Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis.

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.

Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis.

BACKGROUND & AIMS: The prevalence of fatty liver underscores the need for non-invasive characterization of steatosis, such as the ultrasound based controlled attenuation parameter (CAP). Despite good diagnostic accuracy, clinical use of CAP is limited due to uncertainty regarding optimal cut-offs and the influence of covariates. We therefore conducted an individual patient data meta-analysis. METHODS: A review of the literature identified studies containing histology verified CAP data (M probe, vibration controlled transient elastography with FibroScan®) for grading of steatosis (S0-S3). Receiver operating characteristic analysis after correcting for center effects was used as well as mixed models to test the impact of covariates on CAP. The primary outcome was establishing CAP cut-offs for distinguishing steatosis grades. RESULTS: Data from 19/21 eligible papers were provided, comprising 3830/3968 (97%) of patients. Considering data overlap and exclusion criteria, 2735 patients were included in the final analysis (37% hepatitis B, 36% hepatitis C, 20% NAFLD/NASH, 7% other). Steatosis distribution was 51%/27%/16%/6% for S0/S1/S2/S3. CAP values in dB/m (95% CI) were influenced by several covariates with an estimated shift of 10 (4.5-17) for NAFLD/NASH patients, 10 (3.5-16) for diabetics and 4.4 (3.8-5.0) per BMI unit. Areas under the curves were 0.823 (0.809-0.837) and 0.865 (0.850-0.880) respectively. Optimal cut-offs were 248 (237-261) and 268 (257-284) for those above S0 and S1 respectively. CONCLUSIONS: CAP provides a standardized non-invasive measure of hepatic steatosis. Prevalence, etiology, diabetes, and BMI deserve consideration when interpreting CAP. Longitudinal data are needed to demonstrate how CAP relates to clinical outcomes. LAY SUMMARY: There is an increase in fatty liver for patients with chronic liver disease, linked to the epidemic of the obesity. Invasive liver biopsies are considered the best means of diagnosing fatty liver. The ultrasound based controlled attenuation parameter (CAP) can be used instead, but factors such as the underlying disease, BMI and diabetes must be taken into account. Registration: Prospero CRD42015027238.

Concomitant screening for liver fibrosis and steatosis in French type 2 diabetic patients using Fibroscan.

BACKGROUND: 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≥8 kPa, ≥9.6 kPa, ≥13 kPa respectively), half of the patients with LSM≥8 kPa displayed 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≥8 kPa 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≥8 kPa, ≥9.6 kPa and ≥13 kPa 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.

Hepatocellular Carcinoma within Milan Criteria: No-Touch Multibipolar Radiofrequency Ablation for Treatment-Long-term Results.

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.

Prevalence and clinical significance of nodular regenerative hyperplasia in liver biopsies.

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.

Inflammation-adapted liver stiffness values for improved fibrosis staging in patients with hepatitis C virus and alcoholic liver disease.

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 < 0.0001 and ALD: r = 0.34, P < 0.0001). In the absence of elevated transaminases, cut-off values were almost identical between HCV and ALD for F1-2, F3 and F4 (HCV: 5.1, 9.0 and 11.9 kPa vs ALD: 4.9, 8.1 and 10.5 kPa). These cut-off values increased exponentially as a function of median AST level. The impact of AST on LS was higher in lobular-pronounced ALD as compared to portal tract-localized HCV. Most notably, Cohen's weighted Kappa displayed an improved agreement of the novel AST-dependent cut-off values with histological fibrosis stage both for HCV (0.68 vs 0.65) and ALD (0.80 vs 0.76). CONCLUSIONS: The novel AST-adapted cut-off values improve non-invasive fibrosis staging in HCV and ALD and may be also applied to other liver diseases. Especially in HCV, they could help to decide whom to treat first with the novel but expensive antiviral drugs.

Diagnostic performance of controlled attenuation parameter for predicting steatosis grade in chronic hepatitis B.

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 (τ = 0.43; P < 10-10), sex, necro-inflammatory activity, steatosis, age, NASH, and perisinusoidal fibrosis, and with liver fibrosis (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 conclusión CAP is a novel, accurate non-invasive tool and may be suitable for detecting and quantifying steatosis in CHB patients.

Impact of cytokine gene variants on the prediction and prognosis of hepatocellular carcinoma in patients with cirrhosis.

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 IL1ß genes on the risk of hepatocellular carcinoma (HCC) in patients with cirrhosis. METHODS: TNFα (G-238A, C-863A, G-308A), IL6 (C-174G), and IL1ß (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 <0.0001) and the IL1ß-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 IL1ß production, we observed increasing risk of HCC occurrence (Log-rank <0.0001) from group 1 to 4. The 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 <0.0001). CONCLUSIONS: Genetic heterogeneity in the TNFα and IL1ß 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.

Histopathologic comparison of monopolar versus no-touch multipolar radiofrequency ablation to treat hepatocellular carcinoma within Milan criteria.

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.

PNPLA3 rs738409, hepatocellular carcinoma occurrence and risk model prediction in patients with cirrhosis.

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 <0.0001). 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.

ESM-1 expression in stromal cells is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma.

BACKGROUND & AIMS: The prognosis of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA) is mainly linked to tumor recurrence. So far, no tissue biomarker of recurrence has been validated in biopsy samples. We aimed at investigating the prognostic value of tissue biomarkers in HCC biopsy samples of patients treated with RFA. METHODS: All consecutive naive patients from 3 university hospitals, with compensated cirrhosis, early-stage (BCLC 0/A) uninodular HCC treated with RFA, and available tumor biopsy, were included. Edmondson's grade, and the expression of cytokeratin 19, glutamine synthase, beta-catenin, epithelial cell adhesion molecule (EpCAM), and endothelial cell-specific molecule 1 (ESM-1) were assessed. Main clinical end points were overall and early recurrence. Statistical analyses were performed using Kaplan Meier, Log-rank test, and Cox models. RESULTS: 150 patients were included. Recurrence, death or liver transplantation occurred in 85, 51, and 12 patients, respectively. Median follow-up was 27months. ESM-1 expression by HCC stromal endothelial cells was observed in 58 patients (40%) and was associated with higher serum AFP levels, larger tumor, and more frequent expression of EpCAM and surrogate markers of activation of the Wnt-ß-catenin pathway. The 2 independent predictive factors of overall recurrence were serum AFP (HR 1.11 [1.002; 1.22], p=0.045) and ESM-1 expression (HR 1.56 [1.004; 2.43], p=0.048). ESM-1 expression was also an independent predictive factor of early recurrence (HR 1.81 [1.02; 3.21], p=0.042). CONCLUSIONS: ESM-1 expression by stromal endothelial cells, in tumor biopsy samples, has an independent predictive value of early recurrence after RFA.

Severe hepatitis induced by cyproterone acetate: role of corticosteroids. A case report.

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.

Stakeholder perspectives on European priorities for comprehensive liver cancer control: a conjoint analysis.

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.

Survival after radiofrequency ablation and salvage transplantation in patients with hepatocellular carcinoma and Child-Pugh A cirrhosis.

BACKGROUND & AIMS: In patients with hepatocellular carcinoma (HCC) within the Milan criteria, liver transplantation (LT) may be the best therapeutic option. However, the shortage of grafts, leads to attempt liver resection (LR) or radiofrequency ablation (RFA) as a first-line treatment for patients with Child-Pugh A cirrhosis. METHODS: We report results, obtained between 2000 and 2007 from a single center, involving 67 patients (mean age: 57 years) eligible for LT, who were treated with RFA, followed by LT if there was recurrence or liver failure. RESULTS: Eighty three tumors were treated (mean size: 29±9 mm; 16 binodular forms). RFA achieved complete ablation in 96% of nodules. No mortality occurred. During a post-RFA median follow-up of 48 months, 38 patients experienced recurrence, corresponding to a 5-year recurrence rate of 58%. Of these, 14 patients did not receive a transplant because they fell outside the Milan criteria, 21 were transplanted, and 3 were treated by RFA after refusing LT. Binodularity (95% CI HR=2, 1.0-4.0; p=0.049) was the unique risk factor for recurrence. By the study's end-point, 24 patients had undergone LT (21 for HCC recurrence and three for liver failure). No HCC recurrence occurred after LT. Among the 43 non-transplant patients, 12 died due to HCC progression, and 27 were alive without detectable viable tumor. The probability rates for 5-year overall and tumor-free survival were 74% and 69%, respectively. CONCLUSIONS: First line RFA followed by salvage LT allows survival figures that are at least as good as a first-line LT, while limiting the number of grafts.

A variant in myeloperoxidase promoter hastens the emergence of hepatocellular carcinoma in patients with HCV-related cirrhosis.

BACKGROUND & AIMS: Genetic dimorphisms modulate the activities of several pro- or antioxidant enzymes, including myeloperoxidase (MPO), catalase (CAT), manganese superoxide dismutase (SOD2), and glutathione peroxidase 1 (GPx1). We assessed the role of the G(-463)A-MPO, T(-262)C-CAT, Ala16Val-SOD2, and Pro198Leu-GPx1 variants in modulating HCC development in patients with HCV-induced cirrhosis. METHODS: Two hundred and five patients with HCV-induced, biopsy-proven cirrhosis but without detectable HCC at inclusion were prospectively followed-up for HCC development. The influence of various genotypes on HCC occurrence was assessed with the Kaplan-Meier method. RESULTS: During follow-up (103.2±3.4 months), 84 patients (41%) developed HCC, and 66 died. Whereas the Ala16Val-SOD2 or Pro198Leu-GPx1 dimorphisms did not modulate the risk, HCC occurrence was increased in patients with either the homozygous GG-MPO genotype (HR=2.8 [1.7-4.4]; first quartile time to HCC occurrence: 45 vs. 96 months; LogRank <0.0001) or the homozygous CC-CAT genotype (HR=1.74 [1.06-2.82]; first quartile time to HCC occurrence: 55 vs. 96 months; LogRank=0.02). Compared to patients with neither of these two at risk factors, patients with only the CC-CAT genotype had a HR of 2.05 [0.9-4.6] (p=0.08) and patients with only the GG-MPO genotype had a HR of 3.8 [1.5-9.1] (p=0.002), while patients with both risk factors had an HR of 4.8 [2.2-10.4] (p<0.0001). However, only the GG-MPO genotype was independently associated with the HCC risk in multivariate Cox analysis. CONCLUSIONS: The high activity-associated GG-MPO genotype increases the rate of HCC occurrence in patients with HCV-induced cirrhosis.

Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial.

BACKGROUND & AIMS: The Sorafenib Hepatocellular Carcinoma (HCC) Assessment Randomized Protocol (SHARP) trial demonstrated that sorafenib improves overall survival and is safe for patients with advanced HCC. In this trial, 602 patients with well-preserved liver function (>95% Child-Pugh A) were randomized to receive either sorafenib 400mg or matching placebo orally b.i.d. on a continuous basis. Because HCC is a heterogeneous disease, baseline patient characteristics may affect individual responses to treatment. In a comprehensive series of exploratory subgroup analyses, data from the SHARP trial were analyzed to discern if baseline patient characteristics influenced the efficacy and safety of sorafenib. METHODS: Five subgroup domains were assessed: disease etiology, tumor burden, performance status, tumor stage, and prior therapy. Overall survival (OS), time to progression (TTP), disease control rate (DCR), and safety were assessed for subgroups within each domain. RESULTS: Subgroup analyses showed that sorafenib consistently improved median OS compared with placebo, as reflected by hazard ratios (HRs) of 0.50-0.85, similar to the complete cohort (HR=0.69). Sorafenib also consistently improved median TTP (HR, 0.40-0.64), except in HBV-positive patients (HR, 1.03), and DCR. Results are limited by small patient numbers in some subsets. The most common grade 3/4 adverse events included diarrhea, hand-foot skin reaction, and fatigue; the incidence of which did not differ appreciably among subgroups. CONCLUSIONS: These exploratory subgroup analyses showed that sorafenib consistently improved median OS and DCR compared with placebo in patients with advanced HCC, irrespective of disease etiology, baseline tumor burden, performance status, tumor stage, and prior therapy.

Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities.

UNLABELLED: 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.

Telomerase gene mutations are associated with cirrhosis formation.

UNLABELLED: 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.

Keratin 8 variants are infrequent in patients with alcohol-related liver cirrhosis and do not associate with development of hepatocellular carcinoma.

BACKGROUND: Keratins 8/18 (K8/K18) are established hepatoprotective proteins and K8/K18 variants predispose to development and adverse outcome of multiple liver disorders. The importance of K8/K18 in alcoholic liver disease as well as in established cirrhosis remains unknown. METHODS: We analyzed the K8 mutational hot-spots in 261 prospectively followed-up patients with alcoholic cirrhosis (mean follow-up 65 months). PCR-amplified samples were pre-screened by denaturing high-performance liquid chromatography and conspicuous samples were sequenced. RESULTS: 67 patients developed hepatocellular carcinoma (HCC) and 133 died. Fourteen patients harbored amino-acid-altering K8 variants (5xG62C, 8xR341H). The presence of K8 variants did not associate with development of HCC (log-rank=0.5) or death (log-rank=0.7) and no significant associations were obtained for the single K8 variants after a correction for multiple testing was performed. CONCLUSIONS: Keratin variants are expressed in a low percentage of patients with alcoholic cirrhosis and do not influence HCC development. Further studies conducted in larger prospective cohorts are needed to find out whether presence of K8 R341H variant predispose to non-HCC-related liver mortality.

Transient elastography in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a relevant issue in public health owing to its epidemiological burden. It represents the most common chronic liver disease in the general population and is expected to increase in future as a result of an ageing population. Liver biopsy is still considered the "gold standard" for distinguishing the broad range of NAFLD. However, liver biopsy is often not recommended in the NAFLD patients, because of its cost, the potential risk of bleeding and the absence of consensus regarding the histopathological criteria that firmly differentiate between the NAFLD entities. Due to the remarkable increase in the prevalence of NAFLD and the concomitant efforts in developing novel therapies, a non-invasive, simple and reproducible technique is needed in the clinical practice. Transient elastography is a non-invasive technique for liver stiffness measurement (LSM) as a function of the extent of hepatic fibrosis. This review focuses on practical issues in the use of LSM in the NAFLD patients and suggests areas for further research and development.