Vol. 15 Issue 3
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
In patients with advanced liver disease with portal hypertension, portal-systemic collaterals contribute to circulatory disturbance, gastrointestinal hemorrhage, hepatic encephalopathy, ascites, hepatopulmonary syndrome and portopulmonary hypertension. Angiogenesis has a pivotal role in the formation of portal-systemic shunts. Recent research has defined many of the mediators and mechanisms involved in this angiogenic process, linking the central roles of hepatic stellate cells and endothelial cells. Studies of animal models have demonstrated the potential therapeutic impact of drugs to inhibit angiogenesis in cirrhosis. For example, inhibition of VEGF reduces portal pressure, hyperdynamic splanchnic circulation, portosystemic collateralization and liver fibrosis. An improved understanding of the role of other angiogenic factors provides hope for a novel targeted therapy for portal hypertension with a tolerable adverse effect profile.
Bleeding from gastroesophageal varices (GEV) is a serious event in cirrhotic patients and can cause death. According to the explosión theory, progressive portal hypertension is the primary mechanism underlying variceal bleeding. There are two approaches for treating GEV: primary prophylaxis to manage bleeding or emergency treatment for bleeding followed by secondary prophylaxis. Treatment methods can be classified into two categories: 1) Those used to decrease portal pressure, such as medication (i.e., nonselective ?-blockers), radiological intervention [transjugular intrahepatic portosystemic shunt (TIPS)] or a surgical approach (i.e., portacaval shunt), and 2) Those used to obstruct GEV, such as endoscopy [endoscopic variceal ligation (EVL), endoscopic injection sclerotherapy (EIS), and tissue adhesive injection] or radiological intervention [balloon-occluded retrograde transvenous obliteration (BRTO)]. Clinicians should choose a treatment method based on an understanding of its efficacy and limitations. Furthermore, elastography techniques and serum biomarkers are noninvasive methods for estimating portal pressure and may be helpful in managing GEV. The impact of these advances in cirrhosis therapy should be evaluated for their effectiveness in treating GEV.
Background. Chronic hepatitis C(CHC) staging is important for therapeutic decision-making. Identification of noninvasive markers can provide alternatives to liver biopsy. Aim. To assess the value of APRI and FIB4 for CHC fibrosis staging in a cohort of nonselected outpatients from a referral center in Sao Paulo, Brazil. Material and methods. Medical records of 798 adult outpatients were analyzed retrospectively. For calculations of APRI and FIB4, the original descriptions were considered, and markers were compared with degree of liver injury. Results. Overall, 49.3% of participants were female, and mean age was 56.9 ± 12.5 years. Genotype 1 was predominant (71.7vs. 23.7% genotype 3); 64% had significant fibrosis, 44% had advanced fibrosis, and 28% had cirrhosis. The areas under the receiver operating curve for significant fibrosis, advanced fibrosis, and cirrhosis, respectively, were 0.809, 0.819, and 0.815 for the APRI marker and 0.803, 0.836 and 0.852 for FIB4. Using the recommended cut off values, approximately 30-40% of the patients could not be classified. In the remainder, either APRI or FIB4 alone correctly diagnosed 80-85% of cases. Concomitant or consecutive use of both APRI and FIB4 increased the number of the cases correctly diagnosed only slightly, but also increased the number of patients not classified within the cutoff values. Conclusions. In conclusion, use of the APRI or FIB4 markers for detection of hepatic fibrosis may be a viable alternative at referral centers for treatment of CHC in low- and middleincome countries. Despite relatively good accuracy, a significant number of patients could not be assessed by these methods.
Introduction & aim. Faldaprevir is a potent once-daily (q.d.) hepatitis C virus (HCV) NS3/4A protease inhibitor. The STARTVerso1 and STARTVerso2 phase 3 studies evaluated faldaprevir plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in treatment-naïve patients with chronic HCV genotype-1 infection. Material and methods. Patients were randomized 1:2:2 to receive placebo, faldaprevir 120 mg q.d. (12 or 24 weeks) or faldaprevir 240 mg q.d. (12 weeks) all with PegIFN/RBV (24?48 weeks). Faldaprevir 120 mg for 12 weeks only (STARTVerso1 only) required early treatment success (ETS, HCV RNA < 25 IU/mL at week 4 and undetected at week 8). All faldaprevir-treated patients with ETS stopped PegIFN/RBV at week 24. Primary endpoint: sustained virologic response 12 weeks post-treatment (SVR12). Results. SVR12 rates were significantly higher for patients treated with faldaprevir 120 or 240 mg (72% and 73%, respectively) compared with placebo (50%); estimated differences (adjusted for trial, race, and genotype-1 subtype) faldaprevir 120 mg 24% (95% CI: 17?31%, P < 0.0001), faldaprevir 240 mg 23% (95% CI: 16?30%, P < 0.0001). Subgroup analyses consistently showed higher SVR12 rates for patients receiving faldaprevir compared with placebo. The incidence of adverse events (AEs) was similar in faldaprevir 120-mg and placebo groups and slightly higher in the faldaprevir 240-mg group. Serious Aes were reported in 6%, 7%, and 8% of patients in placebo, faldaprevir 120-mg, and faldaprevir 240-mg groups, respectively. Conclusion. Addition of faldaprevir to PegIFN/RBV increased SVR12 in patients with HCV genotype-1, and was well tolerated. Faldaprevir 120 mg is effective in the treatment of HCV genotype-1. ClinicalTrials.gov: NCT01343888 and NCT01297270.
Introduction. Obesity correlates with nonalcoholic fatty liver disease (NAFLD) and occurs in 90 to 100% of severely obese individuals (body mass index [BMI] > 35 kg/m2). Coffee consumption (CC) has been associated with reduced progression of fibrosis in both hepatitis C infection and NAFLD; however, this topic is still under discussion when this liver disease affects severely obese individuals. Objective. To assess the association between CC, insulin resistance (IR) and histological NAFLD morbid obese patients. Material and methods. Cross-sectional study, including obese individuals undergoing bariatric surgery, liver biopsy and histological diagnosis between September 2013 and August 2014. The patients were classified into 3 groups according to their weekly CC: 0- 239.9 mL; 240-2099.9 mL and ≥ 2100 mL. Results. A total of 112 obese individuals were included (BMI = 41.9 ± 4.3 kg/m2), with a mean age of 34.7 ± 7.4 years; 68.6% were women. CC was reported by 72.3% of patients. There were no statistical significant differences between groups regarding the presence of IR (84.8% vs. 74.2% vs. 75.9%; p = 0.536). Progressively higher percentages of individuals with normal liver histology were observed (14.7% vs. 21.9% vs. 24.3%). NASH (65.7% vs. 70.3% vs. 57.5%) were observed among those who consumed greater coffee volumes (p = 0.812). In conclusion, obese individuals with elevated CC exhibited lower frequencies of NASH, although with no statistical significance in this sample.
While liver transplantation is the definitive therapy for end stage liver disease, it remains a major procedure, with many potential complications. Hospital readmissions after the initial hospitalization for liver transplantation can be associated with adverse outcomes, increased cost, and resource utilization. Our aim was to define the incidence and reasons for hospital readmission after liver transplant and the impact of readmissions on patient outcomes. We retrospectively analyzed 30- and 90-day readmission rates and indications in patients who underwent liver transplant at a large-volume transplant center over a 3-year period. Four hundred seventy-nine adult patients underwent their first liver transplant during the study period. The 30-day readmission rate was 29.6%. Recipient and donor age, etiology of liver disease, biological Model for End-Stage Liver Disease score, and cold ischemia time were similar between patients who were readmitted within 30 days and those who were not readmitted. Readmissions occurred in 25% of patients who were hospitalized prior to liver transplant compared to 30% who were admitted for liver transplant. The most common indications for readmission were infection, severe abdominal pain, and biliary complications. Early discharge from hospital (fewer than 7 days after liver transplant), was not associated with readmission; however, a prolonged hospital stay after liver transplant was associated with an increased risk of readmission (p = 0.04). In conclusion, patients who undergo liver transplant have a high rate of readmission. In our cohort, readmissions were unrelated to pre-existing recipient or donor factors, but were associated with a longer hospital stay after liver transplant.
Background and aims. We conducted an individual participant data (IPD) pooled analysis on the diagnostic accuracy of magnetic resonance elastography (MRE) to detect fibrosis stage in liver transplant recipients. Material and methods. Through a systematic literature search, we identified studies on diagnostic performance of MRE for staging liver fibrosis, using liver biopsy as gold standard. We contacted study authors for published and unpublished IPD on age, sex, body mass index, liver stiffness, fibrosis stage, degree of inflammation and interval between MRE and biopsy; from these we limited analysis to patients who had undergone liver transplantation. Through pooled analysis using nonparametric two-stage receiver-operating curve (ROC) regression models, we calculated the cluster-adjusted AUROC, sensitivity and specificity of MRE for any (≥ stage 1), significant (≥ stage 2) and advanced fibrosis(≥ stage 3) and cirrhosis (stage 4). Results. We included 6 cohorts (4 published and 2 unpublished series) reporting on 141 liver transplant recipients (mean age, 57 years; 75.2% male; mean BMI, 27.1 kg/m2). Fibrosis stage distribution stage 0, 1, 2, 3, or 4, was 37.6%, 23.4%, 24.8%, 12% and 2.2%, respectively. Mean AUROC values (and 95% confidence intervals) for diagnosis of any (≥ stage 1), significant (≥ stage 2), or advanced fibrosis (≥ stage 3) and cirrhosis were 0.73 (0.66-0.81), 0.69 (0.62-0.74), 0.83 (0.61-0.88) and 0.96 (0.93-0.98), respectively. Similar diagnostic performance was observed in stratified analysis based on sex, obesity and inflammation grade. Conclusions. In conclusion, MRE has high diagnostic accuracy for detection of advanced fibrosis and cirrhosis in liver transplant recipients, independent of BMI and degree of inflammation.
Background and rationale. The post-Liver Transplant Quality of Life (pLTQ) questionnaire, developed in the United States, is a disease-targeted instrument designed to evaluate health-related quality of life (HRQoL) in liver transplant recipients. Our study sought to validate a version of the pLTQ for use in the Brazilian population. Translation and cross-cultural adaptation were carried out in accordance with international standard practices for questionnaire validation. Validity was measured by means of convergent validity (correlations between pLTQ domains and WHOQOL-Bref domains). Reliability was assessed by measurement of internal consistency (Cronbachs alpha coefficient), reproducibility (intraclass correlation coefficient), sensitivity to change (effect size), and floor and ceiling effects. Results. The study sample comprised 160 liver transplant recipients, with a mean age of 56.9 ± 10.4 years, treated at a tertiary hospital in Southern Brazil. The sample was largely male (62.5%), and the predominant indication for liver transplant was hepatocellular carcinoma (49.4%). Only two questionnaire items were modified during the translation and cross-cultural validation stage. The mean total pLTQ score was 5.58 ± 0.9, with < 20% floor/ceiling effect. Correlations between pLTQ and WHOQOL-Bref domains were acceptable (r = 0.37 - 0.40). For similar dimensions, the correlations between WHOQOL-Bref and pLTQ were statistically significant (p ≤ 0.001). Cronbachs alpha for the total score was 0.91 (95% CI 0.89 - 0.93), with a range of 0.51 to 0.77 across domains. Reproducibility was 0.90, and sensitivity to change was 0.84. Conclusion. In conclusion, the Brazilian Portuguese versión of the pLTQ exhibited good psychometric performance, suggesting that it can be a useful tool in the Brazilian cultural context.
Background and aims. Cytokeratin19 positive (CK19+) hepatocellular carcinoma (HCC) is thought to derive from liver progenitor cells (LPC). However, whether peritumoralductular reaction (DR) differs between CK19+ and CK19 negative (CK19-) HCC patients remains unclear. Material and methods. One hundred and twenty HBV-related HCC patients were enrolled in this study. Clinicopathological variables were collected, and immunohistochemistry staining for CK19, proliferating cell nuclear antigen (PCNA), interleukin-6 (IL-6) and β-catenin were performed in tumor and peritumor liver tissues. Results. CK19+ HCC patients had higher grade of peritumoral DR and proportion of proliferative DR than the CK19- group. The mean number or the proportion of cytoplasmic β-catenin+ DR was higher in the CK19+ group than in the CK19- group. Furthermore, there were more patients with nuclear β-catenin+ peritumoral DR in the CK19+ group as compared to the CK19- group. Conclusion. Peritumoral DR was more abundant and proliferative in CK19+ HCC patients, with higher level of nuclear translocation of β-catenin. However, it is unclear whether peritumoral DR is the cause or result of poor prognosis in these patients.
Background and rationale. Portal hypertensive enteropathy (PHE) remains difficult to diagnose in patients with cirrhosis and portal hypertension. Limited test choices exist for the inspection of the small bowel in these patients. Small bowel capsule endoscopy (SBCE) is ideal in this situation but rarely performed. We aimed to determine the prevalence of PHE using SBCE in a cirrhotic patient population and correlate its presence with clinical and CT imaging findings. Material and methods. We retrospectively analysed data from cirrhotic patients who underwent SBCE at our unit. Studies were evaluated for the presence of cirrhosis-related findings in the oesophagus, stomach and small-bowel. The relationships between PHE and patients clinical characteristics were evaluated. Results. 53 patients with cirrhosis underwent SCBE. We used PillCam®SB on 36 patients and MiroCam® capsule on 17. Thirty patients were referred for iron deficiency anaemia, 15 for obscure gastrointestinal bleeding, and 4 for other indications. Four data sets were not available for review, leaving 49 patients. Mean age was 61.19 ± 14.54 years (M/F = 27/22). Six SBCE examinations were incomplete. Thirty three patients had evidence of portal hypertensive gastropathy (PHG) and 17 had evidence of oesophageal varices. In total, 29 patients had SCBE evidence of PHE (57%). 28/29 (96.5%) patients with PHE had also evidence of PHG. 13/17 (76.4%) patients with oesophageal varices had also evidence of PHE. Conclusions. The prevalence of PHE in our study was 57%. SBCE is a useful tool in evaluating PHE in cirrhotic patients irrespective of aetiology.
Background. Liver cirrhosis is associated with intestinal epithelial barrier dysfunction, which may be affected by oxidative stress. Studies in cirrhotic rats provided evidence for intestinal oxidative stress, but studies in cirrhotic patients are scarce. We have shown intestinal barrier dysfunction in patients with compensated cirrhosis. Aim. The present study aimed to investigate whether oxidative stress occurs in the intestinal mucosa of compensated cirrhotic patients and may contribute to barrier dysfunction. Material and methods. Oxidative stress was studied in duodenal and sigmoid biopsies from 15 cirrhotic patients and 22 controls by analyzing transcription of genes involved in glutathione and uric acid metabolism using quantitative real-time polymerase chain reaction. Protein levels of glutathione and glutathione disulphide were measured and the glutathione/glutathione disulphide ratio was calculated as marker of oxidative stress. In addition, intestinal myeloperoxidase and fecal calprotectin were determined. Results. Gene transcription of glutathione synthetase and glutathione reductase were significantly different in duodenal and sigmoid biopsies of cirrhotic patients vs. controls, but no alterations were found for other genes nor for glutathione, glutathione disulphide, glutathione/glutathione disulphide ratio and intestinal myeloperoxidase and fecal calprotectin concentrations. Conclusion. This study did not find indications for oxidative stress and low-grade inflammation in the small and large intestine of stable compensated cirrhotic patients. Although these preliminary findings need further validation, we found intestinal oxidative stress not to be a major mechanism contributing to epitelial barrier dysfunction in patients with compensated cirrhosis.
Rationale for the study. This cross-sectional multicenter study was conducted to investigate any difference in liver stiffness measurements (LSM), evaluated by transient elastography, between patients affected by ? thalassaemia major, with and without hepatitis C virus (HCV) infection, and healthy blood donors (controls). Secondary aim was to assess any correlation between transient elastography and serum ferritin, liver magnetic resonance imaging (MRI) T2* or superconductive quantum interference device (SQUID) liver susceptometry values. Materials and methods. The study involved three centers. Transient elastography and MRI T2* examinations were performed in all centers. SQUID liver susceptometry was performed in center1 and center2. T-test for independent data or Mann-Whitney U test was used to analyse differences between two groups. Univariate Pearsons r coefficient was used to test correlations between liver stiffness measurements and all other variables. Results. In a study with 119 patients and 183 controls, patients who had never been infected with HCV showed significantly higher LSMs than controls [5.7 (95% CI, 5.2-6.2) kPa vs. 4.3 (95% CI, 4.1-4.4) kPa, p < 0.0001]. A moderate correlation between LSMs and ferritin values, adjusted for gender and age, was found in patients (r = 0.49, p < 0.0001) but not in controls (r = -0.22, p = 0.6). No correlation between LSMs and MRI T2* or SQUID liver susceptometry values was observed. In conclusion, compared to controls B thalassaemia major patients had a significant increase in LSMs independently from HCV infection.
Background and rationale for the study. IL-17, TGF-B1/2 are cytokines involved in the development of kidney, pulmonary and liver fibrosis. However, their expression kinetics in the pathogenesis of cholestatic liver fibrosis have not yet been fully explored. The aim of the study was to analyze the expression of IL-17, ROR?t, NKp46, TGF-B1, and TGF-B2 in the liver of rats with bile duct ligation (BDL). Results. Hepatic IL-17A gene expression analyzed by qRT-PCR showed a dramatic increase of 350 and 10 fold, at 8 and 30 days post BDL, respectively. TGFB1 and TGFB2 gene expression significantly increased throughout the whole fibrotic process. At the protein level in liver homogenates, IL-17, TGF-B1, and ROR?t significantly increased at 8 and 30 days after BDL. Interestingly, a significant increase in the protein levels of TGF-B2 and decrease of NKp46 was observed only 30 days after BDL. Unexpectedly, TGF-B2 exhibited stronger signals than TGF-B1 at the gene expression and protein levels. Histological analysis showed bile duct proliferation and collagen deposition. Conclusions. Our results suggest that pro-fibrogenic cytokines IL-17, TGF-B1 and, strikingly, TGF-B2 might be important players of liver damage in the pathogenesis of early and advanced experimental cholestatic fibrosis. Th17 cells might represent an important source of IL-17, while NK cell depletion may account for the perpetuation of liver damage in the BDL model.
Background. Pulmonary complications are common in acute liver failure (ALF). The role of the lungs in the uptake of harmful soluble endogenous macromolecules was evaluated in a porcine model of ALF induced by hepatic devascularization (n = 8) vs. controls (n = 8). In additional experiments, pulmonary uptake was investigated in healthy pigs. Fluorochrome-labeled modified albumin (MA) was applied to investigate the cellular uptake. Results. As compared to controls, the ALF group displayed a 4-fold net increased lung uptake of hyaluronan, and 5-fold net increased uptake of both tissue plasminogen activator and lysosomal enzymes. Anatomical distribution experiments in healthy animals revealed that radiolabeled MA uptake (taken up by the same receptor as hyaluronan) was 53% by the liver, and 24% by the lungs. The lung uptake of LPS was 14% whereas 60% remained in the blood. Both fluorescence and electron microscopy revealed initial uptake of MA by pulmonary endothelial cells (PECs) with later translocation to pulmonary intravascular macrophages (PIMs). Moreover, the presence of PIMs was evident 10 min after injection. Systemic inflammatory markers such as leukopenia and increased serum TNF-α levels were evident after 20 min in the MA and LPS groups. Conclusion. Significant lung uptake of harmful soluble macromolecules compensated for the defect liver scavenger function in the ALF-group. Infusion of MA induced increased TNF-α serum levels and leukopenia, similar to the effect of the known inflammatory mediator LPS. These observations suggest a potential mechanism that may contribute to lung damage secondary to liver disease.
Hepatitis E virus (HEV) recently emerged in Europe as a cause of autochthonous acute hepatitis and a porcine zoonosis. European autochthonous cases almost exclusively involved viruses of genotype 3, subtype 3a being only recently reported in France, from farm pigs. We report an autochthonous human infection with a HEV related to subtype 3a in Southeastern France. A 55-year-old human immunodeficiency virus-infected man presented liver cytolysis in June 2014. HEV RNA was detected in serum and three months later, anti-HEV IgM and IgG were positive whereas HEV RNA was no more detectable in serum. No biological or clinical complication did occur. HEV phylogeny based on two capsid gene fragments showed clustering of sequences obtained from the case-patient with HEV-3a, mean nucleotide identity being 91.7 and 91.3% with their 10 best GenBank matches that were obtained in Japan, South Korea, USA, Canada, Germany and Hungria from humans, pigs and a mongoose. Identity between HEV sequence obtained here and HEV-3a sequences obtained at our laboratory from farm pigs sampled in 2012 in Southeastern France was only 90.2-91.4%. Apart from these pig sequences, best hits from France were of subtypes 3i, 3f, or undefined. The patient consumed barely cooked wild-boar meat; no other risk factor for HEV infection was documented. In Europe, HEV-3a has been described in humans in England and Portugal, in wild boars in Germany, and in pigs in Germany, the Netherlands, and, recently, France. These findings suggest to gain a better knowledge of HEV-3a circulation in France.
Ursodeoxycholic acid (UDCA) is the first choice medication for most cholestatic hepatopathies, due to its capability to counteract inflammation and bile-acid-induced liver damage, two common features in cholestasis. However, UDCA is usually contraindicated in obstructive cholestasis, due to the alleged risk of biliary integrity disruption due to its choleretic effect. We report on an 83-year-old man with an unsuspected malignant biliary obstruction who received moderate doses of UDCA (8-12 mg/kg/day) for 5 weeks, because the preliminary evidence suggested he had chemotherapy-induced cholestasis. Liver integrity was extensively protected by UDCA, as indicated by a marked decrease in serum liver enzymes, despite a steady increase in the levels of bilirubin and serum bile acids due to the obstructive process. In conclusion, this report shows, for the first time in humans, that moderate UDCA doses can reduce liver injury associated with complete biliary obstruction. This may contribute to a better understanding of the risk-benefit ratio of the use of UDCA in obstructive cholangiopathies.
Cystic lesions of the liver are common and a major proportion is formed by parasitic cysts and simple cysts. Biliary cystic tumors (BCTs), namely biliary cystadenoma (BCA) and biliary cystadenocarcinoma (BCAC), are rare tumors which usually arise from the intrahepatic biliary tree. BCAs have malignant potential and are difficult to differentiate from BCAC pre-operatively on radiological imaging. Here we have presented 4 patients with BCTs and reviewed the literature pertaining to them.The data of four patients with BCA/BCAC diagnosed and treated at our institute were retrieved from our database and records were reviewed for age, sex, history, imaging, surgery, pathology and follow-up. Mean age of the patients was 53.5 years (range 30-71 years). Two male and two female patients presented with abdominal pain, of which one male patient had pancreatitis at diagnosis. Characteristic features were seen on pre-operative imaging (cystic lesions with internal septations) and biliary communication was identified in the patient with pancreatitis. Three patients were diagnosed with a BCA on final histology, while one patient had a BCAC. Following surgical resection, all the patients are asymptomatic and disease free with a mean follow-up of 24 months (range 10-40 months). In conclusion, BCTs should be suspected in the presence of a well-encapsulated, cystic hepatic lesion with internal septations. Although pre-operative distinction between BCA and BCAC is difficult, the lesion, whenever possible, should be completely resected as long-term outcomes are good, especially with BCA.