Validation and Performance of FibroScan®-AST (FAST) Score on a Brazilian Population with Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIM: FAST score has a good performance for diagnosing the composite of NASH + NAS ≥ 4 + F ≥ 2. However, it has not been evaluated in Latin American individuals with nonalcoholic fatty liver disease (NAFLD). We aimed to analyze the performance of the FAST score in a Brazilian NAFLD population. METHODS: Cross-sectional study was held in ≥ 18 years NAFLD patients diagnosed by ultrasonography and submitted to liver biopsy (LB). Liver stiffness (LSM) and CAP measurements were performed with FibroScan®, using M (BMI < 32 kg/m2) or XL probes. Area under receiver operating characteristic (AUROC) curves were calculated as well as sensitivity (S), specificity (Spe), positive predictive value (VPP) and negative predictive value (NPV) for the previously established FAST score cut-offs. RESULTS: Among 287 patients included (75% female; mean age 55 ± 10 years), NASH + NAS ≥ 4 + F ≥ 2 was reported in 30% of LB. For the FAST cut-off of 0.35, the S and NPV to rule out NASH + NAS ≥ 4 + F ≥ 2 were 78.8% and 87.8%, respectively. Regarding the cut-off of 0.67, the Spe and PPV to rule-in NASH + NAS ≥ 4 + F ≥ 2 were 89.1%, 61.8%, respectively. The AUROC of FAST for all included patients was 0.78 (95% CI 0.72-0.84) and for those with ≥ 32 kg/m2 was 0.81 (95% CI 0.74-0.88). CONCLUSION: FAST score has a good performance in a Brazilian NAFLD population, even in patients with higher BMI when the XL probe is adopted. Therefore, FAST can be used as a noninvasive screening tool mainly for excluding the diagnosis of progressive NASH, reducing the number of unnecessary liver biopsies.

Efficacy and safety of glecaprevir/pibrentasvir in treatment-naïve adults with chronic hepatitis C virus genotypes 1-6 in Brazil.

INTRODUCTION AND OBJECTIVES: Glecaprevir/pibrentasvir is a highly effective and well tolerated treatment for hepatitis C infection. Brazilian patients were not included in the original development studies for glecaprevir/pibrentasvir. This study aimed to assess safety and efficacy of glecaprevir/pibrentasvir in treatment-naïve Brazilian adults without cirrhosis or with compensated cirrhosis. PATIENTS AND METHODS: EXPEDITION-3 was a Phase 3, open-label, multicenter study in treatment-naïve Brazilian adults with hepatitis C infection genotype 1-6. Patients without cirrhosis (F2 or F3) or with compensated cirrhosis (F4) received 8 or 12 weeks of glecaprevir/pibrentasvir, respectively. The primary efficacy endpoint was the rate of sustained virologic response at post-treatment Week 12. Secondary endpoints were on-treatment virologic failure and relapse rates. Baseline polymorphisms were assessed in NS3 and NS5A. Adverse events and laboratory abnormalities were monitored. RESULTS: 100 patients were enrolled, 75 received 8 weeks of treatment and 25 received 12 weeks; all patients completed treatment. Overall sustained virologic response at post-treatment Week 12 rate was high (98.0%; 98/100; 95% confidence interval: 93.0-99.4) and remained high regardless of baseline viral or host factors, including demographics, hepatitis C virus RNA levels, polymorphisms in NS3 and/or NS5A, genotype, and relevant comorbidities. 55% of patients reported ≥1 adverse event, the most common being headache (18.0%). Four patients reported serious adverse events; none were considered drug related or led to study drug discontinuation. No hepatic decompensations were observed. CONCLUSIONS: Glecaprevir/pibrentasvir was effective and well tolerated in treatment-naïve Brazilian patients with hepatitis C infection without cirrhosis and with compensated cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03219216.

Latin American Association for the study of the liver (ALEH) practice guidance for the diagnosis and treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) currently represents an epidemic worldwide. NAFLD is the most frequently diagnosed chronic liver disease, affecting 20-30% of the general population. Furthermore, its prevalence is predicted to increase exponentially in the next decades, concomitantly with the global epidemic of obesity, type 2 diabetes mellitus (T2DM), and sedentary lifestyle. NAFLD is a clinical syndrome that encompasses a wide spectrum of associated diseases and hepatic complications such as hepatocellular carcinoma (HCC). Moreover, this disease is believed to become the main indication for liver transplantation in the near future. Since NAFLD management represents a growing challenge for primary care physicians, the Asociación Latinoamericana para el Estudio del Hígado (ALEH) has decided to organize this Practice Guidance for the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease, written by Latin-American specialists in different clinical areas, and destined to general practitioners, internal medicine specialists, endocrinologists, diabetologists, gastroenterologists, and hepatologists. The main purpose of this document is to improve patient care and awareness of NAFLD. The information provided in this guidance may also be useful in assisting stakeholders in the decision-making process related to NAFLD. Since new evidence is constantly emerging on different aspects of the disease, updates to this guideline will be required in future.

Direct antiviral therapy for treatment of hepatitis C: A real-world study from Brazil.

INTRODUCTION AND OBJECTIVES: Direct antiviral agents (DAAs) including sofosbuvir (SOF), daclatasvir (DCV), simeprevir (SIM) and ombitasvir, paritaprevir and dasabuvir were introduced 2015 in Brazil for treatment of hepatitis C virus (HCV) infection. The aims of this study were to assess effectiveness and safety of HCV treatment with DAA in real-life world in a highly admixed population from Brazil. MATERIALS AND METHODS: All Brazilian reference centers for HCV treatment were invited to take part in a web-based registry, prospectively conducted by the Brazilian Society of Hepatology, to assess outcomes of HCV treatment in Brazil with DAAs. Data to be collected included demographics, disease severity and comorbidities, genotype (GT), viral load, DAA regimens, treatment side effects and sustained virological response (SVR). RESULTS: 3939 patients (60% males, mean age 58±10 years) throughout the country were evaluated. Most had advanced fibrosis or cirrhosis, GT1 and were treated with SOF/DCV or SOF/SIM. Overall SVR rates were higher than 95%. Subjects with decompensated cirrhosis, GT2 and GT3 have lower SVR rates of 85%, 90% and 91%, respectively. Cirrhosis and decompensated cirrhosis in GT1 and male sex and decompensated cirrhosis in GT3 were significantly associated with no SVR. Adverse events (AD) and serious AD occurred in 18% and 5% of those subjects, respectively, but less than 1% of patients required treatment discontinuation. CONCLUSION: SOF-based DAA regimens are effective and safe in the heterogeneous highly admixed Brazilian population and could remain an option for HCV treatment at least in low-income countries.

Utility and limitations of APRI and FIB4 to predict staging in a cohort of nonselected outpatients with hepatitis C.

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 (71.7 vs. 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 middle-income countries. Despite relatively good accuracy, a significant number of patients could not be assessed by these methods.

Latin American Association for the Study of the Liver (LAASL) clinical practice guidelines: management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer death, and accounts for 5.6% of all cancers. Nearly 82% of the approximately 550,000 liver cancer deaths each year occur in Asia. In some regions, cancer-related death from HCC is second only to lung cancer. The incidence and mortality of HCC are increasing in America countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Clinical care and survival for patients with HCC has advanced considerably during the last two decades, thanks to improvements in patient stratification, an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and the introduction of novel therapies and strategies in prevention. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. These LAASL recommendations on treatment of hepatocellular carcinoma are intended to assist physicians and other healthcare providers, as well as patients and other interested individuals, in the clinical decision-making process by describing the optimal management of patients with liver cancer.

Validation of the Brazilian version of Chronic Liver Disease Questionnaire.

PURPOSE: The aim of this study was to validate the Chronic Liver Disease Questionnaire (CLDQ) for use in Brazilian population. METHOD: A total of 200 patients with chronic liver disease and varying disease severity answered a socio-demographic questionnaire, t CLDQ, and the Medical Outcome Study Short Form 36 (SF-36). Patients returned in 1-15 days to answer CLDQ again. The Cronbach's alpha of the total CLDQ score was 0.95 and fluctuated between 0.69 and 0.83 in its six domains. RESULTS: The intra-class correlation between total CLDQ scores in two evaluations was 0.97 and in all domains was >0.93. CLDQ was moderately correlated with the SF-36, 0.63 (total CLDQ vs. vitality, SF-36), 0.62 (CLDQ and mental health, SF-36), 0.62 (preoccupation, CLDQ, vs. General Health, SF-36), 0.59 (fatigue, CLDQ, vs. vitality, SF-36), 0.59 (activity, CLDQ, vs. vitality, SF-36), and 0.59 (fatigue, CLDQ, vs. mental health, SF-36). The highest scores were found in non-cirrhotic group. Child A patients had higher average scores than Child B and C groups in all domains, while patients with MELD <15 scored higher than patients with MELD ≥15. CONCLUSION: CLDQ-BR was validated in Brazilian population and was appropriate for use in patients with liver disease of different etiologies and degrees of severity.

BRAZILIAN SOCIETY OF HEPATOLOGY UPDATED RECOMMENDATIONS FOR SYSTEMIC TREATMENT OF HEPATOCELLULAR CARCINOMA.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2020 the updated recommendations for the diagnosis and treatment of HCC. Since then, new data have emerged in the literature, including new drugs approved for the systemic treatment of HCC that were not available at the time. The SBH board conducted an online single-topic meeting to discuss and review the recommendations on the systemic treatment of HCC. The invited experts were asked to conduct a systematic review of the literature on each topic related to systemic treatment and to present the summary data and recommendations during the meeting. All panelists gathered together for discussion of the topics and elaboration of the updated recommendations. The present document is the final version of the reviewed manuscript containing the recommendations of SBH and its aim is to assist healthcare professionals, policy-makers, and planners in Brazil and Latin America with systemic treatment decision-making of patients with HCC.

Re-treatment of previous non-responders and relapsers to interferon plus ribavirin with peginterferon alfa-2a (40KD), ribavirin ± amantadine in patients with chronic hepatitis C: randomized multicentre clinical trial.

INTRODUCTION: A large number of patients with chronic hepatitis C have not been cured with interferon-based therapy. Therefore, we evaluated the efficacy of amantadine combined with the standard of care(pegylated interferon plus ribavirin) in patients who had not responded to or had relapsed after ≥ 24 weeks of treatment with conventional interferon plus ribavirin. MATERIAL AND METHODS: Patients stratified by previous response (i.e., non-response or relapse) were randomized to 48 weeks of open-label treatment with peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 1,000/1,200 mg/day plus amantadine 200 mg/day (triple therapy), or the standard of care (peginterferon alfa-2a [40KD] plus ribavirin). RESULTS: The primary outcome was sustained virological response (SVR), defined as undetectable hepatitis C virus RNA in serum (< 50 IU/mL) at end of follow-up (week 72). Among patients with a previous non-response, 12/53 (22.6%; 95% confidence interval [CI] 12.3-36.2%) randomized to triple therapy achieved an SVR compared with 16/52 (30.8%; 95% CI 18.7-45.1%) randomized to the standard of care. Among patients with a previous relapse 22/39 (56.4%; 95% CI 39.6-72.2%) randomized to triple therapy achieved an SVR compared with 23/38 (60.5%; 95% CI 43.4-76.0%) randomized to the standard of care. Undetectable HCV RNA (< 50 IU/mL) at week 12 had a high positive predictive value for SVR. A substantial proportion of non-responders and relapsers to conventional interferon plus ribavirin achieve an SVR when re-treated with peginterferon alfa-2a (40KD) plus ribavirin. CONCLUSION: Amantadine does not enhance SVR rates in previously treated patients with chronic hepatitis C and cannot be recommended in this setting.

IS HOMEOSTASIS MODEL ASSESSMENT FOR INSULIN RESISTANCE >2.5 A DISTINGUISHED CRITERIA FOR METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE IDENTIFICATION?

BACKGROUND: Insulin resistance (IR), assessed by different criteria, is an important factor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). More recently with the characterization of this metabolic dysfunction-associated fatty liver disease (MAFLD), one of the proposed criteria for this diagnosis has been the determination of the homeostasis model assessment-insulin resistance (HOMA-IR). OBJECTIVE: The purpose of this study was to evaluate the relationship of HOMA-IR>2.5 with clinical, metabolic, biochemical and histological data obtained in non-diabetic patients diagnosed with NAFLD by liver biopsy. METHODS: Cross-sectional, retrospective study was carried out with data from 174 adult individuals of both genders with non-diabetics NAFLD, without obvious signs of portal hypertension. The body mass index (BMI) was classified according to the World Health Organization (1998), and the metabolic syndrome by the criteria of NCEP-ATP-III. Biochemical tests were evaluated using an automated method and insulinemia through immunofluorometric assay. Histological findings were classified according to Kleiner et al. (2005). RESULTS: The mean age of the studied population was 53.6±11.2 years, with 60.3% being female. The average BMI was 30.3 kg/m2 and 75.9% of the patients had increased waist circumference. Among evaluated metabolic parameters, there was a higher prevalence of metabolic syndrome (MS) in patients with HOMA-IR>2.5, with no statistical difference in relation to BMI between studied groups. Values of liver enzymes and serum ferritin were significantly higher in patients with this marker of IR, who had a higher prevalence of non-alcoholic steatohepatitis (NASH) and advanced liver fibrosis. In the multivariate analysis, the clinical diagnosis of MS, hyperferritinemia and the presence of NASH in the liver biopsy were the factors independently associated with the presence of altered HOMA-IR. CONCLUSION: HOMA-IR values >2.5 identify patients with NAFLD with distinct clinical and metabolic characteristics and with a greater potential for disease progression, which validates this parameter in the identification of patients with MAFLD.

OBSTRUCTIVE SLEEP APNEA SYNDROME RISK IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE IS ASSOCIATED WITH OBESITY AND PRESENCE OF NASH.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and refers to a wide spectrum of histological abnormalities ranging from simple steatosis (HE) to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. OBJECTIVE: To assess the risk of obstructive sleep apnea syndrome (OSAS) and relating it to demographic, biochemical and histological data in patients with non-alcoholic fatty liver disease. METHODS: Cross-sectional cohort study in individuals with biopsy-proven NAFLD. Anthropometric and biochemical parameters, presence of metabolic syndrome and insulin resistance were evaluated. The Berlin Questionnaire (BQ) was applied to assess the risk of apnea and a food record was requested. Based on the BQ, participants were classified as high or low risk for OSAS. In the correlation of sleep apnea with the severity of NAFLD, presence of nonalcoholic steatohepatitis (NASH) and the degree of liver fibrosis were evaluated. Statistical analysis used the chi-square test, Student's t and bivariate logistic regression; values were expressed as mean ± standard deviation. This research project was approved by the Ethics Committee. RESULTS: Regarding the parameters evaluated, significant differences were observed between the groups in terms of body mass index (BMI), waist and neck circumference. In the histological evaluation, patients classified as high risk were more likely to have fibrosis and NASH. In bivariate regression, the BMI, presence of fibrosis and steatohepatitis in the biopsy were independently associated with an elevated risk of the syndrome. CONCLUSION: A high prevalence of risk for OSAS was observed in the studied group, with a higher risk being independently associated with BMI and presence of steatohepatitis, suggesting that it is a factor associated with the severity of the disease.

Cardiometabolic disorders, inflammation and the incidence of non-alcoholic fatty liver disease: A longitudinal study comparing lean and non-lean individuals.

BACKGROUND: There is limited knowledge about the risk of non-alcoholic fatty liver disease (NAFLD) associated with cardiometabolic disorders in lean persons. This study examines the contribution of cardiometabolic disorders to NAFLD risk among lean individuals and compares to non-lean individuals. METHODS: We analyzed longitudinal data from 6,513 participants of a yearly voluntary routine health testing conducted at the Hospital Israelita Albert Einstein, Brazil. NAFLD was defined as hepatic ultrasound diagnosed fatty liver in individuals scoring below 8 on the alcohol use disorders identification test. Our main exposure variables were elevated blood glucose, elevated blood pressure (BP), presence of atherogenic dyslipidemia (AD, defined as the combination of elevated triglycerides and low HDL cholesterol) and physical inactivity (<150 minutes/week of moderate activity). We further assessed the risk of NAFLD with elevations in waist circumference and high sensitivity C-reactive protein (HsCRP). RESULTS: Over 15,580 person-years (PY) of follow-up, the incidence rate of NAFLD was 7.7 per 100 PY. In multivariate analysis adjusting for likely confounders, AD was associated with a 72% greater risk of NAFLD (IRR: 1.72 [95% CI:1.32-2.23]). Elevated blood glucose (IRR: 1.71 [95%CI: 1.29-2.28]) and physical inactivity (IRR: 1.46 [95%CI: 1.28-1.66]) were also independently associated with increased risk of NAFLD. In lean individuals, AD, elevated blood glucose and elevated BP were significantly associated with NAFLD although for elevated blood glucose, statistical significance was lost after adjusting for possible confounders. Physical inactivity and elevations in HsCRP were not associated with the risk of NAFLD in lean individuals only. Among lean (and non-lean) individuals, there was an independent association between progressively increasing waist circumference and NAFLD. CONCLUSION: Cardiometabolic risk factors are independently associated with NAFLD. However, there are significant differences in the metabolic risk predictors of NAFLD between lean and non-lean individuals. Personalized cardiovascular disease risk stratification and appropriate preventive measures should be considered in both lean and non-lean individuals to prevent the development of NAFLD.

Nonalcoholic fatty liver disease in Brazil. Clinical and histological profile.

BACKGROUND: The epidemiology and clinical characteristics of nonalcoholic fatty liver disease (NAFLD) in South America are not well known. Brazil is a largest country in this part of the world and the present study aimed to contribute with this information. METHODS: This descriptive study included patients from medical centers around Brazil, who had diagnosis of NAFLD. They were selected from chart review and also prospectively in Hepatology out-clinics. Patients with history of alcohol intake and others liver diseases were excluded. Histological diagnosis included: steatosis or steatohepatitis (steatosis, ballooning of hepatocytes or fibrosis). The criteria to perform a liver biopsy was ALT or AST > 1.5 x normal levels. RESULTS: A total of 1280 patients from 16 Brazilian centers and all five regions were included. The mean age was 49.68 ± 13.59 years; 53.3% were males and 85% were asymptomatic. Hyperlipidemia was observed in 66.8% cases, obesity in 44.7%, overweight in 44.4%, diabetes in 22.7%, and toxins exposure in 10%. Metabolic syndrome was observed in 41.3% cases. Elevated levels of ALT, AST and GGT were observed in 55.8%, 42.2% and 63.1% cases, respectively. Liver biopsy performed in 437 cases showed: isolate steatosis in 42% cases, steatohepatitis in 58% and 27% of them also presented fibrosis. Cirrhosis was observed in 15.4% and hepatocellular carcinoma in 0.7%. CONCLUSIONS: NAFLD in Brazil is more frequent in asymptomatic males; steatohepatitis with fibrosis and cirrhosis were a significant diagnosis. The genetic predisposition and lifestyle should be influenced in the spectrum; however these findings deserve a future investigation.

Factors associated with nutritional status in liver transplant patients who survived the first year after transplantation.

BACKGROUND AND AIMS: Most studies published focus on the evaluation of the impact of nutritional status on the morbidity and mortality during the immediate postoperative period or on the short-term evolution of liver transplant patients. The aim of the study was to evaluate long-term trends in nutritional status. METHODS: Seventy patients consecutively submitted to liver transplantation were studied. Nutritional assessment was performed the day before transplantation and the 45, 90, 180 and 365 days after transplantation, consisting of determination of dietary intake, anthropometric and biochemical analysis. RESULTS: Sixty-nine percent of the patients presented with malnutrition on the day before liver transplantation, decreasing to 44% at end of the first year. The prevalence of protein-calorie malnutrition (PCM) was 63% at 90 days post-transplant. A significant difference of PCM was observed between patients with cirrhosis and non-cirrhotic disease (53.6% x 100%) at 90 days post-transplant. The pre-transplant nutritional diagnosis and 90-day calorie intake were identified as variables independently associated with nutritional status at 90 days post-transplant. The variables independently associated with nutritional status in the 1-year assessment were pre-transplant PCM and 365-day calorie requirements. CONCLUSION: No influence on nutritional status was observed for peri- or postoperative factors after 3 or 12 months of follow up. As expected, dietary factors, especially adequate calorie intake, were always associated with nutritional status during all periods analyzed.

Evaluation of hepatic fibrosis by elastography in patients with schistosomiasis mansoni.

BACKGROUND: Periportal fibrosis is associated with the main complications of schistosomiasis mansoni. The usefulness of hepatic transient elastography (TE) in its evaluation remains to be clarified. METHODS: We conducted a cross-sectional study of schistosomal patients, where the measurements obtained by FibroScan TE were correlated with the degree of liver fibrosis according to the Niamey sonographic protocol, adopted as the gold standard, and its performance was calculated as the area under the receiver operating characteristics curve (AUROC). RESULTS: A total of 117 of 141 adult schistosomiasis patients from endemic areas were selected between May and August 2015. Applying the Niamey protocol, the patients were regrouped into absent fibrosis (A; 34.2%), mild to moderate fibrosis (MM; 27.4%) and intense fibrosis (I; 38.5%). The median of the TE values in the patients of group A was 4.7 kPa, the group MM 9.3 kPa and the group I 10.3 kPa. There was a difference in the TE values between the group A and the groups MM and I (p < 0.05). The TE also presented strong and direct correlation with the clinical form (r ≥ 0.77). The AUROC value to define the presence of fibrosis was 0.92 and for significant fibrosis was 0.79, with cut-offs of 6.1 kPa and 8.9 kPa, respectively. CONCLUSIONS: In this study, the TE was effective in the diagnosis of schistosomal fibrosis, being able to identify the advanced forms of the disease and thus predict the risk of clinical complications in endemic regions.

PERIPHERAL BLOOD ENDOTOXIN LEVELS ARE NOT ASSOCIATED WITH SMALL INTESTINAL BACTERIAL OVERGROWTH IN NONALCOHOLIC FATTY LIVER DISEASE WITHOUT CIRRHOSIS.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease worldwide. Approximately 20% of individuals with NAFLD develop nonalcoholic steatohepatitis (NASH), which is associated with increased risk of cirrhosis, portal hypertension, and hepatocellular carcinoma. Intestinal microflora, including small intestinal bacterial overgrowth (SIBO), appear to play an important role in the pathogenesis of the disease, as demonstrated in several clinical and experimental studies, by altering intestinal permeability and allowing bacterial endotoxins to enter the circulation. OBJECTIVE: To determine the relationship between SIBO and endotoxin serum levels with clinical, laboratory, and histopathological aspects of NAFLD and the relationship between SIBO and endotoxin serum levels before and after antibiotic therapy. METHODS: Adult patients with a histological diagnosis of NAFLD, without cirrhosis were included. A comprehensive biochemistry panel, lactulose breath test (for diagnosis of SIBO), and serum endotoxin measurement (chromogenic LAL assay) were performed. SIBO was treated with metronidazole 250 mg q8h for 10 days and refractory cases were given ciprofloxacin 500 mg q12h for 10 days. RESULTS: Overall, 42 patients with a histopathological diagnosis of NAFLD were examined. The prevalence of SIBO was 26.2%. Comparison of demographic and biochemical parameters between patients with SIBO and those without SIBO revealed no statistically significant differences, except for use of proton pump inhibitors, which was significantly more frequent in patients with positive breath testing. The presence of SIBO was also associated with greater severity of hepatocellular ballooning on liver biopsy. Although the sample, as a whole, have elevated circulating endotoxin levels, we found no significant differences in this parameter between the groups with and without SIBO. Endotoxin values before and after antibiotic treatment did not differ, even on paired analysis, suggesting absence of any relationship between these factors. Serum endotoxin levels were inversely correlated with HDL levels, and directly correlated with triglyceride levels. CONCLUSION: Serum endotoxin levels did not differ between patients with and without SIBO, nor did these levels change after antibacterial therapy, virtually ruling out the possibility that elevated endotoxinemia in non-cirrhotic patients with NAFLD is associated with SIBO. Presence of SIBO was associated with greater severity of ballooning degeneration on liver biopsy, but not with a significantly higher prevalence of NASH. Additional studies are needed to evaluate the reproducibility and importance of this finding in patients with NAFLD and SIBO.

The risk of cardiometabolic disorders in lean non-alcoholic fatty liver disease: A longitudinal study.

BACKGROUND: Recent studies suggest that non-alcoholic fatty liver disease (NAFLD) in lean (BMI<25 â€‹kg/m2) individuals presents a distinct phenotype. We sought to determine the cardiometabolic consequences of lean NAFLD in a population cohort of relatively young asymptomatic individuals who participated in a voluntary routine health promotion evaluation in Brazil. METHODS: We analyzed data in our population collected from 2004 to 2016. Medical and demographic history, anthropometric measures, and fasting blood samples were obtained. Participants had ultrasonography to assess for fatty liver. We defined NAFLD as fatty liver in individuals scoring below 8 on the alcohol use disorders identification test (AUDIT). We included data from 9137 individuals who had complete data at baseline and at follow-up. RESULTS: The prevalence of lean NAFLD in our cohort was 3.8%. Over the median follow-up period of 2.4 years (range 0.5-9.9 years), lean individuals had 74% (HR: 1.74 (1.39-2.18)) and 67% (1.67 (1.29-2.15)) greater risk of developing elevated BP and elevated glucose, and nearly 3 times the risk of atherogenic dyslipidemia (HR: 2.98 (2.10-4.24)) compared to lean individuals without NAFLD. Lean NAFLD individuals also had higher risk of developing elevated glucose (HR: 1.37 (1.07-1.75)) and atherogenic dyslipidemia (1.46 (1.05-2.01)) compared to non-lean individuals without NAFLD. However, there was no significant difference in the risk of elevated BP, elevated glucose or atherogenic dyslipidemia between lean NAFLD and non-lean individuals with NAFLD in fully adjusted models. CONCLUSION: Lean NAFLD is not metabolically benign. Further cardiovascular risk stratification and appropriate preventive measures should be considered in lean individuals who present with NAFLD.

Underlying mechanism of portal hypertensive gastropathy in cirrhosis: a hemodynamic and morphological approach.

BACKGROUND AND AIM: Portal hypertensive gastropathy (PHG) is an important cause of bleeding in patients with cirrhosis associated with portal hypertension. Histologically, the condition is characterized by dilation of the mucosal and submucosal vessels of the stomach; however, its mechanisms remain unclear. The aim of the present cross-sectional study was to evaluate the role of portal and systemic hemodynamic features, humoral factors and hepatocellular function in the development and severity of PHG in patients with cirrhosis. METHODS: Forty-six patients with cirrhosis of different etiologies underwent endoscopy. Portal hypertension was evaluated by hepatic venous pressure gradient (HVPG). The gastric mucosa was analyzed using two diagnostic methods: endoscopy according to the McCormack criteria and histological by histomorphometric analysis. RESULTS: The prevalence of PHG according to the endoscopic and histomorphometric methods was 93.4% and 76.1%, respectively. There were no statistically significant differences in HVPG measurements between the patients with mild (16.0 +/- 5.9 mmHg) and severe PHG (16.9 +/- 6.5 mmHg; P = 0.80) or between patients who did not have (15.2 +/- 8.0 mmHg) and those who had PHG (16.3 +/- 5.7 mmHg). No correlation was found between the presence or severity of PHG and systemic vascular resistance index (P = 0.53 and 0.34, respectively), Child-Pugh classification (P = 0.73 and 0.78, respectively) or glucagon levels (P = 0.59 and 0.62, respectively). CONCLUSIONS: The present data show no correlation between the presence or the severity of PHG and portal pressure, Child-Pugh classification or systemic hemodynamics, suggesting that other factors may be involved in the physiopathology of PHG, such as local gastric mucosal factors or other underlying factors.

N-ACETYLCYSTEINE AND/OR URSODEOXYCHOLIC ACID ASSOCIATED WITH METFORMIN IN NON-ALCOHOLIC STEATOHEPATITIS: AN OPEN-LABEL MULTICENTER RANDOMIZED CONTROLLED TRIAL.

BACKGROUND: Nowadays, pharmacological treatment of non-alcoholic fatty liver disease (NAFLD) is still limited and it is based on the treatment of conditions associated comorbities. Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis. OBJECTIVE: To evaluate the efficacy of N-acetylcysteine (NAC) in combination with metformin (MTF) and/or ursodeoxycholic acid (UDCA) for treatment of non-alcoholic steatohepatitis (NASH). METHODS: Open-label multicenter randomized trial was conducted for 48 weeks. It included patients with biopsy-proven NASH. The patients were randomized into three groups: NAC (1.2 g) + UDCA (15 mg/kg) + MTF (850-1500 mg/day) (n=26); UDCA (20 mg/kg) + MTF (850-1500 mg/day) (n=13); NAC (1.2g) + MTF (850-1500 mg/day) (n=14) for 48 weeks. Clinical, laboratory and the second liver biopsies were performed after 48 weeks. RESULTS: A total of 53 patients were evaluated; 17 (32.1%) were males; median age ±54 (IQR=15, 21-71) years. In the baseline, no difference was seen between groups according clinical and histological parameters. The groups differed only in cholesterol, LDL and triglycerides. No significant differences in biochemical and histologic parameters were found between these the three groups after 48 weeks of treatment. In the intragroup analysis (intention-to-treat) comparing histological and biochemical features, there were significant improvements in the steatosis degree (P=0.014), ballooning (0.027) and, consequently, in the NAFLD Activity Score (NAS) (P=0.005), and in the ALT levels at the end of the treatment only in the NAC + MTF group. No significant evidence of modification in the liver fibrosis could be observed in any of the groups. CONCLUSION: This multicenter study suggests that the association of NAC + MTF could reduce the liver disease activity in patients with NASH. These data stimulate further controlled studies with this therapy for these patients.