?]. / L'apport oral de zinc améliore-t-il l'immunité cellulaire des malades atteints de cirrhose alcoolique?

A depressed response to delayed hypersensitivity skin tests is frequent in patients with alcoholic cirrhosis. Immune dysfunction in these patients is presumably dependent on nutritional factors. Zinc deficiency, a common finding in alcoholic cirrhosis, inhibits cellular immunity and might be one of these factors. The aim of our study was to show that zinc supplementation may improve cellular immunity in patients with alcoholic cirrhosis. We therefore compared 2 groups of patients: patients in the treated group (n = 18) had a daily oral intake of zinc-sulfate, 200 mg, during 2 months, patients in the non treated group (n = 20) received no supplementation. Both groups had a free diet. Delayed hypersensitivity skin tests to 7 antigens were performed with the Multitest IMC System at the beginning and at the end of the study. The immunity score was determined by the number of tests producing a skin induration greater than 2 mm. The evolutive index, calculated in each patient, was the difference between the final and initial immunity scores. The 2 groups were similar for all studied parameters. Cumulated immunity scores improved from 35 to 53 in treated patients (p less than 0.02), and from 42 to 44 (NS) in non treated patients. The evolutive index was 1 +/- 1.4 in treated patients and 0.1 +/- 1 in non treated patients (p less than 0.05). We conclude that in patients with alcoholic cirrhosis, daily intake of zinc sulfate, 200 mg, improves responsiveness to delayed hypersensitivity skin tests.(ABSTRACT TRUNCATED AT 250 WORDS)

[Serum laminin and portal pressure in alcoholic cirrhosis. A study of 39 patients]. / Laminine sérique et pression portale au cours de la cirrhose alcoolique. Une étude chez 39 malades.

A correlation between serum laminin, a glycoprotein found in basement membranes, and hepatic wedge pressure has previously been reported in a small number of patients with various liver diseases. To study this relationship in patients with alcoholic cirrhosis, we measured the wedge hepatic pressure and venous gradient, in comparison with serum concentrations of laminin and collagen metabolism products: N-terminal peptide of type III procollagen, collagen type I, and collagen type III in 39 patients. A statistically significant correlation was observed between serum laminin and wedged hepatic pressure (r = 0.529; p less than 10(-3] or hepatic venous gradient (r = 0.482; p = 0.002). By contrast, no statistically significant correlation was found between hemodynamic parameters and serum concentrations of N-terminal peptide of type III procollagen, collagen type I or collagen type III. These results suggest that, in patients with alcoholic cirrhosis, portal pressure may be estimated by serum concentration of laminin, and that perisinusoidal fibrosis, especially basement membrane thickening, may play an important role in the pathogenesis of portal hypertension in these patients.

[Fibronectin in the ascitic fluid: its diagnostic significance]. / La fibronectine dans le liquide d'ascite: sa signification diagnostique.

We studied fibronectin concentration in the ascitic fluid of 102 patients, 71 with cirrhosis, 13 with hepatocellular carcinoma, 12 with malignant peritonitis, and six with miscellaneous disease. Fibronectin concentrations in the first three groups were 45 +/- 45 mg/l, 54 +/- 84 mg/l, and 144 +/- 123 mg/l, respectively. The difference between patients with cirrhosis and malignant peritonitis was significant (p less than 0.01). However, fibronectin concentration greater than 100 mg/l had a sensitivity of 58 per cent and a specificity of 86 per cent for the diagnosis of malignant peritonitis. Ascitic fluid protein content over 30 g/l had the same sensitivity and specificity was 90 per cent. Among cirrhotic patients, high fibronectin concentrations were demonstrated in those with long-standing ascites (m = 134 +/- 58 mg/l) whereas the lowest concentrations were found in patients with severe hepatocellular failure (m = 12 +/- 9 mg/l). Concentrations were significantly different, according to whether or not spontaneous bacterial peritonitis occurred later (20 +/- 13 mg/l versus 52 +/- 49 mg/l); 83 per cent of patients with spontaneous bacterial peritonitis during their clinical course had initial fibronectin concentrations above 30 mg/l in their ascites. We conclude that: 1) measurement of fibronectin concentration in ascitic fluid is of poor diagnostic value for discrimination between malignant and non malignant ascitic, 2) low concentrations of fibronectin are associated with the occurrence of spontaneous bacterial peritonitis in cirrhotic patients. Hypothetically, the quantitative defect of fibronectin could be responsible for bacterial opsonization impairment in these patients.

[Do latent bacteremia and endotoxinemia exist in cirrhotics? A study of 48 patients]. / Existe-t-il une bactériémie et une endotoxinémie latentes chez les cirrhotiques? Etude de 48 malades.

Forty-eight patients with alcoholic cirrhosis and absence of patent infection were assessed for asymptomatic bacteriemia and endotoxemia. 280 blood cultures have been performed and 190 serum samples collected for study by two different methods of the limulus test (LT). Bacteriemia was found in 7 blood cultures from 3 patients. In these patients, occult infection was demonstrated in each case (cholecystitis, ulcerated rectal adenocarcinoma, cutaneous infection). Sixteen LT from 14 patients were positive initially. Only one LT remained positive after control by two different methods. These results suggest that in patients with alcoholic cirrhosis and in the absence of patent infection: 1) bacteriemia is an infrequent feature and, if present, explained by other causes than cirrhosis. 2) LT is negative in systemic blood when rigorous controls are performed, and endotoxemia cannot be substantiated by this test.

[Significance of type III serum N-terminal peptide procollagen assay in chronic viral hepatitis C]. / Signification du dosage sérique du peptide N-terminal du procollagène de type III au cours des hépatites chroniques à virus C.

The aim of this study was to evaluate the relationship between the serum N-terminal peptide of type III procollagen (PIIINP), Knodell's score and the response to treatment in 79 patients with viral C chronic hepatitis. Liver biopsy and serum PIIINP was assessed in all patients. Serum PIIINP was correlated with Knodell'score (r = 0.60; P = 10(-4)). Correlation between serum alanine amino-transferase and Knodell'score was smaller than for PIIINP (r = 0.38; P = 0.02). Forty-nine patients were treated with interferon alpha. A second biopsy and serum PIIINP determination were performed one year after treatment discontinuation. Means of serum PIIINP and Knodell'score significantly decreased after treatment (P < 0.01; P < 0.03). Among non-responder patients, serum PIIINP was initially more elevated: 37.5 +/- 12.6 ng/mL versus 22.6 +/- 3.8 (P < 10(-3)). Knodell's score decreased only among responder patients (P < 0.01 vs P < 0.7). Positive and negative predictive value for the response to treatment, evaluated by aminotransferases normalization, of serum PIIINP level < or = 24 ng/mL were 0.6 and 0.9 respectively. These findings suggest that serum PIIINP is a relevant marker of activity in patients with viral C chronic hepatitis and that it might have a predictive value of response to treatment.

[Role of hepatitis C virus in the genesis of hepatic lesions observed in alcoholic patients with liver cirrhosis]. / Rôle du virus de l'hépatite C dans la genèse des lésions hépatiques observées chez des malades alcooliques atteints de cirrhose.

The aim of study was to assess the role of hepatitis C virus (HCV) infection in 164 alcoholic cirrhotic patients. We studied the prevalence of anti-HCV antibodies using ELISA and RIBA first and second generation tests. Twenty-two % of the patients had anti-HCV antibodies detected by ELISA 2, RIBA 2 test was positive in 10% of the patients and indeterminate in 3%. We compared epidemiological, biological and histological characteristics according to the results of the tests. By comparing ELISA 2-RIBA 2 positive patients to ELISA 2 negative patients, we observed, in the former, a) a higher serum aminotransferase activity, b) a lower serum gammaglutamyl transpeptidase activity, and c) a lower histological score of alcoholic hepatitis. In addition, in a group of ELISA 2 positive RIBA 2 negative patients, the values were intermediate between those of the two former groups. However, most of these patients had a negative third generation ELISA test. The whole results suggest that HCV is likely to play a role in the pathogenesis of liver damage in a high number of alcoholic cirrhotic patients.

[Association of autoimmune chronic active hepatitis and acquired erythroblastopenia cured by cyclophosphamide]. / Association d'une hépatite chronique active auto-immune et d'une érythroblastopénie acquise guérie par le cyclophosphamide.

To the best of our knowledge this is the reported first case of the successive occurrence in the same patient of chronic active hepatitis and acquired pure red cell aplasia, both probably of autoimmune origin. The diagnosis of autoimmune hepatitis was based on the presence of characteristic lesions at the examination of the liver biopsy specimen, high titer of anti-smooth muscle antibodies in the serum, and remission obtained by steroid therapy. Erythroid aplasia, which appeared during the course of this treatment, was revealed by a regenerative anemia (4.4 g Hb/100 ml) and proved by bone marrow aspiration and biopsy. In vitro bone marrow culture was normal, suggesting the in vivo presence of an inhibitor of erythroblastic differentiation. Red cell aplasia was cured by cyclophosphamide (100 mg/day during 56 days). No recurrence was noted until the death of the patient, which occurred one year later, due to hepatic cholangiocarcinoma. Action of cyclophosphamide on the pure red cell aplasia suggested the immune origin of this disease. The liver and the bone marrow erythroid lineage have probably been the successive targets of immunologic dyscrasia.

[Comparison of six potential serum markers of hepatic fibrosis in alcoholic disease of the liver]. / Comparaison de 6 marqueurs sériques potentiels de la fibrose hépatique au cours de la maladie alcoolique du foie.

The aim of this study was to compare 6 potential serum markers for hepatic fibrosis in patients with alcoholic liver disease. Ninety-three patients (50 +/- 11 years old, 62 males) with biopsy-proven alcoholic liver disease were included in the study. A liver biopsy and serum assays of type I, type III and type IV collagens, N-terminal peptide of type III procollagen, laminin (by radioimmunoassays) and apolipoprotein A1 (by nephelometry) were performed in all patients. A histological score of hepatic fibrosis was established. Alcoholic hepatitis lesions and perisinusoidal fibrosis were assessed separately. A significant correlation was found between the score of hepatic fibrosis and serum levels of type I collagen (r = 0.44, P < 10(-3)), type III collagen (r = 0.36, P < 10(-2)), N-terminal peptide of type III procollagen (r = 0.50, P < 10(-3)), type IV collagen (r = 0.44, P < 10(-3)), laminin (r = 0.50, P < 10(-3)), and apolipoprotein A1 (r = 0.21, P < 0.05). After adjustment for the presence of lesions of alcoholic hepatitis and perisinusoidal fibrosis (partial correlation), serum levels of type I collagen, type III collagen, N-terminal peptide of type III procollagen, type IV collagen, and laminin remained significantly correlated with the score of hepatic fibrosis; in contrast, correlation with serum apolipoprotein A1 was no longer significant. Serum levels of N-terminal peptide of type III procollagen, type IV collagen and laminin were significantly higher in patients with perisinusoidal fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Treatment of alcoholic hepatitis with silymarin. A double-blind comparative study in 116 patients]. / Traitement de l'hépatite alcoolique par la silymarine. Une étude comparative en double insu chez 116 malades.

A randomized double-blind trial of silymarin versus placebo was carried out in 116 patients with histologically proven alcoholic hepatitis, 58 of them with cirrhosis. Patients were not included in case of hepatic encephalopathy, contraindication to percutaneous liver biopsy, hepatocellular carcinoma, evident lack of discipline or refusal to enter the trial. Fifty-seven patients received silymarin orally 420 mg/day and 59 received placebo during 3 months. Biologic parameters were assessed in the serum, and a percutaneous liver biopsy was obtained at the start of the trial and 3 months later. Histologic scores of alcoholic hepatitis and fibrosis were established on each biopsy specimen by two independent pathologists. The 2 groups were comparable at inclusion; 26 p. 100 of patients were lost to follow-up at 3 months, abstinence was obtained in 46 p. 100 of patients at the end of the trial. These percentages were similar in the two groups. Four patients died of hepatic failure during the trial, 3 in the placebo group. Significant improvement in the score of alcoholic hepatitis and serum amino transferase activity, was noted in both groups during the trial, irrespective of treatment with silymarin or placebo. No side-effects were noted. Our results suggest that silymarin 420 mg/d is not clinically relevant in the treatment of moderate alcoholic hepatitis.