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.

Impact of controlled attenuation parameter on detecting fibrosis using liver stiffness measurement.

BACKGROUND: Liver fibrosis is often accompanied by steatosis, particularly in patients with non-alcoholic fatty liver disease (NAFLD), and its non-invasive characterisation is of utmost importance. Vibration-controlled transient elastography is the non-invasive method of choice; however, recent research suggests that steatosis may influence its diagnostic performance. Controlled Attenuation Parameter (CAP) added to transient elastography enables simultaneous assessment of steatosis and fibrosis. AIM: To determine how to use CAP in interpreting liver stiffness measurements. METHODS: This is a secondary analysis of data from an individual patient data meta-analysis on CAP. The main exclusion criteria for the current analysis were unknown aetiology, unreliable elastography measurement and data already used for the same research question. Aetiology-specific liver stiffness measurement cut-offs were determined and used to estimate positive and negative predictive values (PPV/NPV) with logistic regression as functions of CAP. RESULTS: Two thousand and fifty eight patients fulfilled the inclusion criteria (37% women, 18% NAFLD/NASH, 42% HBV, 40% HCV, 51% significant fibrosis ≥ F2). Youden optimised cut-offs were only sufficient for ruling out cirrhosis (NPV of 98%). With sensitivity and specificity-optimised cut-offs, NPV for ruling out significant fibrosis was moderate (70%) and could be improved slightly through consideration of CAP. PPV for significant fibrosis and cirrhosis were 68% and 55% respectively, despite specificity-optimised cut-offs for cirrhosis. CONCLUSIONS: Liver stiffness measurement values below aetiology-specific cut-offs are very useful for ruling out cirrhosis, and to a lesser extent for ruling out significant fibrosis. In the case of the latter, Controlled Attenuation Parameter can improve interpretation slightly. Even if cut-offs are very high, liver stiffness measurements are not very reliable for ruling in fibrosis or 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.

Comparison of two sucralfate dosages presented in tablet form in duodenal ulcer healing.

Two hundred twenty-two patients with endoscopically proven duodenal ulcers participated in a controlled trial to assess and compare the effects of two dosage regimens of sucralfate tablets on ulcer healing, i.e., 1 g four times daily (group A, n = 131) and 2 g twice daily (group B, n = 128). Healing was defined as complete re-epithelialization. Clinical and endoscopic assessments were performed after four weeks (Day 28) and, if complete healing was not achieved, after four more weeks (Day 56). After four weeks, in group A (n = 114: eight patients were lost and nine were withdrawn), the ulcers had healed in 90 patients (79 percent), and in group B (n = 108: six patients were lost and 14 were withdrawn), the ulcers had healed in 80 patients (74 percent). The cumulative healing rates after eight weeks were 94 percent in group A and 95 percent in group B. No serious adverse effect was observed in either group. These results suggest that sucralfate tablets in a dosage of 2 g twice daily are as effective as 1 g four times daily in the treatment of acute duodenal ulcers and could lead to better patient compliance.

Coagulation assays as diagnostic markers of hepatocellular carcinoma.

With the aim of improving the biological diagnosis of hepatocellular carcinoma (HCC), alpha-fetoprotein (AFP), des-gamma-carboxyprothrombin (DCP) and factor V levels were assayed in 119 patients with HCC and 60 cirrhotic patients without HCC. Among the patients with HCC, increased levels of AFP (greater than 300 ng/ml) and of DCP (greater than 15 mU/ml) were observed in 36% and 69% of the cases, respectively. None of the 60 patients without HCC had increased AFP, and one had abnormal DCP; in this patient, DCP level returned to normal value after vitamin K1 injection. No significant correlation was found between increased AFP and DCP, thus indicating that the two tests complement each other for the diagnosis. A factor V level higher than expected from the reduced prothrombin time test of the patient was detected in 50% of patients with HCC and only 7% of those without HCC. No correlation was found between increased factor V and abnormal AFP or DCP. The thrombin time, fibrinogen activity to antigen ratio, and polymerization index failed to differentiate between cirrhosis and HCC. We conclude that AFP, DCP and factor V may give complementary informations in the diagnosis of HCC, one of these markers at least being positive in 88% of the patients.

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.

CA 125 (ovarian tumour-associated antigen) in ascitic liver diseases.

The presence of Ca 125, an ovarian cancer-associated antigen, was assessed in serum from patients with liver diseases with (n = 26) and without (n = 26) ascites. Abnormal levels of serum CA 125 were observed in all patients with ascites and in 4 patients without ascites (15%). We conclude that CA 125 is a non-specific marker of ascites whatever the origin: ovarian carcinoma, cirrhosis or peritoneal inflammatory process.

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.

Use of adult human hepatocytes in primary culture for the study of clometacin-induced immunoallergic hepatitis.

To determine whether specific circulating antibodies from patients with drug-induced immunoallergic hepatitis could be involved in antibody-dependent cell-mediated cytotoxicity, an in vitro model system was set up. Normal human hepatocytes from male kidney transplantation donors were cultured and incubated with clometacin, a drug known to induce immunoallergic hepatitis in humans. After drug exposure and in the presence of lymphoid cells autologous to hepatocytes, addition of sera from patients with clometacin-induced hepatitis consistently resulted in hepatocyte injury characterized by morphological alterations and a decrease in intracellular lactate dehydrogenase and aspartate aminotransferase activities. Sera from patients with hepatitis induced by other drugs, such as cimetidine, halothane or methyldopa, were ineffective and no cytotoxicity occurred in the absence of lymphoid cells or without pre-incubation with clometacin. These results are consistent with the view that clometacin-induced hepatitis has an immunological basis and suggest that human hepatocytes co-cultured with autologous lymphoid cells represent a suitable model to study antibody-dependent cell-mediated cytotoxicity.

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.

Prior residency and the stability of dominance relationships in pairs of green swordtail fish Xiphophorus helleri (Pisces, Poeciliidae).

The stability of dominance relationships between pairs of male green swordtail fish was followed daily for 20 consecutive days. In one experimental sample composed of 21 pairs, dominance of one of the fish had been favoured on the first day by giving the fish prior familiarity (prior residency) with the aquarium where it was to meet an intruder. In a control sample composed of 12 pairs, two intruders met in an unfamiliar aquarium. It was expected that the advantage given to the dominant by familiarity with the aquarium on the first day would disappear as the subordinate acquired in turn familiarity with the milieu. In comparison with pairs composed of two intruders, this would show up by more frequent inversions of the initial dominance relationship in pairs composed of a prior resident and an intruder. Only two inversions occured over the 20 days of follow up and they occured equally in the experimental (5%) and control (8%) samples. These results confirm the great stability of dominance relationships in dyads and invalidate the hypothesis that the prior residency advantage would decay as the subordinate became familiar with the aquarium. Unexpectedly, 13 of the 66 (20%) fish died over the 20 days. Death equally occurred in both samples but 12 (92%) cases implied initial subordinates. The exception was an initial dominant which had become the subordinate pair member three days before death. Various hypotheses are suggested to account for the selective deaths of subordinates.

[Hepatic lipid overload in 2 cases of cholestasis associated with parenteral feeding]. / Etude de la surcharge lipidique hépatique au cours de deux cas de cholestase associée à la nutrition parentérale.

The authors report 2 cases of patients with ileal stenosis who developed progressive jaundice while receiving total parenteral nutrition including lipids (Intralipid). In both cases the histologic and histochemical study of the liver demonstrated lipid overload in Kupffer cells and to a lesser extent hepatocytes. Biochemical study established that linoleic acid, a component of Intralipid, associated with a digalactosyl-diglyceride from vegetal origin were the main components of the hepatic overload. The authors hypothesize that two associated mechanisms were responsible for jaundice in their patients: Kupffer cell dysfunction due, at least in part, to lipid overload and intestinal bacterial overgrowth leading to endotoxinemia.

[Hepatocellular carcinoma and the alpha 1-antitrypsin phenotype]. / Carcinome hépatocellulaire et phénotype de l' alpha 1-antitrypsine.

To determine whether or not alpha 1-antitrypsin phenotype PiMZ is a predisposing factor for hepatocellular carcinoma alpha 1-antitrypsin phenotype was studied in 83 French patients with hepatocellular carcinoma compared with 1,030 blood donors. In 66 patients, alpha 1-antitrypsin phenotype was determined by isoelectric focusing which allows the distinction between subtypes of phenotype M. No difference has been shown between the two groups for alpha 1-antitrypsin alleles or subtypes of allele Pi*M. The authors conclude that phenotype PiMZ is not a significant predisposing factor for hepatocellular carcinoma in French people. As well, a review of literature suggests that, in contrast with the conclusion of previous reports, the link between alpha 1-antitrypsin phenotype PiMZ and hepatocellular carcinoma is either nonexistent or very weak.

[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)

[Severe jaundice in Legionnaires' disease: a case with early hepatic biopsy]. / Ictère intense au cours de la maladie des Légionnaires: un cas avec biopsie hépatique précoce.

Although liver tests are frequently disturbed in Legionnaires' disease, jaundice occurs rarely except as a terminal event. The authors report the case of a 68 year-old man with jaundice as a presenting feature of the disease. Jaundice deepened rapidly until death a few days later. Drugs and other causes of cholestasis could be ruled out. An early liver biopsy was performed. The liver was histologically normal except for mitochondrial margination in the hepatocytes. No Legionella could be demonstrated by direct fluorescent assay. These findings suggest that: jaundice in Legionnaires' disease is not related to direct bacterial insult, cholestasis is probably consecutive to endotoxinemia, the mitochondrial margination, a rare histologic finding, could result from Legionnaires' disease. This last point needs confirmation by further studies.

[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.

[Prevalence and prognostic value of serum anti-p53 antibodies in hepatocellular carcinoma. A study of 159 patients]. / Prévalence et valeur pronostique des anticorps sériques anti-p53 au cours du carcinome hépatocellulaire. Etude chez 159 malades.

OBJECTIVES: Genetic alterations in the p53 protein may induce serum anti-p53 antibodies. The aim of this study was to assess the prevalence of serum anti-p53 antibodies in a large series of Western patients with hepatocellular carcinoma and the prognostic value of these antibodies on survival. METHODS: Serum anti-p53 antibodies were assayed in 159 patients with hepatocellular carcinoma, at diagnosis, using an immunoenzymatic method. The initial patient characteristics were compared according to anti-p53 status. The prognostic value of these antibodies on survival was determined by univariate and multivariate analysis. RESULTS: One hundred fifty nine patients with hepatocellular carcinoma were included in the study (129 men, mean age: 68 years). The main associated causes of chronic liver disease were alcohol (n=86), virus C (n=34), and virus B (n=18); 151 patients had cirrhosis. Median follow-up was 306 days. Among the 159 patients, 19 (12%) had serum anti-p53 antibodies. Detection of serum anti-p53 antibodies was significantly correlated with the presence of a multinodular or infiltrative tumor (P<0.03). Survival was not influenced by the presence of anti-p53 antibodies. Serum albumin, ALAT, and alfa-fetoprotein levels were independent prognostic variables. CONCLUSION: In our study, anti-p53 antibodies were rarely found in the serum of patients with hepatocellular carcinoma. Although they were correlated with multinodular or infiltrative tumors, they had no prognostic influence on survival. Thus, assaying serum anti-p53 antibodies does not seem to have any clinical value in those patients.

[Severe hepatic steatosis: a cause of sudden death in the alcoholic patient]. / La stéatose hépatique massive: une cause de décès brutal chez le malade alcoolique.

The authors report the cases of 4 patients with heavy chronic alcoholic intake who presented with hepatomegaly and jaundice without obvious hepatic failure and who died rapidly. In all 4 cases, histological examination of the liver showed massive microvesicular and macrovesicular steatosis involving approximately 100% of hepatocytes and, in 2 cases, minimal lesions of alcoholic hepatitis. Histochemical study, performed in 3 cases, showed that steatosis was constituted of triglycerides only, and that hepatic glycogen was completely depleted in 2 of 3 cases. No obvious cause of death was found in these 4 patients. Shortly, before their death, the 4 patients had increased their ethanol and decreased their food intake. The authors suggest that death as well as microvesicular steatosis could have be due to acute mitochondrial dysfunction.