Vol. 13 Issue 4
On the cover: The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver
Primary biliary cirrhosis (PBC) is a slowly progressive autoimmune liver disease that may ultimately result in liver failure and premature death. Predicting outcome is of key importance in clinical management and an essential requirement for patients counselling and timing of diagnostic and therapeutic interventions. The following factors are associated with progressive disease and worse outcome: young age at diagnosis, male gender, histological presence of cirrhosis, accelerated marked ductopenia in relation to the amount of fibrosis, high serum bilirubin, low serum albumin levels, high serum alkaline phosphatase levels, esophageal varices, hepatocellular carcinoma (HCC) and lack of biochemical response to ursodeoxycholic acid (UDCA). The prognostic significance of symptoms at diagnosis is uncertain. UDCA therapy and liver transplantation have a significant beneficial effect on the outcome of the disease. The Mayo risk score in PBC can be used for estimating individual prognosis. The Newcastle Varices in PBC Score may be a useful clinical tool to predict the risk for development of esophageal varices. Male gender, cirrhosis and non-response to UDCA therapy in particular, are risk factors for development of HCC.
Hepatic cavernous hemangioma accounts for 73% of all benign liver tumors with a frequency of 0.4-7.3% at autopsy and is the second most common tumor seen in the liver after metastases. Patients affected by hemangioma usually have their tumor diagnosed by ultrasound abdominal examination for a not well defined pain, but pain persist after treatment of the hemangioma. The causes of pain can be various gastrointestinal pathologies including cholelithiasis and peptic ulcer disease.The malignant trasformation is pratically inexistent. Different imaging modalities are used to diagnosis liver hemangioma including ultrasonography, computed tomography (CT), magnetic resonance (MR) imaging, and less frequently scintigraphy, positronemission tomography combined with CT (PET/CT) and angiography. Imaging-guided biopsy of hemangioma is usually not resorted to except in extremely atypical cases. The right indications for surgery remain rupture, intratumoral bleeding, Kasabach-Merritt syndrome and organ or vessels compression (gastric outlet obstruction, Budd-Chiari syndrome, etc.) represents the valid indication for surgery and at the same time they are all complications of the tumor itself. The size of the tumor do not represent a valid indication for treatment. Liver hemangiomas, when indication exist, have to be treated firstly by surgery (hepatic resection or enucleation, open, laproscopic or robotic), but in the recent years other therapies like liver transplantation, radiofrequency ablation, radiotherapy, trans-arterial embolization, and chemotherapy have been applied.
Background and aims. The histologic hallmarks of chronic HCV include inflammation and fibrosis. The impact of interferon therapy on liver histology was evaluated. Material and methods. The study population consisted of 348 patients with chronic HCV who underwent a baseline liver biopsy, received either no treatment or a single course of interferon based therapy, were followed for 5 years without any treatment or additional treatment and then underwent a repeat liver biopsy. The patients were divided into 3 groups; deferred treatment (NoTx = 47), received interferon based therapy but failed to achieve SVR (NoSVR = 189) and achieved SVR (SVR = 112). Results. Patients with NoTx and NoSVR had significant increases in mean inflammation scores (from 4.3 to 6.3 and 5.4 to 6.7 respectively; p < 0.001 for both) and fibrosis scores (from 0.9 to 1.8 and 1.9 to 2.5; p < 0.001 for both). The amounts by which inflammation, fibrosis and rate of fibrosis progression increased were not significantly different between the two groups. Increases in total inflammation and the piecemeal necrosis sub-score over time were strongly associated with fibrosis progression. Patients with SVR had a significant decline in mean inflammation and fibrosis scores (from 6.7 to 2.2 and 3.3 to 1.8; p < 0.001 for both); 40% of patients resolved all fibrosis and 50% of patients resolved cirrhosis. Conclusion. Increases in inflammation are associated with fibrosis progression and in the absence of SVR interferon treatment does not appear to affect the long term natural history of this process. Patients with SVR have resolution of inflammation and fibrosis and many resolve cirrhosis.
Background and aim. The treatment efficacy of peginterferon plus ribavirin for patients with HCV genotype 1 is inferior to that in patients with HCV genotype 2, but the efficacy among patients with mixed HCV genotype 1 + 2 is less clear. We compared the treatment outcome of peginterferon alpha-2b plus ribavirin among naïve chronic hepatitis C patients in Taiwan with HCV genotype 1 and 2, and mixed genotype 1 + 2. Material and methods. In this retrospective cohort study, 150 patients were treated with peginterferon alpha-2b once weekly, plus ribavirin, for 24 weeks. The endpoint was sustained virological response after receiving at least one dose of the study medication. Results. There were no differences in clinical characteristics among the 3 groups. There were significant differences in rapid virological response rate between patients with genotype 1 and genotype 2 (64.7 vs. 85.5%, respectively; p < 0.05) and a sustained virological response rate (55.9 vs. 83.6%, respectively; p = 0.001). The rapid virological response rate differed between the genotype 1 and mixed genotype 1 + 2 groups (64.7 vs. 85.2%, respectively; p < 0.05), but the sustained virological response rate was similar (55.9 vs. 74.1%; p = 0.101). Conclusions. Using peginterferon alpha-2b plus ribavirin for 24 weeks to treat patients with HCV genotype 1 + 2 achieved a 74.1% sustained virological response rate; the treatment efficacy was not inferior to patients with HCV genotype 1, but the percentage of liver cirrhosis in mixed genotype 1 + 2 group was higher to 22%, it is worth to be appropriately valued and studied.
Background. Hepatitis C virus (HCV) is associated with a higher prevalence of steatosis compared to the general population. Aim. Our aim was to assess the impact of PNPLA3 rs738409 G-allele on steatosis in HCV patients. Material and methods. We included 474 HCV patients treated with peginterferon plus ribavirin. PNPLA3 rs738409 was genotyped and patients were classified according to alleles and genotypes. Steatosis was detected in 46.4% (220/474). Fibrosis was assessed by Scheuer score. Gene expression was analyzed in Huh7.5 and Huh7 cells using Real Time-PCR. Results. PNPLA3 allele-G was associated with steatosis [54.1% (126/233) vs. 39% (94/241)] (p = 0.0001). In HCV-1, allele-G was related to steatosis [50.6% (82/162) vs. 32.3% (53/164)] (p = 0.001), but did not in HCV-3 [61.9% (26/42) vs. 62% (31/50)] (p = 0.993). PNPLA3 allele-G was associated with steatosis in patients with IL28B-CT/TT [57.7% (82/142) vs. 37.1% (56/151)] (p = 0.0001), but did not in IL28B-CC [47.8% (43/90) vs. 42% (37/88)] (p = 0.442). Independent variables associated with steatosis were: PNPLA3 G-allele [O.R. 1.84 (CI95%: 1.06-3.21); p = 0.007], age [O.R. 1.04 (CI95%: 1.01-1.07); p = 0.017], HCV-genotype 3 [O.R. 2.46 (CI95%: 1.30-4.65); p = 0.006], HOMA > 4 [O.R. 2.72 (CI95%: 1.27-5.82); p = 0.010]. Since PNPLA3 RNA could not be detected on PBMC from HCV patients, an in vitro analysis was performed. Huh7.5 cells infected with JFH1 had a decreased PNPLA3 gene expression (fold inhibition = 3.2 ± 0.2), while Huh7 cells presented increased PNPLA3 gene expression (fold induction = 1.5 ± 0.2). Conclusion. PNPLA3 allele-G modulated the development of steatosis, particularly in patients with HCV-1 and IL28B-CT/TT genotype, but was not associated with SVR. Metabolic but not viral steatosis seems to be PNPLA3 regulated. Gene interaction may result in differential PNPLA3 gene expression levels in HCV infection.
Objectives. Filibuvir is a non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study evaluated the safety and efficacy of filibuvir plus pegylated interferon alfa-2a (pegIFN)/ribavirin. Material and methods. Treatment-naïve, HCV genotype-1 patients were randomized to receive filibuvir 300 or 600 mg twice daily (BID) or placebo plus pegIFN (180 μg/wk) and ribavirin (1,000/1,200 mg BID) for 24 weeks. Filibuvir patients who achieved defined response through week 24 discontinued therapy at week 24. All other patients continued on open-label pegIFN/ribavirin through week 48. The primary endpoint was the proportion of patients who achieved sustained virologic response (SVR) defined as HCV RNA < 15 IU/mL at end of treatment (weeks 24 or 48) and week 72. Results. Overall, 288 patients were randomized and treated. SVR was achieved by 41.7, 39.6, and 45.8% of patients in the filibuvir 300 mg, 600 mg, and placebo arms, respectively. While the addition of filibuvir to pegIFN/ribavirin improved on-treatment virologic response parameters, this did not translate into improved SVR rates due to a high rate of virologic relapse following completion of therapy (300 mg: 35.9%; 600 mg: 42.9%; placebo: 25.4%). The most commonly reported adverse events were nausea, fatigue, headache, and insomnia, and were reported at similar rates across arms. Conclusions. Filibuvir plus pegIFN/ribavirin did not improve the percentage of patients achieving SVR compared with administration of pegIFN/ribavirin alone. However, the agent was well tolerated and was associated with higher on-treatment virologic response parameters. Further evaluation of filibuvir in combination with other direct-acting antiviral agents may be considered.
Background and rationale of the study. Effect of Long-term nucleoside/nucleotide (NUC) on hepatocellular carcinoma (HCC) incidence in a population of HBeAg-negative genotype D patients has not been adequately studied in real-life cohorts. Our aim was to evaluate the impact of liver fibrosis and other variables on HCC incidence in this population of patients. Of 745 patients with chronic hepatitis B (CHB), 306 HBeAg-negative genotype D were selected and included in this study. All patients received treatment with NUC for at least 18 months. Patients with CHB or compensated cirrhosis were included. Patients with HCC diagnosed before or during the first 18 months of NUC therapy were excluded. Results. HCC was diagnosed in 2 CHB patients (1.0%) and 23 cirrhosis patients (20%) (OR = 24.41, 95% CI 5.40 < OR < 153.2; p < 0.0001). Multivariate analysis revealed that HCC risk was independently associated with age ≥ 60 years (OR = 6.45, 95% CI 1.22 to 34.0; p = 0.02) and liver cirrhosis (OR = 12.1, 95% CI 1.39 to 106.2; p = 0.02), but not with virological response (VR), and previous resistance to NUC, or rescue therapy. Multivariate analysis in cirrhosis patients revealed that only age ≥ 60 years was an independent risk factor associated with HCC (p = 0.003). Conclusions. Liver cirrhosis and age ≥ 60 years are the stronger risk factors for HCC in genotype D HBeAgnegative patients. Previous resistance to NUC in patients that achieved a VR after rescue therapy was not a predictive factor regarding HCC. VR does not appear to significantly reduce the overall incidence of HCC when a patient has already progressed to liver cirrhosis.
Background and aim. The lack of information about hepatocellular carcinoma (HCC) in Brazil weakens health policy in preventing deaths from the illness. The aim of this study was to establish the cumulative incidence and the risk factors for hepatocellular carcinoma development in patients under a surveillance program. Material and methods. 884 patients with compensated cirrhosis were prospectively followed up for at least five years, from August 1998 until August 2008, with at least one annual ultrasonography liver examination and serum alpha fetoprotein (AFP) measurement. Results. Among 884 patients, 72 (8.1%) developed a tumor with a median follow up of 21.4 months. In the hepatocellular carcinoma group, hepatitis C virus infection was the major etiological factor (65.3%), 56.9% (41/72) were male and the mean average age was 57 ± 10 years. The annual incidence of hepatocellular carcinoma was 2.9%. 79.2% (57/72) of HCCs were detected within Milan Criteria, and the mean survival time was 52.3 months, significantly higher than for those outside Milan, with a mean time of 40.6 months (p = 0.0003). Conclusion. The annual incidence of HCC among this large series of Brazilian cirrhotic patients was around 2.9% with a detection rate of 8.1%, or a cumulative incidence rate over five years of 14.3%. The three variables related to HCC risk were low serum albumin [HR: 0.518 (0.46-0.78)], high AFP > 20 ng/mL [HR: 3.16 (1.86-5.38)], and ethnicity (Brazilian-East Asian descendants vs. other mixed Brazilian ethnicities) [HR: 2.86 (1.48-5.53)].
Background and aim. The effect of preoperative transcatheter arterial chemoembolization (TACE) on the short- and long-term outcome of resectable hepatocellular carcinoma (HCC) is controversial. We conducted a retrospective evaluation of this aspect using data from our center. Material and methods. A total of 656 consecutive patients who underwent curative resection of HCC were divided into two groups based on the preoperative TACE: the liver resection (LR) group (405 cases) and the TACE-LR group (183 cases). Overall and disease-free survival curves were constructed using the Kaplan-Meier method and compared with the log-rank test. The significance of differences in survival was tested using a log-rank test. Univariate and multivariate analyses were used to identify the factors that best predicted overall survival or tumorfree survival. Results. Although the cost of LR showed no difference between groups, the overall cost was significantly higher in the combined group than in the LR group (P < 0.001). The complication rate after resection was also comparable between the two groups. In regard to long-term outcome, the 1-, 3-, and 5-year overall survival rates were 83.7, 68.9 and 57.5%, respectively, after direct liver resection and 80.9, 65.0 and 54.1%, respectively, after combined TACE and resection (P = 0.739). The 1-, 3-, and 5-year recurrence- free survival rates were also comparable between two groups (P = 0.205). Both univariate analysis and multivariate analysis showed that macro-vascular invasion was the factor that best predicted overall survival or tumor-free survival rate. Conclusion. Preoperative TACE has comparable intraoperative and short-term outcomes but more overall cost due to repeated TACE, and the procedure did not significantly improve the overall or tumor-free survival rate. Preoperative TACE should not, therefore, be recommended as a routine procedure before resection for resectable HCCs particularly in cases due to underlying hepatitis B virus (HBV).
Aims. To define if there is an imbalance in plasma levels of proinflammatory, fibrogenic and antifibrogenic cytokines in patients with liver cirrhosis (LC) and impaired glucose tolerance (IGT) or diabetes mellitus (DM). Material and methods. We randomly selected 54 out of 100 patients with LC who had normal fasting plasma glucose (FPG) levels. Three groups were formed based on an oral glucose tolerance test (OGTT) results: 18 patients were normal, 18 had IGT, and 18 had DM. Plasma levels of cytokines were measured: TNF- α, soluble tumor necrosis factor receptor 1 (sTNF-R1), leptin, TGF-β1, and hepatocyte growth factor (HGF). Also, fasting plasma insulin (FPI) levels were determined and HOMA2-IR was calculated. Results were compared with those of a control group of 18 patients without liver disease nor DM. Intergroup comparison was performed using non parametric tests. Results. Significantly higher sTNF-R1 and lower TGF-β1 were found in patients with IGT and DM compared to controls. Leptin, HGF, and TNF-α levels showed no significant differences. According to Child-Pugh classification all cytokines levels were impaired in groups B or C as compared to group A. Positive correlations between sTNF-R1 and HOMA2-IR and between leptin and HOMA2-IR were found. Conclusions. IGT and DM were associated with abnormalities of sTNF-R1 and TGF-β1 compared to non cirrhotic controls. Among cirrhotic patients impairment of all cytokines were more marked in advanced liver disease. Finally, sTNF-R1and leptin correlated with IR. These findings suggest that IGT and DM may be causally implicated with liver inflammation process.
Purpose. To elucidate the impact of right atrial (RA) pressure on early mortality after transjugular intrahepatic portosystemic shunt (TIPS). Material and methods. In this single institution retrospective study, 125 patients (M:F = 75:50, mean age 55 years) who underwent TIPS with recorded intra-procedural RA pressures between 1999-2012 were studied. Demographic (age, gender), liver disease (Child-Pugh, Model for End Stage Liver Disease or MELD score), and procedure (indication, urgency, Stent type, portosystemic gradient or PSG reduction, baseline and post-TIPS RA pressure) data were identified, and the influence of these parameters on 30- and 90-day mortality was assessed using binary logistic regression. Results. TIPS were created for variceal hemorrhage (n = 55) and ascites (n = 70). Hemodynamic success rate was 99% (124/125) and mean PSG reduction was 13 mmHg. 30- and 90-day mortality rates were 18% (19/106) and 28% (29/106). Baseline and final RA pressure were significantly associated with 30- (12 vs. 15 mmHg, P = 0.021; 18 vs. 21 mmHg, P = 0.035) and 90-day (12 vs. 14 mmHg, P = 0.022; 18 vs. 20 mmHg, P = 0.024) survival on univariate analysis. Predictive usefulness of RA pressure was not confirmed in multivariate analyses. Area under receiver operator characteristic (AUROC) curve analysis revealed good pre- and post-TIPS RA pressure predictive capacity for 30- (0.779, 0.810) and 90-day (0.813, 0.788) mortality among variceal hemorrhage patients at 14.5 and 21.5 mm Hg thresholds. Conclusion. Intra-procedural RA pressure may have predictive value for early post-TIPS mortality. Pre-procedure consideration and optimization of patient cardiac status may enhance candidate selection, risk stratification, and clinical outcomes, particularly in variceal hemorrhage patients.
Background. Carvedilol appears to be more effective than propranolol in the treatment of portal hypertension in cirrhotic patients. Aim. To compare the effects of carvedilol vs. propranolol on systemic and splanchnic haemodynamics and to evaluate the adverse events associated with these treatments. Material and methods. We performed a systematic review following the Cochrane and PRISMA recommendations. Randomised controlled trials comparing carvedilol versus propranolol, in the treatment of portal hypertension in cirrhotic patients with oesophageal varices, with or without bleeding history were included. The primary outcome measure was the haemodynamic response to treatment. Results. Four randomised trials and 153 patients were included; 79 patients received carvedilol (6.25-50 mg/d) and 74 patients received propranolol (10-320 mg/d). The hepatic vein pressure gradient (HVPG) decreased more with carvedilol than with propranolol (MD 2.21; 95% CI: 2.83 to 1.60, I2 = 0%, P < 0.00001). Carvedilol was superior to propranolol for reducing HVPG by ≥ 20% from the baseline value or to ≤ 12 mmHg (OR: 2.93; 95% CI: 1.50 to 5.74, I2 = 22%, P = 0.002). Overall adverse events did not differ between. In conclusion, there is limited evidence suggesting that carvedilol is more effective than propranolol for improving the haemodynamic response in cirrhotic patients with portal hypertension. Long-term randomized controlled trials are needed to confirm this information.
Background. The 20S proteasome is the proteolytic core of the major intracellular protein degradative system, the ubiquitin-proteasome system. Since little is known about proteasomes of human liver, we have investigated the proteasome spectrum in adult human liver. Material and methods. 20S proteasomes were chromatographically purified from adult human liver and from HuH7 cells. They were divided into subpopulations and subtypes and characterized with regard to their proteolytic activities using short fluorogenic oligo- and long poly-peptide substrates. Their subunit composition was studied by immunoblotting. Results. Proteasomes from adult human liver tissue can be separated into three subpopulations (I, II, III), each of which is composed of several subtypes, which total to a spectrum of 14 different subtypes. Two minor subtypes contain only the immuno-subunits β1i and β5i but not their standard counterparts; all others are intermediate subtypes containing β1 and β5 standard- and β1i and β5i immuno-subunits in various compositions. With regard to the proteolytic activities we observed that a decreasing content of subunit β1i in the subtypes goes along with a decreasing ratio of chymotrypsin-like/caspase-like activity, whereas the degradation rate of a 30 mer polypeptide substrate increased with decreasing β1i content. By comparison, 20S proteasomes from HuH7 cells do not contain immuno-subunits but are pure standard proteasomes, which can be separated into three subtypes. Conclusion. These findings suggest that adult human liver contains a spectrum of 14 different 20S proteasome subtypes with different enzymatic properties reflecting most probably an adaptive response of liver cell functions to challenging factors during lifetime.
Aim. Recent studies have suggested miRNA dysregulation in liver tissue mediates the pathogenesis of various liver diseases especially liver fibrosis, but the microRNA changes during PS-induced hepatic fibrosis are still unknown. The purpose of this study was to screen the miRNA differences in rat liver fibrosis model and clarify the relationship of miRNAs with the development of PS-induced liver fibrosis. Material and methods. Two fibrotic and two normal liver tissues from 20 SpragueDawley rats were collected and sequenced. MiRNA profiling results and fibrosis-related genes were validated by quantitative real-time polymerase chain reaction (qRT-PCR) and bioinformatics was used to predict miRNA targets. Results. In total, 48 miRNAs were detected to be aberrantly expressed in fibrosis tissue compared to normal tissue. Further functional analysis of the deregulated miRNA targets revealed the miRNAs are involved in several biological functions and pathways. In addition, the expression level of miR-27a and miR-146b and fibrosis-related genes were significantly up-regulated by using qRT-PCR in fibrotic liver tissues when compared to the normal liver tissues. Conclusion. PS-induced hepatic fibrosis results in up-regulation of the miR-27a and miR-146b in liver tissues, suggestingmiR-27a and miR-146b would be associated with the development of PS-induced liver fibrosis and be potential therapeutic targets during hepatic fibrosis.
A 46-year old man with a chronic hepatitis C virus infection received triple therapy with ribavirin, pegylated interferon and telaprevir. The patient also received simvastatin. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed rhabdomyolysis. At admission simvastatin and all antiviral drugs were discontinued because toxicity due to a drug-drug interaction was suspected. The creatine kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patients renal function remained unaffected. Fourteen days after hospitalization, creatine kinase level had returned to 230 IU/L and the patient was discharged. Telaprevir was considered the probable causative agent of an interaction with simvastatin according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated simvastatin clearance. Simvastatin plasma concentration increased 30 times in this patient and statin induced muscle toxicity is related to the concentration of the statin in blood. In conclusion, with this case we illustrate that telaprevir as well as statins are susceptible to clinical relevant drug-drug interactions.
Hepatic encephalopathy is a frequent complication of cirrhosis, when this event becomes persistent, treatment compliance should be verified and any precipitating factor need to be identified. Also the presence of portosystemic shunts, which are a rare cause of decompensation or persistence hepatic encephalopathy need to be ruled out. In this paper we report the case of a 57 year old man with persistent hepatic encephalopathy secondary to the presence of a porto-onfalo-femoral shunt successfully closed with the placement of an Amplatzer device.
Hepatitis B virus (HBV) reactivation is a well-established complication of severe immunosuppression in patients with hematologic malignancy and positive hepatitis B surface antigen (HBsAg). Patients who receive high-dose chemotherapy, corticosteroids, rituximab, or have a bone marrow transplant are particularly at increased risk for HBV reactivation. However, limited information is available in the literature regarding HBV reactivation in patients with isolated anti-HBc, particularly in the setting of multiple myeloma (MM). We report two cases of HBV reactivation in MM patients with isolated anti-HBc positive with a rather atypical presentation. In conclusion, our cases highlight that clinicians need to be cognizant about this potentially fatal but preventable complication of chemotherapy and immunosuppression.