Liver stiffness measurement predicts long-term survival and complications in non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: In non-alcoholic fatty liver disease (NAFLD), fibrosis is the strongest prognostic factor and can be assessed by non-invasive methods. We evaluated the ability of liver stiffness measurement (LSM) to predict overall survival and liver, cardiovascular and oncologic complications. METHODS: We prospectively collected data on 2251 consecutive NAFLD patients (mean age 59 years, male 53%, mean body mass index 28 kg/m2 ) in two centres. At inclusion, all patients had LSM, clinical and biological evaluation. During follow-up, we recorded cardiovascular events, cancers, liver complications, liver transplantation and death. The primary endpoint was overall survival. Survival curves according to LSM were first performed using Kaplan-Meier method for the primary endpoint, and Aalen-Johansen method for secondary outcomes to take into account competitive risks. In a second step, a Cox proportional hazard model analysis was done to identify independent predictors of overall survival. RESULTS: Median follow-up was 27 months [IQR: 25-38]. Fifty-five patients died and three patients had liver transplantation. Overall survival significantly decreased as baseline LSM increased. Twenty-one patients (0.9%) had a liver event, 142 (6.3%) developed cancer (excluding HCC) and 151 (6.7%) had a cardiovascular event during follow-up. By multivariable analysis, independent predictors of overall survival were as follows: baseline LSM (adjusted HR (aHR) = 2.85 [1.65-4.92], P = .0002), age (aHR = 1.11 [1.08-1.13], P < .0001) and male sex (aHR = 2.05 [1.17-3.57], P = .012). Patients with elevated LSM were also more likely to develop cardiovascular, and liver events but not other cancers. CONCLUSION: LSM can be used to predict survival, cardiovascular and liver complications in NAFLD patients.

Prediction of hepatocellular carcinoma recurrence after liver transplantation: Comparison of four explant-based prognostic models.

AIM: Discordance between pre-LT imaging and explanted liver findings have been reported after liver transplantation (LT) for hepatocellular carcinoma (HCC), suggesting the need of reassessing the risk of HCC recurrence post-LT. Our aims were to compare pre-LT imaging and explants features and to test the performances of four explant-based predictive models of recurrence in an external cohort. METHODS: Staging according to pre-LT imaging and explant features were compared. Four explants-based models were retrospectively tested in a cohort of 372 patients transplanted for HCC in 19 French centres between 2003 and 2005. Accuracies of the scores were compared. RESULTS: Pre-LT imaging underestimated tumour burden in 83 (22.7%) patients according to Milan criteria. The highest AUCs for prediction of 5-years recurrence were observed in the "Up to seven" (0.7915 [95% CI: 0.7339-0.849]) and Decaens models (0.747 [95% CI: 0.6877-0.806]), with two levels of risk: low (10%) and high (>50%). Chan and Iwatsuki models identified 3 and 4 levels of risk, but had lower AUCs (0.68 and 0.70) respectively. Accuracy of the "Up to seven" model was superior to the Decaens model (P=.034), which was superior to the Chan model (P=.0041) but not to the Iwatsuki model (P=.17). CONCLUSION: Pre-LT imaging underestimates tumour burden, and prediction of recurrence should be reassessed after LT. The explant-based "Up to seven" and Decaens models provided the best accuracy for prediction of 5-year recurrence, identifying only two levels of risk. New models are needed to further refine the prediction of recurrence after LT.

Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis.

BACKGROUND & AIMS: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS: Among patients given telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.

Radiofrequency ablation versus surgical resection for hepatocellular carcinoma within the Milan criteria: A study of 281 Western patients.

OBJECTIVES: The aim of this study was to compare survival between radiofrequency ablation (RFA) and surgical resection (SR) in patients with hepatocellular carcinoma (HCC) within Milan criteria. METHODS: From January 2004 to December 2013 we consecutively and retrospectively included all patients with first occurrence of HCC within Milan criteria receiving SR or RFA as first-line treatment. The cumulative overall survival (OS) and disease-free survival (DFS) were compared after inverse probability weighting (including confounding factor). RESULTS: A total of 281 patients (RFA 178, SR 103) were enrolled. In multivariate Cox regression RFA and SR were not independent predictors of survival or recurrence. The respective weighted 5 years OS and DFS for patients with propensity scores between 0.1-0.9 in the SR and RFA groups were 54-33% and 60-16.9%, P = 0.695 and P = 0.426, respectively. Local tumour progression rate did not differ according to treatment (P = 0.523). Major complication rate was higher in the SR group, P = 0.001. Hospitalisation duration was lower in the RFA group (mean 2.19 days, range 2-7) than in the SR group (mean 10.2 days, range 3-30), P < 0.001. CONCLUSION: This large Western study has shown that OS and DFS did not differ after RFA (using mainly multipolar devices) and SR, for HCC within the Milan criteria in a European population, with a shorter hospitalisation time and a lower complication rate for RFA.

Covered vs. uncovered stents for transjugular intrahepatic portosystemic shunt: a randomized controlled trial.

BACKGROUND & AIMS: The first studies comparing covered stents (CS) and bare stents (BS) to achieve Transjugular Intrahepatic Portosystemic Shunt (TIPS) were in favor of CS, but only one randomized study has been performed. Our aim was to compare the primary patency of TIPS performed with CS and BS. METHODS: The study was planned as a multicenter, pragmatic (with centers different in size and experience), randomized, single-blinded (with blinding of patients only), parallel group trial. The primary endpoint was TIPS dysfunction defined as either a portocaval gradient ⩾12mmHg, or a stent lumen stenosis ⩾50%. A transjugular angiography with portosystemic pressure gradient measurement was scheduled every 6months after TIPS insertion. RESULTS: 137 patients were randomized: 66 to receive CS, and 71 BS. Patients who were found to have a hepato-cellular carcinoma, or whose procedure was cancelled were excluded, giving a sample of 129 patients (62 vs. 67). Median follow-up for CS and BS were 23.6 and 21.8months, respectively. Compared to BS, the risk of TIPS dysfunction with CS was 0.60 95% CI [0.38-0.96], (p=0.032). The 2-year rate of shunt dysfunction was 44.0% for CS vs. 63.6% for BS. Early post TIPS complications (22.4% vs. 34.9%), risk of hepatic encephalopathy (0.89 [0.53-1.49]) and 2-year survival (70% vs. 67.5%) did not differ in the two groups. The 2-year cost/patient was 20k€ [15.9-27.5] for CS vs. 23.4k€ [18-37] for BS (p=0.52). CONCLUSIONS: CS provided a significant 39% reduction in dysfunction compared to BS. We did not observe any significant difference with regard to hepatic encephalopathy or death.

Long term results of liver transplantation for Wilson's disease: experience in France.

BACKGROUND & AIMS: Liver transplantation (LT) is the therapeutic option for severe complications of Wilson's disease (WD). We aimed to report on the long-term outcome of WD patients following LT. METHODS: The medical records of 121 French patients transplanted for WD between 1985 and 2009 were reviewed retrospectively. Seventy-five patients were adults (median age: 29 years, (18-66)) and 46 were children (median age: 14 years, (7-17)). The indication for LT was (1) fulminant/subfulminant hepatitis (n = 64, 53%), median age = 16 years (7-53), (2) decompensated cirrhosis (n = 50, 41%), median age = 31.5 years (12-66) or (3) severe neurological disease (n = 7, 6%), median age = 21.5 years (14.5-42). Median post-transplant follow-up was 72 months (0-23.5). RESULTS: Actuarial patient survival rates were 87% at 5, 10, and 15 years. Male gender, pre-transplant renal insufficiency, non elective procedure, and neurological indication were significantly associated with poorer survival rate. None of these factors remained statistically significant under multivariate analysis. In patients transplanted for hepatic indications, the prognosis was poorer in case of fulminant or subfulminant course, non elective procedure, pretransplant renal insufficiency and in patients transplanted before 2000. Multivariate analysis disclosed that only recent period of LT was associated with better prognosis. At last visit, the median calculated glomerular filtration rate was 93 ml/min (33-180); 11/93 patients (12%) had stage II renal insufficiency and none had stage III. CONCLUSIONS: Liver failure associated with WD is a rare indication for LT (<1%), which achieves an excellent long-term outcome, including renal function.

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890.

BACKGROUND & AIMS: In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS: 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS: A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS: The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria.

BACKGROUND & AIMS: The aim of this study was to generate an improved prognostic model for predicting recurrence in liver transplant candidates with hepatocellular carcinoma (HCC). METHODS: Predictors of recurrence were tested by a Cox model analysis in a training cohort of 537 patients transplanted for HCC. A prognostic score was developed and validated in a national cohort of 435 patients followed up prospectively. RESULTS: α-Fetoprotein (AFP) independently predicted tumor recurrence and correlated with vascular invasion and differentiation. At a Cox score threshold of 0.7 (area under the receiver operating characteristic curve, 0.701; 95% confidence interval, 0.63-0.76; accuracy, 75.8%), a model combining log(10) AFP, tumor size, and number was highly predictive of tumor recurrence and death. By using a simplified version of the model, with untransformed AFP values, a cut-off value of 2 was identified. In the validation cohort, a score greater than 2 predicted a marked increase in 5-year risk of recurrence (50.6% ± 10.2% vs 8.8% ± 1.7%; P < .001) and decreased survival (47.5% ± 8.1% vs 67.8% ± 3.4%; P = .002) as compared with others. Among patients exceeding Milan criteria, a score of 2 or lower identified a subgroup of patients with AFP levels less than 100 ng/mL with a low 5-year risk of recurrence (14.4% ± 5.3% vs 47.6% ± 11.1%; P = .006). Among patients within Milan criteria, a score greater than 2 identified a subgroup of patients with AFP levels greater than 1000 ng/mL at high risk of recurrence (37.1% ± 8.9% vs 13.3% ± 2.0%; P < .001). Net reclassification improvement showed that predictability of the AFP model was superior to Milan criteria. CONCLUSIONS: Prediction of tumor recurrence is improved significantly by a model that incorporates AFP. We propose the adoption of new selection criteria for HCC transplant candidates, taking into account AFP.

Recurrence after liver transplantation for hepatocellular carcinoma according to up-to-seven criteria.

BACKGROUND/AIMS: The Up7 criteria for HCC have recently emerged to identify potential candidates for OLT. The aim of this study was to assess the validity of the Up7 criteria according to the pathological analysis of the explanted livers. METHODOLOGY: For recurrence risk calculation 669 HCC transplanted patients were classified according to both the pathological Milan and Up7 criteria. In order to identify potential predictors of recurrence, selected biological tumor markers and morphological features were then tested by Cox regression. RESULTS: The 5-year HCC recurrence rate for the Milan out/Up7 in subgroup (n=87), was significantly higher than patients meeting Milan criteria (n=299), 15.8% vs. 9.4% (p=0.0290). For patients within the Up7 criteria (n=383), only pre-OLT AFP level >1000ng/mL and microvascular invasion were significant predictors for recurrence, and for those beyond the Up7 criteria (n=286), pre-OLT AFP level >1000ng/mL, poor differentiation grade and microvascular invasion remained significant. CONCLUSIONS: Compared to the current Milan staging system, HCC patients within the pathological Up7 criteria were associated with a higher, but acceptable risk of recurrence after OLT, and along with tumor burden, other parameters can potentially be used for further refinement of HCC staging, such as AFP levels and microvascular invasion.

Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C.

BACKGROUND & AIMS: Liver stiffness can be measured noninvasively to assess liver fibrosis in patients with chronic hepatitis C. In patients with chronic liver diseases, level of fibrosis predicts liver-related complications and survival. We evaluated the abilities of liver stiffness, results from noninvasive tests for fibrosis, and liver biopsy analyses to predict overall survival or survival without liver-related death with a 5-year period. METHODS: In a consecutive cohort of 1457 patients with chronic hepatitis C, we assessed fibrosis and, on the same day, liver stiffness, performed noninvasive tests of fibrosis (FibroTest, the aspartate aminotransferase to platelet ratio index, FIB-4), and analyzed liver biopsy samples. We analyzed data on death, liver-related death, and liver transplantation collected during a 5-year follow-up period. RESULTS: At 5 years, 77 patients had died (39 liver-related deaths) and 16 patients had undergone liver transplantation. Overall survival was 91.7% and survival without liver-related death was 94.4%. Survival was significantly decreased among patients diagnosed with severe fibrosis, regardless of the noninvasive method of analysis. All methods were able to predict shorter survival times in this large population; liver stiffness and results of FibroTest had higher predictive values. Patient outcomes worsened as liver stiffness and FibroTest values increased. Prognostic values of stiffness (P<.0001) and FibroTest results (P<.0001) remained after they were adjusted for treatment response, patient age, and estimates of necroinflammatory grade. CONCLUSIONS: Noninvasive tests for liver fibrosis (measurement of liver stiffness or FibroTest) can predict 5-year survival of patients with chronic hepatitis C. These tools might help physicians determine prognosis at earlier stages and discuss specific treatments, such as liver transplantation.

Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations.

UNLABELLED: Liver stiffness measurement (LSM) based on transient elastography (TE, FibroScan) is gaining in popularity for noninvasive assessment of liver fibrosis. However, LSM has limitations, which have not yet been thoroughly evaluated. We prospectively investigated the frequency and determinants of LSM failure and unreliable results over a 5-year period, based on 13,369 examinations (134,239 shots). LSM failure was defined as zero valid shots, and unreliable examinations were defined as fewer than 10 valid shots, an interquartile range (IQR)/LSM greater than 30%, or a success rate less than 60%. LSM failure occurred in 3.1% of all examinations (4% at first examination [n = 7261]) and was independently associated at first examination with body mass index (BMI) greater than 30 kg/m(2) (odds ratio [OR], 7.5; 95% confidence interval [CI], 5.6-10.2; P = 0.0001), operator experience fewer than 500 examinations (OR 2.5 [1.6-4.0]; P = 0.0001); age greater than 52 years (OR 2.3 [1.6-3.2]; P = 0.0001), and type 2 diabetes (OR 1.6 [1.1-2.2]; P = 0.009). Unreliable results were obtained in a further 15.8% of cases (17% at first examination) and were independently associated at first examination with BMI greater than 30 kg/m(2) (OR 3.3 [2.8-4.0]; P = 0.0001), operator experience fewer than 500 examinations (OR 3.1 [2.4-3.9]; P = 0.0001), age greater than 52 years (OR 1.8 [1.6-2.1]; P = 0.0001), female sex (OR 1.4 [1.2-1.6], P = 0.0001), hypertension (OR 1.3 [1.1-1.5]; P = 0.003), and type 2 diabetes (OR 1.2 [1.0-1.5]; P = 0.05). When metabolic syndrome and waist circumference were taken into account in a subgroup of 2835 patients, waist circumference was the most important determinant of LSM failure and unreliable results. CONCLUSION: In our experience, liver stiffness measurements are uninterpretable in nearly one in five cases. The principal reasons are obesity, particularly increased waist circumference, and limited operator experience. These results emphasize the need for adequate operator training and for technological improvements in specific patient subpopulations.

Impact of tumour differentiation to select patients before liver transplantation for hepatocellular carcinoma.

AIM: To generate a new score with improved accuracy compared with Milan criteria to select patients. PATIENTS: The training cohort comprised 373 patients transplanted for hepatocellular carcinoma (HCC) between 1988 and 1998 (cohort 1). An algorithm was derived from the analysis of patient data by the proportional hazard Cox regression model. The area under the receiver operating characteristic (AUROC) was used to determine a cut-off value. The validation cohort comprised 140 patients transplanted between 1999 and 2001 (cohort 2). RESULTS: Multivariate analysis identified three predictors of 5-year tumour-free survival: tumour differentiation (P=0.02), diameter (P<0.0001) and number of nodules (P=0.04). A cut-off value of 4 was derived from the AUROC of the final score. Five-year tumour-free survival was 60.2 ± 3.1% in patients with as score <4 and 36.4 ± 4.7% in individuals with a score ≥4, P<0.0001. In the validation cohort, 5-year tumour-free survival was 82.8 ± 3.6% (score <4) and 50.0 ± 10.7% (score ≥4), P=0.0003. In patients with a score <4, there was no significant difference in 5-year tumour-free survival between Milan+ and Milan- patients, either in cohort 1 or 2. Five-year tumour-free survival of Milan- patients was significantly better in individuals with a score <4 compared with those with a score ≥4, both in cohort 1 (61.5 ± 9.1 vs 31.4 ± 4.6%, P=0.009) and in cohort 2 (P=0.02). CONCLUSION: A novel score taking into account tumour differentiation shows higher accuracy than Milan criteria in predicting 5-year tumour-free survival following liver transplantation for HCC. Prospective studies should validate these findings.

Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus.

BACKGROUND: The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use. AIM: To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients. METHODS: A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors. RESULTS: Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naïve group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo. CONCLUSION: The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.

Hepatitis B virus genotypes: a retrospective survey in Southwestern France, 1999-2004.

OBJECTIVE: To determine the prevalence of HBV genotypes in Southwestern France and the association between HBV genotypes and patients characteristics. METHODS: 194 HBsAg-positive patients (median age: 45 yrs, range: 7-77, male: 78%) followed in Bordeaux Hospital in 1999-2004 were included. HBV genotype, pre-core (PC) and core promoter (CP) mutations were determined by sequencing. RESULTS: Genotype distribution was A 51%, B 6.7%, C 5.7%, D 26.3%, E 7.7%, F 0.5%, G 2.1%. Among the 146 patients documented, 71.2% were Caucasians, 15.8% Africans, 13.0% Asians. Fifty-seven patients (36%) were HIV-infected. Eighty-two (42.3%) patients were HBeAg-positive. Genotype A was almost exclusively carried by Caucasians (96%), Africans were most frequent among genotype E (82%), and Asians were most prevalent among genotypes B and C (82% and 80%, respectively). Genotype A was associated with a higher prevalence of HBeAg than genotype D (53% versus 35.3%, P=0.03). PC variant was detected in 35% and CP variant in 43% of patients. PC variant was uncommon in genotype A patients (7.3%). CONCLUSION: Distribution of HBV genotypes differs according to ethnic origin, genotypes A and D being the most frequently found. Genotype A was more frequently associated with HBeAg-positivity and genotype D with HBeAg-negativity.

Fatal Acute Liver Failure as a Consequence of Regorafenib Treatment in a Metastatic Colon Cancer.

Regorafenib is a multikinase inhibitor which showed benefits in pretreated metastatic colorectal cancer patients. Hepatotoxicity has been described as a frequent side effect. We report the case of a 65-year-old patient presenting with jaundice, fever, and hepatocellular insufficiency which led to death of the patient. She had previously been treated with several lines of chemotherapy for sub- and diaphragmatic ganglionic metastases of a colon adenocarcinoma. There were no liver metastases. The fatal liver failure occurred at the beginning of treatment with regorafenib at a dosage of 3 tablets per day. No concomitant treatment was given, and other causes of liver damage were eliminated. The liver biopsy showed hepatocyte necrosis with lymphocyte infiltration. This observation illustrates the risk of severe hepatic involvement typically occurring within the first 2 months of treatment. Monitoring liver biology every 2 weeks is essential during the first 2 months to detect any hepatotoxicity.

Prevalence and factors associated with failure of liver stiffness measurement using FibroScan in a prospective study of 2114 examinations.

Liver stiffness measurement using FibroScan is a novel rapid and non-invasive technique that evaluates liver fibrosis. In some cases, however, no elasticity measurement is obtained. The aim of this prospective study was to assess the prevalence and factors associated with failure (no value obtained after 10 measurements) of liver stiffness measurement in patients with chronic liver disease. Two thousand one hundred and fourteen liver stiffness measurements were analyzed. Failure was observed in 96 cases (4.5%). Failure was not associated with operator, gender, or transaminase level. By multivariate analysis, the only factor associated with failure was body mass index greater than 28 (odds ratio, 10.0 degrees; 95% confidence interval, 5.7-17.9, P=0.001). In conclusion, liver stiffness is a good method for the evaluation of liver fibrosis that is feasible in more than 95% of patients. Other non-invasive methods such as biochemical methods or liver biopsy could therefore be used only in patients with failure of FibroScan examination.

Psychological impact of chronic hepatitis C: comparison with other stressful life events and chronic diseases.

AIM: To examine the psychological impact of chronic hepatitis C (CHC) diagnosis in a large cohort of CHC patients as compared with other stressful life events and chronic diseases carrying a risk of life-threatening complications. METHODS: One hundred and eighty-five outpatients with compensated CHC were asked to self-grade, using a 100-mm visual analogue scale (VAS), the degree of stress caused by the learning of CHC diagnosis and the perceived severity of their disease. Diagnosis-related stress was compared to four other stressful life events and perceived CHC severity was compared to four other common chronic diseases. RESULTS: Learning of CHC diagnosis was considered a major stressful event (mean+/-SD scores: 72+/-25), significantly less than death of a loved-one (89+/-13, P<0.0001) and divorce (78+/-23, P<0.007), but more than job dismissal (68+/-30, P<0.04) and home removal (26+/-24, P<0.0001). CHC was considered a severe disease (74+/-19), after AIDS (94+/-08, P<0.001) and cancer (91+/-11, P<0.001), but before diabetes (66+/-23, P<0.001) and hypertension (62+/-20, P<0.001). Perceived CHC severity was not related to the actual severity of liver disease, assessed according to Metavir fibrosis score. In multivariate analysis, diagnosis-related stress was related to perceived disease severity (P<0.001), trait anxiety (P<0.001) and infection through blood transfusion (P<0.001). CONCLUSION: Our results show the considerable psychological and emotional burden that a diagnosis of CHC represents, even in the absence of significant liver disease. They should be taken into account when announcing a diagnosis of CHC in order to reduce its negative effects.

Modifications of T-lymphocyte subsets before and during interferon and ribavirin treatment for chronic hepatitis C infection.

Our purpose was to determine in HCV-infected patients whether T-lymphocyte sub-populations were modified before and during interferon-alpha and ribavirin treatment, and whether this correlated with virological response. Twenty-two naive patients were given IFN-alpha 3 Million Units three times per week for 24 or 48 weeks and ribavirin. Sustained virological response corresponded to undetectable serum HCV RNA at treatment completion and 6 months later. Total blood lymphocyte counts and CD3(+)CD4(+), CD3(+)CD8(+), CD3(+)CD4(+)HLA-DR(+), and CD3(+)CD8(+)HLA-DR(+) lymphocyte subsets evaluated before, during, and after treatment were compared to values from 37 healthy subjects. At inclusion, patients and controls had similar total lymphocyte counts. CD3(+)CD4(+) counts and percentages were significantly higher in HCV patients. HLA-DR expression was also increased in CD4(+) (p < 0.0001) and CD8(+) T-cells (p = 0.0008) as compared with controls. During treatment, all lymphocyte subset counts and percentage decreased except the CD3(+)CD4(+) T-cell percentage which increased. Moreover, after 1 month of treatment, virological responders exhibited higher CD4(+) counts than nonresponders (p = 0.025), whereas they did not differ at inclusion or during the 2nd to 6th months of treatment. After treatment completion, all populations returned to baseline values. These results suggest that CD3(+)CD4(+) T-lymphocyte percentage increase under treatment could be related to IFN immunomodulation and associated with virological response.

Fibrosis is worse in HIV-HCV patients with low-level immunodepression referred for HCV treatment than in HCV-matched patients.

Hepatitis C virus (HCV) infection is frequent in human immunodeficiency virus (HIV)-infected patients. It is known to have an aggressive course in significantly immunosuppressed patients, and cirrhosis C has become one of the main causes of mortality in HIV-HCV coinfected patients since the improvement of antiretroviral therapy. The reasons for this severe fibrotic evolution are unclear. This prospective study compared chronic HCV lesions, liver immunocompetent cells, fibrosis and liver HCV loads in 2 cohorts of naive patients referred for HCV treatment: 33 HIV-HCV coinfected patients with CD4 >250/microL and 33 HCV-infected patients matched for the main risk factors of fibrosis. Fibrosis, particularly perisinusoidal fibrosis, was more marked in the coinfected patients. This occurred in the absence of a significant difference in disease activity. The number of CD3+ cells in the liver was higher in the HIV-HCV patients than in the HCV patients. Conversely, the number of liver CD4+ cells was lower in HIV-HCV patients than in HCV patients. The numbers of CD8+ and CD68+ cells were similar in the 2 groups. Finally, liver HCV load, assessed by immunostaining and reverse-transcription polymerase chain reaction, was similar in the 2 groups. We conclude that in the population of HIV-HCV coinfected patients with low-level immunosuppression referred for HCV treatment, fibrosis is worse than in HCV patients and the proportion of CD4+ lymphocytes among CD3+ cells is markedly decreased in the liver, whereas intrahepatic viral load is similar. Our data confirm the need to treat such patients against HCV, and suggest that HIV infection could favor fibrosis via the modulation of the intrahepatic immune response.

Detection of nodules in liver cirrhosis: spiral computed tomography or magnetic resonance imaging? A prospective study of 88 nodules in 34 patients.

Detection and characterization of all focal lesions in the liver are critical for screening patients with chronic liver disease. The aim of this prospective study was to investigate the accuracy of magnetic resonance imaging (MRI) and spiral computed tomography for the diagnosis of hepatic nodules in cirrhotic patients when compared with pathological findings of the explanted liver. From February 1997 to July 1999, 34 cirrhotic patients waiting for orthotopic liver transplantation (OLT) (mean age, 53.5 +/- 9.3 years; 24 males) were included. All patients had MRI and spiral computed tomography examinations, and findings were matched with the histological findings. Data analyses were made using the McNemar chi-square test. Mean time between radiological examination (MRI or spiral computed tomography) and OLT was 43.8 +/- 39 days. A total of 88 nodules were found in the 34 patients: 54 hepatocellular carcinoma (HCC) (mean size, 18 +/- 10 mm) in 21 patients, 22 dysplastic nodules (mean size, 10.7 +/- 4.3 mm) in 11 patients, and 12 macroregenerative nodules in 13 patients. Lesion-by-lesion analyses showed that sensitivity of MRI and spiral computed tomography for nodule, HCC or dysplastic nodule diagnosis was 44.3 and 31.8% (P = 0.02), 61.1 and 51.9% (P = 0.2), and 27.3 and 0% (P = 0.04), respectively. Patient-by-patient analyses showed no statistical difference between spiral computed tomography and MRI for nodule diagnosis. In conclusion, in patients with liver cirrhosis, MRI is more accurate than spiral computed tomography for the detection of liver nodules and dysplastic nodules. However, tumour size is always a restricting factor for these two techniques, which are unable to detect small HCC in more than 60% of cases.