Michel Beaugrand

Clinical Management of Hepatocellular Carcinoma. Conclusions of the Barcelona-2000 EASL Conference

Hepatocellular carcinoma (HCC) is a neoplasm the incidence of which is increasing worldwide, but striking geographical differences are observed for both risk factors and occurrence [1]. HCC represents more than 5% of all cancers and the estimated annual number of cases exceeds 500 000. It mostly affects patients with liver cirrhosis and currently represents their most common cause of death. Its clinical relevance and the existence of several diagnostic and therapeutic controversies explain the huge interest raised by this neoplasm. This prompted the European Association for the Study of the Liver (EASL) to organize a Monothematic Conference on Clinical Management of Hepatocellular Carcinoma, which was held in Barcelona in September 2000. During the meeting, a panel of international experts (Appendix A) met to prepare the present document that gives up-dated guidelines for the current clinical practice, and an overview of those aspects that should be the target of future clinical research.

Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C

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 F ≥ 2, 0.91 (0.87‐0.96) for F ≥ 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 F ≥ 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. (HEPATOLOGY 2005;41:48–54.)

Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases

A proper diagnosis of cirrhosis is essential for the management of patients with chronic liver diseases. We assessed the accuracy of liver stiffness measurement by Fibroscan for the diagnosis of cirrhosis in 1,257 patients with chronic liver diseases of various causes enrolled in a prospective multicenter study as well as clarified causes of discrepancies between liver histology and Fibroscan. One hundred thirty‐two patients had unsuitable biopsy specimens, and 118 had unreliable liver stiffness measurements. Because 232 patients overlapped with a previous study, analysis was performed in the 775 new patients then derived in the whole population (1,007; 165 cirrhosis). Diagnostic accuracy was assessed by receiver operator curve (ROC) analysis. Liver samples were re‐analyzed in case of discrepancies. The area under the ROC (AUROC) was 0.95 (95% CI, 0.93‐0.96) for the diagnosis of cirrhosis in either 775 or 1,007 patients. The cutoff value with optimal diagnosis accuracy was 14.6 kPa in 1,007 patients (positive and negative predictive values, 74% and 96%) with discrepancies among the etiological groups. Eighty patients were misclassified: (1) among 45 patients without cirrhosis with liver stiffness 14.6 kPa or greater, 27 (60%) had extensive fibrosis and 10 (22%) significant perisinusoidal fibrosis; and (2) among 35 patients with cirrhosis and liver stiffness less than 14.6 kPa, 10 (29%) had a macronodular pattern and 25 (71%) either none or mild activity. In conclusion, Fibroscan is a reliable method for the diagnosis of cirrhosis in patients with chronic liver diseases, better at excluding than at predicting cirrhosis using a threshold of 14.6 kPa. False‐negatives are mainly attributable to inactive or macronodular cirrhosis. (HEPATOLOGY 2006;44:1511–1517.)

Non‐invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B

Background: The need for new non‐invasive tools to assess liver fibrosis in chronic liver diseases has been largely advocated. Liver stiffness measurement (LSM) using transient elastography (FibroScan®, Echosens™) has been shown to be correlated to liver fibrosis in various chronic liver diseases. This study aims to assess its diagnosis accuracy in patients with chronic hepatitis B.

A new prognostic classification for predicting survival in patients with hepatocellular carcinoma

BACKGROUND/AIMS In patients with hepatocellular carcinoma, prediction of survival is difficult. The aim of this prospective study was to provide a simple classification for predicting survival of patients with hepatocellular carcinoma, based on a multivariable Cox model. METHODS Seven hundred and sixty-one patients who presented with hepatocellular carcinoma from 24 Western medical centers were enrolled over a 30-month period. Patients were randomly assigned to either a training sample (n=506, with 418 deaths) from which a classification system was established, or a test sample (n=255, with 200 deaths) for validating its prognostic significance. RESULTS Five prognostic factors were selected at the 0.0001 level: Karnofsky index <80% (relative risk of death=2.2, 95% confidence interval: 1.7-2.7), serum bilirubin >50 micromol/l (relative risk=2.1, 95% confidence interval: 1.7-2.6), serum alkaline phosphatase at least twice the upper limit of normal range (relative risk=1.6, 95% confidence interval: 1.3-2.0), serum alpha-fetoprotein >35 microg/l (relative risk=1.7, 95% confidence interval: 1.4-2.1), and ultrasonographic portal obstruction (relative risk=1.3, 95% confidence interval: 1.1-1.7). Three risk groups with different 1-year survival rates (72%, 34%, 7%) were derived, and independently validated in the test sample (79%, 31%, 4%). CONCLUSION This classification could be useful in the assessment of prognosis from homogeneous groups of patients with respect to their expected outcome.

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.

Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC.

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 (Spearmans ρ = 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) ≥2, 0.95 for F ≥ 3 and 0.96 for F = 4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed F ≥ 2, F ≥ 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. (HEPATOLOGY 2006;43:1118–1124.)

Liver stiffness values in apparently healthy subjects: Influence of gender and metabolic syndrome ☆

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+/-1.59 kPa. Transient elastography failure was observed in 4.6% of the cases. The failure rate increased with BMI, reaching 88% for values above 40 kg/m2. Liver stiffness values were higher in men than in women (5.81+/-1.54 vs 5.23+/-1.59 kPa, p=0.0002) and in subjects with BMI>30 kg/m2 (6.26+/-1.89 vs 5.37+/-1.51 kPa, 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+/-1.51 kPa, p<0.0001). CONCLUSIONS Liver stiffness values in the general population are influenced independently by gender, BMI and metabolic syndrome.

Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis

Screening is widely used to detect early hepatocellular carcinoma in Asian patients with cirrhosis. Its effectiveness in Caucasian patients has been suggested, but remains to be proven. Therefore we prospectively studied 118 French patients (68 males, 50 females, age 55 +/- 12) with Child-Pugh A or B cirrhosis (alcoholic in 82) and without detectable hepatocellular carcinoma. The screening program consisted of ultrasound examination of the liver and determination of blood alpha-fetoprotein and des-gamma-carboxyprothrombin levels every 6 months. The median follow up was 36 months (range 4-48). Only four patients were lost to follow up. Fourteen hepatocellular carcinomas were detected, in six cases by ultrasonography alone, in four by alpha-fetoprotein alone, in three by ultrasonography and alpha-fetoprotein and in one case by ultrasonography and des-gamma-carboxyprothrombin, but never by des-gamma-carboxyprothrombin alone. The tumor presented as a unique nodule in nine patients. The tumor was less than 3 cm in diameter without portal thrombosis or metastasis in three cases. Surgery was performed in only one case. In this study, the annual incidence of hepatocellular carcinoma was high (5.8%), but the screening methods used did not effectively identify potentially resectable tumors in Caucasian patients with cirrhosis.

Controlled attenuation parameter (CAP): a novel VCTE™ guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes.

There is a need for noninvasive methods to detect liver steatosis, which can be a factor of liver fibrosis progression. This work aims to evaluate a novel ultrasonic controlled attenuation parameter (CAP) devised to target, specifically, liver steatosis using a sophisticated process based on vibration control transient elastography (VCTE™). CAP was first validated as an estimate of ultrasonic attenuation at 3.5 MHz using Field II simulations and tissue-mimicking phantoms. Performance of the CAP was then appraised on 115 patients, taking the histological grade of steatosis as reference. CAP was significantly correlated to steatosis (Spearman ρ = 0.81, p < 10(-16)). Area under receiver operative characteristic (ROC) curve (AUC) was equal to 0.91 and 0.95 for the detection of more than 10% and 33% of steatosis, respectively. Furthermore, results show that CAP can efficiently separate several steatosis grades. These promising results suggest that CAP is a noninvasive, immediate, objective and efficient method to detect and quantify steatosis.