Predicting liver-related events in NAFLD: A predictive model.

BACKGROUND AND AIMS: Management of NAFLD involves noninvasive prediction of fibrosis, which is a surrogate for patient outcomes. We aimed to develop and validate a model predictive of liver-related events (LREs) of decompensation and/or HCC and compare its accuracy with fibrosis models. APPROACH AND RESULTS: Patients with NAFLD from Australia and Spain who were followed for up to 28 years formed derivation (n = 584) and validation (n = 477) cohorts. Competing risk regression and information criteria were used for model development. Accuracy was compared with fibrosis models using time-dependent AUC analysis. During follow-up, LREs occurred in 52 (9%) and 11 (2.3%) patients in derivation and validation cohorts, respectively. Age, type 2 diabetes, albumin, bilirubin, platelet count, and international normalized ratio were independent predictors of LRE and were combined into a model [NAFLD outcomes score (NOS)]. The NOS model calibrated well [calibration slope, 0.99 (derivation), 0.98 (validation)] with excellent overall performance [integrated Brier score, 0.07 (derivation) and 0.01 (validation)]. A cutoff ≥1.3 identified subjects at a higher risk of LRE, (sub-HR 24.6, p < 0.001, 5-year cumulative incidence 38% vs 1.0%, respectively). The predictive accuracy at 5 and 10 years was excellent in both derivation (time-dependent AUC,0.92 and 0.90, respectively) and validation cohorts (time-dependent AUC,0.80 and 0.82, respectively). The NOS was more accurate than the fibrosis-4 or NAFLD fibrosis score for predicting LREs at 5 and 10 years ( p < 0.001). CONCLUSIONS: The NOS model consists of readily available measures and has greater accuracy in predicting outcomes in patients with NAFLD than existing fibrosis models.

FIB-4 score as a predictor of COVID-19-related severity in hospitalized patients.

AIM: to determine the impact of liver fibrosis on the prognosis of COVID and liver injury associated with the infection. METHODS: retrospective multicenter study including 575 patients requiring admission for COVID-19 between January and June 2020. Fibrosis index-4 (FIB-4) was calculated within six months prior to infection and at six months post-infection. RESULTS: baseline FIB-4 was elevated in patients who died (1.91 ± 0.95 vs 1.43 ± 0.85; p < 0.001). In addition, 17.1 % (32/187) of patients with baseline FIB-4 < 1.45 died vs 52.9 % (9/17) with FIB-4 > 3.25 (p < 0.001). In the adjusted multivariate analysis, baseline FIB-4 (OR 1.61 [95 % CI: 1.19-2.18]; p = 0.002) was independently associated with mortality. Parameters associated with liver injury, including aspartate aminotransferase (AST) (28 ± 10 vs 45 ± 56 IU/l; p < 0.001) and alanine aminotransferase (ALT) (20 ± 12 vs 38 ± 48 IU/l; p < 0.001) were significantly higher at admission compared to baseline. Furthermore, FIB-4 increased from baseline to the time of admission (1.53 ± 0.88 vs 2.55 ± 1.91; p < 0.001), and up to 6.9 % (10/145) of patients with FIB-4 < 1.45 on admission died vs 47.5 % if FIB-4 > 3.25 (58/122) (p < 0.001). In the adjusted multivariate analysis, FIB-4 on admission (OR 1.14 [95 % CI: 1.03-1.27]; p = 0.015) was independently associated with mortality. In addition, AST (42 ± 38 vs 22 ± 17 IU/l; p < 0.001) and ALT (40 ± 50 vs 20 ± 19 IU/l; p < 0.001) were significantly reduced at six months after the resolution of infection. Accordingly, FIB-4 decreased significantly (2.12 ± 1.25 vs 1.32 ± 0.57; p < 0.001) six months after the infection. CONCLUSION: increased FIB-4, either at baseline or at the time of admission, was associated with severity and mortality related to respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the liver damage expressed by elevated transaminases and FIB-4 levels was reversible in most of patients.

Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles.

BACKGROUND AND AIMS: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. APPROACH AND RESULTS: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A. CONCLUSIONS: Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.

ABIDE: An Accurate Predictive Model of Liver Decompensation in Patients With Nonalcoholic Fatty Liver-Related Cirrhosis.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is an increasingly important cause of liver cirrhosis and subsequent complications. We retrospectively developed and validated a model to predict hepatic decompensation in patients with NAFLD and cirrhosis and compared this with currently available models. APPROACH AND RESULTS: Baseline variables from an international cohort of 299 patients with biopsy-proven NAFLD with compensated cirrhosis were examined to construct a model using competing risk multivariate regression and Akaike/Bayesian information criteria. Validation was performed in 244 patients with biopsy-proven NAFLD cirrhosis from the United States. Prognostic accuracy was compared with the NAFLD fibrosis score (NFS), fibrosis-4 (FIB-4), Model for End-Stage Liver Disease (MELD), Child-Turcotte-Pugh (CTP), and albumin-bilirubin (ALBI)-FIB-4 score using time-dependent area under the curve (tAUC) analysis. During a median follow-up of 5.6 years (range 2.4-14.1) and 5.4 years (range 1.5-13.8), hepatic decompensation occurred in 81 and 132 patients in the derivation and validation cohorts, respectively. In the derivation cohort, independent predictors of hepatic decompensation (Aspartate aminotransferase/alanine aminotransferase ratio, Bilirubin, International normalized ratio, type 2 Diabetes, and Esophageal varices) were combined into the ABIDE model. Patients with a score ≥4.1 compared with those with a score <4.1 had a higher risk of decompensation (subhazard ratio, 6.7; 95% confidence interval [CI], 4.0-11.2; P < 0.001), a greater 5-year cumulative incidence (37% vs. 6%, P < 0.001), and shorter mean duration to decompensation (3.8 vs 6.7 years, P < 0.001). The accuracy of the ABIDE model at 5 years was good in the derivation (tAUC, 0.80; 95% CI, 0.73-0.84) and validation cohorts (0.78; 95% CI, 0.74-0.81) and was significantly more accurate than the NFS (0.72), FIB-4 (0.74), MELD (0.69), CTP (0.72), and ALBI-FIB-4 (0.73) (all P < 0.001). CONCLUSIONS: In patients with NAFLD and compensated cirrhosis, ABIDE, a predictive model of routine clinical measures, predicts future hepatic decompensation.

Type 2 Diabetes and Metformin Use Associate With Outcomes of Patients With Nonalcoholic Steatohepatitis-Related, Child-Pugh A Cirrhosis.

BACKGROUND & AIMS: Factors that affect outcomes of patients with nonalcoholic steatohepatitis (NASH)-related cirrhosis are unclear. We studied associations of type 2 diabetes, levels of hemoglobin A1c (HbA1c), and use of antidiabetic medications with survival and liver-related events in patients with NASH and compensated cirrhosis. METHODS: We collected data from 299 patients with biopsy-proven NASH with Child-Pugh A cirrhosis from tertiary hospitals in Spain, Australia, Hong Kong, and Cuba, from April 1995 through December 2016. We obtained information on the presence of type 2 diabetes, level of HbA1c, and use of antidiabetic medications. Cox proportional and competing risk models were used to estimate and compare rates of transplant-free survival, hepatic decompensation, and hepatocellular carcinoma (HCC). RESULTS: A total of 212 patients had type 2 diabetes at baseline and 8 of 87 patients developed diabetes during a median follow-up time of 5.1 years (range, 0.5-10.0 y). A lower proportion of patients with diabetes survived the entire follow-up period (38%) than of patients with no diabetes (81%) (adjusted hazard ratio [aHR], 4.23; 95% CI, 1.93-9.29). Higher proportions of patients with diabetes also had hepatic decompensation (51% vs 26% of patients with no diabetes; aHR, 2.03; 95% CI, 1.005-4.11) and HCC (25% vs 7% of patients with no diabetes; aHR, 5.42; 95% CI, 1.74-16.80). Averaged annual HbA1c levels over time were not associated with outcomes. Metformin use over time was associated with a significant reduction in risk of death or liver transplantation (aHR, 0.41; 95% CI, 0.26-0.45), hepatic decompensation (aHR, 0.80; 95% CI, 0.74-0.97), and HCC (aHR, 0.78; 95% CI, 0.69-0.96). Metformin significantly reduced the risk of hepatic decompensation and HCC only in subjects with HbA1c levels greater than 7.0% (aHR, 0.97; 95% CI, 0.95-0.99 and aHR, 0.67; 95% CI, 0.43-0.94, respectively). CONCLUSIONS: In an international cohort of patients with biopsy-proven NASH and Child-Pugh A cirrhosis, type 2 diabetes increased the risk of death and liver-related outcomes, including HCC. Patients who took metformin had higher rates of survival and lower rates of decompensation and HCC.

Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study.

BACKGROUND & AIMS: Little is known about the natural course of nonalcoholic fatty liver disease (NAFLD) with advanced fibrosis. We describe long-term outcomes and evaluate the effects of clinical and histologic parameters on disease progression in patients with advanced NAFLD. METHODS: We conducted a multi-national study of 458 patients with biopsy-confirmed NAFLD with bridging fibrosis (F3, n = 159) or compensated cirrhosis (222 patients with Child-Turcotte-Pugh scores of A5 and 77 patients with scores of A6), evaluated from April 1995 through November 2013 and followed until December 2016, death, or liver transplantation at hepatology centers in Spain, Australia, Hong Kong, and Cuba. Biopsies were re-evaluated and scored; demographic, clinical, laboratory, and pathology data for each patient were collected from the time of liver biopsy collection. Cox proportional and competing risk models were used to estimate rates of transplantation-free survival and major clinical events and to identify factors associated with outcomes. RESULTS: During a mean follow-up time of 5.5 years (range, 2.7-8.2 years), 37 patients died, 37 received liver transplants, 88 had initial hepatic decompensation events, 41 developed hepatocellular carcinoma, 14 had vascular events, and 30 developed nonhepatic cancers. A higher proportion of patients with F3 fibrosis survived transplantation-free for 10 years (94%; 95% confidence interval [CI], 86%-99%) than of patients with cirrhosis and Child-Turcotte-Pugh A5 (74%; 95% CI, 61%-89%) or Child-Turcotte-Pugh A6 (17%; 95% CI, 6%-29%). Patients with cirrhosis were more likely than patients with F3 fibrosis to have hepatic decompensation (44%; 95% CI, 32%-60% vs 6%, 95% CI, 2%-13%) or hepatocellular carcinoma (17%; 95% CI, 8%-31% vs 2.3%, 95% CI, 1%-12%). The cumulative incidence of vascular events was higher in patients with F3 fibrosis (7%; 95% CI, 3%-18%) than cirrhosis (2%; 95% CI, 0%-6%). The cumulative incidence of nonhepatic malignancies was higher in patients with F3 fibrosis (14%; 95% CI, 7%-23%) than cirrhosis (6%; 95% CI, 2%-15%). Death or transplantation, decompensation, and hepatocellular carcinoma were independently associated with baseline cirrhosis and mild (<33%) steatosis, whereas moderate alcohol consumption was associated with these outcomes only in patients with cirrhosis. CONCLUSIONS: Patients with NAFLD cirrhosis have predominantly liver-related events, whereas those with bridging fibrosis have predominantly nonhepatic cancers and vascular events.

Analytical, anthropometric and dietary factors associated with the development of fibrosis in patients with nonalcoholic fatty liver disease.

BACKGROUND: a prolonged non-alcoholic steatohepatitis (NASH) condition can lead to advanced stages of liver disease and the development of hepatocellular carcinoma. AIM: to evaluate analytical, anthropometric and dietary factors associated with the presence of fibrosis as this is the factor that most influences survival and evolution. METHODS: seventy-six patients with liver biopsy-diagnosed non-alcoholic fatty liver disease (NAFLD) were included. Biopsies were scored considering the NASH criteria of Kleiner. Analytical, anthropometric and dietary (survey) parameters were obtained. NAFLD-FS is a non-invasive fibrosis index and was assessed for each patient. Leptin, adiponectin, resistin and TNF-alpha serum levels were determined. RESULTS: fifty-six patients were male (73.7%) and the mean age was 44.5 ± 11.3 years of age (19-68). Thirty-nine (51.3%) (F1-F2: 84.6%; F3-4: 15.4%) patients had fibrosis in the liver biopsy. Seventeen females (85%) had fibrosis versus 22 males (39%), which was statistically significant by univariate analysis (p < 0.01). Patients with advanced fibrosis were older, with lower platelet counts, lower serum albumin, greater homeostatic model assessment insulin resistance (HOMA-IR), lower dietary lipids percentage, higher serum leptin levels and higher NAFLD Fibrosis Score (NAFLD-FS) values. This index had a negative predictive value of 98% and a positive predictive value of 60% for the detection of fibrosis. Variables independently associated with fibrosis (logistic regression) included male gender (protective factor) (0.09, 95% CI 0.01-0.7; p < 0.05) and HOMA-IR (1.7, 95% CI, 1.03-2.79; p < 0.05). CONCLUSIONS: gender and HOMA-IR were the only independent factors associated with fibrosis. NAFLD-FS could be considered as an accurate scoring system to rule out advanced fibrosis.

Impact of the endoscopist's experience on the negative predictive value of capsule endoscopy. / Influencia de la experiencia acumulada del explorador en el valor predictivo negativo de la cápsula endoscópica.

INTRODUCTION: The impact of the accumulated experience of the capsule endoscopy (CE) reader on the accuracy of this test is discussed. AIM: To determine whether the negative predictive value of CE findings changes along the learning curve. METHODS: We reviewed the first 900 CE read by 3 gastroenterologists experienced in endoscopy over 8 years. These 900 CE were divided into 3 groups (300 CE each): group 1 consisted of the sum of the first 100 CE read by each of the 3 endoscopists; group 2, the sum of the second 100 and groups 3, the sum of the third 100. Patients with normal CE were monitored for at least 28 months to estimate the negative predictive value. RESULTS: A total of 54 (18%) CE in group 1, 58 (19.3%) in group 2 and 47 (15.6%) in group 3 were normal, although only 34 patients in group 1, 38 in group 2 and 36 in group 3 with normal CE completed follow up and were eventually studied. The negative predictive value was 88.2% in group 1, 89.5% in group 2 and 97% in group 3 (P>.05). CONCLUSION: The negative predictive value tended to increase, but remained high and did not change significantly after the first 100 when readers are experienced in conventional endoscopy and have preliminary specific training.

Nutrition and Chronic Liver Disease.

Malnutrition is common in chronic liver diseases and worsens the patient's prognosis. Many liver disorders are associated with nutritional deficiencies. Some of the main factors that can lead to malnutrition in patients with chronic liver disease include decreased lipid absorption and reduced albumin production. In addition, these patients are sometimes candidates for a liver transplant that requires nutritional intervention after surgery to improve their prognosis. Thus, it is very important to recognise malnutrition in patients with liver failure in order to resolve it, mainly by a complete history of the patient, dietary survey, determination of muscle mass and a subjective assessment. To ensure a good nutritional status, exercise and lifestyle changes are considered, including dietary modifications, especially with a Mediterranean pattern. This article reviews these topics, including dietary modifications before and after liver transplantation. Additionally, nutritional recommendations are offered to patients with metabolic hepatic steatosis.

[Amoxicillin-induced cholestatic hepatitis]. / Hepatitis colestásica por amoxicilina.

Drug-induced hepatotoxicity is a challenge in daily clinical practice. One of the most frequent causes is antibiotics. However, amoxicillin-induced liver injury is uncommon. We report the case of an 87-year-old man who developed cholestatic hepatitis after ingesting amoxicillin 500 mg/8 hours for dental disease. A review of the literature on this topic is provided.

Histopathological differences in patients with biopsy-proven non-alcoholic fatty liver disease with and without type 2 diabetes.

BACKGROUND AND AIMS: Prevalence of non-alcoholic fatty liver disease (NAFLD) in developed countries is 30% in the general population and 50% in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to compare the severity of NAFLD, as assessed by liver biopsy and using the non-invasive index NAFLD Fibrosis Score (NFS), in subjects with and without T2DM. PATIENTS AND METHODS: The study sample consisted of 217 patients with biopsy-proven NAFLD. Anthropometric assessments, laboratory tests, histological criteria established by the Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN), and the NFS were recorded. RESULTS: Patients with T2DM (n=36; 16.5%) had higher HOMA-IR values (6.3±3.6 vs. 3.3±2.4; p<0.0001), GGT levels (125.2±102.3 vs. 82.5±70.6IU/l; p<005), and NFS index (-0.6±0.2 vs. -1.8±0.1; p<0.001) than subjects with no T2DM. Patients with T2DM were found higher rates of NASH (72.2% vs. 48.6%; p<0.05), advanced steatosis (80.6% vs. 63%; p<0.05), and liver fibrosis (75% vs. 43.1%, p<0.05) than patients with no T2DM. Patients with T2DM also had higher NFS values (-0.6±1.2 vs. -1.8±1.8: p=0.01). A logistic regression analysis adjusting for age, gender and BMI showed a significant independent association between NASH and presence of T2DM (OR=4.2: 95% CI: 1.4-12.1; p=0.007). A second model adjusting for the same covariates showed T2DM to be an independent factor associated to advanced fibrosis (OR=4.1; 95% CI: 1.7-9.7). CONCLUSION: Patients with T2DM have more advanced degrees of NAFLD and advanced fibrosis as assessed by liver biopsy and the NFS index. Particular attention should be paid to the study and monitoring of NASH in patients with T2DM.

Metabolomic-based noninvasive serum test to diagnose nonalcoholic steatohepatitis: Results from discovery and validation cohorts.

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease worldwide and includes a broad spectrum of histologic phenotypes, ranging from simple hepatic steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). While liver biopsy is the reference gold standard for NAFLD diagnosis and staging, it has limitations due to its sampling variability, invasive nature, and high cost. Thus, there is a need for noninvasive biomarkers that are robust, reliable, and cost effective. In this study, we measured 540 lipids and amino acids in serum samples from biopsy-proven subjects with normal liver (NL), NAFL, and NASH. Using logistic regression analysis, we identified two panels of triglycerides that could first discriminate between NAFLD and NL and second between NASH and NAFL. These noninvasive tests were compared to blinded histology as a reference standard. We performed these tests in an original cohort of 467 patients with NAFLD (90 NL, 246 NAFL, and 131 NASH) that was subsequently validated in a separate cohort of 192 patients (7 NL, 109 NAFL, 76 NASH). The diagnostic performances of the validated tests showed an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.88 ± 0.05, 0.94, and 0.57, respectively, for the discrimination between NAFLD and NL and 0.79 ± 0.04, 0.70, and 0.81, respectively, for the discrimination between NASH and NAFL. When the analysis was performed excluding patients with glucose levels >136 mg/dL, the area under the receiver operating characteristic curve for the discrimination between NASH and NAFL increased to 0.81 ± 0.04 with sensitivity and specificity of 0.73 and 0.80, respectively. Conclusion: The assessed noninvasive lipidomic serum tests distinguish between NAFLD and NL and between NASH and NAFL with high accuracy. (Hepatology Communications 2018;2:807-820).