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Background: PEG (percutaneous endoscopic gastrostomy) is a well established endoscopic procedure for enteral feeding. However, patients with a shorter life expectancy will not benefit from PEG tube placement. Furthermore, some specific evolving diseases will never benefit from PEG. The aim of the study focuses on short and long term mortality rates after PEG tube placement in a referral gastroenterology centre (Geneva University Hospital). 219 patients were enrolled in this study. Patients and methods: All patients scheduled for a PEG procedure between January 2011 and December 2014 were included. Nine patient parameters were collected for further analysis as well as the main underlying disease requiring PEG tube placement. Patients were subsequently divided into 4 groups according to underlying disease: Group 1) swallowing disorders of neurologic origin; Group 2) swallowing disorders associated with upper digestive tract neoplasia ; Group 3) nutritional support for a non GI reason ; Group 4) Other. Results: 219 patients had undergone a PEG tube placement. 33 patients died within 60 days after the procedure. After one year, 71 patients died. Global survival was 870 days. The nutritional support group had the better survival rate with 1276 days compared to the swallowing groups and others. The multivariate analysis has highlighted the underlying disease as the only associated parameter with short and long term mortality. Conclusions: PEG tube placement is associated with high short and long term mortality depending on the underlying disease. We outlined the potential role of PEG tube insertion as a supportive transient approach for nutritional support.

Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT).We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated.A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H.We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals.There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.

Background & Aims Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. Methods We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naive patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. Results RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. Conclusions We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

Background/Aims In alcoholic hepatitis (AH), soluble TNFα receptor-1 (sTNF-R1) is increased. Elevated TNFα predicts mortality, but infection influences TNFα values. In patients with AH, we determined the prognostic value of TNFα, sTNF-R1, and lipopolysaccharide binding protein (LBP) and CD14, both involved in endotoxemia-associated inflammation. Methods One hundred and eight cirrhotic patients (Pugh score 10 [6–13]) and biopsy-proven AH (Maddrey's DF n =46; ≥32: n =62) without associated infection were included within 8 days of admission and followed-up for 3 months. Cytokines were measured using specific immunoassays. Patients with severe AH received steroids. Results Twenty four patients died at a median time of 35 days (range: 3–89). The overall survival was 78%. Multivariate Cox regression analysis showed that sTNF-R1 was an independent predictor of mortality, (OR 4.33: 95% CI [1.12–16.75]). Pugh's score ( P =0.618), Maddrey's DF ( P =0.182), creatinine ( P =0.197), TNFα ( P =0.319), LBP ( P =0.362), and CD14 ( P =0.347) were not related to survival. Conclusions In patients with AH, sTNF-R1 measured at admission is an independent predictor of survival at 3 months. Provided that TNF-R1 mediates the cytotoxic actions of TNFα, these results support the concept of dysregulated TNFα metabolism in AH.

Background/Aims: In alcoholic hepatitis (AH), enhanced expression of intercellular adhesion molecule-1 (ICAM-1) correlates to neutrophil infiltration and histology. In severe AH under steroids, the evolution of the hepatocyte membranous ICAM-1 expression and its soluble form (sICAM-1) is not known. Methods : Twenty-six consecutive patients with biopsy-proven severe AH had liver tissue studies for hepatocyte membranous ICAM-1 expression by immunostaining. Lobular neutrophils (mean per high power field) were counted after chloracetate esterase staining. Histological damage was assessed semiquantitatively. Circulating levels of sICAM-1 and TNF α in peripheral and hepatic vein were measured using immunoassays. After 8 days on steroids, 19 patients had repeat biopsy. Results : At baseline, hepatocyte membranous ICAM-1 correlated both to histology ( r =0.55, P 0.01) and to lobular neutrophils ( r =0.56, P 0.01). On steroids, sICAM-1 in hepatic vein and TNF α in both vascular beds decreased. Hepatocyte membranous ICAM-1 and hepatocellular damage decreased, but lobular neutrophils increased. Changes in sICAM-1 in hepatic vein correlated to histological changes ( r =0.68, P 0.01). Conclusions : In severe AH under steroids, the short term histological improvement was associated with a decrease in circulating TNF α , a decrease in ICAM-1 expression, and correlated to hepatic vein sICAM-1 changes.

Background: The rate of spontaneous migration of bile duct stones through the duodenal papilla is not well known. Endoscopic retrograde cholangiography (ERC) has been the standard method to diagnose bile duct stones, but accumulating data show there is a good agreement between ERC and endoscopic ultrasonography (EUS). The aim of the study was to evaluate the incidence and time course of stone migration in patients with bile duct stones by analyzing discrepancies between EUS and ERC as a function of the elapsed time between these two procedures. Stone migration was considered as the absence of stones at time of ERC regardless of the number of stones seen at EUS. Methods: The main criterion for inclusion was the presence of bile duct stone as shown by EUS. Ninety-two consecutive patients were prospectively included in this study. Results: Choledocholithiasis was absent at ERC in 12 patients. In univariate analysis, presence of gallbladder was significantly associated with an increased rate of stone migration (correction for multiple testing would remove this statistical significance). The size of the stone was the only independent factor to predict migration. Conclusion: Migration occurred in about 21% of cases within 1 month. Our study emphasizes the need to analyze carefully the results of comparative imaging studies of bile duct stones. (Gastrointest Endosc 2000;51:175-9.)

ORTHOTOPIC LIVER transplantation (OLT) has now achieved a 1-year survival of 80% to 90%. Most deaths occur within 3 months after OLT, primary graft dysfunction (PGD), or infection (these are the most common causes). PGD can be categorized as primary nonfunction (PNF) or initial poor function. PNF has a poor prognosis, with a near 100% mortality rate without retransplantation. In cases of retransplantation, morbidity and mortality rates are much higher than in primary grafts. Ischemia reperfusion injury can be considered one of the most important causative determinants in PGD. 1,2 Reperfusion injury is associated with the re-establishment of the blood flow and oxygen to a previously anoxic organ, leading to the production of oxygen-derived free radicals (ODFRs), cytokines, and other cytotoxic products such as tromboxanes and leukotrienes, which can activate and damage endothelial cells, leading to parenchymal damage and eventually to graft failure. 3–5 The beneficial effect of prostaglandin E 1 (PGE 1 ) administration for the prevention of liver reperfusion injury and primary graft dysfunction has been observed in animal experimental models, 6–9 in clinical studies, 10–13 and has been confirmed in a recent clinical trial in which it was administered during 21 days. 14 To show the beneficial effect of prophylactic administration of PGE 1 during a shorter period, we conducted a trial of prophylactic use of PGE 1 immediately after reperfusion of the grafted liver. Follow-up after OLT in 21 consecutive patients receiving PGE 1 was compared with a group of OLT patients previously transplanted who did not receive PGE 1 .

Liver tests abnormalities during pregnancy should encourage the clinician to seek liver diseases of pregnancy. The liver diseases of pregnancy are those proper to pregnancy including hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, all the "hypertensive" related diseases and acute fatty liver of pregnancy. These pathologies can involve the vital prognosis of the mother and the child. An adequate management reduces maternal-fetal complications. Close monitoring of pregnancy with sometimes induction of labour and verification of the normalization of liver tests after childbirth are essential.

Complement receptor type 1 (CR1) is an integral membrane protein of many hematopoietic cells and is found in a soluble form in plasma. Preliminary data have indicated that soluble complement receptor 1 (sCR1) levels in serum were increased in patients with cirrhosis. In this study, sCR1 was measured in patients with various liver diseases with a newly established enzyme-linked immunosorbent assay (ELISA). sCR1 level was elevated in chronic active hepatitis C (24 patients, 62.6 +/- 31 ng/ML; 31 normal controls, 31.4 +/- 7.8 ng/mL, P.001), and in cirrhosis (35 patients, 143.7 +/- 61 ng/mL, P.001). The levels increased transiently in 3 patients who had amanita phalloides intoxication. In 25 patients with advanced cirrhosis (pretransplantation screening), there were significant inverse correlations between sCR1 and both the prothrombin index (rs = -.60, P.002) and the aminopyrine breath test (rs = -.51, P.01). Following liver transplantation, the levels dropped from 166 +/- 70 to 49 +/- 24 ng/mL (P.0001), and serial measurements in the posttransplantation period showed a correlation with liver dysfunction, regardless of etiology. Since CR1 is not produced by hepatocytes, the most likely explanation for the increased level of sCR1 is reduced is reduced catabolism. Thus, sCR1 may be added to the short list of large glycoproteins that accumulate in liver disease.

Long-term treatment with proton pump inhibitors (PPI) is becoming more prevalent. Although they are well tolerated in the short term, serious concerns about long-term use have arisen. Recent data suggest that the latter is associated with an increased risk for osteoporotic fracture (especially vertebral), Clostridium difficile infection and rebound acid hypersecretion after treatment discontinuation. Acute interstitial nephritis is rare but may progress to chronic renal failure. An increased risk of community-acquired pneumonia has not been established in the general population and seems limited to the most vulnerable patients. Consistent data are still missing to correctly assess the risk of iron deficiency, vitamin B12 deficiency or hypomagnesaemia and the risk of digestive malignant diseases, despite the pathophysiological basis that exists concerning gastric malignancy. Many drug interactions can occur on long-term treatment, including some that imply the cytochrome P450 enzymes. Finally, the risk-benefit balance for a chronic PPI use in children seems unfavorable in most cases.

C receptor type 1 (CR1, CD35) is present in a soluble form in plasma (sCR1). Soluble CR1 was measured with a specific ELISA assay in normal individuals and in patients with different diseases. The mean serum concentration of sCR1 in 31 normal donors was 31.4 +/- 7.8 ng/ml, and was identical in plasma. An increase in sCR1 was observed in 36 patients with end-stage renal failure on dialysis (54.8 +/- 11.7 ng/ml, p < 0.0001), and in 22 patients with liver cirrhosis (158.3 +/- 49.9 ng/ml, p < 0.0001). The mean sCR1 levels dropped from 181 +/- 62.7 to 52.1 +/- 24.0 ng/ml (p < 0.001) in nine patients who underwent liver transplantation, and was 33.5 +/- 7.3 in 10 patients with functioning renal grafts, indicating that the increase in sCR1 was reversible. Soluble CR1 was elevated in some hematologic malignancies (> 47 ng/ml), which included B cell lymphoma (12/19 patients), Hodgkin's lymphoma (4/4), and chronic myeloproliferative syndromes (4/5). By contrast, no increase was observed in acute myeloid or lymphoblastic leukemia (10) or myeloma (5). In two patients with chronic myeloproliferative syndromes, sCR1 decreased rapidly after chemotherapy. The mean concentration of sCR1 was not significantly modified in 181 HIV-infected patients at various stages of the disease (34.8 +/- 14.4 ng/ml), and in 13 patients with active SLE (38.3 +/- 19.6 ng/ml), although in both groups the number of CR1 was diminished on E. There was a weak but significant correlation between sCR1 and CR1 per E in HIV infection and SLE (r = 0.39, p < 0.0001, and r = 0.60, p < 0.03 respectively). In vitro, monocytes, lymphocytes, and neutrophils were found to release sCR1 into culture supernatants. In vivo, sCR1 was detected in the serum of SCID mice populated with human peripheral blood leukocytes. The sCR1 levels correlated with those of human IgG (r = 0.97, p < 0.0001), suggesting synthesis of sCR1 by the transferred lymphocytes. The mechanisms underlining the increased levels of sCR1 and its biologic consequences remain to be defined.

We have conducted a multicenter randomized controlled trial comparing two doses of recombinant human α-interferon for efficacy in 60 patients with chronic non-A, non-B hepatitis. The source of infection appeared to be transfusion in 30 patients, intravenous drug abuse in 16 patients and was unknown in 14 patients. Patients were randomly assigned to no treatment or to treatment with either 1 or 3 MU of α-interferon given three times a week for 24 wk. Forty-five patients (75%) were positive for antibody to hepatitis C virus. During the 24-wk treatment period, mean serum ALT levels decreased in both treatment groups, but the decrease was statistically significant only in the 3 MU group. However, at 24 wk, the proportion of patients with normal ALT levels was similar in the 3 MU group (39%) and the 1 MU group (45%), and both were significantly higher than in controls (0%). Repeat liver biopsy specimens showed a significant decrease in the severity of histological changes in the 3 MU group but not in the 1 MU group or in controls. Responses to α-interferon did not correlate with patients' age, gender, source of infection, pretreatment serum ALT, presence of anti-hepatitis C virus or cirrhosis. After treatment, the mean ALT levels rose in both treated groups. The proportion of patients with normal ALT levels at wk 48 was 28% in the 3 MU group and 20% in the 1 MU group. In conclusion, a dose of 3 MU was superior to 1 MU of α-interferon given three times weekly for 24 wk in inducing improvements in serum ALT levels and liver histological examinations. Relapse in disease activity occurred in approximately half of the responders when interferon was stopped. The response to α-interferon did not correlate with the source of infection or with the presence or absence of anti-hepatitis C virus. (HEPATOLOGY 1991;13:393–397.)

Wilson's disease is a rare genetic condition, transmitted on a recessive autosomal mode, which involves a disturbance of copper metabolism. Its prevalence is 1: 30000. It is treatable but may be lethal if not managed early and treated adequately. It is caused by the loss of function of an adenosine triphosphatase (ATP 7B), which is due to a mutation in the ATP 7B gene on chromosome 13. This leads to a decrease or absence of copper transport to the bile and its accumulation within certain organs, particularly the liver and the brain. In this article we present two cases of Wilson's disease in two young male patients. We also briefly review the pathophysiology of the illness, discuss the latest guidelines for diagnosis and treatment and outline the recent genetic discoveries.

The pegylated interferon is now the first choice of treatment for patients without a counter-indication. The association of this treatment with lamivudine does not increase the effectiveness. For patients non-responders to the PEG-IFN or presenting counter-indications, the long-term administration of lamivudine is limited by the frequent appearance of mutations, so that escape from the treatment requires the use of other antivirals. Adefovir is currently the treatment of choice in the event of resistance to lamivudine. Its effectiveness is confirmed by many studies and the risk of emergence of resistance is very low. Entecavir is a selective inhibitor of polymerase HBV and shows a better efficacy than lamivudine. It is well tolerated and is associated only with a weak risk of resistance, even after a prolonged treatment.

Background The aim of this retrospective study was to evaluate clinical presentation and long-term outcome of patients treated surgically for complicated liver hydatid cysts. Patients and Methods Eighty-four patients with liver hydatid cysts underwent an operation at the Geneva University Hospital between 1980 and 1999. Clinical presentation, postoperative morbidity, mortality, and long-term recurrence rate were evaluated. Results Among the 84 patients with liver hydatid disease, 35 patients (41%) presented complicated cysts (ie, cysts that had developed a fistula into adjacent structures or organs). In most patients, the fistula communicated with the biliary tree (n = 25), but we also observed communication with the right lung (n = 3), the right diaphragm (n = 2), liver parenchyma (n = 1), and peritoneal cavity (n = 1). Complete removal of the cystic disease was possible in 24 of 35 patients (70%). In 11 patients, fragments of cysts were not removed because of their location adjacent to main vessels. Postoperatively, 8 patients (23%) developed a severe complication (grade II and III). There were no postoperative deaths, and no recurrences of hydatid disease were observed with a median follow-up of 8.6 years (complete follow-up was obtained in 69% of patients). Conclusions Complicated liver hydatid disease is frequent and was observed in almost half of patients operated for liver hydatid cysts at our center. Using a surgical strategy aimed at complete removal of cystic and pericystic tissue with simultaneous treatment of the fistulous tract, we observed 23% postoperative morbidity, no mortality, and no recurrence of disease with a median follow-up of >8 years.

The aim of this study is to evaluate the tolerance and effects of infliximab combined with steroids in severe alcoholic hepatitis (AH).Twenty patients with biopsy-proven severe AH (Maddrey's score32) received prednisone 40 mg/day for 28 days and either infliximab 5mg/kg IV (group A) or placebo (group B) at day 0. Histology, plasma interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured at baseline and at day 10.Infliximab was well tolerated. Histology showed no significant changes. At day 28, Maddrey's score significantly improved in group A (39 (32-53) to 12 (7-52), P0.05 vs. baseline) but not in group B (44 (33-50) to 22 (2-59), P=NS). At day 10, IL-6 and IL-8 decreased in group A (25 pg/ml (10-85 pg/ml) to 4.5 pg/ml (2-25 pg/ml); 301 pg/ml (107-1207 pg/ml) to 14 6 pg/ml (25-252 pg/ml), P0.01, P0.05 vs. baseline, respectively). In group B, changes were not significant (38 pg/ml (13-116 pg/ml) to 16 pg/ml (4-128); 315 pg/ml (26-1698 pg/ml) to 110 pg/ml (27-492 pg/ml)).In severe AH, infliximab was well tolerated and associated with significant improvement in Maddrey's score at day 28. Although the size of this study does not allow comparison between groups, these promising results should encourage larger trials assessing the effects of this therapy on survival.

Background Nitric oxide synthase (NOS) inhibition has been demonstrated to correct systemic vasodilation and renal hypoperfusion in studies of patients with cirrhosis. In patients with decompensated cirrhosis, NOS blockade increases arterial pressure, but the acute effects on hepatic and renal hemodynamics are not known. Methods We examined the acute systemic, hepatic, and renal hemodynamic effects of NG-monomethyl-l-arginine (l-NMMA) in 10 patients with decompensated cirrhosis. After baseline measurements, 3 mg/kg l-NMMA was administered as an IV bolus. At 20 minutes, if mean arterial pressure did not increase by at least 10 mm Hg above the baseline value, a second injection of 6 mg/kg was administered. Results In 5 of 10 patients, the second injection of l-NMMA 6mg/kg was necessary to achieve at least a 10 mm Hg increase in mean arterial pressure. Acute NOS inhibition increased systemic vascular resistance and decreased cardiac output, without causing changes in the hepatic venous pressure gradient. Hepatic blood flow decreased, but the indocyanine green intrinsic clearance and extraction remained unchanged. Plasma renin activity (from 9.5±2.9 to 6.7±1.6 ng/ml/h) and urinary prostaglandin E2 (from 299±40 to 112±36 pg/ml) significantly decreased. No significant changes in glomerular filtration rate, renal plasma flow, and natriuresis occurred, however. Conclusions Acute l-NMMA infusion in patients with decompensated cirrhosis reduced hepatic blood flow and decreased plasma renin activity and urinary prostaglandin E2, without causing significant changes in renal hemodynamics.

Type 1 hepatorenal syndrome (HRS) is a severe complication of cirrhosis associated with a short median survival time (2 weeks). Although the administration of terlipressin improves renal function, its effect on survival is unknown. This study investigated predictive factors of survival in patients with type 1 HRS treated with terlipressin.Ninety-nine patients with type 1 HRS treated with terlipressin in 24 centers were retrospectively studied. Terlipressin-induced improved renal function was defined as a decrease in serum creatinine value to130 micromol/L or a decrease of at least 20% at the end of treatment.At inclusion, the Child-Pugh score was 11.8 +/- 1.6 (mean +/- SD). Terlipressin (3.2 +/- 1.3 mg/day) was administered for 11 +/- 12 days. Renal function improved in 58% of patients (serum creatinine decreased by 46% +/- 17% from 272 +/- 114 micromol/L). Median survival time was 21 days. Survival rate was 40% at 1 month. Multivariate analysis showed that improved renal function and Child-Pugh scoreor =11 at inclusion were independent predictive factors of survival (P0.0001 and 0.02, respectively). Thirteen patients underwent liver transplantation (92 +/- 95 days after HRS onset), 10 of whom had received terlipressin and had had improved renal function.This retrospective uncontrolled study shows that in patients with type 1 HRS, terlipressin-induced improved renal function is associated with an increase in survival. Thus, a randomized trial investigating the effect of terlipressin on survival in patients with type 1 HRS should be performed.

To identify factors associated with liver steatosis in chronic hepatitis C.Occurrence and severity of liver steatosis in 254 chronic hepatitis C patients were compared with presence of alcohol abuse, body mass index (BMI)26, history of intravenous drug addiction and hepatitis C virus (HCV) genotype. Steatosis was found in 109 (43%) patients. The occurrence of steatosis was significantly associated with ongoing alcohol abuse (P=0.03) or HCV genotype 3 (P= 0.003), but not with BMI26. A moderate to severe steatosis was present in 60% of patients infected with HCV genotype 3, irrespective of the presence of alcohol abuse, BMI26 or history of intravenous drug addiction. Using a multivariable stepwise logistic regression analysis, infection with genotype 3 had an odds ratio (OR) of 10 (95% confidence interval (CI)=4.56-22) for a liver steatosis, whereas the presence of a cirrhosis at histology had an OR=0.256 (95% CI=0.07-0.92).A moderate to severe degree of steatosis of the liver is a morphological sign suggestive of infection with HCV genotype 3, independent of other risk factors of a fatty liver, but it may disappear at late stages of the disease.

Color Doppler EUS (CD-EUS) allows minimally invasive measurement of azygos blood flow (AzBF) in portal hypertension, but further validation of the method is needed. Because a limited number of patients has been studied, the acute hemodynamic effects of somatostatin and octreotide on AzBF and gastric mucosal perfusion are poorly defined in portal hypertension.A double-blind hemodynamic study was designed to assess rapid changes in AzBF over a 60-minute period after intravenous administration of somatostatin, octreotide, and placebo in 30 stable patients with biopsy-proven cirrhosis. AzBF was measured by using both CD-EUS and the invasive thermal dilution technique in the first 10 patients (phase 1). Then, with CD-EUS alone, the hemodynamic study was extended to a further 20 patients (phase 2). In addition, gastric mucosal perfusion changes were assessed by using laser Doppler flowmetry at endoscopy.In phase 1, the 2 methods for AzBF measurement showed significant correlations both for baseline values (r = 0.685) and for AzBF changes over 60 minutes after drug administration (r = 0.733). In phase 2, a reduction was observed in AzBF 10 minutes after octreotide or somatostatin administration (-47% and -23%, p0.0001 vs. placebo, p = 0.058 vs. placebo, respectively). After 60 minutes of somatostatin infusion, AzBF increased 27% over placebo values (p0.04). Gastric mucosal perfusion was transiently reduced 5 minutes after octreotide or somatostatin (-21% and -32%, respectively, p0.02 vs. placebo).This is the first study to validate CD-EUS AzBF measurement with reference to the invasive thermodilution technique in cirrhosis. It confirmed the transient effects of somatostatin and octreotide on both AzBF and gastric mucosal perfusion. In addition, a significant rebound phenomenon after 60 minutes of continuous intravenous somatostatin infusion was observed.

The shortage of cadaver organs has prompted transplant centres to seek new sources of grafts. While living-donor left lobe transplantation (segments II and III) is an established procedure for children, living donor right liver transplantation (segments V, VI, VII, VIII), which can provide adequate liver mass for an average-sized adult patient, is technically more demanding and potentially associated with higher risks for the donor. In view of the permanent shortage of organs in Switzerland, we started an adult living donor liver transplantation programme in 1999 with the approval of the Clinical Ethics Committee of Geneva University Hospitals. Donor evaluation was performed only after the recipient had been officially registered for transplantation in the national waiting list. Preoperative evaluation consisted of a preliminary information phase with blood tests and Doppler ultrasonography, a second phase with radiological non invasive investigations (CT scan with volume measurements, magnetic resonance cholangiography) and a third phase including liver biopsy and angiography. A formal psychiatric evaluation was performed in all cases and detailed consent was required. Eight potential donors were investigated, 5 were not retained because of too small right liver or steatosis, and 3 were accepted (wife, son, sister). Living-donor hepatectomy was performed without interrupting the vascular blood flow. The liver graft was perfused ex-situ with University of Wisconsin solution. The grafts were anastomosed to the preserved vena cava of the recipient and the portal and arterial anastomoses were performed without interposition grafts, with short cold ischaemic times in the 3 cases. The graft-to-recipient weight ratio ranged from 1.04 to 1.12%. The grafts worked immediately; the post-operative course in the 3 recipients was unremarkable and no rejection episode occurred. Significant complications were observed in one donor (percutaneously drained bilioma and spontaneously resolved popliteal sensory palsy). Living-donor right liver transplantation is a potentially valuable solution to the increasing shortage of donor organs. The procedure can be performed safely provided stringent criteria for donor selection, for donor-recipient coupling (1% graft to body weight ratio) and for centre selection (experience in liver surgery, reduced and split liver transplantation) are applied.

A patient with chronic hepatitis B virus (HBV) and chronic renal failure received a renal transplantation. Hepatitis B surface antigen (HBsAg) disappeared, and antibodies to HBsAg appeared 10 months before transplantation. Liver tests showed no abnormality at transplantation. Six months later, chronic hepatitis reactivated, antibodies to HBsAg disappeared, and HBsAg reappeared. Hepatitis B virus DNA was demonstrated with polymerase chain reaction in the serum collected before transplantation. This observation suggests that low level HBV replication was present before transplantation despite the absence of detectable HBsAg and was reactivated under immunosupressive therapy after transplantation.

Chronic hepatitis C is often associated with liver iron overload, which may affect the long-term prognosis and the response to antiviral treatment. The occurrence of hemochromatosis (HFE) mutations were studied to determine whether may contribute to the liver iron overload of chronic hepatitis C patients. The prevalence of two HFE mutations (C282Y and H63D) in 120 chronic hepatitis C patients was determined and the findings were correlated with clinical, histological and virological features. Hepatic iron was determined semiquantitatively by a histochemical hepatic iron index, defined as the ratio of a histochemical staining score to the patient's age, after correction for heterogeneous lobular iron distribution. Serum hepatitis C virus (HCV) RNA was measured by bDNA assay and typed by restriction fragment length polymorphism. Liver HCV RNA was measured by a semi-quantitative strand-specific reverse transcription-polymerase chain reaction (RT-PCR). Excess liver iron was stained in the liver of 36 patients (30%). Siderotic patients had the same geographic origin, serum and liver HCV RNA levels and H63D and C282Y mutations frequency as non-siderotic patients. However, siderotic patients were older (P = 0.015), more frequently males (P = 0.02), less frequently infected with HCV genotype 3 (P = 0.037) and had a higher liver fibrosis score (P = 0.008). The liver iron content did not correlate with the serum or liver HCV RNA titers. Ten of the 36 patients with liver siderosis had neither a history of excess alcohol intake, multiple transfusions, or HFE mutations. In conclusion, the pathogenesis of the liver iron overload in chronic hepatitis C patients cannot be fully explained by the occurrence of HFE mutations. The exact mechanism of iron accumulation in these patients therefore remains unexplained. J. Med. Virol. 60:21–27, 2000. © 2000 Wiley-Liss, Inc.

Between July 1987 and August 1998, 173 orthotopic liver transplantations (OLT) were performed in Geneva. We studied a homogeneous group of 114 OLT performed during the 6 years between 1992 and 1997 on 107 patients (89 adults and 18 children; 7 retransplantations). Although Geneva has the largest transplantation programme in Switzerland and is the only centre performing paediatric liver transplantation, the mean number of procedures per year was 19, corresponding to only a small transplantation programme in Europe. It could be reasonably questioned, therefore, whether Swiss patients are not at a disadvantage as compared with patients from European countries with larger liver transplantation centres. Although the perioperative morbidity was still considerable, the results of this series -90% of actuarial patient survival at 1 and 2 years and 84% at 5 years-compare favourably with the results of the European Liver Transplantation Registry: 76% of actuarial patient survival at 1 year and 65% at 5 years. In this series, 95 patients (89%) were alive on January 1, 1998. As no patient was refused on the severity of the liver disease and as more than 10% of OLT were performed as emergencies, a bias due to the selection of the best cases cannot explain the good results. This series demonstrates that a small liver transplantation centre may obtain results that compare favourably with the results of large European centres, and that Swiss patients are not at a disadvantage as compared with patients of other European countries.

Cancer chemotherapy in chronic carriers of hepatitis B virus is known to promote viral replication, and, when immunosuppressive treatment is stopped, the return of immune competence can be followed by a fulminant hepatitis. Liver transplantation may be required and has been successfully performed for this condition. However, malignancy recurrence after transplantation has not been reported yet.We here report the case of an asymptomatic hepatitis B surface antigen carrier who developed a malignant lymphoma, which was treated by chemotherapy. After cessation of chemotherapy, he developed a fulminant hepatitis, requiring liver transplantation. Three years later, he developed a recurrent malignant lymphoma, which was treated successfully by autologous bone marrow transplantation. In order to prevent viral replication, lamivudine and intermittent administration of fresh-frozen plasma highly concentrated in anti-HBs immunoglobulin was initiated before the bone marrow transplantation. The patient remains well 12 and 56 months after autologous bone marrow and liver transplantation, respectively.This experience suggests that all hepatitis B surface antigen-positive patients for whom chemotherapy is indicated would benefit from prophylactic antiviral hepatitis B virus therapy. Furthermore, successful autologous bone marrow transplantation is possible after liver transplantation.

Tacrolimus is metabolized by cytochrome P450 3A4 and 2D6 and has a narrow therapeutic range. We report a serious kinetic interaction between tacrolimus and mibefradil, a potent cytochrome P450 inhibitor.A 62-year-old women who had undergone liver transplantation was treated with tacrolimus for immunosuppression. For control of blood pressure, the patient was treated with nifedipine. She developed ankle edema, and nifedipine was replaced by mibefradil. Four days later, she presented with mental confusion, renal failure, and hyperglycemia, compatible with tacrolimus toxicity. In agreement with this assumption, the tacrolimus blood concentration was 100 ng/ml. Mibefradil and tacrolimus were both stopped, and the patient recovered within 1 week. Eight days after stopping mibefradil, tacrolimus was restarted at the same dosage and the subsequent plasma concentrations remained in the therapeutic range.Mibefradil increases the tacrolimus blood concentration by inhibiting its metabolism and should, therefore, not be used in patients treated with tacrolimus.

Introduction Les troubles du sommeil, chez les cirrhotiques sont ameliores par certains anti-histaminergiques. Les effets neuropsychologiques de l’hydroxyzine, un anti-histaminergique H1 chez le cirrhotique sont mal connus. Objectifs S’assurer de l’absence de deterioration cognitive chez les patients avec cirrhose qui recoivent un anti- histaminique H1, l’hydroxyzine dans le but de retablir un rythme circadien physiologique. Methodes Trente-cinq patients cirrhotiques avec encephalopathie hepatique minime et sommeil fragmente, non deprimes, durablement abstinent d’alcool et sans traitement de psychotropes ont ete randomises en double aveugle sur une periode de 18 mois. Un bras (n = 15) a recu 25 mg/jour d’hydroxyzine, un autre (n = 18) le placebo. Une evaluation neuropsychologique, orientee sur les fonctions executives (fluence, Trail making), l’attention (code et D2) et la memoire (Buschke 16 items) a ete effectuee avant et apres traitement. Resultats Il n’y avait pas de correlation entre la severite des troubles du sommeil et des troubles cognitifs avant traitement. Tous les patients, sous hydroxyzine, ont ameliore tant subjectivement qu’objectivement leur sommeil. La moyenne de Z-score des differents tests ne montrent aucune modification (placebo t = 1.6, t2 = 1.76 ; hydroxyzine t1 = 1,2, t2 = 1,15 ; ANOVA, F (1,28) = 0,38, p = 0,54). Les moyennes de chaque test sont egalement stables. Un patient, sous hydroxyzine, a aggrave de maniere reversible son encephalopathie. Discussion Ces resultats montrent une stabilite des performances cognitives, chez les cirrhotiques avec encephalopathie hepatique sous hydroxyzine comme sous placebo, alors que cet antihistaminique H1 ameliore selectivement la rythmicite nycthemerale. L’amelioration du sommeil se fait independamment de l’evolution des performances cognitives. Conclusion Contrairement a certains autres antihistaminiques, l’hydroxyzine n’aggrave pas les fonctions cognitives et peut etre utilisee chez les patients cirrhotiques avec encephalopathie hepatique minime, avec la surveillance d’usage.

Background/Aims: The aims of the study were to determine, in patients with chronic hepatitis C treated with alpha interferon: (i) changes in the morphometric evaluation of liver fibrosis at the end of treatment and 6, 12 and 18 months after treatment; (ii) the predictive value of histologic lesions for the response to treatment, in particular the predictive value of morphometric evaluation of liver fibrosis. Methods: Seventy patients with chronic hepatitis C who participated in two trials of recombinant interferon alpha 2b treatment were studied. Liver specimens were obtained before and at the end of treatment and 6, 12 or 18 months later. Histologic lesions were assessed according to the Knodell system. Quantitative study of total fibrosis and of Disse space collagen was done by the computerized automated morphometric method. Results: A significant decrease in morphometric Disse space collagen was observed at the end of treatment and 6 months later. This decrease was also observed, although it was not significant, 12 and 18 months after treatment. There was no relationship between this decrease and the biochemical and virological responses or the dose of interferon. The pretreatment Knodell activity score, but not the morphometric evaluation of fibrosis, was a significant predictor of sustained response. Conclusion: A decrease in Disse space collagen, as assessed by the sensitive morphometric method, was observed at the end of and 6 months after treatment. This observation is consistent with an anti-fibrogenetic effect of alpha interferon. Mild or moderate histologic activity was associated with a sustained response to therapy.

HEPATIC STELLATE CELLS (HSCs) are located in the Disse's spaces in close contact with hepatocytes on one side and endothelial cells on the other; they participate in retinoid metabolism. 1–3 During the last years, it has been shown that HSCs modulate into myofibroblasts in response to liver tissue injury. 2,4–6 This process is characterized by the loss of vitamin A containing lipid droplets coupled with the acquisition of several ultrastructural and biochemical features of smooth muscle (SM) cells. The most accepted marker of this modulation is α-SM actin expression. 5 Myofibroblasts play a key role in hepatic fibrogenesis because they are responsible for production of the excessive extracellular matrix deposits. 6 Generally, the modulation of mesenchymal cells toward the myofibroblastic phenotype is considered an irreversible and possibly terminal change. 7 Ischemia reperfusion injury is a potentially reversible complication that may develop after many types of liver surgery, including transplantation and tumor resection, as well as circulatory shock of different origins. This study was undertaken to analyze HSC changes during this condition. During the acute ischemia reperfusion injury due to liver transplantation in humans or during ex vivo pig liver perfusion, HSCs express significant amounts of α-SM actin coupled with the appearance of intracytoplasmic microfilaments. These changes are reversible, suggesting that α-SM actin expression is not necessarily related to the modulation of HSCs into myofibroblasts but may reflect other functional adaptations of these cells.

IN THE ABSENCE of passive immunoprophylaxis, the recurrence rate of hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) is as high as 80%, possibly due to the presence of HBV in extrahepatic sites. 1 The European multicenter study has shown that the administration of antibodies to hepatitis B surface antigen (anti-HBs) immune globulins was associated with a reduced risk of HBV recurrence in hepatitis B surface antigen (HBsAg)-positive OLT recipients with low levels of viral replication, and that patients who remained HBsAg-negative after transplantation had a better overall actuarial survival. 2 These data underscore the need for long-term administration of anti-HBs immune globulins in HBsAg-positive patients after liver transplantation. However, despite regular administration of anti-HBs immune globulins to maintain serum anti-HBs levels higher than 100 international units per liter (IU/L), the reinfection rate is still approximately 30% 2 years after transplantation. 3 These results suggest that a serum anti-HBs level of 100 IU/L may be too low to confer protection against HBV recurrence and that, to further reduce the HBV reinfection rate, a serum anti-HBs level of 200 to 500 IU/L may be more effective. 4 However, the cost of such immunoprophylaxis might be deemed too expensive by insurance companies. It has been estimated that the cost of standard prophylaxis may be as high as US$ 30,000 for the first year, 5 prompting Medicare to exclude HBsAg-positive patients from liver transplantation coverage. 5 Addressing the cost issue, we explored an alternative approach by using fresh frozen plasma (FFP) from blood donors with past HBV infections, selected on the basis of high anti-HBs antibody titers. The present report evaluated the efficacy, safety, and cost of this prophylaxis.

Type I familial amyloid polyneuropathy (FAP), or Andrade's disease, is an inherited autosomal dominant disease, always fatal, involving mixed progressive polyneuropathy associated with systemic amyloid deposits. The disease is secondary to mutations of a gene (located on chromosome 18) which encodes for a serum protein, transthyretin. This variant protein is essentially (90%) produced in the liver and constitutes the biological marker of the disease. Many surgical teams have established a liver transplantation program for this non-cirrhotic pathology. Between January and August 1994, we performed three orthotopic liver transplantations (OLT) in patients with FAP. The patients were men aged between 30 and 33 years and the mean duration of symptoms was 3 years. The diagnosis of FAP was confirmed by rectal biopsy and detection of the genetic mutation (PCR analysis). All patients presented a severe sensory, motor and autonomic neuropathy with major digestive and urologic dysfunction. Two other patients were not accepted for OLT because of advanced disease with ulcerous lesions of the inferior limbs and cardiopathy. All patients survived with excellent post-operative hepatic function. One month after OLT, one patient had hepatocellular rejection which responded favorably to steroids. Another patient developed post-transfusional B hepatitis 10 months after the graft, but without major hepatic lesions. In the three cases, we observed stabilization of the peripheral neuropathy and an objective improvement of the autonomic affection (neurogenic bladder, diarrhea). The patients who did not undergo transplantation died within a year. Thus, in patients suffering from familial amyloid polyneuropathy OLT must be performed, especially in the early stage of the disease and especially in young patients before serious neurological complications set in.

Small bowel transplantation is theoretically the best treatment for patients with short bowel syndrome and receiving total parenteral nutrition (TPN). The aim of our study was to determine the number of potential candidates for small bowel transplantation in Switzerland. We analyzed the clinical parameters of patients treated by TPN for short bowel syndrome obtained from university pediatric clinics, the SVK (Schweizerischer Verband für Gemeinschaftsaufgaben der Krankenkassen) and referring physicians. In 1995, 7 adults and 2 children were under TPN for short bowel syndrome. In the adult group (mean age 57), the causes of short bowel syndrome were 3 cases of mesenteric infarct, 2 cases of mechanical ileus, one Gardner syndrome and one inflammatory bowel disease. In the pediatric group, the causes of intestinal insufficiency were in one chronic enteropathy with malabsorption and in one congenital malformation. The average duration of TPN was 4.4 (1-10) years for the adults and 13 months for the children. The various complications related to TPN were repeated catheter sepsis in 5 patients, 2 cases of catheter thrombotic occlusion and 3 cases of cholestatic hepatopathy. The contraindications to small bowel transplantation were age, a history of malignant tumor, pulmonary hypertension and a psychiatric disorder. 4 patients were considered potential candidates for transplantation: 2 adults and 2 children, corresponding to an incidence of 0.5/million inhabitants. Considering that the prevalence and incidence of short bowel syndrome in Switzerland are comparable to those in other western countries, we think it should be possible to initiate a small bowel transplantation program in Switzerland.