Impact of new DAA therapy on real clinical practice: a multicenter region-wide cohort study.

BACKGROUND: Management of chronic hepatitis C (CHC) has significantly accelerated in the last few years. Currently, second generation direct acting antivirals (DAAs) promise clearance of infection in most of patients. Here we present the results of the first analysis carried out on data of Lazio clinical network for DAAs. METHODS: The study was designed as a multicenter cohort: a) to assess the evolution of treatment during the first 24 months of the activity of the Clinical Network; b) to report overall efficacy of treatments; c) to analyze potential factors associated with lack of virological response at 12 weeks after therapy (SVR12); d) to evaluate the variation of ALT at baseline and 12 weeks after therapy in those who achieved SVR12 in comparison to those who did not. Analyses of efficacy were carried out with multilevel mixed effect logistic regression model. ALT temporal variation was assessed by mixed effect model mixed models with random intercept at patient's level and random slope at the level of the time; i.e. either before or after therapy. RESULTS: Between 30 December 2014 and 31 December 2016 5279 patients started a DAA treatment; of those, 5127 (in 14 clinical centers) had completed the 12-week follow-up. Overall proportion of SVR12 was 93.41% (N = 4780) with no heterogeneity between the 14 clinical centers. Interruption as the consequence of severe side effect was very low (only 23 patients). Unadjusted analysis indicates that proportion of SVR12 significantly changes according to patient's baseline characteristics, however after adjusting for potential confounders only adherence to current guidelines, stage of liver diseases, gender, transplant and HIV status were independently associated with the response to therapy. Analysis of ALT temporal variation showed that ALT level normalized in most, but not, all patients who achieved SVR12. CONCLUSION: Our study confirmed the extraordinary efficacy of DAAs outside clinical trials. The advantage of DAAs was particularly significant for those patients who were previously considered as difficult-to-treat and did not have treatment options before DAAs era. Intervention based on network of select centers and prioritization of patients according to diseases severity was successful. Further studies are needed to establish whether clearance of HCV after DAAs therapy can arrest or even revert liver fibrosis in non-cirrhotic patients and/or improve life quality and expectancy in those who achieve SVR12 with cirrhosis.

Prognostic ability of BCLC-B Subclassification in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

Prognostic ability of BCLC-B Subclassification in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization Background and aims. A subclassification system for intermediate hepatocellular carcinoma (HCC) was recently proposed to optimize treatment allocation. The aim of this study was to assess the prognostic ability of that substaging proposal. PATIENTS AND METHODS: This is a retrospective multicenter cohort study including patients with intermediate HCC treated with transarterial chemoembolization (TACE). Predictors of survival were identified using the Cox proportional regression model. RESULTS: 289 Barcelona Clinic Liver Cancer (BCLC) B patients were included. Median overall survival of the whole cohort was 23 months (C.I. 95% 20.2- 25.8). Child A status (H.R. 1.35, C.I. 95% 1.02-1.78) and tumour burden beyond the up-to-seven criterion (H.R. 1.39, C.I. 95% 1.07- 1.80) were independent prognostic factors for overall survival on multivariate analysis. Analysis of the substages showed that median survival was 33.0 months for B1 stage (n = 81), 20.8 months for B2 stage (n = 106), 16.1 months for B3 stage (n = 24), 22.2 months for B4 stage (n = 42) and 15.0 months for quasi-C stage (n = 36). Regarding the discriminatory ability of the substaging proposal, the log rank test showed a significant survival difference for B1vs. B4 (p = 0.003) and B1 vs. Quasi-C (p = 0.039) and a trend for B1 vs. B2 (p = 0.05) and B1 vs. B3 (p = 0.05). CONCLUSIONS: Apart from substage B1, BCLC-B subclassification does not discriminate perfectly patients treated with TACE. Also some patients in substage B4 can benefit from TACE.

Patterns of treatment and costs of intermediate and advanced hepatocellular carcinoma management in four Italian centers.

BACKGROUND: Hepatocellular carcinoma (HCC) is a severe health condition associated with high hospitalizations and mortality rates, which also imposes a relevant economic burden. PURPOSE: The aim of the present survey is to investigate treatment strategies and related costs for HCC in the intermediate and advanced stages of the disease. PATIENTS AND METHODS: The survey was conducted in four Italian centers through structured interviews with physicians. Information regarding the stage of disease, treatments performed, and related health care resource consumption was included in the questionnaire. Direct health care cost per patient associated with the most relevant treatments such as sorafenib, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE) was evaluated. RESULTS: Between 2013 and 2014, 285 patients with HCC were treated in the four participating centers; of these, 80 were in intermediate stage HCC (Barcelona Clinic Liver Cancer Classification [BCLC] B), and 57 were in the advanced stage of the disease (BCLC C). In intermediate stage HCC, the most frequent first-line treatment was TACE (63%) followed by sorafenib (15%), radiofrequency ablation (14%), and TARE (1.3%). In the advanced stage of HCC, the most frequently used first-line therapy was sorafenib (56%), followed by best supportive care (21%), TACE (18%), and TARE (3.5%). The total costs of treatment per patient amounted to €12,214.54 with sorafenib, €13,418.49 with TACE, and €26,106.08 with TARE. Both in the intermediate and in the advanced stage of the disease, variability in treatment patterns among centers was observed. CONCLUSION: The present analysis raises for the first time the awareness of the overall costs incurred by the Italian National Healthcare System for different treatments used in intermediate and advanced HCC. Further investigations would be important to better understand the effective health care resource usage.

[Therapeutic decisions and treatment with sorafenib in hepatocellular carcinoma: final analysis of GIDEON study in Italy]. / Scelte terapeutiche e trattamento con sorafenib nell'epatocarcinoma: analisi finale dello studio GIDEON in Italia.

INTRODUCTION: Sorafenib, an oral multikinase inhibitor, is the only targeted agent approved for the treatment of patients with hepatocellular carcinoma (HCC) after demonstration to increase overall survival compared to placebo in two randomized phase III study. GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) is the largest, global, non-interventional, prospective study of patients with uHCC (n>3200) treated with sorafenib in real-life clinical practice conditions. Here we report the final analysis of safety and efficacy in the Italian cohort of patients. METHODS: Patients with unresectable HCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Patients demographics disease characteristics and treatment history were recorded at baseline visit. Sorafenib dose, concomitant medications, performance status, liver function, adverse events and efficacy (survival and response rate) were collected throughout the study. RESULTS: In the Italian cohort of the GIDEON study 278 patients were included in 36 centers. The global rate of adverse events was 81%. Drug-related events accounted for 67%, mostly of grade 1 and 2, and only 8% were classified as serious. The most common were diarrhea (24%), fatigue (23%), dermatological (14%), rash/exfoliation (10%), hypertension (9%), hemorrage/bleeding of gastrointestinal tract (6%). Overall survival was 14.4 months and time to progression 6.2 months. Objective responses were observed in 14 patients (5%) with 3 complete responses (1%). Stable diseases of at least 6 weeks were observed in 113 patients (41%) with a 30% of disease control rate. DISCUSSION: The safety profile of sorafenib in terms of rate and type of adverse events is similar to that emerged in the global international GIDEON study as well as in the pivotal registration studies.

Woodchuck hepatitis virus core gene deletions and proliferative responses of peripheral blood mononuclear cells stimulated by an immunodominant epitope: a viral immune escape in the woodchuck model of chronic hepatitis B?

Marmota monax and its natural infection by woodchuck hepatitis virus (WHV) could be used as a predictive model for evaluating mechanisms of viral persistence during chronic hepatitis B virus (HBV) infection. The aim of this study was to investigate the presence of viral variants in the core gene of chronically WHV-infected woodchucks that showed two different patterns of peripheral blood mononuclear cells' (PBMCs') responses after stimulation with a specific WHV core peptide. Sequences' analysis of the WHV core region from eight WHV chronically infected woodchucks have been performed after in vitro stimulation with an immunodominant epitope of the WHV core protein (amino acids [aa] 96-110). Following this stimulation, positive PBMC responses at each point of follow-up were observed for four animals (group A), and weak immune responses at one or a few points of follow-up were observed for the remaining four animals (group B). The WHV core gene sequences contained amino acid deletions (aa 84-126, aa 84-113) in three of four group A animals and in none of group B animals. In the group A animals, the same deletions were observed in liver specimens and in two of four tumor specimens. Hepatocellular carcinoma (HCC) was diagnosed in all group A animals and in one group B animal. In conclusion, internal deletions in the core region correlated with a sustained PBMC response to the immunogenic peptide (96-110) of the core protein. A possible role of this relationship in hepatocarcinogenesis could be hypothesized; however, this needs to be investigated in patients with chronic HBV infection. The evaluation of virus-specific T-cell responses and T-cell epitopes that are possibly related to the mechanisms of viral evasion should be further investigated in order to design combined antiviral and immune approaches to control chronic HBV infection.

Transplantation of human fetal biliary tree stem/progenitor cells into two patients with advanced liver cirrhosis.

BACKGROUND: Efforts to identify cell sources and approaches for cell therapy of liver diseases are ongoing, taking into consideration the limits recognized for adult liver tissue and for other forms of stem cells. In the present study, we described the first procedure of via hepatic artery transplantation of human fetal biliary tree stem cells in patients with advanced cirrhosis. METHODS: The cells were immune-sorted from human fetal biliary tree by protocols in accordance with current good manufacturing practice (cGMP) and extensively characterized. Two patients with advanced liver cirrhosis (Child-Pugh C) have been submitted to the procedure and observed through a 12 months follow-up. RESULTS: The resulting procedure was found absolutely safe. Immuno-suppressants were not required, and the patients did not display any adverse effects correlated with cell transplantation or suggestive of immunological complications. From a clinical point of view, both patients showed biochemical and clinical improvement during the 6 month follow-up and the second patient maintained a stable improvement for 12 months. CONCLUSION: This report represents proof of the concept that the human fetal biliary tree stem cells are a suitable and large source for cell therapy of liver cirrhosis. The isolation procedure can be carried out under cGMP conditions and, finally, the infusion procedure is easy and safe for the patients. This represents the basis for forthcoming controlled clinical trials.

Hepatocellular carcinoma in cirrhotic patients with transjugular intrahepatic portosystemic shunt: a retrospective case-control study.

BACKGROUND: An association between Transjugular Intrahepatic Porto-Systemic Shunt (TIPS) and the development of hepatocellular carcinoma in patients with cirrhosis has been suggested, but not confirmed. AIM: To evaluate the potential role of TIPS in hepatocellular carcinoma development. METHODS: We performed a retrospective case-control study among patients with cirrhosis; all cases had undergone TIPS placement. Cases and controls were followed as outpatients at a single liver care centre in the same timeframe. RESULTS: Overall, 101 patients with cirrhosis (mean age 58 ± 9 years, 64.3% male) were included in each group. Median duration of follow-up was 56.7 months (range 8.2-174.5) for TIPS patients and 67.8 months (range 8.3-183.1) for controls (p=0.08). In both groups 94% of patients had Child-Pugh Class A or B cirrhosis. The cumulative incidence of hepatocellular carcinoma at 1, 3, 5, and 10 years was 2%, 7%, 18%, and 46% among TIPS patients, and 3%, 10%, 19%, and 39% among controls (log rank test p=0.19). Compared to controls, hepatocellular carcinoma nodules in TIPS patients were more frequently situated in the right lobe (p<0.05). CONCLUSIONS: TIPS does not seem to increase the risk of hepatocellular carcinoma in patients with Child-Pugh Class A or B cirrhosis; for these patients ultrasound surveillance should not be modified.

PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis.

BACKGROUND & AIMS: Environmental and genetic factors contribute to alcoholic cirrhosis onset. In particular, age at exposure to liver stressors has been shown to be important in progression to fibrosis in hepatitis C individuals. However, no definite data on the role of age at onset of at-risk alcohol consumption are available. Moreover, patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M (rs738409) variant has been associated with alcoholic cirrhosis, but only in cross-sectional studies. The aim of this study was to investigate the role of age at onset of at-risk alcohol consumption and PNPLA3 I148M variant on alcoholic cirrhosis incidence. METHODS: A total of 384 at-risk alcohol drinkers were retrospectively examined. The association among age at onset of at-risk alcohol consumption, PNPLA3 I148M variant and cirrhosis incidence was tested. RESULTS: A higher incidence of alcoholic cirrhosis was observed in individuals with an older (≥24 years) compared with a younger (<24) age at onset of at-risk alcohol consumption (P-value < 0.001). Moreover, PNPLA3 148M allele carriers showed an increased incidence of cirrhosis (P-value < 0.001). Both age at onset of at-risk alcohol consumption and PNPLA3 148M allele were independent risk factors for developing cirrhosis (H.R. (95% C.I.): 2.76 (2.18-3.50), P-value < 0.001; 1.53(1.07-2.19), P-value = 0.021 respectively). The 148M allele was associated with a two-fold increased risk of cirrhosis in individuals with a younger compared with an older age at onset of at-risk alcohol consumption (H.R. (95% C.I.): 3.03(1.53-6.00) vs. 1.61(1.09-2.38). CONCLUSIONS: Age at onset of at-risk alcohol consumption and PNPLA3 I148M genetic variant are independently associated with alcoholic cirrhosis incidence.

Recipient perioperative cholesterolaemia and graft cholesterol metabolism gene expression predict liver transplant outcome.

BACKGROUND & AIMS: We analysed for the first time whether recipient perioperative serum total cholesterol (sTC) concentration is associated with liver transplantation outcome. METHODS: We studied noncholestatic cirrhotics submitted to primary deceased-donor liver transplantation in a prospective group (n=140) from Rome and in a validation retrospective cohort (n=157) from Udine, Italy. Pre-ischaemia and post-reperfusion cholesterol metabolism gene mRNA was measured by RT-PCR in 74 grafts of the study group. RESULTS: At Cox regression analysis, independently from confounders including recipient MELD score, the recipient pre-operative sTC pooled quintiles 2-5, compared with the lowest quintile showed HR (95% CI) and significances for overall graft loss (GL) of 0.215 (0.104-0.444) P<0.001 in the study group and 0.319 (0.167-0.610) P=0.001 in the validation cohort. Analysing sTC as a continuous variable, the risk of overall GL for every 10-mg/dl decrease in pre-operative sTC increased by 13% and by 9% in the study group and in the validation cohort respectively. In the study group, independent associations at multivariate analyses were: (a) high graft pre-ischaemia expression of INSIG-1, which indicates hepatocellular cholesterol depletion, with post-reperfusion graft necrosis; (b) GL with inadequate graft post-reperfusion response to cholesterol depletion, shown by a failure to reduce the PCSK9 to LDLR expression ratio; (c) GL with a relative increase of sTC on post-operative day-7, selectively because of the LDL fraction, which indirectly suggests poor cholesterol uptake from blood. CONCLUSIONS: Low recipient pre-transplant sTC concentration, its post-operative day-7 increase and a genetically determined low graft cholesterol availability predict poor liver transplant outcome.

Beneficial effect of sulphate-bicarbonate-calcium water on gallstone risk and weight control.

AIM: To investigate the effect of drinking sulphate-bicarbonate-calcium thermal water (TW) on risk factors for atherosclerosis and cholesterol gallstone disease. METHODS: Postmenopausal women with functional dyspepsia and/or constipation underwent a 12 d cycle of thermal (n = 20) or tap (n = 20) water controlled drinking. Gallbladder fasting volume at ultrasound, blood vitamin E, oxysterols (7-ß-hydroxycholesterol and 7-ketocholesterol), bile acid (BA), triglycerides, total/low density lipoprotein and high density lipoprotein cholesterol were measured at baseline and at the end of the study. Food consumption, stool frequency and body weight were recorded daily. RESULTS: Blood lipids, oxysterols and vitamin E were not affected by either thermal or tap water consumption. Fasting gallbladder volume was significantly (P < 0.005) smaller at the end of the study than at baseline in the TW (15.7 ± 1.1 mL vs 20.1 ± 1.7 mL) but not in the tap water group (19.0 ± 1.4 mL vs 19.4 ± 1.5 mL). Total serum BA concentration was significantly (P < 0.05) higher at the end of the study than at baseline in the TW (5.83 ± 1.24 µmol vs 4.25 ± 1.00 µmol) but not in the tap water group (3.41 ± 0.46 µmol vs 2.91 ± 0.56 µmol). The increased BA concentration after TW consumption was mainly accounted for by glycochenodeoxycholic acid. The number of pasta (P < 0.001), meat (P < 0.001) and vegetable (P < 0.005) portions consumed during the study and of bowel movements per day (P < 0.05) were significantly higher in the TW than in the tap water group. Body weight did not change at the end of the study as compared to baseline in both groups. CONCLUSION: Sulphate-bicarbonate-calcium water consumption has a positive effect on lithogenic risk and intestinal transit and allows maintenance of a stable body weight despite a high food intake.

Ribavirin priming improves the virological response to antiviral treatment in transplanted patients with recurrent hepatitis C: a pilot study.

INTRODUCTION: Patients with hepatitis C recurrence after liver transplantation represent a clinical challenge. Antiviral treatment in transplant patients has usually poor tolerability and limited efficacy, with a mean sustained virological response (SVR) of 30%. Our pilot study was aimed at evaluating whether 8-week ribavirin pre-treatment could increase either adherence or antiviral effect of a 48-week combination therapy. METHODS: Ribavirin pre-treatment (8 weeks) was started with 600 mg daily and increased to 10.4 mg/kg/day. After pre-treatment, 1.5 µg/kg/week pegylated interferon-α2b was added for 48 additional weeks of combination therapy. Blood count, liver function tests and plasma HCV-RNA were examined monthly. Ribavirin plasma concentrations were determined by HPLC. RESULTS: Thirteen patients (mean age 53±2 years, 11 males) were treated: eight were HCV genotype 1/4; five were genotype 2/3. The median baseline HCV RNA level was 6.5 log(10) (range 5.84-7.42 log(10)). During ribavirin pre-treatment the median HCV RNA levels decreased significantly (5.7 log(10) ; P=0.023). During combination therapy 6/13 (46%) patients exhibited a rapid virological response (RVR) and 10/13 (77%) patients a complete early virological response, two were non-responders. A decline of 0.5 log(10) HCV RNA during pre-treatment predicted RVR. SVR occurred in six patients (46%): four were genotype 2/3. Stable ribavirin dose reduction was required in only two patients (15%) in whom transient interferon reduction was also required. CONCLUSION: This proof-of-concept study indicates that ribavirin pre-treatment increased the tolerability of the antiviral treatment, and improved its efficacy in liver transplant patients. Moreover, the degree of HCV RNA decline during pre-treatment allowed one to predict on-treatment response.

Transjugular intrahepatic portosystemic shunt with expanded-polytetrafuoroethylene-covered stents in non-cirrhotic patients with portal cavernoma.

AIMS: To evaluate the feasibility and efficacy of Transjugular intrahepatic portosystemic shunt (TIPS) in non-cirrhotic patients with symptomatic portal hypertension secondary to portal cavernoma. METHODS: Our cohort includes 13 consecutive patients. Eleven were considered for Transjugular intrahepatic portosystemic shunt placement for complications not manageable by medical/endoscopic treatment and two because of the need of oral anticoagulation in presence of high-risk varices. Expanded-polytetrafluoroethylene-covered stents were used in all. RESULTS: One of the 13 patients was excluded because of a thrombosis of the superior cava and jugular veins. In 10 patients, Transjugular intrahepatic portosystemic shunt was successfully implanted [83.3%; 95% confidence interval: 52-98%]. One patient had an early shunt dysfunction with recurrence of variceal bleeding which required an emergency surgical shunt. Late shunt dysfunction occurred in two patients, successfully treated with angioplasty and re-stenting. Two patients experienced an episode of encephalopathy. CONCLUSIONS: Transjugular intrahepatic portosystemic shunt is feasible in most of the patients with portal cavernoma and should be considered in those with severe complications uncontrolled by conventional therapy. The use of Transjugular intrahepatic portosystemic shunt to achieve a lifelong anticoagulation therapy in selected patients with high-risk varices may be another possible indication. These patients should be referred to selected Units with large experience in Transjugular intrahepatic portosystemic shunt placement.

Cirrhotic patients are at risk for health care-associated bacterial infections.

BACKGROUND & AIMS: Bacterial infections are a frequent and serious burden among patients with cirrhosis because they can further deteriorate liver function. We assessed the epidemiology, risk factors, and clinical consequences of bacterial infections in hospitalized cirrhotic patients. METHODS: In a cohort of hospitalized cirrhotic patients (n = 150) referred to a tertiary care setting, all episodes of bacterial infections were recorded prospectively. Infections were classified as community-acquired (CA), health care-associated (HCA), or hospital-acquired (HA). Site of infection, characteristics of bacteria, and prevalence of antibiotic resistance were reported; consequences for liver function and patient survival were evaluated. RESULTS: Fifty-four infections were observed among 50 patients (12 CA, 22 HCA, and 20 HA). Bacterial resistance was more frequent among patients with HCA or HA infections (64% of isolates). Mortality was 37% from HA, 36% from HCA, and 0% from CA infections. Independent predictors of infection included a previous infection within the past 12 months (P = .0001; 95% confidence interval [CI], 2.2-10.6), model of end-stage liver disease score ≥ 5 (P = .01; 95% CI, 1.3-6.1), and protein malnutrition (P = .04; 95% CI, 1.5-10). Infectious episodes worsened liver function in 62% of patients. Patients with infection more frequently developed ascites, hepatic encephalopathy, hyponatremia, hepatorenal syndrome, or septic shock. Child class C (P = .006; 95% CI, 1.67-23.7), sepsis (P = .005; 95% CI, 1.7-21.4), and protein malnutrition (P = .001; 95% CI, 2.8-38.5) increased mortality among patients in the hospital. CONCLUSIONS: In hospitalized cirrhotic patients, the most frequent infections are HCA and HA; these infections are frequently resistant to antibiotics. As infections worsen, liver function deteriorates and mortality increases. Cirrhotic patients should be monitored closely for infections.

Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with different diameters: results of a randomized controlled trial.

BACKGROUND & AIMS: The incidence of post-TIPS hepatic encephalopathy (HE) could be reduced by using stents with a small diameter. The aim of this study was to compare the incidence of HE and the clinical efficacy of TIPS created with 8- or 10-mm PTFE-covered stents. METHODS: Consecutive cirrhotics submitted to TIPS for variceal bleeding or refractory ascites were randomized to receive a 8- or 10-mm covered stent. As recommended by our Ethical Committee, the trial was stopped after the inclusion of 45 patients. RESULTS: The two groups were comparable for age, sex, etiology, and psychometric performance. After TIPS, the portosystemic pressure gradient was significantly higher in the 8-mm stent group (8.9+/-2.7 versus 6.5+/-2.7 mmHg; p=0.007). Consequently, the probability of remaining free of complications due to portal hypertension was significantly higher in the 10-mm than in the 8-mm stent group: 82.9% versus 41.9% at one year; log-rank test, p=0.002. In particular, the persistence of ascites with the need for repeated paracentesis was significantly more frequent in the patients treated with 8-mm stent diameter for refractory ascites (log-rank test, p=0.008). The probability of remaining free of HE was similar in both groups. Cumulative survival rate was similar in both groups. CONCLUSIONS: The use of 8-mm diameter stents for TIPS leads to a significantly less efficient control of complications of portal hypertension. HE remains an unsolved major problem after TIPS.

Natural history of gallstone disease: Expectant management or active treatment? Results from a population-based cohort study.

BACKGROUND AND AIMS: The knowledge of natural history is essential for disease management. We evaluated the natural history (e.g. frequency and characteristics of symptoms and clinical outcome) of gallstones (GS) in a population-based cohort study. METHODS: A total of 11 229 subjects (6610 men, 4619 women, age-range: 29-69 years, mean age: 48 years) were studied. At ultrasonography, GS were present in 856 subjects (338 men, 455 women) (7.1%). GS were followed by means of a questionnaire inquiring about the characteristics of specific biliary symptoms. RESULTS: At enrollment, 580 (73.1%) patients were asymptomatic, 94 (11.8%) had mild symptoms and 119 (15.1%) had severe symptoms. GS patients were followed up for a mean period of 8.7 years; 63 subjects (7.3%) were lost to follow up. At the end of the follow up, of the asymptomatic subjects, 453 (78.1%) remained asymptomatic; 61 (10.5%) developed mild symptoms and 66 (11.4%) developed severe symptoms. In subjects with mild symptoms, the symptoms disappeared in 55 (58.5%), became severe in 23 (24.5%), remained stable in 16 (17%); in subjects with severe symptoms, the symptoms disappeared in 62 (52.1%), became mild in 20 (16.8%) and remained stable in 37 (31.1%). A total of 189 cholecystectomies were performed: 41.3% on asymptomatic patients, 17.4% on patients with mild symptoms and 41.3% on patients with severe symptoms. CONCLUSIONS: This study indicates that: (i) asymptomatic and symptomatic GS patients have a benign natural history; (ii) the majority of GS patients with severe or mild symptoms will no longer experience biliary pain; and (iii) a significant proportion of cholecystectomies are performed in asymptomatic patients. Expectant management still represents a valid therapeutic approach in the majority of patients.

Atorvastatin-induced prolonged cholestasis with bile duct damage.

We report a case of acute-onset, long-lasting cholestasis induced by atorvastatin. This antihyperlipidaemic drug was taken for 40 days by a 72-year-old male as a treatment for his mixed dyslipidaemia. At that point, the patient presented with asthenia, nausea, painless icterus, acholic stools and hyperchromic urine with biochemical analyses showing a dramatic increase in bilirubin (total bilirubin 22 mg/dL; direct bilirubin 21 mg/dL) and alkaline phosphatase (up to 4-fold over the normal level) with less marked increases in transaminases. Liver histology showed a pattern of cholestasis with evident signs of cholangiolitis and damage of the interlobular bile ducts. Serum transaminase and bilirubin levels returned to normal within 5 months after atorvastatin withdrawal while alkaline phosphatase normalized after only 8 months. Scores on both the Maria and Victorino clinical scale for the diagnosis of drug-induced hepatitis and the Naranjo Adverse Drug Reaction Probability Scale indicated that atorvastatin was the probable cause of prolonged cholestasis in this patient. This is a rare case of cholestasis probably caused by atorvastatin and unusually characterized by bile duct damage.

Long-term effect of liver transplantation on cirrhotic autonomic cardiac dysfunction.

There is little information on the long-term effect of liver transplantation (LT) on cardiac autonomic dysfunction in cirrhotic patients. We compared cardiac autonomic function before and in the long-term after LT. In a transversal study, we investigated 30 cirrhotics awaiting LT, 15 clinically stable patients 2-6 years after LT and 27 healthy controls. Seven cirrhotic patients were studied before LT, and 6, 12 and 33 months after LT, in a prospective fashion. Cardiac autonomic function was measured by heart rate variability (HRV) analysis during 24-h electrocardiogram recording. In the transversal study, patients with cirrhosis as compared to healthy controls had significantly reduced standard deviation of normal-to-normal RR intervals (SDNN) (p<0.001) and of the square root of the mean of squared differences between adjacent NN intervals (RMS-SD) (p<0.01), while the ratio between low frequency (LF) and high frequency (HF) at night was significantly (p<0.05) increased. Liver transplanted patients had significantly (p<0.001) higher SDNN values than cirrhotics, while RMS-SD and LF/HF at night did not differ. In the prospective study, SDNN progressively increased after LT and was significantly (p<0.05) higher at 12 and 33 months, compared to the pre-operative value. RMS-SD and LF/HF at night did not change after LT. In conclusion, the overall HRV decrease present in cirrhosis, measured by SDNN values, is partially corrected in the long-term after LT. However, parasympathetic impairment, measured by RMS-SD and LF/HF at night, is not affected even in the long-term after operation.

Systemic thrombolysis of portal vein thrombosis in cirrhotic patients: a pilot study.

BACKGROUND: Portal vein thrombosis is a frequent complication in liver cirrhosis. Encouraging reports of systemic thrombolysis in non-cirrhotic patients suffering from acute portal vein thrombosis led us to start a pilot study on the efficacy and safety of systemic low dose recombinant tissue plasminogen activator (Actilyse, Boheringer Ingelheim, Florence, Italy). PATIENTS: Nine cirrhotic patients (6 males and 3 females) with recent portal vein thrombosis were enrolled. Exclusion criteria were portal cavernomatosis, recent (30 days) surgery, active bleeding, hepatocellular carcinoma and cancer in other sites. METHODS: All cases were treated for a maximum of 7 days by continuous i.v. infusion of 0.25mg/kg/die of r-tPA plus subcutaneous low molecular weight heparin. Efficacy was evaluated by colour doppler sonography monitoring and confirmed by contrast enhanced computerized tomography. RESULTS: The combined r-tPA/LMWH treatment was well tolerated without clinically significant side effects. Complete resolution of thrombosis occurred in 4 cases, partial regression in 4 and none in 1. Retreatment of a complete recurrence in 1 patient was successful. Variceal pressure dropped from 30.7+/-4.5 mmHg to 21.2+/-6.6 mmHg (p=0.012). CONCLUSIONS: Our preliminary data demonstrate that thrombolytic treatment of recent portal vein thrombosis with i.v. r-tPA and LMWH in patients with cirrhosis appears to be safe and effective and can significantly reduce pressure in oesophageal varices.