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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.

SummaryBackground Type 2 diabetes is a risk factor for steatohepatitis and fibrosis. Non-invasive liver stiffness (LS) and controlled attenuation parameter (CAP) measurements by Fibroscan allow assessing liver fat and fibrosis. Aim To determine the prevalence of steatosis and significant fibrosis in a community-based diabetic population Methods LS and CAP were measured in 705 patients using the standard “M probe”. A second “XL probe” was used, without CAP measurement, in case of failure with the “M probe”. Results LS and CAP measurements were obtained in 437 patients (the M group), LS measurements (LSM) with the XL probe being available in additional 232 patients. After the combined use of both probes, LSM failure and unreliable result were 1.6% and 5.6%, respectively. Overall, 12.7% (n=85), 7.3% and 2.1% exhibited significant or advanced fibrosis or cirrhosis (LSM ≥8kPa, ≥9.6kPa, ≥13kPa, respectively), half of patients with LSM ≥8kPa displaying normal liver tests. Significant and severe steatosis were measured in 75% and 24% of the M group patients. By multivariate analysis, factors associated with severe fibrosis were age, overweight, high GGT. Forty-seven patients with LSM ≥8kPa underwent liver biopsy; 93% had steatosis and 51% severe fibrosis. A significant correlation was found between LSM values and fibrosis score with an accuracy rate of 83%, 68% and 83% for LSM≥8kPa, ≥9.6kPa and ≥13kPa, respectively. Conclusions The prevalence of significant steatosis is very high and significant fibrosis affect 12.7% of the patients. Fibroscan is an effective procedure to screen for fibrosis and steatosis in diabetic patients. This article is protected by copyright. All rights reserved.

Background & aims. A novel controlled attenuation parameter (CAP) using the signals acquired by the FibroScan® has been developed as a method for evaluating steatosis. The aim of this study is to assess the performance of the CAP for the detection and quantification of steatosis in patients with chronic hepatitis B (CHB).Material and methods. 136 subjects with CHB underwent liver biopsy and FibroScan® within 60 days. CAP was evaluated retrospectively using raw FibroScan® data. Steatosis was graded as follows: S0 (steatosis < 10% of hepatocytes), S1 (10 to < 30%), S2 (30 to < 60%) or S3 (≥ 60%). Performance was evaluated by area under the receiver operating characteristic (AUROC) curve.Results. Proportions of each steatosis grade (S0-S3) were 78, 10, 9 and 3%, respectively. Using univariate analysis, liver stiffness measurement (LMS) significantly correlated with fibrosis stage (τ = 0.43; P < 10-10), sex, necro-inflammatory activity, steatosis, age, NASH, and perisinusoidal fibrosis, and with liver fibrosis stage (P < 10-8) and perisinusoidal fibrosis (P = 0.008) using multivariate analysis. CAP correlated with steatosis (τ = 0.38, P < 10-7), body mass index, NASH, fibrosis and perisinusoidal fibrosis using univariate analysis, but only steatosis (P < 10-10) and perisinusoidal fibrosis (P = 0.002) using multivariate analysis. AUROCs for LSM were: 0.77 (0.69-0.85), 0.87 (0.80-0.95), and 0.93 (0.83-1.00), respectively, for fibrosis stages F ≥ 2, F ≥ 3 and F = 4. AUROCs for CAP were: 0.82 (0.73-0.92), 0.82 (0.69-0.95), and 0.97 (0.84-1.00) for ≥ S1, ≥ S2 and S3 steatosis, respectively.Conclusions. In conclusion CAP is a novel, accurate non-invasive tool and may be suitable for detecting and quantifying steatosis in CHB patients.

Background Nodular regenerative hyperplasia (NRH) is a rare histological disorder associated with a wide variety of systemic diseases. Aims We aimed (i) to report the prevalence of NRH in a database of liver biopsies (LBs) and the frequency of portal hypertension (PHT) at diagnosis, and (ii) to investigate whether associated diseases and/or specific histological lesions, including abnormalities of the microvasculature, were related to PHT. Methods Patients with a histological diagnosis of NRH, referred by seven clinical departments, were retrospectively selected. Clinical, biological, radiological, haemodynamic and endoscopic data at diagnosis were recorded. LBs were reassessed for microvascular abnormalities. Results NRH was diagnosed in 4.4% of LBs (n = 159, male: 52%, mean age: 54). Among patients referred for unexplained liver enzyme abnormalities, 15% had NRH. PHT was present at diagnosis in 45 patients (38%), including 13 with portal thrombosis; 65% of patients had an associated disorder. Obliteration of portal vein branches, observed in the LBs of 17 patients (11%), was significantly associated with PHT (P = 0.02). Periportal angiomatosis, observed in 101 patients (63%), was associated with the absence of PHT (P < 10−4). Conclusion We suggest that NRH is a frequent histological lesion in the setting of unexplained liver enzyme abnormalities. PHT is present at the time of diagnosis in 1/3 of patients regardless of the presence of associated disease. The frequency of periportal angiomatosis in NRH without obliteration of portal vein branches, and its association with the absence of PHT suggest that obstructive portal venopathy would not represent the most frequent mechanism involved in NRH.

Background & Aims It is well known that inflammation increases liver stiffness (LS) in patients with chronic hepatitis C (HCV) and alcoholic liver disease (ALD) independent of fibrosis stage, but no inflammation-adapted cut-off values have been settled so far. An early identification of rapid fibrosers, however, is essential to decide whom to treat first with the novel but expensive antiviral drugs. Methods Liver stiffness, biopsy-proven fibrosis stages F0–F4 (METAVIR or Kleiner score) and routine laboratory parameters were studied in 2068 patients with HCV (n = 1391) and ALD (n = 677). Results Among the routine parameters for liver damage, AST correlated best with LS (HCV: r = 0.54, P

Background & Aims: More than 90% of cases of hepatocellular carcinoma (HCC) occur in patients with cirrhosis, of which alcohol is a major cause. The CIRRAL cohort aimed to assess the burden of complications in patients with alcoholic cirrhosis, particularly the occurrence of HCC. Methods: Patients with biopsy-proven compensated alcoholic cirrhosis were included then prospectively followed. The main endpoint was the incidence of HCC. Secondary outcomes were incidence of hepatic focal lesions, overall survival (OS), liver-related mortality and event-free survival (EFS). Results: From October 2010 to April 2016, 652 patients were included in 22 French and Belgian centers. During follow-up (median 29 months), HCC was diagnosed in 43 patients. With the limitation derived from the uncertainty of consecutive patients’ inclusion and from a sizable proportion of dropouts (153/652), the incidence of HCC was 2.9 per 100 patient-years, and one- and two-year cumulative incidences of 1.8% and 5.2%, respectively. Although HCC fulfilled the Milan criteria in 33 cases (77%), only 24 patients (56%) underwent curative treatment. An explorative prognostic analysis showed that age, male gender, baseline alpha-fetoprotein, bilirubin and prothrombin were significantly associated with the risk of HCC occurrence. Among 73 deaths, 61 had a recorded cause and 27 were directly attributable to liver disease. At two years, OS, EFS and cumulative incidences of liver-related deaths were 93% (95% CI 90.5–95.4), 80.3% (95% CI 76.9–83.9), and 3.2% (95% CI 1.6–4.8) respectively. Conclusion: This large prospective cohort incompletely representative of the whole population with alcoholic cirrhosis showed: a) an annual incidence of HCC of up to 2.9 per 100 patient-years, suggesting that surveillance might be cost effective in these patients; b) a high proportion of HCC detected within the Milan criteria, but only one-half of detected HCC cases were referred for curative treatments; c) a two-year mortality rate of up to 7%. Lay summary: Cirrhosis is a risk factor for primary liver cancer, leading to recommendations for periodic screening. However, for alcohol-related liver disease the rational of periodic screening for hepatocellular carcinoma (HCC) is controversial, as registry and databased studies have suggested a low incidence of HCC in these patients and highly competitive mortality rates. In this study, a large cohort of patients with biopsy-proven alcoholic cirrhosis prospectively screened for HCC demonstrated a high annual incidence of HCC (2.9%) and a high percentage of small cancers theoretically eligible for curative treatment. This suggests that patients with liver disease related to alcohol should not be ruled out of screening., SCOPUS: ar.j, info:eu-repo/semantics/published

Background & Aims Genetic polymorphisms modulate the expression of proinflammatory cytokines. We prospectively assessed the influence of 6 single nucleotide polymorphisms (SNPs) in TNFα , IL6 , and IL1β genes on the risk of hepatocellular carcinoma (HCC) in patients with cirrhosis. Methods TNFα (G-238A, C-863A, G-308A), IL6 (C-174G), and IL1β (C-31T, C-511T) SNPs were assessed in 232 alcoholics and 253 HCV-infected patients with biopsy-proven cirrhosis, prospectively followed-up and screened for HCC. Their influence on HCC development was assessed using the Kaplan-Meier method. Results These variants did not influence the risk of HCC in alcoholic patients. Conversely, two variants influenced the risk of HCC occurrence in patients with HCV-related cirrhosis, namely the TNFα -308 (A) allele (HR=2.4 [1.6–3.7], Log-rank IL1β -31 (T) allele (HR=1.5 [1.1–2.1], Log-rank=0.004). When stratifying HCV-infected patients into four genotypic associations expected to progressively increase TNFα and IL1β production, we observed increasing risk of HCC occurrence (Log-rank TNFα -308 (A) allele was the only genetic trait independently associated with risk of HCC in these patients, along with older age, male gender, BMI, and platelet count. These variables led to construction of a predictive score able to separate patients with HCV-related cirrhosis into three subgroups with progressively increasing 5-year cumulative incidences of 4.7%, 14.1%, and 36.3%, respectively (Log-rank Conclusions Genetic heterogeneity in the TNFα and IL1β gene promoters influences the risk of HCC in patients with HCV-induced cirrhosis. These genetic data, when incorporated into clinical scores, are able to refine selection of risk classes of HCC.

Paucisymptomatic forms of Turner's syndrome (TS), in which short stature is the predominant clinical abnormality, remain underdiagnosed. Abnormal liver tests are extremely frequent in adult TS patients reflecting various types of hepatic lesions.The objective of the study was to investigate whether unexplained elevated liver enzymes in women with short stature could reveal X chromosome abnormalities of undiagnosed TS.Thirty-one consecutive short stature women displaying elevated liver enzymes and no previous diagnosis of TS were compared with 31 age-matched controls in a prospective study. Liver biopsy was performed in 26 patients.Systematic karyotype analysis and fluorescence in situ hybridization.X chromosome abnormalities were found in 27 patients and one control (87.0% vs 3.2%, P.0001), including a 45,X/46,XX mosaicism in 24 patients and isochromosome of the long arm in three. Liver histological analysis showed architectural changes in 17 patients with nodular regenerative hyperplasia in 12. Biliary lesions were present in 13 patients and liver steatosis in 20.X chromosome abnormalities indicative of cryptic TS are extremely frequent in short-stature women with unexplained elevated liver enzymes. In short-stature women, abnormal liver tests should lead to systematic karyotype analysis.

Purpose To compare histopathologically the completeness of radiofrequency (RF) ablation to treat hepatocellular carcinoma (HCC) with monopolar or multipolar technique. Materials and Methods Thirty-five consecutive patients (mean age, 59 y) with cirrhosis and HCC (n = 59) within Milan criteria received RF ablation and subsequently underwent liver transplantation (LT) for tumor progression or liver failure. Data were extracted retrospectively from a prospective database. Thirty nodules were treated with a monopolar device with internally cooled (n = 17) or perfused (n = 13) electrodes, and 29 were treated with a multipolar technique with internally cooled electrodes based on the "no-touch" concept. This consisted of inserting two or three straight electrodes around the nodule to avoid intratumor puncture to the greatest extent possible. Effectiveness of the three devices was compared by histopathologic examination of explants. Fisher exact and χ 2 tests and multivariate logistic regression analysis were performed. Results Mean sizes of nodules ablated (25, 22, and 21.6 mm) and median times from ablation to LT (11, 7.5, and 8.4 months) for patients treated with the monopolar internally cooled electrode device (MoICD), monopolar perfused electrode device (MoPED), and multipolar internally cooled electrode device (MuICD), respectively, were similar ( P = .8 and P = .9, respectively). Pathologic examination showed complete necrosis for eight of 17 and six of 13 nodules treated with the MoICD and MoPED, respectively, versus 26 of 29 treated with the MuICD ( P = .0019). In multivariate analysis, RF technique remained the predictive factor for complete necrosis ( P = .005). Conclusions Ablation of small HCCs with multipolar RF ablation based on the no-touch concept improves the rate of complete necrosis during pathologic examination compared with monopolar techniques.

We report a case of complete hemidiaphragmatic necrosis with liver abscess complicating radiofrequency ablation of a large subdiaphragmatic hepatocellular carcinoma in a patient with unrecognized history of endoscopic oddi sphincterotomy. At 2-year follow-up after surgical repair using a pedicled latissimus dorsi flap, clinical examination and imaging did not show complication or cancer recurrence. The risk of complete hemidiaphragmatic necrosis resulting from both thermal and septic injuries should be considered when radiofrequency ablation is performed for liver dome tumors, particularly in patients with impaired oddi sphincter. In this septic situation, a latissimus dorsi flap appears as the unique opportunity to repair the injured hemidiaphragm.

Background: As liver cancer incidence and mortality remain high in many parts of Europe, a more comprehensive response is required to reduce the burden. Expert stakeholders should be involved in the design of responses because they have important insights about potentially effective responses and will be affected by policy changes. We aimed to prioritize liver cancer control strategies based on European liver cancer stakeholders’ views of which strategies would have the greatest impact in a comprehensive liver cancer control plan. Methods: One hundred liver cancer clinical, policy and advocacy stakeholders from France, Germany, Italy, Spain and Turkey were surveyed. Respondents completed 12 conjoint choice tasks in which they chose which of two subsets of 11 strategies would have the greatest impact in their country. Results: All strategies were considered likely to have a positive impact ( P < 0.01). The highest priority strategy was monitoring of at-risk populations , followed by centres of excellence , clinical education , multidisciplinary management , national guidelines , measuring social burden , public awareness , risk assessment and referral , research infrastructure and access to treatments . Conclusions: Canvassing stakeholder views through a conjoint analysis survey provided a robust quantitative prioritization that can complement traditional qualitative consultation processes. The prioritized strategies provide a logical starting point for decision makers considering developing national plans or collaborative efforts to achieve comprehensive liver cancer control in Europe.

Background & Aims Several studies have reported an association between the genetic variant rs738409 (G) in the PNPLA3 gene and the risk of cirrhosis in various liver diseases. Our purpose was to assess the influence of this polymorphism on the risk of hepatocellular carcinoma (HCC) occurrence in two distinct longitudinal cohorts of patients with cirrhosis as well as its possible usefulness in HCC-risk model prediction. Methods PNPLA3 rs738409 genotypes were assessed in 279 patients with alcoholic- and 253 patients with HCV-related cirrhosis. These patients were followed-up and screened for the risk of HCC, and the influence of rs738409 on the occurrence of liver cancer was assessed using the Kaplan–Meier method, then according to the multivariate Cox model. Results In patients with HCV-related cirrhosis, rs738409 genotypes did not influence the risk of HCC development (log-rank=0.7) or death (log-rank=0.2). Conversely, in patients with alcoholic cirrhosis, the rs738409 (GG) genotype was an independent risk factor for HCC occurrence (HR=1.72 [1.21–2.45], log-rank=0.002) as well as older age, male gender, and higher BMI. Combining these features enabled HCC-risk stratification of this population into three groups with the 6-year cumulative incidence ranging from 3.4% (low risk, n=58), 12.2% (intermediate risk, n=163), and 51.7% (high risk, n=58), respectively (HR=4.3 [2.7–6.4]; log-rank Conclusions This study provides key data that affirm the influence of the rs738409 (GG) genotype on the occurrence of HCC in patients with alcoholic cirrhosis. Its combination with clinical features refines the selection of patients at higher risk of liver cancer development.

Cyproterone acetate (CPA) is an oral anti-androgen commonly used to treat advanced prostate cancer. A variety of hepatotoxic reactions has been reported with CPA. Here we describe a case of a male patient who developed severe drug-induced hepatotoxicity during the treatment with CPA. The case, presenting sub-acute hepatitis, was characterized by a rapid evolution of cirrhosis and a protracted activity during the period of a few months despite the treatment withdrawal and an apparent benefits of corticosteroids, suggesting their indication in life threatening cases.

Purpose To assess the long-term outcome in 108 consecutive patients treated with no-touch multibipolar radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) that met the Milan criteria. Materials and Methods This retrospective study was approved by the ethical review board, and the need to obtain informed consent was waived. Between November 1, 2006, and December 31, 2011, 132 HCC tumors (diameter, 10-45 mm; 39 tumors ≥ 30 mm) in 108 consecutive patients (106 with cirrhosis) that met Milan criteria were treated with no-touch multibipolar RFA, which consisted of activating, in bipolar mode, three or four electrodes inserted just beyond the tumor margins. Follow-up was performed every 3 months for 2 years and every 6 months thereafter with computed tomographic or magnetic resonance imaging. Survival probabilities were computed by using the Kaplan-Meier method. Predictive factors of tumor progression and overall survival were assessed by using the Cox proportional hazard model. Results No technical failure occurred, and complete ablation was achieved for all the nodules. After a median of 40.5 months (range, 2-84 months) of follow-up, 3- and 5-year local and overall tumor progression-free survival were 96%, 94%, 52%, and 32%, respectively. Neither tumor diameter greater than 30 mm nor location abutting a large vessel were associated with local tumor progression. Tumor diameter greater than 30 mm was the only parameter predictive of overall tumor progression (P = .0036). Independent factors associated with shorter overall survival were Child-Pugh class B disease, age greater than 65 years, and platelet count of less than 150 g/L (P < .003). Three major complications occurred (2.7%): hemothorax in one patient and liver failure in two, with major portal-systemic shunts. One patient (0.9%) died, and one underwent transplantation. Conclusion No-touch multibipolar RFA for HCC tumors that meet Milan criteria provides a high local tumor progression-free survival rate. An ongoing randomized trial might help to clarify the role of this new approach for the treatment of early HCC. (©) RSNA, 2016 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on March 30, 2016.

Hepatocellular carcinoma is responsible for around 6 000 deaths each year in France. About 90% of patients have underlying liver cirrhosis. The annual incidence rate in such patients is estimated at between 2% and 4%, but it is largely dependent on the cause and severity of the underlying liver disease, as well as on epidemiological factors such as age, sex, and the body mass index. Multiple genetic polymorphisms are also involved. Screening for hepatocellular carcinoma is indicated for patients with cirrhosis, based on ultrasonographic examination every six months. It allows early diagnosis and curative treatment in most cases but is still under-used.

International audience; Detection of small hepatocellular carcinoma (HCC) eligible for curative treatment is increased by surveillance, but its optimal periodicity is still debated. Thus, this randomized trial compared two ultrasonographic (US) periodicities: 3 months versus 6 months. A multicenter randomized trial was conducted in France and Belgium (43 sites). Patients with histologically proven compensated cirrhosis were randomized into two groups: US every 6 months (Gr6M) or 3 months (Gr3M). For each focal lesion detected, diagnostic procedures were performed according to European Association for the Study of the Liver guidelines. Cumulative incidence of events was estimated, then compared using Gray's test. The prevalence of HCC ≤30 mm in diameter was the main endpoint. A sample size of 1,200 patients was required. A total of 1,278 patients were randomized (Gr3M, n = 640; Gr6M, n = 638; alcohol 39.2%, hepatitis C virus 44.1%, hepatitis B virus 12.5%). At least one focal lesion was detected in 358 patients (28%) but HCC was confirmed in only 123 (9.6%) (uninodular 58.5%, ≤30 mm in diameter 74%). Focal-lesion incidence was not different between Gr3M and Gr6M groups (2-year estimates, 20.4% versus 13.2%, P = 0.067) but incidence of lesions ≤10 mm was increased (41% in Gr3M versus 28% in Gr6M, P = 0.002). No difference in either HCC incidence (P = 0.13) or in prevalence of tumors ≤30 mm in diameter (79% versus 70%, P = 0.30) was observed between the randomized groups. Conclusion: US surveillance, performed every 3 months, detects more small focal lesions than US every 6 months, but does not improve detection of small HCC, probably because of limitations in recall procedures. (HEPATOLOGY 2011;)

International audience; Background/aim: Cirrhosis is considered as a risk factor for osteoporosis whose prevalence is poorly known. The aim was to assess prospectively bone mineral density (BMD) in patients with alcoholic or viral compensated cirrhosis. Methods: From 2006 to 2008, patients with viral or alcoholic compensated cirrhosis had BMD assessment by dual-energy X-ray absorptiometry. The prevalence of osteopenia (-2.5 SD < T-score < -1 SD) and osteoporosis (T-score

SUMMARY. A novel controlled attenuation parameter (CAP) has been developed for Fibroscanto 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 Fibroscanand liver biopsy, were analysed. Fibrosis was graded using METAVIR score. Steatosis was categorized by visual assess- ment as S0: steatosis in

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.

International audience; Context: Insulin resistance plays a role in hepatocarcinogenesis and is decreased by metformin treatment. Objective: The aim of the study was to assess the influence of metformin treatment on the prognosis of compensated hepatitis C virus (HCV) cirrhosis in patients with type 2 diabetes. Design and Setting: We studied an observational prospective cohort (1988-2007) at a university hospital referral center. Patients: A total of 100 consecutive diabetic patients (53 men, age 61 +/- 11 yr) with ongoing HCV cirrhosis and no contraindication for metformin were included in a screening program for hepatocellular carcinoma (HCC). Main Outcomes: The patients were prospectively followed up for HCC incidence, liver-related death, or hepatic transplantation. Results: The level of platelet count was significantly lower in patients treated with metformin (n = 26) compared with those not treated with metformin (n = 74) [117 (interquartile range, 83-166) vs. 149 (105-192) Giga/liter, P = 0.045]. During a median follow-up of 5.7 (3.8-9.5) yr, one patient was lost to follow-up, 39 developed a HCC, and 33 died from liver causes or were transplanted. The 5-yr incidence of HCC was 9.5 and 31.2% (P = 0.001) and of liver-related death/transplantation, 5.9 and 17.4% (P = 0.013), in patients who received metformin treatment and in those who did not, respectively. In multivariate analysis, metformin treatment was independently associated with a decrease in HCC occurrence [hazard ratio, 0.19 (95% confidence interval, 0.04-0.79); P = 0.023] and liver-related death or transplantation [hazard ratio, 0.22 (95% confidence interval, 0.05-0.99); P = 0.049]. Conclusions: In patients with type 2 diabetes and HCV cirrhosis, use of metformin is independently associated with reduced incidence of HCC and liver-related death/transplantation. (J Clin Endocrinol Metab 96: 2601-2608, 2011)

Background: This study explores the influence of two functional genetic polymorphisms in the regulated on activation in normal T-cell expressed and secreted(RANTES) promoter on the risk of hepatocellular carcinoma (HCC) occurrence in patients with alcoholic or Hepatitis C Virus (HCV)-related cirrhosis. Methods: RANTES C-28G and G-403A promoter dimorphisms and RANTES serum levels were assessed in 243 HCV-infected patients and 253 alcoholic patients, included at the time of diagnosis of cirrhosis and prospectively followed-up. Results: During a mean follow-up time of 76 months, 137 (27.6%) patients developed HCC and 170 (34.2%) died or were transplanted. During follow-up, patients with alcoholic cirrhosis and bearing two copies of the RANTES G-403 variant (2G-403 genotype, n = 156/253) had a higher rate of HCC occurrence compared with patients carrying at least one RANTES A-403 allele (26.3% vs. 8.2%, P = 0.0004). The RANTES 2G-403 genotype was a risk factor for HCC occurrence [HR = 3.0 (1.3–5.8); first quartile time to HCC occurrence: 60 vs. 120 months; LogRank = 0.007] and death [HR = 1.4 (1.0–2.0); median time to death: 55 vs. 79 months; LogRank = 0.01] in this subgroup. Carriage of the RANTES 2G-403 genotype was not associated with HCC development or death in patients with HCV-related cirrhosis. The RANTES C-28G dimorphism did not influence the occurrence of death or HCC in either cohort of patients. Conclusion: This study suggests an influence of the chemokine RANTES G-403A dimorphism on the occurrence of HCC in patients with alcoholic cirrhosis. Impact: Our findings provide clues for future studies on RANTES gene in relation to HCC susceptibility. Cancer Epidemiol Biomarkers Prev; 20(7); 1439–46. ©2011 AACR.

International audience; Iron-induced oxidative stress promotes hepatic injury in hereditary hemochromatosis, which can be influenced by genetic traits affecting antioxidant enzymes. We assessed the influence of Ala16Val-superoxide dismutase 2, Pro198Leu-glutathione peroxidase 1, and -463G/A-myeloperoxidase genotypes (high activity for the Ala, Pro, and G alleles, respectively) on the risks of cirrhosis and hepatocellular carcinoma (HCC) in patients homozygous for the C282Y-hemochromatosis (HFE) gene mutation. Both the 2G-myeloperoxidase genotype and carriage of one or two copies of the Ala-superoxide dismutase 2 allele were more frequent in patients with cirrhosis or HCC. Patients cumulating these two genetic traits had higher rates of cirrhosis and HCC than other patients.

Telomere shortening impairs liver regeneration in mice and is associated with cirrhosis formation in humans with chronic liver disease. In humans, telomerase mutations have been associated with familial diseases leading to bone marrow failure or lung fibrosis. It is currently unknown whether telomerase mutations associate with cirrhosis induced by chronic liver disease. The telomerase RNA component (TERC) and the telomerase reverse transcriptase (TERT) were sequenced in 1,121 individuals (521 patients with cirrhosis induced by chronic liver disease and 600 noncirrhosis controls). Telomere length was analyzed in patients carrying telomerase gene mutations. Functional defects of telomerase gene mutations were investigated in primary human fibroblasts and patient-derived lymphocytes. An increased incidence of telomerase mutations was detected in cirrhosis patients (allele frequency 0.017) compared to noncirrhosis controls (0.003, P value 0.0007; relative risk [RR] 1.859; 95% confidence interval [CI] 1.552-2.227). Cirrhosis patients with TERT mutations showed shortened telomeres in white blood cells compared to control patients. Cirrhosis-associated telomerase mutations led to reduced telomerase activity and defects in maintaining telomere length and the replicative potential of primary cells in culture. Conclusion: This study provides the first experimental evidence that telomerase gene mutations are present in patients developing cirrhosis as a consequence of chronic liver disease. These data support the concept that telomere shortening can represent a causal factor impairing liver regeneration and accelerating cirrhosis formation in response to chronic liver disease. (HEPATOLOGY 2011;)

Mechanisms linking obesity and unfavourable outcomes in patients with viral hepatitis C (HCV) cirrhosis are not well understood. Obesity is associated with insulin resistance, increased leptin, and decreased adiponectin serum levels.We assessed the predictive value of those factors for the occurrence of hepatocellular carcinoma (HCC) and liver-related death or transplantation in a cohort of 248 patients (mean age 58 (12 years, BMI 25.4 ± 4.4 kg/m(2)) with compensated HCV cirrhosis and persistent infection prospectively followed and screened for HCC.The mean baseline serum levels of adiponectin and leptin were 16.8 ± 15 mg/L and 16.8 ± 19 ng/ml, respectively. The mean homeostasis model assessment of insulin resistance (HOMA) index was 3.8 ± 3; median 2.9. After a median follow-up of 72 months, 61 patients developed HCC, 58 died of liver causes, and 17 were transplanted. The incidences (Kaplan Meier) of HCC were 7%, 18%, and 27% at 5 years (p=0.017) and of liver-related death or transplantation 15%, 15% and 29% (p=0.002) according to the lowest, middle and highest tertile of HOMA, respectively. In multivariate analysis, the HOMA index was associated with HCC occurrence (HR=1.10, [1.01-1.21] p=0.026) and was a strong predictor of liver-related death or transplantation (HR=1.13, [1.07-1.21] p0.0001). Serum levels of adiponectin and leptin were not associated with the outcome.In patients with compensated HCV cirrhosis, insulin resistance but not serum levels of adiponectin and leptin predicted the occurrence of HCC and of liver-related death or transplantation.

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.

To examine the relationships between fibrosis amounts evaluated by morphometric analysis and liver stiffness measurement (LSM) as well as the influence of steatosis, of activity grade and of the type of chronic liver injury.One hundred and fifty-two consecutive patients were selected from a prospective cohort of patients with concurrent liver biopsy and LSM on the basis of a more than 25 mm long liver biopsy. Morphometric quantification of collagen deposition was expressed as fibrosis area fraction (FAF). Steatosis, activity grade, and predominant type of liver injury (chronic hepatitis or steatohepatitis) were assessed.In the whole population (chronic viral hepatitis n = 96, alcoholic or nonalcoholic steatohepatitis n = 56), FAF was significantly correlated to LSM (rho = 0.6, P0.0001). Steatosis independently influenced LSM in patients without cirrhosis, but not activity grade. In the absence of cirrhosis, LSM and FAF were correlated in patients with chronic hepatitis (rho = 0.49, P0.0001) but not in those with steatohepatitis (rho = 0.22, P = 0.16). In cirrhotic patients, LSM was correlated with fibrosis amount. (rho = 0.43, P = 0.006). The area under the receiver operating characteristics curve of LSM was 0.75 for separating no or minor fibrosis from significant fibrosis and 0.9 for the diagnosis of cirrhosis.LSM was significantly correlated with collagen deposition. However, the relationships between LSM and fibrosis amount seems to differ according to steatosis and to the pattern of liver fibrosis below the cirrhotic stage. Its performances are fair for segregating patients with no or minor fibrosis from those with significant fibrosis and high for the diagnosis of cirrhosis.

Alcohol increases reactive oxygen species (ROS) formation in hepatocyte mitochondria and by reduced nicotinamide adenine dinucleotide phosphate oxidases and myeloperoxidase (MPO) in Kupffer cells and liver-infiltrating neutrophils. Manganese superoxide dismutase (MnSOD) converts superoxide anion into hydrogen peroxide, which, unless detoxified by glutathione peroxidase or catalase (CAT), can form the hydroxyl radical with iron. Our aim was to determine whether Ala16Val-superoxide dismutase 2 (SOD2), G-463A-MPO, or T-262C-CAT dimorphisms modulate the risks of hepatocellular carcinoma (HCC) and death in alcoholic cirrhosis. Genotypes and the hepatic iron score were assessed in 190 prospectively followed patients with alcoholic cirrhosis. During follow-up (61.1 ± 2.7 months), 51 patients developed HCC, and 71 died. The T-262C-CAT dimorphism did not modify hepatic iron, HCC, or death. The GG-MPO genotype did not modify iron but increased the risks of HCC and death. The hazard ratio (HR) was 4.7 (2.1–10.1) for HCC and 3.6 (1.9–6.7) for death. Carriage of one or two Ala-SOD2 allele(s) was associated with higher liver iron scores and higher risks of HCC and death. The 5-year incidence of HCC was 34.4% in patients with both the GG-MPO genotype and one or two Ala-SOD2 alleles, 5.1% in patients with only one of these two traits, and 0% in patients with none of these traits. Corresponding 5-year death rates were 37.6%, 11.6%, and 5%. Conclusion: The combination of the GG-MPO genotype (leading to high MPO expression) and at least one Ala-SOD2 allele (associated with high liver iron score) markedly increased the risks of HCC occurrence and death in patients with alcoholic cirrhosis. (HEPATOLOGY 2009.)

The development of sclerosing cholangitis (SC) is observed in up to 50% of children followed up for autoimmune hepatitis (AIH). In adults, the prevalence is less known, although a recent study found evidence of SC in 10% of AIH patients using magnetic resonance cholangiopancreatography (MRCP). The aim of this study was to assess prospectively the prevalence of SC in adults with AIH. Fifty-nine consecutive patients with AIH diagnosed according to International Autoimmune Hepatitis Group score (women, 71%; mean age, 48 years; cirrhosis, 23%) underwent both MRCP and percutaneous liver biopsy. Twenty-seven patients with cirrhosis of nonbiliary or non-autoimmune etiology served as controls. Fourteen AIH patients (24%) showed mild MRCP abnormalities of intrahepatic bile ducts (IHBDs). None had abnormal common bile duct or convincing evidence of SC on MRCP or biopsy. A diagnosis of overlapping SC was nevertheless retained in one patient with MRCP abnormalities who subsequently developed symptomatic cholestasis despite corticosteroid therapy. Fibrosis score was the only independent parameter associated with bile duct abnormalities on MRCP (odds ratio 2.4; 95% confidence interval 1.4-4.7) and the percentage of patients with IHBD MRCP abnormalities was not different among F3-F4 AIH patients (n = 24) and cirrhotic controls (46% versus 59%; NS). Conclusion: In this cohort of adult patients with AIH, the prevalence of SC was much lower than previously reported (1.7%). Mild MRCP abnormalities of IHBD were seen in a quarter of patients, but these abnormalities resulted from hepatic fibrosis and not SC. In the absence of cholestatic presentation, MRCP screening does not seem justified in adult-onset AIH. (HEPATOLOGY 2009.)

Background/Aims: Data on the efficacy of adefovir dipivoxil (ADV) in elderly and cirrhotic patients with lamivudine-resistant (LAM-R) chronic hepatitis B are scarce. This retrospective cohort study evaluated the safety and efficacy of ADV in this specific patient population. Methods: Sixty-eight cirrhotic LAM-R patients, of whom 19 (27.9%) were elderly (≥65 years of age) and nine had severe disease (two post-orthotopic liver transplantation, four pre-orthotopic liver transplantation and three decompensated), with hepatitis B virus (HBV) infection received ADV. Virological and biochemical responses to the addition of ADV were analysed. Results: At inclusion, all patients were receiving LAM; ADV was added. 75.4% of patients received a combination of LAM and ADV throughout this study for a median treatment duration of 12.6 months; the remainder received ADV with an overlap with LAM treatment for a median duration of 7.9 months. At the end of follow-up, 41.2% of patients had undetectable HBV DNA (≤2000 copies/ml) with a median reduction of 3.4 log10 copies/ml. Time to reach undetectable HBV DNA was dependent on baseline alanine aminotransferase (ALT) levels and HBeAg status. Normalization of serum ALT levels was observed in 55.2% (32/58) of patients. In patients who were HBeAg positive at baseline, HBeAg loss and seroconversion occurred in 23% (9/39) and 10% (4/39) respectively. No resistance mutations and no significant side effects were observed during the study period. Conclusion: Adefovir dipivoxil provides effective and safe treatment in cirrhotic and elderly patients who failed LAM therapy.

Although autoantibodies have been found in the serum of patients with chronic hepatitis C virus (HCV) there has been no convincing evidence of the presence of antimitochondrial antibodies, until now. Sera from 460 untreated patients with chronic hepatitis C were tested for antimitochondrial antibodies, using an indirect immunofluorescence technique; and if they tested positive for the antibodies (titer more than 1:50), they also were treated by Western blot analysis. Seven (1.5%) sera were positive. None of the patients had biological or histological evidence of primary biliary cirrhosis. Antimitochondrial antibodies recognized one of the oxo-dehydrogenase multienzyme complexe's epitopes by Western blot assay in three patients only. All seven patients were then treated by interferon alpha for six months. None showed exacerbation of liver disease during treatment. HCV-RNA disappeared from the serum in one patient who became negative for anti-M2 antibodies. The four patients who did not respond to interferon-alpha therapy, and the two who relapsed after treatment withdrawal, had sustained positive antimitochondrial antibodies. These data suggest that: 1) antimitochondrial antibodies present in patients with chronic hepatitis C do not always recognize the same epitopes as in primary biliary cirrhosis; 2) these antibodies may disappear after eradication of HCV, suggesting that the production of antimitochondrial antibodies is linked to the presence of the virus and 3) the clinical and biological course of chronic hepatitis C, and the response to interferon-alpha therapy, does not seem to be different in patients who are positive for antimitochondrial antibodies.

Summary Background Hepatic venous pressure gradient (HVPG) is the gold standard for assessing the presence and the severity of portal hypertension (PHT). Liver stiffness measurement (LSM) is a non-invasive method for liver fibrosis assessment. Aims To assess the relationship between LSM and HVPG in patients with compensated cirrhosis related to hepatitis C virus (HCV) or alcohol and to define the performance and the best cut-off of LSM for the diagnosis of PHT in these patients. Methods Between January 2004 and September 2006, we studied all the consecutive patients with compensated HCV or alcohol-related-cirrhosis referred for transjugular liver biopsy with HVPG measurement and LSM performed the same day. Results Ninety-two patients were eligible, 44 had HCV related-cirrhosis and 48 alcoholic cirrhosis. LSM was positively correlated to HVPG in both groups. The area under the receiver operating characteristic curve for the diagnosis of significant PHT was 0.76 ± 0.07 in HCV patients (best cut-off at 20.5 kPa) and 0.94 ± 0.03 (best cut-off at 34.9 kPa) in alcoholic patients. Conclusions Liver stiffness measurement and HVPG were significantly correlated in patients with compensated cirrhosis because of HCV infection or alcohol. LSM could predict significant PHT in both these groups of patients with a higher cut-off and a better performance in alcoholic patients.

To prospectively evaluate the safety and effectiveness of percutaneous multipolar radiofrequency (RF) ablation for the treatment of large (or=5.0 cm in diameter) hepatocellular carcinomas (HCCs).Twenty-six patients (four women, 22 men; median age, 72 years) with cirrhosis (Child-Pugh class A disease, 22 patients; Child-Pugh class B disease, four patients) and at least one 5.0-9.0-cm-diameter HCC without invasion of the portal trunk or main portal branches were treated with multipolar RF ablation performed by a single operator. The procedure was performed with three separate bipolar linear internally cooled electrodes with ultrasonographic guidance. Twenty-seven of the 33 tumors treated had a diameter of 5.0 cm or greater (median diameter, 5.7 cm; range, 5.0-8.5 cm); 12 of these 27 tumors were infiltrative, and four invaded segmental portal vein branches. Ten patients had a serum alpha-fetoprotein level higher than 400 microg/L. Results were assessed by using computed tomography. Primary effectiveness, complications, tumor progression, and survival rates were recorded. Probabilities of survival were calculated by using the Kaplan-Meier method.One to two RF ablation procedures per patient (mean, 1.15 +/- 0.43 [standard deviation]) led to the complete ablation of 22 (81%) of the 27 tumors (18 tumors after one and four tumors after two procedures), including three tumors that showed segmental portal vein invasion. All patients experienced postablation syndrome, and one experienced subcapsular hematoma and a segmental liver infarct, but no major complication occurred. After a mean follow-up of 14 months (range, 3-34 months), local and distant tumor progression and actual survival rates were 14% (three of 22), 24% (five of 21), and 65% (17 of 26), respectively. The probabilities of 1- and 2-year survival, respectively, were 68% (95% confidence interval: 49%, 86%) and 56% (95% confidence interval: 51%, 81%).HCCs larger than 5.0 cm (but smaller than 9.0 cm)--even those that are infiltrative and those that involve a segmental portal vein--can be completely and safely ablated with multipolar RF ablation.

Background/Aims Liver stiffness measurement by transient elastography is a very promising non-invasive method for the diagnosis of fibrosis in chronic liver diseases. However, studies on normal values of liver stiffness in healthy subjects are still lacking. The aim of the present study was to prospectively assess liver stiffness values in the general population and to determine potential factors, which may influence these values. Methods Liver stiffness measurements were performed in 429 consecutive apparently healthy subjects, without overt cause of liver disease and normal liver enzymes, undergoing a free medical check-up. Results Mean liver stiffness value was 5.49±1.59kPa. Transient elastography failure was observed in 4.6% of the cases. The failure rate increased with BMI, reaching 88% for values above 40kg/m 2 . Liver stiffness values were higher in men than in women (5.81±1.54 vs 5.23±1.59kPa, p =0.0002) and in subjects with BMI>30kg/m 2 (6.26±1.89 vs 5.37±1.51kPa, p =0.0003). Metabolic syndrome was diagnosed in 59 (13.7%) subjects. After adjustment for gender and BMI, liver stiffness values were higher in subjects with metabolic syndrome than in those without (6.51±1.64 vs 5.33±1.51kPa, p Conclusions Liver stiffness values in the general population are influenced independently by gender, BMI and metabolic syndrome.

Background/Aims Liver lesions associated with primary hypogammaglobulinemia have been poorly described. We aimed to assess the clinical, histological and immune features and outcome of hepatic injury in patients with primary hypogammaglobulinemia. Methods The medical records of 51 patients (23 patients with liver biopsy) with primary hypogammaglobulinemia and liver abnormalities were retrospectively reviewed. Forty-three controls with primary hypogammaglobulinemia but with no hepatic manifestations were analyzed in parallel. Results Cholestasis (65%), mainly anicteric, and portal hypertension (50%) were the main hepatic manifestations. Histological analysis revealed non-fibrosing architectural abnormalities consistent with nodular regenerative hyperplasia (NRH) in 84% of CVID patients and in all HIGM and XLA patients. Intrasinusoidal lymphocytic infiltration, abnormalities of portal vessels and epithelioid granulomas were observed in 90%, 43% and 44% of patients, respectively. NRH was associated with portal hypertension in 75% of the cases. These patients more often presented with autoimmune diseases and peripheral lymphocytic abnormalities than control patients ( p Conclusions Liver involvement in primary hypogammaglobulinemia mainly consists of NRH leading to chronic cholestasis and portal hypertension. Association with intrasinusoidal T cell infiltration, portal vein endotheliitis, autoimmune diseases and peripheral lymphocytic abnormalities suggests an autoimmune mechanism.

Resume Objectif Evaluer les risques d’echec du traitement par radiofrequence des carcinomes hepato-cellulaires (CHC) lies au contact des gros vaisseaux. Materiel et methodes De mai 2000 a octobre 2002, parmi 83 patients traites par radiofrequence pour CHC dans un meme centre, 13 patients qui avaient une tumeur ≤ 3,5 cm situee au contact d’un vaisseau ≥ 3 mm (groupe A) ont ete apparies a 13 malades presentant des tumeurs de meme taille mais situees a distance des vaisseaux (groupe B). La reponse immediate et l’incidence des recidives locales ont ete evaluees par tomodensitometrie. Resultats Apres un delai de surveillance moyen de 39 ± 16,5 mois dans le groupe A et de 39 ± 14 mois dans le groupe B, une recidive locale a ete identifiee respectivement dans 7/12 versus 1/12 tumeurs (P = 0,03). Dans le groupe A, 6/7 recidives locales etaient clairement au contact d’un vaisseau. Conclusion L’effet refroidissant des flux sanguins accroit largement le risque de controle local incomplet des petits CHC peri vasculaires traites par radiofrequence.

Resume Objectif Comparer le rapport cout /efficacite de l′alcoolisation et de la radiofrequence pour le traitement du petit carcinome hepatocellulaire (CHC). Methodes Les resultats de L′alcoolisation chez 57 malades ayant 72 CHC ont ete retrospectivement compares a ceux observes chez 60 malades avec 72 CHC traites par radiofrequence. Tous les malades avaient une cirrhose classee Child-Pugh A et un CHC de moins de 35 mm de diametre. L′efficacite du traitement etait jugee sur un scanner helicoidal. Le cout de l′hospitalisation, du suivi incluant la prise en charge des complications et les examens morphologiques de controle ont ete evalues. La survie a ete estimee par la methode de Kaplan-Meier et l′impact du type de traitement sur le pronostic par le test du Log Rank et le modele de Cox. Resultats Les deux groupes avaient des caracteristiques cliniques initiales identiques. Le taux de complication severe liee a la radiofrequence etait de 15 % (9/60) versus 6,9 % (4/57) apres alcoolisation (P = 0,11). Les taux de survie global, de survie sans recidive et sans recidive locale chez les malades traites par alcoolisation et radiofrequence etaient respectivement de 70,8 % vs 91,2 % (OR = 3,7, P = 0,006), 48,6 % vs 71,1 % (OR = 2,2, P = 0,01), et 68,5 % vs 80,7 %(OR = 1,9, P = 0,09). Le type de traitement etait le seul facteur significativement associe a la survie globale et a la survie sans recidive. Le cout moyen du traitement par malade etait respectivement de 1534 euros pour l′alcoolisation et 1196 euros pour la radiofrequence. Conclusion Cette etude retrospective suggere que la radiofrequence a un meilleur rapport cout /efficacite et une survie sans recidive superieure a l′alcoolisation.

Little is known about the role of specific hepatitis C virus (HCV) CD8+ T cells in liver damage, especially for the progression of fibrosis, during the highly variable course of chronic C hepatitis. The aim of this study was to investigate the presence of HCV-specific CD8+ T cells in the liver of patients with chronic C hepatitis and to examine their clinical significance by relating the response to liver fibrosis and progression rate, serum viral load, serum aminotransferase levels, inflammatory activity and in situ characteristics of the intrahepatic infiltrate. Fifteen patients were prospectively included in the study. Intrahepatic lymphocytes were tested for interferon gamma (IFNg) production in response to HCV class I-restricted epitopic peptides using enzyme-linked immunospot analysis. Liver biopsy samples were evaluated for fibrosis, fibrosis progression rate, activity, and in situ number of CD8+ cytotoxic lymphocytes and apoptotic cells. An IFNg-specific CD8+ T-cell response was detected in the liver samples of 47% of patients which was significantly related to a lower stage of fibrosis (P = 0.02) and a lower progression rate of fibrosis (P = 0.01). It was neither related to the number of cytotoxic lymphocytes infiltrating the liver nor to hepatocyte apoptosis. In conclusion, our results indicate that the presence of HCV-specific IFNg-secreting T cells in the liver of patients with chronic C hepatitis is associated with low liver fibrosis and fibrosis progression rate, suggesting that these IFNg-secreting T cells might limit the progression of liver damage.

Manganese superoxide dismutase (MnSOD) converts the superoxide anion into H2O2, which, unless it is detoxified by glutathione peroxidase 1 (GPx1), can increase hepatic iron and can react with iron to form genotoxic compounds. We investigated the role of Ala/Val-MnSOD and Pro/Leu-GPx1 polymorphisms on hepatic iron accumulation and hepatocellular carcinoma development in patients with alcoholic cirrhosis. Genotypes were determined in 162 alcoholic patients with cirrhosis but without hepatocellular carcinoma initially, who were prospectively followed up for hepatocellular carcinoma development. We found that patients with two Val-MnSOD alleles (slow H2O2 production) and two Pro-GPx1 alleles (presumably quick H2O2 detoxification) had a lower risk of hepatocellular carcinoma development than other patients (χ2 trend test, P = 0.001; log-rank, P = 0.0009). Indeed, hepatocellular carcinoma percentage was 0% in subjects with this “2Val-MnSOD/2Pro-GPx1” genotype versus 16%, 27%, and 32% in “2Val-MnSOD/1or2Leu-GPx1,” “1or2Ala-MnSOD/2Pro-GPx1,” and “1or2Ala-MnSOD/1or2Leu-GPx1” patients, respectively. The percentage of patients with stainable hepatic iron increased progressively with these genotypic associations: 22%, 28%, 50%, and 53%, respectively (χ2 trend test, P = 0.005). Stainable iron was a risk factor for hepatocellular carcinoma (log-rank, P = 0.0002; relative risk, 3.40). In conclusion, polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in French alcoholic patients with cirrhosis. (Cancer Res 2006; 66(5): 2844-52)

Early diagnosis of hepatocellular carcinoma (HCC) is the key to the delivery of effective therapies. The conventional serological diagnostic test, estimation of serum alpha-fetoprotein (AFP) lacks both sensitivity and specificity as a screening tool and improved tests are needed to complement ultrasound scanning, the major modality for surveillance of groups at high risk of HCC. We have analysed the serum proteome of 182 patients with hepatitis C-induced liver cirrhosis (77 with HCC) by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI). The patients were split into a training set (84 non-HCC, 60 HCC) and a 'blind' test set (21 non-HCC, 17 HCC). Neural networks developed on the training set were able to classify the blind test set with 94% sensitivity (95% CI 73-99%) and 86% specificity (95% CI 65-95%). Two of the SELDI peaks (23/23.5 kDa) were elevated by an average of 50% in the serum of HCC patients (P0.001) and were identified as kappa and lambda immunoglobulin light chains. This approach may permit identification of several individual proteins, which, in combination, may offer a novel way to diagnose HCC.

International audience; Hepatitis C virus subtype 3a (HCV-3a) originates from Asia and has spread widely among injecting drug users as well as other patient groups in industrialized countries. HCV subtype 3a infection remains highly prevalent and frequently transmitted in the population of intravenous drug users. The objective of this study was to understand better the mechanisms of the worldwide HCV-3a epidemics in drug users. Ninety-three sera from HCV-3a-infected IDUs from France, the United States, Brazil, Argentina, and Australia were studied. Phylogenetic analyses of the non-structural 5B region showed no specific clustering according to the continent of the patient's origin. Non-exclusive clusters of viral sequences from South America, Australia, and California were observed, but topologies were not supported by strong bootstrap values. The results suggest that HCV-3a has been transmitted from a common origin through a unique worldwide epidemic that rapidly spread among drug users. Regional transmission occurred in the recent past, leading to an embryonic genetic diversification of HCV-3a among local injecting drug user population.Hepatitis C virus subtype 3a (HCV-3a) originates from Asia and has spread widely among injecting drug users as well as other patient groups in industrialized countries. HCV subtype 3a infection remains highly prevalent and frequently transmitted in the population of intravenous drug users. The objective of this study was to understand better the mechanisms of the worldwide HCV-3a epidemics in drug users. Ninety-three sera from HCV-3a-infected IDUs from France, the United States, Brazil, Argentina, and Australia were studied. Phylogenetic analyses of the non-structural 5B region showed no specific clustering according to the continent of the patient's origin. Non-exclusive clusters of viral sequences from South America, Australia, and California were observed, but topologies were not supported by strong bootstrap values. The results suggest that HCV-3a has been transmitted from a common origin through a unique worldwide epidemic that rapidly spread among drug users. Regional transmission occurred in the recent past, leading to an embryonic genetic diversification of HCV-3a among local injecting drug user population.

Noninvasive measurement of liver stiffness with transient elastography has been recently validated for the evaluation of hepatic fibrosis in chronic hepatitis C. The current study assessed the diagnostic performance of liver stiffness measurement (LSM) for the determination of fibrosis stage in chronic cholestatic diseases. One hundred one patients with primary biliary cirrhosis (PBC, n=73) or primary sclerosing cholangitis (PSC, n=28) were prospectively enrolled in a multicenter study. All patients underwent liver biopsy (LB) and LSM. Histological and fibrosis stages were assessed on LB by two pathologists. LSM was performed by transient elastography. Efficiency of LSM for the determination of histological and fibrosis stages were determined by a receiver operating characteristics (ROC) curve analysis. Analysis failed in six patients (5.9%) because of unsuitable LB (n=4) or LSM (n=2). Stiffness values ranged from 2.8 to 69.1 kPa (median, 7.8 kPa). LSM was correlated to both fibrosis (Spearman's rho= 0.84, P.0001) and histological (0.79, P.0001) stages. These correlations were still found when PBC and PSC patients were analyzed separately. Areas under ROC curves were 0.92 for fibrosis stage (F)or =2, 0.95 for For =3 and 0.96 for F=4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed For =2, For =3 and F=4, respectively. LSM and serum hyaluronic acid level were independent parameters associated with extensive fibrosis on LB. In conclusion, transient elastography is a simple and reliable noninvasive means for assessing biliary fibrosis. It should be a promising tool to assess antifibrotic therapies in PBC or PSC.

Surgery is often not a treatment option in patients with hepatocellular carcinoma with the numerous limitations of liver transplantation or surgical resection due to coexisting cirrhosis in the later case. Non-surgical treatments deal with 3 types of methods: local ablation with curative purpose, transarterial treatments with many technical variants and systemic treatment. Local treatments rely on chemical or thermic agents to achieve ablation of liver lesions, which not exceed initially 3 cm in diameter. The use of radiofrequency ablation allows now larger limits. Intra-arterial treatment usually combines intra-arterial chemotherapy with embolisation of hepatic artery in a procedure called chemoembolisation. Its antitumoral effect mainly due to ischemia is well documented but the influence on survival remains controversial. Finally systemic treatments have yet to be demonstrated useful: new agents and new randomised trials are still needed.

Screening programs for patients with cirrhosis are designed to detect hepatocellular carcinoma at an early stage when effective treatment is feasible and may provide long-term survival benefits. However, only a minority of these patients will be considered candidates for liver transplantation or surgical resection and hence, most cases will be evaluated for other medical options. While systemic therapy has never been shown to bear a relevant antitumoral activity with an impact on survival, there are several locoregional options that can achieve a high rate of objective responses (this includes complete necrosis or partial reduction in tumor burden). Percutaneous ablation by any of the available methods (ethanol injection, radiofrequency, microwave, acetic acid injection, laser) is extremely useful in patients with small solitary tumors. Results indicate that 90% of tumors < 2 cm will be completely ablated using the percutaneous approach. However, when tumor size exceeds 3 cm and/or the number of nodules is greater than 3, the rate of treatment success is significantly reduced. In patients with large/multifocal disease, the sole option that has been shown to provide treatment efficacy with moderate improvement in survival is chemoembolization. New therapeutic agents should target biological mechanisms in a tailored strategy, and the demonstration of beneficial results for patients should be obtained by large, randomized, controlled trials comparing active intervention versus no treatment.

Background & Aims: A genetic dimorphism encodes for either alanine (Ala) or valine (Val) in the mitochondrial targeting sequence of manganese superoxide dismutase (MnSOD), and modulates its mitochondrial import. However, the role of this dimorphism in the susceptibility of alcoholic patients to develop cirrhosis is controversial, and its influence on the occurrence of hepatocellular carcinoma (HCC) and death in patients with alcoholic cirrhosis is unknown. Methods: We compared MnSOD genotypes in 94 control subjects and 264 patients with alcoholic cirrhosis. Patients were included at the time of the first liver biopsy examination showing cirrhosis, and were followed-up prospectively. Results: Alcohol consumption was similar, whatever the patients' genotype. At inclusion, the percentage of Val/Val homozygotes was lower in patients than in controls (16% vs. 31%), whereas the percentage of Ala/Ala homozygotes was higher in patients than in controls (30% vs. 21%) ( P = .008). During follow-up evaluation, only 9% of Val/Val patients developed HCC, vs. 30% and 29% of Ala/Val and Ala/Ala patients, respectively ( P = .02). Only 28% of Val/Val patients died or were transplanted, vs. 49% and 50% of Ala/Val and Ala/Ala patients, respectively ( P = .03). Because of the progressive decrease in surviving Ala patients, the genotypic distribution in patients surviving for 5 or 10 years no longer differed from the genotypic distribution in controls. Conclusions: The presence of at least 1 Ala MnSOD allele increases the risk for developing cirrhosis in French alcoholics, and increases the rates of HCC development and death in cirrhotic patients.

Liver fibrosis is the main predictor of the progression of chronic hepatitis C, and its assessment by liver biopsy (LB) can help determine therapy. However, biopsy is an invasive procedure with several limitations. A new, noninvasive medical device based on transient elastography has been designed to measure liver stiffness. The aim of this study was to investigate the use of liver stiffness measurement (LSM) in the evaluation of liver fibrosis in patients with chronic hepatitis C. We prospectively enrolled 327 patients with chronic hepatitis C in a multicenter study. Patients underwent LB and LSM. METAVIR liver fibrosis stages were assessed on biopsy specimens by 2 pathologists. LSM was performed by transient elastography. Efficiency of LSM and optimal cutoff values for fibrosis stage assessment were determined by a receiver-operating characteristics (ROC) curve analysis and cross-validated by the jack-knife method. LSM was well correlated with fibrosis stage (Kendall correlation coefficient: 0.55; P.0001). The areas under ROC curves were 0.79 (95% CI, 0.73-0.84) for For =2, 0.91 (0.87-0.96) for For =3, and 0.97 (0.93-1) for F=4; for larger biopsies, these values were, respectively, 0.81, 0.95, and 0.99. Optimal stiffness cutoff values of 8.7 and 14.5 kPa showed For =2 and F=4, respectively. In conclusion, noninvasive assessment of liver stiffness with transient elastography appears as a reliable tool to detect significant fibrosis or cirrhosis in patients with chronic hepatitis C.

Chronic hepatitis is accompanied by progressive deposit of hepatic fibrosis, which may lead to cirrhosis. Evaluation of liver fibrosis is, thus, of great clinical interest and, up to now, has been assessed with liver biopsy. This work aims to evaluate a new noninvasive device to quantify liver fibrosis: the shear elasticity probe or fibroscan. This device is based on one-dimensional (1-D) transient elastography, a technique that uses both ultrasound (US) (5 MHz) and low-frequency (50 Hz) elastic waves, whose propagation velocity is directly related to elasticity. The intra- and interoperator reproducibility of the technique, as well as its ability to quantify liver fibrosis, were evaluated in 106 patients with chronic hepatitis C. Liver elasticity measurements were reproducible (standardized coefficient of variation: 3%), operator-independent and well correlated (partial correlation coefficient = 0.71, p0.0001) to fibrosis grade (METAVIR). The areas under the receiver operating characteristic (ROC) curves were 0.88 and 0.99 for the diagnosis of patients with significant fibrosis (/= F2) and with cirrhosis ( = F4), respectively. The Fibroscan is a noninvasive, painless, rapid and objective method to quantify liver fibrosis.

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.

SUMMARY Within 5 years after percutaneous ablation of hepatocellular carcinoma, roughly 70% of patients experience tumor recurrence. Relapses beyond curative options affected patients’ survival. Ablation shares with resection common predictive factors of recurrence as size of the tumor, multinodularity and presence of vascular invasion. High serum α-fetoprotein level and markers of severity of underlying liver disease have also been found to be associated with recurrence and even survival. However, predictive values for recurrence of technical factors, histopathological and molecular tumors’ features have been rarely studied. Few comparative studies have shown that ablation techniques impact recurrence rates. Moreover, although ablation does not allow analysis of the whole tumor, some reports suggest that biopsies allow histopathological and even molecular testing of the risk of recurrence.