Comparison of transient elastography (FibroScan), FibroTest, APRI and two algorithms combining these non-invasive tests for liver fibrosis staging in HIV/HCV coinfected patients: ANRS CO13 HEPAVIH and FIBROSTIC collaboration.

OBJECTIVES: Combining noninvasive tests increases diagnostic accuracy for staging liver fibrosis in hepatitis C virus (HCV)-infected patients, but this strategy remains to be validated in HIV/HCV coinfection. We compared the performances of transient elastography (TE), Fibrotest (FT), the aspartate aminotransferase-to-platelet ratio index (APRI) and two algorithms combining TE and FT (Castera) or APRI and FT (SAFE) in HIV/HCV coinfection. METHODS: One hundred and sixteen HIV/HCV-coinfected patients (64% male; median age 44 years) enrolled in two French multicentre studies (the HEPAVIH cohort and FIBROSTIC) for whom TE, FT and APRI data were available were included in the study. Diagnostic accuracies for significant fibrosis (METAVIR F ≥ 2) and cirrhosis (F4) were evaluated by measuring the area under the receiver-operating characteristic curve (AUROC) and calculating percentages of correctly classified (CC) patients, taking liver biopsy as a reference. RESULTS: For F ≥ 2, both TE and FT (AUROC = 0.87 and 0.85, respectively) had a better diagnostic performance than APRI (AUROC = 0.71; P < 0.005). Although the percentage of CC patients was significantly higher with Castera's algorithm than with SAFE (61.2% vs. 31.9%, respectively; P < 0.0001), this percentage was lower than that for TE (80.2%; P < 0.0001) or FT (73.3%; P < 0.0001) taken separately. For F4, TE (AUROC = 0.92) had a better performance than FT (AUROC = 0.78; P = 0.005) or APRI (AUROC = 0.73; P = 0.025). Although the percentage of CC patients was significantly higher with the SAFE algorithm than with Castera's (76.7% vs. 68.1%, respectively; P < 0.050), it was still lower than that for TE (85.3%; P < 0.033). CONCLUSIONS: In HIV/HCV-coinfected patients, TE and FT have a similar diagnostic accuracy for significant fibrosis, whereas for cirrhosis TE has the best accuracy. The use of the SAFE and Castera algorithms does not seem to improve diagnostic performance.

[Prognosis factors of cholangiocarcinoma: contribution of recent molecular biology tools]. / Facteurs pronostiques des cholangiocarcinomes : apport des données récentes de biologie moléculaire.

Cholangiocarcinoma represents the second most common primary hepatobiliary cancer. Although few patients are candidates for surgery, surgical resection represents the only potential curative option. The prognosis for patients remains poor, despite advances in the understanding of mechanisms involved in carcinogenesis. This review aims to assess clinicopathological factors and biological markers for the ability to predict prognosis. Clinicopathologic factors most often cited are tumor size, lymph node involvement, resecability and surgical margins involvement. Molecular biomarkers have been examined and a number of these, including mdm2, p27, matrix metalloproteinases and vitamin D receptor appear to have prognostic utility. The advent of 'omic'-based profiling offers the potential to assess many different biomarkers at the same time. This 'protein/gene signature' could open the way for developing valid and reproducible predictors of survival based on protein or gene profiles.

[Epidemiology, prevention, screening and diagnosis of hepatocellular carcinoma]. / Epidémiologie, prévention, dépistage et diagnostic du carcinome hépatocellulaire.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and occurs mainly in patients with cirrhosis. This work aimed at reviewing the main data and trends about HCC epidemiology in France, and about prevention, screening and diagnosis in patients with chronic liver diseases. The six following research topics were considered as priorities: 1) to improve epidemiological knowledge of HCC in France; 2) to clarify the epidemiology of HCC occuring in normal liver and to identify predictive factors; 3) to prevent cancer occurrence in patients with cirrhosis; 4) to improve the knowledge of predictive factors for HCC occurrence in patients with cirrhosis; 5) to improve the diagnostic procedure of nodules below 2 cm in diameter in patients with cirrhosis; 6) to understand functioning of medical networks in order to identify the reasons for late diagnosis and treatment of HCC in patients with cirrhosis.

[Cholangiocarcinoma: epidemiology and global management]. / Cholangiocarcinomes: épidémiologie et prise en charge globale.

SCOPE: Cholangiocarcinoma, or biliary tract tumors, are rare tumors for which survival is short, as diagnosis is often made at an advanced stage. Indeed, diagnosis remains difficult, since symptoms are often unspecific and appear at latest stages. This article presents an update of recent data and therapeutic options. CURRENT SITUATION AND SALIENT POINTS: Several etiologic factors have been identified, but for most patients, none of these factors can be found. Prognosis is often poor, and remains difficult to establish because of the lack of sufficient large-scale studies looking at the impact on preexisting tumor characteristics on overall survival. Surgery remains when possible the gold standard. When tumor removal is impossible, due to a local extension, the appropriate care of patients remains to be defined. Chemotherapy has been proposed with evidence of objective response but limited data on its ability to prolong overall survival and to enhance quality of life. Active chemotherapies appear to be made from combination of an antimetabolite, such as 5-fluorouracile or gemcitabine, and a platinum drug. PERSPECTIVES: In the near future, indications of chemotherapy could be enlarged and targeted therapy might also be used, since several molecules have been tested in preclinical studies, and be offered to patients in clinical trials.

UDP-glucuronosyltransferase UGT1A7 genetic polymorphisms in hepatocellular carcinoma: a differential impact according to seropositivity of HBV or HCV markers?

BACKGROUND: We conducted a case-control study to evaluate the role of UDP-glucuronosyltransferase 1A7 (UGT1A7) polymorphisms in the onset of hepatocellular carcinoma (HCC). METHODS: The study included 165 patients with HCC, 134 with cirrhosis and 142 controls without liver disease, matched for age and hospital. All were men younger than 75 years. HCC and cirrhosis patients were stratified according to time since cirrhosis diagnosis. RESULTS: We found a positive association between the UGT1A7*3/*3 genotype and HCC when the comparison was restricted to patients whose disease was of viral origin [OR = 3.4 (0.3-45)] but a negative association when it included only alcoholic patients [OR = 0.1 (0.02-0.6), p = 0.01]. CONCLUSION: Our study shows that UGT1A7 may play a role in hepatocellular carcinogenesis and that this role may differ according to the primary cause of the cirrhosis.

A prospective study of the evolution of lamivudine resistance mutations in patients with chronic hepatitis B treated with lamivudine.

Lamivudine resistance has been described in subjects with chronic hepatitis B infections, associated with mutations in the viral polymerase gene. The objective of this study was to estimate the emergence rate of lamivudine-resistant viral strains and their consequences over a 2-year period. We evaluated 283 lamivudine-naïve subjects with chronic hepatitis B. Clinical and virological features were assessed at inclusion and every 6 months thereafter. Viral DNA was characterized using polymerase chain reaction (PCR)-based sequencing. Potential risk factors for the emergence of lamivudine resistance mutations were assessed using logistic regression analysis. The annualized incidence rate for viral polymerase mutations was 22%. The only independent risk factor identified was high viral load, at inclusion. Detectable viral DNA and elevated transaminases were more frequent in subjects harbouring mutant viral strains, and these underwent a lower rate of hepatitis B e seroconversion. All subjects responded favourably to treatment, with no difference in symptoms between the two groups. This prospective cohort study identified lamivudine-resistant mutations emerging in 22% of subjects, yearly, which were apparently not associated with clinical aggravation over the study period.

Reinforced interferon alpha-2b and ribavirin is more effective than standard combination therapy in the retreatment of chronic hepatitis C previously nonresponsive to interferon: a randomized trial.

Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only.

Nosocomial and community-acquired spontaneous bacterial peritonitis: comparative microbiology and therapeutic implications.

In order to compare the microbiological characteristics of nosocomial and community-acquired episodes of bacterial peritonitis, 95 consecutive, spontaneous episodes were reviewed. Seventy of these episodes were bacteriologically documented. Fifty-three (55.8%) episodes were nosocomial and 42 (44.2%) were community acquired. A total of 78 pathogens were isolated, including 40 gram-positive cocci (34 streptococci, 6 Staphylococcus aureus), 35 gram-negative bacilli (including 23 Escherichia coli), 2 gram-positive bacilli and 1 yeast. Streptococci were found more frequently in community-acquired episodes (53.8%) than in nosocomial episodes (33.3%). Gram-negative bacilli were significantly more frequent in nosocomial episodes than in community-acquired episodes (56.4% vs. 33.3%, P<0.05). Nosocomial isolates were significantly more resistant to amoxicillin-clavulanic acid (48.7% vs. 18.4%, P<0.01) and cefotaxime (33.3% vs. 13.2%, P<0.05) than community-acquired isolates, but no difference was detected regarding resistance to ciprofloxacin. The results indicate that the empirical treatment of spontaneous bacterial peritonitis should differ for nosocomial and community-acquired cases.

Resection of hepatocellular carcinoma: a European experience on 328 cases.

BACKGROUND/AIMS: Surgical liver resection has been demonstrated in Asian countries to be the best therapeutic option in patients with hepatocellular carcinoma. Because the value of this treatment is still debated in Western countries, the aim of this paper was to report a European experience of resection for hepatocellular carcinoma. METHODOLOGY: From 1990 to 1999, 239 men and 61 women aged from 15 to 77 years old underwent 328 resections including major resection in 138 (42%) cases. Normal liver was present in 53 patients (17%) and chronic liver disease was present in 247 including 152 (50%) with cirrhosis. RESULTS: In-hospital mortality was 6.4% and was significantly influenced by the presence of chronic liver disease (1.7% vs. 7.4%). Mortality after resection in alcoholic patients (14%), in patients with hepatitis C (9%) was significantly higher than in patients chronic hepatitis B (1%) (P < 0.05). The overall survival rates were 81%, 57%, 37%, and 13% at 1, 3, 5 and 10 years. Five-year survival rate was significantly higher (P < 0.05) in patients with normal liver as compared to chronic liver disease (50% vs. 34%). In patients with chronic liver disease parameters, which significantly influenced survival rate, were vascular invasion, tumor differentiation and the extent of resection. CONCLUSIONS: In this European study with varied profile of etiologies associated with hepatocellular carcinoma we showed that a five-year survival rate of 40% can be expected after resection and that chronic liver disease is a major factor influencing short and long-term prognosis.

Biochemical markers of liver fibrosis in patients infected by hepatitis C virus: longitudinal validation in a randomized trial.

A liver fibrosis index was recently prospectively validated in a cross-sectional study where patients infected by hepatitis C virus (HCV) had only one biopsy and no longitudinal follow-up. The aim of this study was to retrospectively assess the diagnostic value of this index in patients included in a randomized trial of interferon (IFN) using repeated measurements, two biopsies and hyaluronic acid as a comparative reference. One-hundred and sixty-five patients who had had two interpretable liver biopsies and at least one stored serum sample before IFN treatment were selected. Seventy-eight patients received 3 MU of IFN-alpha thrice weekly for 24 weeks and 87 followed a reinforced regimen for 48 weeks. A fibrosis index combining five biochemical markers (alpha2-macroglobulin, haptoglobin, apolipoprotein A1, gamma-glutamyl transpeptidase (GGT) and total bilirubin adjusted for gender and age) as well as hyaluronic acid was assessed on 461 samples available at baseline, at the end of treatment and at the end of follow-up (72 weeks). There was a significant decrease of the fibrosis index score among the 17 sustained virologic responders, from 0.33 +/- 0.06 (mean +/- SE) at baseline to 0.18 +/- 0.06 at 72 weeks in comparison with 92 nonresponders (from 0.41 +/- 0.03 at baseline to 0.44 +/- 0.03 at 72 weeks; P < 0.001) and in comparison with 56 relapsers (from 0.36 +/- 0.03 at baseline to 0.32 +/- 0.03 at 72 weeks; P=0.05). No significant differences were observed for hyaluronic acid.Hence, this fibrosis index could be used as a surrogate marker of the antifibrotic effect of treatments in patients with chronic hepatitis C.

The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: a long-term retrospective cohort study.

In this study we analyzed the influence of human immunodeficiency virus (HIV) infection on the course of chronic hepatitis C through multivariate analysis including age, alcohol consumption, immune status, and hepatitis C virus (HCV)-related virologic factors. Eighty HIV-positive and 80 HIV-negative injection drug users included between 1980 and 1995 were matched according to age, gender, and duration of HCV infection and followed-up during 52 months. The progression to cirrhosis was the primary outcome measure. The impact of HIV on HCV-RNA load, histologic activity index, response to interferon therapy, and liver-related death was also considered. In HIV-positive patients, chronic hepatitis C was characterized by higher serum HCV-RNA levels (P =.012), higher total Knodell score (P =.011), and poorer sustained response to interferon therapy (P =.009). High serum HCV-RNA level was associated with low CD4-lymphocyte count (P =.001). Necroinflamatory score was higher in HIV-positive patients (P =.023) independently of the CD4-lymphocyte count, whereas increased fibrosis was related to decreased CD4-lymphocyte count (P =.011). The progression to cirrhosis was accelerated in HIV-positive patients with low CD4 cell count (RR = 4.06, P =.024) and in interferon-untreated patients (RR = 4.76, P =.001), independently of age at HCV infection (P =.001). Cirrhosis caused death in 5 HIV-positive patients. The risk of death related to cirrhosis was increased in heavy drinkers (RR = 10.8, P =.001) and in HIV-positive patients with CD4 cell count less than 200/mm(3) (RR = 11.9, P =.007). In this retrospective cohort study, HIV coinfection worsened the outcome of chronic hepatitis C, increasing both serum HCV-RNA level and liver damage and decreasing sustained response to interferon therapy. Age and alcohol were cofactors associated with cirrhosis and mortality. Interferon therapy had a protective effect against HCV-related cirrhosis no matter what the patient's HIV status was.

Cigarette smoking and hepatic lesions in patients with chronic hepatitis C.

A possible hepatotoxicity of cigarette smoke has been recently suggested by epidemiological and experimental studies. Our aim was to study the possible relationships between smoking and liver fibrosis and activity in patients with chronic hepatitis C. A cross-sectional study was performed in a group of 310 patients with chronic hepatitis C consecutively hospitalized for their first liver biopsy. The relationships between age, gender, alcohol consumption, route of contamination, tobacco consumption, and Knodell fibrosis and activity scores were examined in univariate, age-adjusted, and multivariate analyses. One hundred and seventy-six patients (57%) were current smokers. Smokers were younger (P <.001), more often of male gender (P =.001), more often alcohol consumers (P =.001), and more often had a history of intravenous drug use (P =.0001) than never smokers. Smoking was related to increased fibrosis and activity scores in age-adjusted (P =.009 and P =.005, respectively) and multivariate analyses (P =.03 and P =.04, respectively). Smoking increases the severity of hepatic lesions in patients with chronic hepatitis C.

Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe.

The aim of this study was to evaluate the distribution and clinical significance of hepatitis C virus (HCV) genotypes in European patients with compensated cirrhosis due to hepatitis C (Child class A) seen at tertiary referral centres. HCV genotypes were determined by genotype-specific primer PCR in 255 stored serum samples obtained from cirrhotics followed for a median period of 7 years. Inclusion criteria were biopsy-proven cirrhosis, absence of complications of cirrhosis and exclusion of all other potential causes of chronic liver disease. The proportion of patients with types 1b, 2, 3a, 1a, 4 and 5 were 69%, 19%, 6%, 5%, 0.5% and 0.5%, respectively. Kaplan-Meier 5-year risk of hepatocellular carcinoma (HCC) was 6% and 4% for patients infected by type 1b and non-1b, respectively (P=0.8); the corresponding figures for decompensation were 18% and 7% (P=0.0009) and for event-free survival were 79% and 89% (P=0.09), respectively. After adjustment for baseline clinical and serological features, HCV type 1b did not increase the risk for HCC [adjusted relative risk=1.0 (95% confidence interval=0.47-2.34)], whereas it increased the risk for decompensation by a factor of 3 (1.2-7.4) and decreased event-free survival by a factor of 1.7 (0.9-3.10). In conclusion, type 1b and, to a lesser extent, type 2, are the most common HCV genotypes in European patients with cirrhosis. HCV type 1b is not associated with a greater risk for HCC, but increases the risk for decompensation by threefold in patients with cirrhosis.

The tolerance and efficacy of interferon-alpha in haemodialysis patients with HCV infection: a multicentre, prospective study.

BACKGROUND: A prospective multicentre study was initiated in HCV-infected haemodialysis patients to assess the tolerance and efficacy of alpha-2b interferon. METHODS: We had planned to include 120 patients with HCV RNA detectable by polymerase chain reaction (PCR) (Amplicor Roche) and histologically documented chronic hepatitis. The dose of alpha-interferon was 3 million units (MU) three times weekly (TTW), to be reduced to 1.5 MU TTW in case of side-effects. Tolerance was evaluated monthly; virological efficacy was evaluated by PCR. A liver biopsy was performed at month 18 (M18). RESULTS: (a) TOLERANCE: After 37 patients had been included, the study was discontinued by the promoting institution because of severe side-effects requiring that treatment be stopped in 19 patients. The side-effects were: cardiac (4) neuropsychiatric (2), digestive (3), acute necrosis of the graft (1), severe asthenia (9), minor side-effects were observed in 22 patients. A complete 12-month course was completed in 12 patients for the 3 MU TTW dose and in six patients for the 1.5 MU TTW reduced dose. Normal ALT level (OR, 0.16; CI 95%, 0.03-0.89) at inclusion was associated with interruption of treatment (univariate analysis). (b) EFFICACY: Sustained virological response was observed in only seven (18.9%), of the 18 patients who completed the treatment (38%). Increased ALT at inclusion (OR, 1.04; CI 95%, 1.01-1.09) and cumulated doses of interferon (OR, 1.01; CI 95%, 1.004-1.026) were jointly associated with a sustained response, while positive PCR at M2 was strongly predictive of treatment failure. CONCLUSION: Tolerance of interferon is poor in haemodialysis patients. Sustained response is fairly high in patients who have 12 months of treatment and seems to be based on the immune status of the patients (ALT) and the cumulative doses of interferon.

[Practices of transcutaneous liver biopsies in France. Results of a retrospective nationwide study]. / Pratiques de la ponction-biopsie hépatique transpariétale en France. Résultats d'une étude nationale.

OBJECTIVES: Few nationwide studies have evaluated the number of transcutaneous liver biopsies performed for diffuse parenchymal liver diseases and the practices of this procedure. The aims of this retrospective nationwide survey were to precise these data. METHODS: In 1997, a confidential questionnaire was mailed to all AFEF and ANGH members. Parameters studied were annual number of transcutaneous liver biopsies performed by center for diffuse parenchymal liver diseases, sedation and/or premedication, haemostasis parameters required for choosing transcutaneous liver biopsy route, fasting liver biopsy, use of venous access, ultrasonography use during liver biopsy (determination of puncture site), modalities of follow-up after liver biopsy, number of biopsies performed as day-care procedure. RESULTS: Sixty seven centers were involved in the study. About 12 000 transcutaneous liver biopsies are performed each year in France for diffuse liver parenchymal diseases. Mean number of biopsies per center is 130 (median 70, ranges 5-600). Sedation is routinely used before liver biopsy in 31% of centers; APTT is not measured in 20% of centers and bleeding time is measured in 30% of centers before liver biopsy. Ultrasonography for determination of puncture site is used in 41% of centers. Venous access is implemented in 36% of centers. Outpatient liver biopsies are performed in less than 15% of cases by 64% of centers whereas 30% of centers practice outpatient liver biopsy of more than 50% of cases. Heterogeneity of biopsy practices are related to individual choices rather than the type or location of medical practice. CONCLUSIONS: Many transcutaneous liver biopsies are performed each year in France for diffuse parenchymal liver diseases, and practices vary greatly. Ultrasonography use and outpatient liver biopsy should be developed.

[Hepatic granulomas of infectious origins]. / Granulomatoses hépatiques d'origine infectieuse.

Hepatic granulomas of infectious origin are due to several causes. Bacterial and rickettsial infections are the most frequent (mainly tuberculosis, infections due to atypical mycobacteria, Q fever). However parasitic and fungal infections may also be involved. Histological characteristics of the granuloma are sometimes suggestive of the cause, but the aetiological diagnosis often results from a careful confrontation of clinical, biological, and histological data. One should always have in mind the possibility of tuberculosis, where an effective treatment must be given as early as possible. The cause of granulomas remains unknown in approximately half the cases after careful investigations.

Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF).

A nationwide prospective study was conducted in France in 89 university and primary referral hospitals' liver units to evaluate practices of liver biopsy and the occurrence of complications. A total of 2,084 biopsies were analyzed, recording the indication, hemostasis parameters, experience of operator, route of biopsy, use of ultrasonography (US), type of hospitalization, side effects, and complications. Pain, anxiety, and discomfort were evaluated by patients by visual analogue scale (VAS). Biopsies were performed by experienced physicians (>150 procedures performed) in 72%, and hepato-gastroenterologists in 89% of the cases. Hepatitis C was the indication in 54%. Sedation or premedication (atropine) was given in 46%. US-guidance was used in 56% of the cases. A day-care procedure was used in 27%. No deaths occurred, but severe complications were observed in 0.57% and increased with the number of passes and decreased with experience of operator, use of atropine, and US-guidance. Pain was independently related to general anesthesia, experience of the operator, female sex, and hepatitis C. Anxiety was increased in women. Discomfort was increased by venous access and decreased with an experienced operator. Acceptance of additional biopsies was related to a day-care procedure and independently related to general anesthesia and multiples passes. This study showed that (1) liver biopsy procedures vary greatly in France, (2) hepatitis C is the main indication for liver biopsy at present, (3) US-guidance should be developed to reduce severe complications, and (4) day-care procedures increase acceptance of a future biopsy and should also be used more often.

Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases.

Hepatocellular carcinoma (HCC) occurring in nonfibrotic liver represents a rare, ill-defined subgroup of HCC without cirrhosis in which mechanisms of hepatocarcinogenesis remain unclear. The aim of our study was to assess epidemiological factors and detailed histopathologic changes in the nontumoral liver of patients developing such tumors. Of 330 HCCs resected in our institution between 1985 and 1998, we retrospectively analyzed 80 cases (53 men, 27 women; mean age, 51 +/- 16 years) in which the nontumoral liver showed no (n = 28) or minimal (n = 52) portal fibrosis without any septal fibrosis. In the group with no portal fibrosis there was no male predominance, and patients were significantly younger (44 +/- 19 years vs. 54 +/- 14 years) than those with minimal portal fibrosis. Sixty-seven tumors were typical HCCs, 8 were of fibrolamellar type, and 5 were hepatocholangiocarcinomas. Mean tumor size was 10 +/- 5 cm. Risk factors for HCC development were found in 30 patients: hepatitis B (n = 17) or C (n = 2) virus infections, alcohol consumption (n = 11), and hemochromatosis (n = 1). In the nontumoral liver, periportal and lobular necrosis, mild portal inflammation, steatosis, and iron overload were present in 15%, 57%, 52%, and 54% of cases, respectively. Liver cell changes were noted in 6%. This study emphasizes the need for strict criteria to classify HCC without cirrhosis. HCC in nonfibrotic liver is a distinct subgroup in which nontumoral liver shows nonspecific minimal changes without regeneration or premalignant lesion. Etiologic factors are often unidentified, although presence of HBV infection in 21% suggests a direct oncogenic role of this virus.