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In patients with polycystic liver disease (PLD), development of cysts induces hepatic venous outflow obstruction (HVOO) and parenchymal modifications, challenging the paradigm of a normal noncystic liver parenchyma. The aims were to reappraise the pathology of the noncystic parenchyma, by focusing on HVOO lesions; and to investigate the association with outflow obstruction at imaging and perioperative course after liver resection. This is a retrospective study conducted in one tertiary center between 1993 and 2014. PLD patients (n = 125) who underwent resection (n = 90) or transplantation (n = 35) were included. HVOO parenchymal lesions were assessed for all patients and a liver congestion score was built. Imaging was analysed for 45 patients with computed tomography scan, and perioperative course was assessed in resected patients. At pathology, 92% of patients had HVOO lesions, with sinusoidal dilatation being the most common feature. HVOO was more severe in patients who underwent transplantation compared to liver resection, as assessed by the congestion score. At imaging, all patients had HVOO with at least two hepatic veins involved. Mosaic enhancement pattern of the parenchyma was associated with the severity of hepatic vein obstruction (P = 0.045) and the compression of the inferior vena cava (P = 0.014). In case of liver resection, intraoperative course was characterized by hemorrhage, related to HVOO at imaging. Ascites (44%) and liver failure (9%) in the postoperative period were associated with blood losses and transfusions., Conclusion: Hepatic venous outflow obstruction, including development of venous collaterality and parenchymal changes, is frequent in PLD and has major consequences on intraoperative bleeding and postoperative ascites and liver failure. Hepatic venous outflow obstruction should be taken into account to choose the most appropriate surgical treatment. (Hepatology 2017)., (© 2017 by the American Association for the Study of Liver Diseases.)

Unlabelled: Fibrolamellar hepatocellular carcinoma (FLC) is a rare subtype of liver cancer occurring mostly in children and young adults. We have shown that FLC comprises two separate entities: pure (p-FLC) and mixed-FLC (m-FLC), differing in clinical presentation and course. We show that p-FLCs have a distinct gene expression signature different from that of m-FLCs, which have a signature similar to that of classical hepatocellular carcinomas. We found p-FLC profiles to be unique among 263 profiles related to diverse tumoral and nontumoral liver samples. We identified two distinct molecular subgroups of p-FLCs with different outcomes. Pathway analysis of p-FLCs revealed ERBB2 overexpression and an up-regulation of glycolysis, possibly leading to compensatory mitochondrial hyperplasia and oncocytic differentiation. Four of the sixteen genes most significantly overexpressed in p-FLCs were neuroendocrine genes: prohormone convertase 1 (PCSK1); neurotensin; delta/notch-like EGF repeat containing; and calcitonin. PCSK1 overexpression was validated by immunohistochemistry, yielding specific, diffuse staining of the protein throughout the cytoplasm, possibly corresponding to a functional form of this convertase., Conclusion: p-FLCs have a unique transcriptomic signature characterized by the strong expression of specific neuroendocrine genes, suggesting that these tumors may have a cellular origin different from that of HCC. Our data have implications for the use of genomic profiling for diagnosis and selection of targeted therapies in patients with p-FLC., (© 2014 by the American Association for the Study of Liver Diseases.)

Unlabelled: Simultaneous liver and kidney transplantation (SLKT) remains the procedure of choice for patients with both endstage liver disease and kidney failure. Stringent guidelines are needed to avoid unnecessary kidney transplantation. A recent consensus meeting proposed criteria based on the Modified Diet in Renal Disease (MDRD)-6 equation to estimate glomerular filtration rate (GFR). The aims of this study were to compare GFR equations to true GFR in candidates for liver transplantation (LT) and to determine the impact of inaccuracies on the current guidelines for SLKT. Three hundred stable cirrhosis patients evaluated for LT were studied. All patients had iohexol clearance to measure GFR at evaluation under stable conditions. Measured GFR (mGFR) was compared to MDRD-4, MDRD-6, and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. MDRD-6 was the most accurate equation to predict GFR. In the 290 patients with mGFR >30 mL/min/1.73 m(2), 15 patients (7%) had estimated GFR (eGFR) ≤40 mL/min/1.73 m(2) based on the MDRD-6 equation, defining "discordant" patients. Among them, two underwent SLKT and 13 underwent LT alone. None of those who survived more than 1 year after LT alone (n = 8) developed renal dysfunction thereafter. In multivariate analysis, discordant patients were older (P = 0.03) and had lower sodium level (P = 0.02)., Conclusion: The MDRD-6 equation was superior to other equations at identifying cirrhosis patients with true GFR <30 mL/min/1.73 m(2). However, the MDRD-6 equation also tended to underestimate renal function in a subgroup of patients with true GFR >30 mL/min/1.73 m(2), with a potential risk of unnecessary kidney transplantation if applying current U.S. recommendations for SLKT., (© 2014 by the American Association for the Study of Liver Diseases.)

Unlabelled: Microvascular invasion (MiVI) is a major risk factor in postoperative tumor recurrence and mortality in hepatocellular carcinoma (HCC). Unfortunately, this histological feature is usually missed by liver biopsy because of limited sampling, and MiVI is commonly detected only after surgery and examination of the full resected specimen. To date, there exists no reliable tool for identifying MiVI prior to surgical procedures. This study aimed to compare the proteome of HCC with and without MiVI in order to identify surrogate biomarkers of MiVI. A training cohort comprising surgically resected primary HCC with MiVI (n = 30) and without MiVI (n = 26) was subjected to matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS). Comparative analysis of acquired mass spectra of the two groups yielded 30 differential protein peaks, among which 28 were more strongly expressed in HCC with MiVI. Among these, two peaks were identified as N-term acetylated histone H4 dimethylated at lysine (K) 20, and N-term acetylated histone H4 dimethylated at K20 and acetylated at K16. Both peaks were validated in the training cohort and in an independent validation cohort (n = 23) by immunohistochemistry and western blot., Conclusion: These results demonstrate the potential of MALDI IMS for uncovering new relevant biomarkers of MiVI in HCC, and highlight the role of epigenetic modifications in the prognosis of HCC. Preoperative detection of modified forms of histone H4 expression in tumor biopsies would be helpful in management of patients with HCC., (© 2013 by the American Association for the Study of Liver Diseases.)

Unlabelled: Liver resection (LR) for hepatocellular carcinoma (HCC) as the first-line treatment in transplantable patients followed by "salvage transplantation" (ST) in case of recurrence is an attractive concept. The aim was to identify patients who gain benefit from this approach in an intention-to-treat study. From 1998 to 2008, among 329 potential candidates for liver transplantation (LT) with HCC within the Milan criteria (MC), 138 with good liver function were resected (LR group) from a perspective of ST in case of recurrence, and 191 were listed for LT first (LT group). The two groups were compared on an intention-to-treat basis with special reference to management of recurrences and transplantability after LR. Univariate and multivariate analyses were performed to identify resected patients who developed recurrence beyond MC. Five-year overall and disease-free survival was similar in both groups: LT versus LR group, 60% versus 77% and 56% versus 40%, respectively. Among the 138 patients in the LR group, 20 underwent LT before recurrence, 39 (28%) had ST, and 51 (37%) with recurrence were not transplanted including 21 within MC who were excluded for advanced age, acquired comorbidities, or refusal and 30 (22%) with recurrence beyond MC. Predictive factors for nontransplantability due to recurrence beyond MC included microscopic vascular invasion (hazard ratio [HR] 2.38 [range, 1.10-7.29]), satellite nodules (HR 2.46 [range, 1.01-6.68]), tumor size > 3 cm (HR 1.34 [range, 1.03-3.12]), poorly differentiated tumor (HR 3.18 [range, 1.31-7.70]), and liver cirrhosis (HR 1.90 [range, 1.04-3.12])., Conclusion: The high risk of failure of ST after initial LR for HCC within MC suggests the use of tissue analysis as a selection criterion. The salvage LT strategy should be restricted to patients with favorable oncological factors., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Unlabelled: Hepatocellular adenomas (HCAs) are divided into genotype/phenotype subgroups associated with different evolutive profiles. Therefore, recognition of subtype is of clinical importance in patient management. Magnetic resonance imaging (MRI) is considered the most informative imaging modality and liver biopsy a key diagnostic tool whose role in HCA subtyping has never been extensively studied. The purpose of our study was to evaluate the diagnostic performance of MRI and liver biopsy with and without immunohistochemistry and to assess the interobserver agreement for MR classification in a consecutive series of resected HCAs. Forty-seven HCAs with preoperative MRI and biopsy were retrospectively included. MRI data were reviewed independently by two abdominal radiologists blind to the pathological results and classification. Subtyping of HCAs on liver biopsy was made blindly to clinical, biological, and imaging data and to final classification. Routine histological analysis was based on morphological criteria and immunohistochemistry was systematically performed when enough tissue was available. Final subtyping of HCA was based on the examination of the surgical specimen. Radiologists correctly classified HCAs in 85%. The interobserver kappa correlation coefficient was 0.86. Routine histological analysis led to 76.6% of correct classification and 81.6% when immunophenotypical characteristics were available. The additional value of immunophenotypical markers is best in HCAs containing steatosis. Agreement between MRI findings and routine histological analysis was observed in 74.5%, leading to a likelihood ratio of subtype diagnosis higher than 20., Conclusion: MRI and biopsy analysis are two efficient methods in subtyping HCAs and their association increases the diagnosis confidence. Interobserver variability in MRI criteria is very low., (2011 American Association for the Study of Liver Diseases.)

Unlabelled: Metabolic syndrome (MS) is a newly identified risk factor in chronic liver disease (CLD) and hepatocellular carcinoma (HCC). The aim of this study was to analyze the pathological characteristics of HCC and nontumoral liver in patients with MS as the only risk factor for liver disease in comparison with those that developed in the course of other CLDs in order to provide further insight into the physiopathology of HCC associated with MS. HCC patients with features of MS as the only risk factor for liver diseases (MS group, n = 31) were compared to HCC patients with overt causes of CLD (CLD group, n = 81) or without causes of CLD (cryptogenic group, n = 16) who underwent surgical resection during the same period of time. Among the patients of the MS group, there were 30 males and 1 female. In comparison with the patients with HCC of the CLD group, the patients with MS were older (mean age: 67+/- 7 versus 59 +/- 14 years, P < 0.01), and the background liver was significantly more often free of significant fibrosis (F0-F2: 65% in the MS group versus 26% in the CLD group, P < 0.001). In addition, HCCs associated with MS were more often well differentiated (65% versus 28%, P < 0.001). Five HCCs, all from the MS group, developed on a preexisting liver cell adenoma, with three of them showing typical histological features of telangiectatic adenoma., Conclusion: This study shows that HCCs in patients with features of MS as the only risk factor for liver disease have distinct morphological characteristics and mainly occur in the absence of significant fibrosis in the background liver. In addition, some of them arise through malignant transformation of a preexisting liver cell adenoma.

Unlabelled: What were previously called telangiectatic focal nodular hyperplasias are in fact true adenomas with telangiectatic features (TAs) without overt characterized genetic abnormalities. The aim of our study was to review a surgical series of TAs in order to describe clinical, biological, and radiological findings of these lesions and to evaluate their outcomes. From January 1996 to November 2005, 284 patients with benign hepatocellular nodules underwent surgical resection at Beaujon Hospital. Among them, 32 TAs from 27 patients were diagnosed. Ninety-two percent of the patients were women. Mean age was 38 years (range 17-63). Mean body mass index was 28 (range 18-49), with 16 patients being overweight. Symptoms revealed lesions in 10 patients. In 13 patients, TA was associated with another benign liver lesion. Mean size of the TAs was 5 cm (range 1-17 cm). Histological analysis showed cellular atypias in 6 cases (19%), steatosis in 17 cases (53%), vascular changes in 19 cases (59%), and significant inflammatory infiltrate in 29 cases (91%). In 1 case, the TA had foci of well-differentiated hepatocellular carcinoma. In 18 of the 26 cases (69%), adjacent liver showed significant steatosis. Serum biomarkers of inflammation were increased in 90% of patients (19 of 22). After surgical resection, inflammatory marker levels returned to normal values in all patients tested., Conclusion: This study has shown that TAs occur in a characteristic background of overweight patients and are often associated with a biological inflammatory syndrome. Moreover, a TA may progress to malignancy.

Unlabelled: Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. We further investigated transcriptome-genotype-phenotype correlations in HCC. Global transcriptome analyses were performed on 57 HCCs and 3 hepatocellular adenomas and validated by quantitative RT-PCR using 63 additional HCCs. We determined loss of heterozygosity, gene mutations, promoter methylation of CDH1 and CDKN2A, and HBV DNA copy number for each tumor. Unsupervised transcriptome analysis identified 6 robust subgroups of HCC (G1-G6) associated with clinical and genetic characteristics. G1 tumors were associated with low copy number of HBV and overexpression of genes expressed in fetal liver and controlled by parental imprinting. G2 included HCCs infected with a high copy number of HBV and mutations in PIK3CA and TP53. In these first groups, we detected specific activation of the AKT pathway. G3 tumors were typified by mutation of TP53 and overexpression of genes controlling the cell cycle. G4 was a heterogeneous subgroup of tumors including TCF1-mutated hepatocellular adenomas and carcinomas. G5 and G6 were strongly related to beta-catenin mutations that lead to Wnt pathway activation; in particular, G6 tumors were characterized by satellite nodules, higher activation of the Wnt pathway, and E-cadherin underexpression., Conclusion: These results have furthered our understanding of the genetic diversity of human HCC and have provided specific identifiers for classifying tumors. In addition, our classification has potential therapeutic implications because 50% of the tumors were related to WNT or AKT pathway activation, which potentially could be targeted by specific inhibiting therapies.

The 1-year spontaneous mortality rate in patients with Budd-Chiari syndrome (BCS) approaches 70%. No prospective assessment of indications and impact on survival of current therapeutic procedures has been performed. We evaluated a therapeutic strategy uniformly applied during the last 8 years in a single referral center. Fifty-one consecutive patients first received anticoagulation and were treated for associated diseases. Symptomatic patients were considered for hepatic vein recanalization; then for transjugular intrahepatic portosystemic shunt (TIPS), and finally for liver transplantation. The absence of a complete response led to the next procedure. Assessment was according to the strategy, whether procedures were technically applicable and successful. At entry, median (range) Child-Pugh score and Clichy prognostic index were 8 (5-12), and 5.4 (3.1-7.7), respectively. A complete response was achieved on medical therapy alone in 9 patients; after recanalization in 6, TIPS in 20, liver transplantation in 9, and retransplantation in 1. Of the 41 patients considered for recanalization, the procedure was not feasible in 27 and technically unsuccessful in 3. Of the 34 patients considered for TIPS, the procedure was considered not feasible in 9 and technically unsuccessful in 4. At 1 year of follow-up, a complete response to TIPS was achieved in 84%. One- and 5-year survival from starting anticoagulation were 96% (95% CI, 90-100) and 89% (95% CI, 79-100), respectively. In conclusion, excellent survival can be achieved in BCS patients when therapeutic procedures are introduced by order of increasing invasiveness, based on the response to previous therapy rather than on the severity of the patient's condition.

Surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS) is a proteomic technique that enables the profiling of proteins present in any biological material studied. We used this approach to identify new biomarkers of hepatocellular carcinoma (HCC) in the sera of patients with cirrhosis. Sera from 82 patients with cirrhosis, either without (n = 38) or with (n = 44) HCC, were analyzed by SELDI-TOF MS, and the results of the two groups were compared. The most efficient protein peaks leading to discrimination of patients with HCC were selected (receiver operative characteristic curves). The highest-scoring peak combination was established in a first group of serum samples (multinomial regression) and was tested in an independent group. The protein corresponding to the highest discrimination was purified and characterized further. The intensity of 30 protein peaks significantly differed between cirrhotic patients with and without HCC. An algorithm including the six highest-scoring peaks allowed correct classification (presence or absence of HCC) of 92.5% of patients in the test sample set and 90% in the validation sample set. The highest discriminating peak (8900 Da) was purified further and was characterized as the C-terminal part of the V10 fragment of vitronectin. An in vitro study suggested that the increase of the 8900-Da fragment in the serum of patients with HCC may proceed from the cleavage of native vitronectin with metalloproteases, a family of enzymes whose activity is enhanced in HCC. In conclusion, global protein profiling is an efficient approach that enabled us to identify a catalytic fragment ofvitronectin as a new serum marker of HCC in patients with chronic liver diseases.

Hepatic parenchymal changes associated with Budd-Chiari syndrome (BCS) have been tentatively explained by combined arterial and portal perfusion disturbances in addition to the complete occlusion of hepatic veins. The aim of this study was to correlate pretransplant course and vascular imaging with pathologic findings in livers explanted for BCS. Seventeen consecutive white patients who underwent transplantation for severe classic BCS were retrospectively analyzed. Pretransplant course was 1 year or less in 8 patients and more than 1 year in 9 patients. Thrombophilia was found in 16 patients (94%). Imaging showed decreased portal perfusion in 16 patients (94%) and increased arterial perfusion in 9 patients. Histology showed obstructive portal venopathy and nodular regenerative hyperplasia (NRH) aspects in all cases, large regenerative nodules resembling focal nodular hyperplasia (FNH) in 9 cases, and cirrhosis in 2 cases. Patients with increased arterial inflow had large regenerative nodules and a protracted pretransplant course. Patients with acute thrombi in portal veins had parenchymal infarcts (2 cases) and a short pretransplant course. In conclusion, patients with severe BCS have a constant impaired perfusion inflow unrelated to progression of cirrhosis but related to the outcome. An early decrease in portal perfusion is observed in the short term and is responsible for NRH or infarcts if complicated with large thrombi. An increase in arterial perfusion compensates impaired portal flow in chronic BCS. Arterial hyperemia contributes to the development of large regenerative nodules that are FNH-like. This pathologic situation offers an interesting vascular model to further understand the parenchymal response to changes in hepatic blood flow.

Portopulmonary hypertension represents a major risk factor for transplantation; therefore, preoperative detection is crucial. The aims of this study were to determine (1) whether Doppler echocardiography performed at evaluation is a reliable tool for detecting portopulmonary hypertension and (2) the incidence of acquired portopulmonary hypertension profile after evaluation. One hundred sixty-five patients had Doppler echocardiography and right heart catheterization at evaluation over a 9-year period. All patients had a prospective follow-up, and the results of catheterization at evaluation were compared with those obtained at the time of transplantation. Seventeen of 165 patients met the criteria for portopulmonary hypertension on Doppler echocardiography. Portopulmonary hypertension was confirmed by catheterization in 10 patients and ruled out in 7. There were no false negatives for echocardiography. Mean pulmonary artery pressure was significantly higher during the initial phase of transplantation than at evaluation (17.8 +/- 4.3 vs. 20.3 +/- 5.5 mm Hg, respectively, P <.0001), and there was no significant correlation between values obtained at these 2 time points. Three patients showed to have acquired portopulmonary hypertension profile while waiting for a graft within time intervals ranging from 2.5 to 5 months. In conclusion, Doppler echocardiography is a highly sensitive tool for detecting portopulmonary hypertension. However, because this technique has a poor positive predictive value, right heart catheterization is recommended for confirming portopulmonary hypertension. In addition, the absence of portopulmonary hypertension at evaluation does not exclude the occasional occurrence of acquired portopulmonary hypertension profile after listing.

The contribution of radio-guided transcutaneous biopsy in the diagnosis of focal nodular hyperplasia (FNH) of the liver was compared with the findings on surgical specimens to assess its contribution in clinical and radiologic atypical cases. This retrospective study involved 30 patients with atypical tumors on imaging who underwent liver biopsy and then surgery. All surgical specimens were diagnosed as FNH, either classical (n = 18) or nonclassical (n = 12). Imaging data were reviewed according to 4 radiologic criteria on magnetic resonance imaging (MRI) and/or computed tomography (CT) scan (hypervascularity, homogeneity, nonencapsulation, and presence of a central scar), and classified depending on the number of criteria found (group I, 4 of 4; group II, 3 of 4; group III, 2 or fewer). Histologic assessment of ultrasound (US)-guided liver biopsy recorded major diagnostic features (fibrous bands, thick-walled vessels, reactive ductules, and nodularity) and minor features (sinusoidal dilatation and perisinusoidal fibrosis). "Definite FNH" (3 or 4 major features) was diagnosed in 14 biopsies, "possible FNH" (2 major and 1 or 2 minor features) in 7 cases, and "negative for FNH" (2 or fewer major features without minor features) in 9 cases. The diagnosis of FNH on biopsy was reached in 14 cases (58.3%) in patients with 2 or fewer imaging criteria (group III; n = 24). Biopsies with a diagnosis of "possible FNH" corresponded to a large proportion of telangiectatic-type FNH on the specimen. In conclusion, liver biopsy does not appear to be necessary in cases in which imaging is typical. However, the absence of radiologic diagnostic criteria in FNH does not preclude a positive diagnosis on liver needle biopsy. Using the proposed histologic scoring system, surgical management may be avoided in these 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.

The aim of this study was to assess the factors, including surgical portosystemic shunts, which affect survival in adults with Budd-Chiari syndrome. Multivariate retrospective analysis was performed using characteristics recorded at the time of diagnosis in 120 patients admitted from 1970 to 1992, of whom 82 were treated with surgical portosystemic shunts and 38 received only medical therapy. The 1-, 5-, and 10-year survival rates were 77 +/- 4%, 64 +/- 5%, and 57 +/- 6%, respectively. Survival was significantly better in the subgroup of patients diagnosed after versus before 1985. In both subgroups, and in patients with, as well as in patients without surgical shunts, 4 factors were found to be inversely and independently related to survival: age, response of ascites to diuretics, Pugh score, and serum creatinine. In patients diagnosed since 1985, an index combining these 4 factors allowed to differentiate patients with a good outcome (5-year survival 95%) from those with a poor outcome (5-year survival 62%; P <.05). There was no statistically significant and independent influence of surgical portosystemic shunts on survival. In conclusion, age, severity of liver failure, and presence of refractory ascites are the main prognostic factors in Budd-Chiari syndrome. Increased survival in recent years is consistent with improved management of hypercoagulable states as well as improved general care. It is uncertain whether surgical portosystemic shunting favorably modifies survival. Therefore, we recommend that surgical shunting should be restricted to management of refractory ascites or variceal bleeding in patients with otherwise good prognostic factors.

The cellular tropism of hepatitis C virus (HCV) is an important but much debated issue. Permissivity to HCV of biliary cells has never been demonstrated. In this context, we used gallbladder epithelial cells (GBEC) as a model of the more proximal biliary epithelium. These cells were isolated from HCV-positive and -negative individuals and cultured for up to 40 days. Biliary cells from HCV-negative subjects were infected in vitro with various inocula. The retention of GBEC functional characteristics was assessed by the expression of cystic fibrosis transmembrane conductance regulator (CFTR). All 12 GBEC tested from HCV-negative patients were successfully infected by HCV. This was assessed by: 1) the detection of HCV-RNA positive and negative strands; 2) the detection of the viral capsid by immunofluorescence; and 3) the combination of single-strand conformation polymorphism (SSCP) and HVR1 sequence analysis demonstrating the distinct majoritary HCV genomes in serum and in GBEC. The level of HCV RNA in cell extracts and supernatants was low, but HCV infection was highly reproducible. Our results expand those showing the cellular tropism of HCV, and demonstrate the sensitivity of biliary cells to HCV infection. This might have an important impact in terms of pathogenesis and pathological features of HCV infection. In addition, given the easy access to these cells and the high reproducibility of in vitro infection, they should constitute an important tool for studies aimed at analyzing the issue of HCV penetration and neutralizing antibodies.

In contrast with the well-recognized membranous obstruction of the inferior vena cava, short-length hepatic vein stenoses are not well-recognized causes of hepatic venous outflow block. The aim of this study was to ascertain the prevalence, causes, manifestations, and outcome of short-length hepatic vein stenoses. We performed a retrospective study of patients with short-length hepatic vein stenosis among 86 patients with hepatic venous outflow block who were seen between 1970 and 1992. There were 25 patients with short-length hepatic vein stenosis. A thrombogenic condition was identified in 14 patients (56%). The lesions of the accompanying hepatic veins in these patients were variable (short-length stenoses, thromboses, or nonspecific changes) and similar to that seen in patients without short-length hepatic vein stenosis. In 3 necropsied cases, the venous lesions were suggestive of fibrous sequela of prior thromboses. In patients with short-length hepatic vein stenosis, splenomegaly (28% vs. 55%, P < .05) and hypersplenism were significantly less common; serum transaminase (P < .001) and creatinine levels (P < .02) were lower, prothrombin was higher (P < .001), and 5-year survival was significantly better (Kaplan-Meier estimates: 80% vs. 50%, P < .05). In patients with hepatic venous outflow block, short-length hepatic vein stenosis is a common lesion that appears to be the sequela of localized thrombosis. Long-term anticoagulation and percutaneous angioplasty (with or without stenting) are potentially applicable in these lesions. The long-term results of these treatments merit further evaluation.

Auxiliary liver transplantation (LT) is a special procedure of LT which could be proposed to patients with fulminant hepatic failure (FHF) and has for aim that complete regeneration of the native liver (NL) left in place will allow the graft recipient to resume normal liver function after allograft withdrawal. We report 30 cases of auxiliary LT performed for FHF in 12 European centers. Twenty-five of 30 patients were younger than 50 years. The cause of FHF was hepatitis A virus (HAV) in 4 patients, hepatitis B virus (HBV) in 7, paracetamol overdose in 5, ecstasy in 2, hepatotoxic drugs in 4, autoimmune hepatitis in 2, liver lesions of preeclampsia in 1 and unknown in 5. A postoperative, both clinical and histological follow-up of more than 3 weeks was obtained in 22 patients, enabling us to look for indicators predictive of NL regeneration and outcome. Histological changes observed in the NL included complete regeneration in 68%, incomplete regeneration with obvious fibrous sequelae in 14% and severe liver fibrosis or cirrhosis in 18%, of the 22 patients studied. The percentage and distribution of necrosis observed in tissue samples of the NL at the time of transplantation was not related to the final outcome. Complete NL regeneration was observed in 15 patients, out of whom 14 were younger than 40 years. Patients with complete regeneration were mainly affected by FHF due to HAV, HBV, or paracetamol overdose. After a follow-up of 18/11 (mean/median) months (range, 3 to 67 months), 19 of the 30 patients (63%) survived and 13 of them (68%), i.e., 43% of the 30 patients, had resumed normal NL function, with interrupted immunosuppression, the ultimate goal of emergency auxiliary LT. We conclude that, in patients with FHF, auxiliary LT is a procedure feasible in a number of centers and is associated with a complete regeneration capability of the NL in a majority of survivors, especially in those younger than 40 years. Confirmation of these encouraging preliminary results by large-scale prospective studies is required.

Isoniazid and pyrazinamide are well-known hepatotoxic drugs, often used in combination. The aim of this study was to assess the prognostic influence of pyrazinamide on the outcome of fulminant or subfulminant liver failure caused by antituberculous therapy. Eighteen patients with fulminant or subfulminant liver failure due to antituberculous therapy were studied. Nine patients received isoniazid and rifampicin without pyrazinamide (group 1), and nine patients received isoniazid and rifampicin together with pyrazinamide (group 2). The severity of fulminant and subfulminant liver failure, as judged by the prevalence of coma and the lowest level of factor V, was similar in the two groups. Spontaneous survival was greater in group 1 (eight of nine) than in group 2 (two of nine) (P < .02). The authors conclude that pyrazinamide co-administration was associated with an increased mortality in patients with fulminant or subfulminant hepatitis occurring during antituberculous therapy. In these patients, pyrazinamide administration and an interval of more than 15 days between the onset of antituberculous treatment and jaundice, combined with grade III encephalopathy and factor V below 20%, predicted death without liver transplantation.

Experimental and clinical observations indicate that the liver allograft is less immunogenic than other organ transplants and can promote immune tolerance. Because interleukin-10 recently emerged as a macrophage and T-cell-derived cytokine with potent immunosuppressive properties, we studied its production in 28 patients undergoing orthotopic liver transplantation. Plasma levels of immunoreactive interleukin-10 dramatically increased within 2 hr after liver allograft reperfusion, with peak levels ranging between 214 and 4998 pg/ml (median = 677 pg/ml). This systemic release of interleukin-10 was transient because it returned to low levels by 48 hr (range = 26 to 51 pg/ml). The higher interleukin-10 levels measured in right atrial blood as compared with portal blood indicated that interleukin-10 was most likely synthesized within the liver graft. To get insight into the cellular origin of interleukin-10, we also measured serum levels of interleukin-4 and interferon-gamma, both produced by T cells, and interleukin-8, a cytokine secreted by macrophages, in eight patients. Interleukin-4 and interferon-gamma levels remained undetectable in most of the patients, whereas interleukin-8 levels paralleled those of interleukin-10. Portal endotoxemia was probably not involved in interleukin-10 production because endotoxin levels remained low (< 20 pg/ml) before and after liver allograft reperfusion. Interleukin-10 plasma levels did not correlate either with cold ischemia time or with the occurrence of rejection episodes. We conclude that orthotopic liver transplantation is associated with a massive release of interleukin-10 and interleukin-8, most likely produced by allograft macrophages.

In the course of alcoholic chronic pancreatitis, increased serum alkaline phosphatase level is usually caused by common bile duct stenosis but may also be due to alcoholic liver disease. The aims of this prospective study were to investigate whether clinical, biochemical and radiological factors could predict liver histopathological appearance. The study comprised 48 patients with chronic alcoholic pancreatitis, common bile duct stenosis and increased serum alkaline phosphatase levels; clinical, biochemical, radiological and histological data were recorded in all cases. Liver biopsy examination (surgical [n = 45] or intercostal [n = 3]) showed (a) biliary obstructive liver abnormalities (n = 33), which were severe in 20 cases (biliary fibrosis in 15, secondary biliary cirrhosis in 3, secondary sclerosing cholangitis in 2) and moderate in 13 cases; (b) alcoholic liver disease in 9; and (c) normal liver in 6. Clinical, biochemical and radiological data were not statistically different between patients with biliary obstructive liver disease and those with alcoholic liver disease. Forty-five patients underwent surgery; two patients with alcoholic hepatitis died after surgery, at the beginning of this study. We conclude that in chronic alcoholic pancreatitis with common bile duct stenosis and increased serum alkaline phosphatase levels, clinical, biochemical and radiological data cannot be used to predict the type of liver lesions. Therefore liver biopsy is warranted to identify (a) alcoholic hepatitis, which increases operative risk; and (b) biliary obstructive liver disease, frequent and often severe, in which surgical biliary decompression should be considered.

Portal pressure and portal-systemic collateral circulation after orthotopic liver transplantation have not been investigated. We studied systemic and splanchnic hemodynamics in 17 patients with cirrhosis before and 205 +/- 146 days after orthotopic liver transplantation. Among the 17 orthotopic liver transplantation patients, 12 had undergone hemodynamic study in the 6 mo before orthotopic liver transplantation. Controls were 50 patients with normal liver architecture. Cardiac index remained elevated in orthotopic liver transplantation patients compared with controls (3.6 +/- 0.9 vs 3.1 +/- 0.4 L/min.m2; p < 0.05). Azygos blood flow, which was elevated before orthotopic liver transplantation (585 +/- 402 ml/min), remained elevated after orthotopic liver transplantation (553 +/- 343 ml/min). In transplant patients, hepatic blood flow was higher than it was in controls (2.26 +/- 0.86 vs. 1.38 +/- 0.57 L/min; p < 0.05). Elevated hepatic blood flow correlated with cardiac index (r = 0.647, p < 0.025). In patients with normal graft function, hepatic venous pressure gradient was normal (2 +/- 1 mm Hg). In a patient with acute rejection, a sharp elevation in the hepatic venous pressure gradient was observed; it returned to normal 45 days after treatment. We conclude that despite normal portal pressure, portal-systemic collateral blood flow remains elevated after orthotopic liver transplantation. Possibly because of persistent collateral circulation, which may keep portal tributary blood flow elevated, hepatic blood flow is increased after orthotopic liver transplantation. Elevated splanchnic blood flow, in turn, contributes to the high cardiac index in liver recipients. Finally, a sharp elevation in portal pressure, which may be observed during acute rejection and subsides after treatment, merits further study.

Mutant p53 has been found in a wide variety of human malignancies including carcinomas of the lung, breast and colon. Because of the controversial mutational rate of the p53 gene in hepatocellular carcinoma, a large series of liver tumors from white patients with different risk factors was examined immunohistochemically for expression of the p53 mutant to assess its prevalence and the relationships between p53 overexpression and clinicopathological data. Nine of 58 specimens were found to have detectable evidence of p53 gene mutation by virtue of the immunohistochemical detection of mutant p53 protein. The p53 mutation was more frequent in patients with serological hepatitis B and C markers than in patients without these markers (p = 0.046). The prevalence of p53-positive tumors was also significantly higher in the group of tumors with invaded portal branches than in the group without (p = 0.02). Our results showed that p53-positive hepatocellular carcinoma is a rare finding in patients exposed to a low dietary aflatoxin intake and that p53 mutation seems to occur at a late stage of the tumoral process and could contribute to an aggressive tumoral phenotype.