Search

Background: Biomarkers for metabolic dysfunction-associated steatohepatitis (MASH) have been considered based on proteomic and lipidomic data from plasma and liver tissue without clinical benefits. This study evaluated proteomics-based plasma and liver tissue biomarkers collected simultaneously from patients with metabolic dysfunction-associated steatotic liver disease (MASLD)., Methods: Liver tissue and plasma samples were collected during liver biopsy to diagnose MASLD. Untargeted proteomics was performed on 64 patients., Results: Twenty plasma proteins were up- or downregulated in patients with MASH compared with those without MASH. The potential biomarkers utilizing the best combinations of these plasma proteins had an area under the receiver operating curve (AUROC) of 0.671 for detecting those with MASH compared with those without it. However, none of the 20 plasma proteins were represented among the significantly regulated liver tissue proteins in patients with MASH. Ten of them displayed a trend and relevance in liver tissue with MASLD progression. These 10 plasma proteins had an AUROC of 0.793 for MASH identification and higher positive and negative predictive values., Conclusion: The plasma and liver protein expressions of patients with MASH were not directly comparable. Plasma protein biomarkers that are also expressed in liver tissue can help improve MASH detection., (© 2024 Wiley‐VCH GmbH.)

Hepatocellular death contributes to progression of alcohol-associated (ALD-associated) and non-alcohol-associated (NAFL/NASH) liver diseases. However, receptor-interaction protein kinase 3 (RIP3), an intermediate in necroptotic cell death, contributes to injury in murine models of ALD but not NAFL/NASH. We show here that a differential role for mixed-lineage kinase domain-like protein (MLKL), the downstream effector of RIP3, in murine models of ALD versus NAFL/NASH and that RIP1-RIP3-MLKL can be used as biomarkers to distinguish alcohol-associated hepatitis (AH) from NASH. Phospho-MLKL was higher in livers of patients with NASH compared with AH or healthy controls (HCs). MLKL expression, phosphorylation, oligomerization, and translocation to plasma membrane were induced in WT mice fed diets high in fat, fructose, and cholesterol but not in response to Gao-binge (acute on chronic) ethanol exposure. Mlkl-/- mice were not protected from ethanol-induced hepatocellular injury, which was associated with increased expression of chemokines and neutrophil recruitment. Circulating concentrations of RIP1 and RIP3, but not MLKL, distinguished patients with AH from HCs or patients with NASH. Taken together, these data indicate that MLKL is differentially activated in ALD/AH compared with NAFL/NASH in both murine models and patients. Furthermore, plasma RIP1 and RIP3 may be promising biomarkers for distinguishing AH and NASH.

Unlabelled: The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age ≥65 years) and 735 nonelderly (18-64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P = 0.02), and advanced fibrosis (25% versus 44%, P = 0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P = 0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies (P ≤ 0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR] = 1.12, P = 0.007) and lower platelets (OR = 0.98, P = 0.02); and independent determinants of advanced fibrosis included higher AST (OR = 1.08, P = 0.007), lower alanine aminotransferase value (OR = 0.91, P = 0.002), and an increased odds of having low high-density lipoprotein (OR = 8.35, P = 0.02)., Conclusion: Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis., (© 2013 by the American Association for the Study of Liver Diseases.)

Aim: Non-alcoholic steatohepatitis (NASH) patients are at increased risk for progression to cirrhosis. The aim of this study was to assess all-cause and liver-specific mortality in a cohort of non-alcoholic fatty liver disease (NAFLD) patients., Methods: Biopsy-proven NAFLD patients with and without NASH from two historic databases were included. Clinico-demographic information from the time of biopsy was available. Mortality data were obtained from National Death Index-Plus and used for estimating overall and cause-specific mortality. The non-parametric Kaplan-Meier method with log-rank test and multivariate analyses with Cox proportional hazard model were used to compare cohorts., Results: Two hundred eighty-nine NAFLD patients were included (50.3 ± 14.5 years old, 39.4 % male, 78.6 % Caucasian, 46.0 % obese, 26.0 % diabetic, 5.9 % with family history of liver diseases). Of these, 59.2 % had NASH whereas 40.8 % had non-NASH NAFLD. NASH patients were predominantly female, had higher aspartate aminotranserase, alanine aminotransferase and fasting serum glucose. During follow-up (median 150 months, maximum 342 months), patients with NASH had higher probability of mortality from liver-related causes than non-NASH NAFLD patients (p value = 0.0026). In the entire NAFLD cohort, older age [aHR = 1.07 (95 % CI = 1.05-1.10)] and presence of type II diabetes [aHR = 2.09 (1.39-3.14)] were independent predictors of overall mortality. However, in addition to age [aHR = 1.06 (1.02-1.10)] having histologic NASH [aHR = 9.16 (2.10-9.88)] was found to be an independent predictor of liver-related mortality. Additionally, presence of type II diabetes was associated with liver-related mortality [aHR = 2.19 (1.00-4.81)]., Conclusions: This long-term follow-up of NAFLD patients confirms that NASH patients have higher risk of liver-related mortality than non-NASH. Additionally, patients with NAFLD and type II diabetes are at highest risk for overall and liver-related mortality.

Fetuin-A is synthesized in the liver and may be associated with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Lifestyle-induced weight loss reduces fetuin-A, but the effect of exercise alone is unknown. We determined the effect of short-term exercise training on plasma fetuin-A in 13 (50.5 ± 3.4 yr) obese adults (body mass index, 33.3 ± 0.9 kg/m(2)) with clinically diagnosed NAFLD. Subjects participated in 7 days of supervised exercise training (60 min/day at ∼85% maximum heart rate) and were instructed to maintain their normal caloric and macronutrient intake. Insulin resistance was assessed by an oral glucose tolerance test. Hepatic triglyceride content (HTGC) was determined by proton MRI. We used C2C12 skeletal muscle cells to examine the direct effect of fetuin-A on 2-deoxyglucose uptake, insulin signaling [phosphorylation of Akt and AS160 (pAkt and pAS160, respectively)], and glucose transporter-4 (GLUT-4) translocation. Insulin resistance was reduced by 29% (P < 0.05), and glucose area under the curve (AUC) was decreased by 13% (P < 0.01) after the 7 days of exercise. Furthermore, circulating fetuin-A was decreased by 11% (4.2 ± 03 vs. 3.6 ± 0.2 nM; P < 0.02), and this change correlated with reduced insulin resistance (r = 0.62; P < 0.04) and glucose AUC (r = 0.58; P < 0.04). Importantly, the exercise program did not change body weight (P = 0.12), HTGC (P = 0.73), or aerobic capacity (P = 0.14). In vitro experiments revealed that fetuin-A decreased skeletal muscle glucose uptake by downregulating pAkt and pAS160 and subsequent GLUT-4 translocation to the plasma membrane. Together, our findings highlight a role for fetuin-A in skeletal muscle insulin resistance and suggest that part of the exercise-induced improvement in glucose tolerance in patients with NAFLD may be due to lowering fetuin-A.

Background: Metabolic risk factors are associated with non-alcoholic fatty liver disease (NAFLD), but they are less frequent in inflammatory bowel disease (IBD)., Aim: This study evaluates the frequency of NAFLD and its risk factors among IBD patients including anti-TNF-α therapy., Methods: IBD patients who underwent abdominal imaging from January, 2009 to December, 2010 were analyzed in this nested, case-controlled study. IBD patients with NAFLD by imaging were compared with those who had no evidence of NAFLD (control)., Results: Among 928 IBD patients, 76 (8.2%) had evidence of NAFLD by imaging, and were compared to 141 patients without NAFLD evaluated (study: control ratio=~1:2). NAFLD patients were older (46.0 ± 13.3 vs. 42.0 ±14.1 years; p=0.018) and had a later onset of IBD compared to the control group (37.2 ± 15.3 vs. 28.7 ± 23.8 years; p=0.002). Metabolic syndrome was present in 29.0% of NAFLD patients, with a median Adult Treatment Panel risk factor of 2 [Interquartile range 1,3]. Patients not receiving anti-TNF-α therapy had a higher occurrence of NAFLD (p=0.048). In multivariate analysis, hypertension (OR=3.5), obesity (OR=2.1), small bowel surgeries (OR=3.7), and use of steroids at the time of imaging (OR=3.7) were independent factors associated with NAFLD., Conclusion: NAFLD occurred in 8.2% of the IBD population. NAFLD patients were older and had a later onset of IBD disease. IBD patients develop NAFLD with fewer metabolic risk factors than non-IBD NAFLD patients. It is also less common among patients who received anti-TNF-α therapy., (Copyright © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Context: Hepatic steatosis, insulin resistance, inflammation, low levels of polyunsaturated lipids, and adiponectin are implicated in the development and progression of nonalcoholic fatty liver disease (NAFLD)., Objective: We examined the effects of short-term aerobic exercise on these metabolic risk factors., Design and Participants: Obese individuals (N = 17, 34.3 ± 1.0 kg/m²) with clinically confirmed NAFLD were enrolled in a short-term aerobic exercise program that consisted of 7 consecutive days of treadmill walking at ~85% of maximal heart rate for 60 minutes per day. Preintervention and postintervention measures included hepatic triglyceride content, and a lipid saturation index and polyunsaturated lipid index (PUI) of the liver, obtained by (1)H magnetic resonance spectroscopy (N = 14). Insulin sensitivity was estimated from an oral glucose tolerance test (OGTT), and mononuclear cells were isolated to assess reactive oxygen species production during the OGTT. Circulating glucose, insulin, and high molecular weight (HMW) adiponectin were determined from plasma., Main Outcome: Short-term aerobic exercise training improved hepatic lipid composition in patients with NAFLD., Results: Exercise training resulted in an increase in liver PUI (P < .05), increased insulin sensitivity (Matsuda Index: P < .05), HMW adiponectin (P < .05), and maximal oxygen consumption (P < .05). Reactive oxygen species production during the OGTT was reduced following exercise training (P < .05). HMW adiponectin was increased after the exercise program and the increase was positively correlated with the increase in liver PUI (r = 0.52, P = .05). Body weight remained stable during the program (P > .05)., Conclusion: Short-term exercise can target hepatic lipid composition, which may reduce the risk of NAFLD progression. The improvement in hepatic lipid composition may be driven by adiponectin.

Background: Ascites usually occurs in the setting of end-stage liver disease and low serum albumin and is associated with increased mortality. However, some patients develop ascites despite normal serum albumin (NSA), when a higher portal pressure and/or enhanced renal sodium retention would be expected. This study investigated the relationship between the hepatic venous pressure gradient (HVPG) and serum albumin in ascitic patients with different etiologies of cirrhosis and mortality., Methods: Records of all patients with non-malignant ascites who underwent HVPG measurement from 2005 to 2009 were reviewed., Results: One hundred and thirty-eight 138 patients met inclusion criteria; 18.8% had NSA. No difference in sodium excretion or diuretic use was noted in patients with and without NSA. NASH patients were more likely to have a NSA (34.2% vs 12.4%; P=0.001) as well as lower HVPG (15 vs 17.9 mmHg; P=0.009) compared to other etiologies. MELD and HVPG predicted overall survival. However, mortality did not differ by disease etiology, though NASH patients had lower CTP (7.6 vs 8.5; P<0.001) and MELD (15.6 vs 18.1; P=0.09) scores, particularly among patients who died., Conclusions: In patients with ascites and NSA, there were no increase in HVPG or urinary sodium retention. NASH patients with ascites had lower HVPG and a higher prevalence of NSA. They also had a higher mortality relative to MELD and CTP scores in other patients. In these patients, mechanisms other than portal and oncotic pressures and sodium retention play a role in ascites development, and increase mortality rate when complicated by low albumin., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Unlabelled: Pentoxifylline (PTX) improved the histological features of nonalcoholic steatohepatitis (NASH) in a recent randomized placebo-controlled trial. However, the underlying mechanism responsible for the beneficial effects of PTX in NASH remains unidentified. A key role of lipid oxidation in the pathogenesis and progression of NASH has been established. PTX is known to decrease free-radical-mediated oxidative stress and inhibit lipid oxidation. The primary aim of this study was to evaluate the effects of PTX on levels of lipid oxidation products in patients with NASH. Levels of multiple structurally specific oxidized fatty acids including hydroxy-octadecadienoic acids (HODEs), oxo-octadecadienoic acids (oxoODEs), and hydroxy-eicosatetraenoic acids (HETEs) were quantified by mass spectrometry in plasma obtained at baseline and at study completion in patients who completed 1 year of therapy with PTX or placebo in a randomized controlled trial. Therapy with PTX resulted in significant decreases in 9-HODE and 13-oxoODE, oxidized lipid products of linoleic acid (LA) linked to histological severity in nonalcoholic fatty liver disease. Similarly, PTX therapy was associated with significant decreases in 8-HETE, 9-HETE, and 11-HETE compared to placebo. Statistically significant correlations were demonstrated between the decrease in HODEs and oxoODEs and improved histological scores of fibrosis and between the decrease in HETEs and improved lobular inflammation., Conclusion: Therapy with PTX compared to placebo was associated with a significant reduction of oxidized fatty acids. This novel evidence supports that the beneficial effects of PTX in patients with NASH are likely partly mediated through decreasing lipid oxidation, largely free-radical-mediated lipid oxidation. Additionally, this is the first report on the link between decreased oxidized lipid products and improved histological disease in the setting of a therapeutic trial in NASH., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a cardiovascular risk factor. Although modest alcohol consumption may reduce the risk for cardiovascular mortality, whether patients with NAFLD should be allowed modest alcohol consumption remains an important unaddressed issue. We aimed to evaluate the association between modest alcohol drinking and non-alcoholic steatohepatitis (NASH), among subjects with NAFLD., Methods: In a cross-sectional analysis of adult participants in the NIH NASH Clinical Research Network, only modest or non-drinkers were included: participants identified as (1) drinking >20 g/day, (2) binge drinkers, or (3) non-drinkers with previous alcohol consumption were excluded. The odds of having a histological diagnosis of NASH and other histological features of NAFLD were analyzed using multiple ordinal logistic regression., Results: The analysis included 251 lifetime non-drinkers and 331 modest drinkers. Modest drinkers compared to non-drinkers had lower odds of having a diagnosis of NASH (summary odds ratio 0.56, 95% CI 0.39-0.84, p=0.002). The odds of NASH decreased as the frequency of alcohol consumption increased within the range of modest consumption. Modest drinkers also had significantly lower odds for fibrosis (OR 0.56 95% CI 0.41-0.77) and ballooning hepatocellular injury (OR 0.66 95% CI 0.48-0.92) than lifetime non-drinkers., Conclusions: In a large, well-characterized population with biopsy-proven NAFLD, modest alcohol consumption was associated with lesser degree of severity as determined by lower odds of the key features that comprise a diagnosis of steatohepatitis, as well as fibrosis. These findings demonstrate the need for prospective studies and a coordinated consensus on alcohol consumption recommendations in NAFLD., (Copyright © 2012 European Association for the Study of the Liver. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease with a histological spectrum ranging from steatosis alone, to nonalcoholic steatohepatitis (NASH). The latter is associated with an increased risk for progression to cirrhosis. Ceramides are a lipid species that exert biological effects through cellular proliferation, differentiation, and cell death, and interact with several pathways involved in insulin resistance, oxidative stress, inflammation, and apoptosis, all of which are linked to NAFLD. We propose a mechanism through which ceramides contribute to the development of NAFLD and progression to NASH, due in part to second messenger effects via tumor necrosis factor (TNF)-α. A better understanding of the role of ceramides in steatohepatitis has both diagnostic and therapeutic implications for the treatment of fatty liver disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease. Nonalcoholic steatohepatitis (NASH), the more severe form of NAFLD, has an increased risk for progression to cirrhosis. The available data suggest increased morbidity and mortality among those patients with advanced histologic severity such as NASH and fibrosis. Despite the lack of a universally accepted histologic definition of NAFLD and inconsistency among pathologists regarding histologic findings essential to the diagnosis of NASH, a few studies have identified specific histologic findings (particularly fibrosis regardless of stage) that are able to predict NAFLD-related mortality as being most important., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Increased hepatocyte apoptosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and contributes to the profibrogenic state responsible for the progression to nonalcoholic steatohepatitis (NASH). Strategies aimed at reducing apoptosis may result in better outcomes for individuals with NAFLD. We therefore examined the effect of a short-term exercise program on markers of apoptosis-plasma cytokeratin 18 (CK18) fragments, alanine aminotransferase (ALT), aspartate aminotransferase (AST), soluble Fas (sFas), and sFas ligand (sFasL)-in 13 obese individuals with NAFLD [body mass index 35.2 ± 1.2 kg/m(2), >5% intrahepatic lipid (IHL) assessed by (1)H-MR spectroscopy]. Exercise consisted of treadmill walking for 60 min/day on 7 consecutive days at ∼85% of maximal heart rate. Additionally, subjects underwent an oral glucose tolerance test and a maximal oxygen consumption (Vo(2max)) test before and after the exercise intervention. The Matsuda index was used to assess insulin sensitivity. We observed significant decreases in CK18 fragments (558.4 ± 106.8 vs. 323.4 ± 72.5 U/l, P < 0.01) and ALT (30.2 ± 5.1 vs. 24.3 ± 4.8 U/l, P < 0.05), and an increase in whole body fat oxidation (49.3 ± 6.1 vs. 69.4 ± 7.1 mg/min, P < 0.05), while decreases in circulating sFasL approached statistical significance (66.5 ± 6.0 vs. 63.0 ± 5.7 pg/ml, P = 0.06), as did the relationship between percent change in circulating CK18 fragments and ALT (r = 0.55, P = 0.05). We also observed a significant correlation between changes in fat oxidation and circulating sFasL (rho = -0.65, P < 0.05). There was no change in IHL following the intervention (18.2 ± 2.5 vs. 17.5 ± 2.1%, NS). We conclude that short-term exercise reduces a circulatory marker of hepatocyte apoptosis in obese individuals with NAFLD and propose that changes in the proapoptotic environment may be mediated through improved insulin sensitivity and increased oxidative capacity.

Background: A possible association between nonalcoholic fatty liver disease (NAFLD) and hypothyroidism has been suggested. The recognized link between hypothyroidism and elements of the metabolic syndrome may explain this association., Aim: The purpose of this study was to determine the prevalence of hypothyroidism in a cohort of patients with NAFLD and analyze the potential factors associated with hypothyroidism in this patient population., Methods: Two hundred forty-six patients with biopsy-proven NAFLD attending hepatology clinics at the Cleveland Clinic between October 2006 and June 2009, and 430 age-, gender-, race- and BMI-matched control subjects seen in the general internal medicine clinic were included. Patients with a clinical diagnosis of hypothyroidism who were on thyroid replacement therapy were considered to be hypothyroid., Results: Hypothyroidism was more frequent among patients with NAFLD (21% vs. 9.5%; P < 0.01) compared to controls, and was higher in NASH patients than NAFLD patients without NASH (25% vs. 12.8%, P = 0.03). Subjects with hypothyroidism were 2.1 (95% CI 1.1-3.9, P = 0.02) and 3.8 (95% CI 2-6.9, P < 0.001) times more likely to have NAFLD and NASH, respectively. By multivariate analysis, female gender (P < 0.001) and increased BMI (P = 0.03) were associated with hypothyroidism. NAFLD subjects who reported mild alcohol consumption were less likely to have hypothyroidism compared to those who reported complete abstinence (OR 0.37, P = 0.008)., Conclusions: A higher prevalence of hypothyroidism was demonstrated in patients with NAFLD compared to controls. Among subjects with NALFD, female gender, increased BMI and history of abstinence from alcohol were associated with hypothyroidism. Patients with hypothyroidism were also more likely to have NASH.

Unlabelled: The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of nonalcoholic steatohepatitis (NASH). In all, 55 adults with biopsy-confirmed NASH were randomized to receive PTX at a dose of 400 mg three times a day (n = 26) or placebo (n = 29) over 1 year. The primary efficacy endpoint was defined as improvement in histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥ 2 points in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 1 year, intention-to-treat analysis showed a decrease of ≥ 2 points in the NAS in 38.5% of patients on PTX versus 13.8% of those on placebo (P = 0.036). Per protocol analysis, a decrease of ≥ 2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo (P = 0.01). The mean change in NAS score from baseline was -1.6 in the PTX group, versus -0.1 in the placebo group (P < 0.001). PTX significantly improved steatosis (mean change in score -0.9 versus -0.04 with placebo, P < 0.001) and lobular inflammation (median change -1 versus 0 with placebo, P = 0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was -0.2 among those on PTX versus +0.4 among those on placebo, P = 0.038). Although not statistically significant (P = 0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups., Conclusion: PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH., (Copyright © 2011 American Association for the Study of Liver Diseases.)

The metabolic syndrome is a common complex entity that has emerged as a worldwide epidemic and major public health care concern with a prevalence of approximately 25% in the United States. There have been a number of different definitions of the metabolic syndrome but all center around the metabolic abnormalities of central obesity, hypertension, decreased high-density lipoproteins and elevated triglycerides with insulin resistance as the uniting physiologic factor. The importance of the metabolic syndrome is not just related to its high prevalence rate but also because it predicts the development of diabetes and cardiovascular disease. Nonalcoholic fatty liver disease is now recognized to be the hepatic component of the metabolic syndrome, which along with its individual components - particularly diabetes and elevated triglycerides, are the major risk factors for the development of nonalcoholic steatohepatitis (NASH); the most severe form of nonalcoholic fatty liver disease. NASH may progress to cirrhosis, hepatocellular carcinoma, and liver failure. It is currently the third most common cause for liver transplantation and is projected to be the leading cause for liver transplantation in 2020. Weight loss (via diet or bariatric surgery) and vitamin E have recently been demonstrated to be effective treatments of NASH. Although these and other agents may prove to be effective treatments for NASH, the most effective therapeutic strategy would be early screening and intervention to prevent the development of insulin resistance and oxidative stress at a societal level., (© 2011 The Author. Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.)

Unlabelled: Nonalcoholic fatty liver disease is a common cause of chronic liver disease in the general population. Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease, is associated with an increased risk of liver-related mortality and cardiovascular disease. At present, a liver biopsy is the only generally acceptable method for the diagnosis of NASH and assessment of its progression toward cirrhosis. Although several treatments have shown evidence of efficacy in clinical trials of varying design, there are no approved treatments for NASH, and published trials are often too divergent to allow meaningful comparisons. There is thus a lack of established noninvasive, point-of-care diagnostics and approved treatment on one hand and a substantial population burden of disease on the other. These provide the rationale for developing consensus on key endpoints and clinical trial design for NASH., Conclusion: This article summarizes the consensus arrived at a meeting of the American Association for the Study of Liver Diseases on the key endpoints and specific trial design issues that are germane for development of diagnostic biomarkers and treatment trials for NASH., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Background: Data from studies in patients with nonalcoholic steatohepatitis (NASH) suggest an increased hepatic fatty acid oxidation. We have previously shown higher fasting plasma bile acid concentrations in patients with NASH. In-vivo and in-vitro studies suggest that bile acids by binding to peroxisome proliferator-activated receptor α activate fibroblast growth factor 21 (FGF21) and increase hepatic fatty acid oxidation., Methods: Plasma bile acid levels were quantified in healthy controls (n=38) and patients with biopsy-proven NASH (n=36). Plasma concentration of fatty acids, β-hydroxybutyrate, insulin, glucose, leptin, alanine aminotransferase, FGF21, and 8-hydroxydeoxyguanosine, a measure of oxidative stress, were measured in 16 healthy controls and 10 patients with NASH in the fasted state and in response to 3 h of infusion of intralipid. In a subgroup of these patients (n=6 each), plasma ceramide subspecies were quantified., Results: Fasting plasma bile acids, FGF21, and leptin concentrations were significantly higher in patients with NASH. In response to intralipid infusion there was an increase in plasma β-hydroxybutyrate and free fatty acid levels in both controls and NASH; however, the ratio of β-hydroxybutyrate/free fatty acid was higher in NASH (P=0.02). Plasma FGF21 concentration increased in response to intralipid in patients with NASH only (P<0.01). Plasma leptin, insulin, glucose, and alanine transferase concentrations did not change in either group after infusion of intralipid. Increase in total ceramides in response to intralipid was greater in NASH., Conclusion: Elevated bile acids and FGF21 may be responsible for the higher hepatic fatty acid oxidation in NASH.

Unlabelled: The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) was formed to conduct multicenter studies on the etiology, contributing factors, natural history, and treatment of nonalcoholic steatohepatitis (NASH). The aim of this study was to determine the associations of readily available demographic, clinical, and laboratory variables with the diagnosis of NASH and its key histological features, and determine the ability of these variables to predict the severity of nonalcoholic fatty liver disease (NAFLD). A total of 1266 adults were enrolled in NASH CRN studies between October 2004 and February 2008, of whom 1101 had available liver histology. The median age was 50 years; 82% were white and 12% Hispanic. The median body mass index was 33 kg/m(2); 49% had hypertension and 31% had type 2 diabetes. On liver biopsy, 57% were judged to have definite NASH and 31% bridging fibrosis or cirrhosis. Using data from the 698 patients with liver biopsies within 6 months of clinical data, patients with definite NASH were more likely to be female and have diabetes, higher levels of aspartate and alanine aminotransferases, alkaline phosphatase, gamma glutamyl transpeptidase, and homeostasis model assessment of insulin resistance (HOMA-IR). Progressive models for predicting histological diagnoses performed modestly for predicting steatohepatitis or ballooning (area under receiver operating characteristic curves [AUROC] ranged from 0.70-0.79), and better for advanced fibrosis (AUROC 0.73-0.85)., Conclusion: Readily available clinical and laboratory variables can predict advanced fibrosis in adults with NAFLD, but additional information is needed to reliably predict the presence and severity of NASH. Prospective studies of this well-characterized population and associated tissue bank samples offer a unique opportunity to better understand the cause and natural history of NAFLD and develop more precise means for noninvasive diagnosis.

Background: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease., Methods: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance., Results: Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups., Conclusions: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.), (2010 Massachusetts Medical Society)

Background/aims: Ultrasound is used to screen for hepatic steatosis, the most common liver disease in the United States. However, few studies have prospectively evaluated the accuracy of ultrasound to diagnose hepatic steatosis. Therefore, a double blinded prospective study was performed in consecutive patients undergoing liver biopsy to evaluate the accuracy of ultrasound to diagnose hepatic steatosis., Methods: Real time ultrasound was performed just prior to the biopsy by a single investigator masked to the clinical diagnosis. The liver biopsy was reviewed by a pathologist masked to the clinical indication or sonographic findings., Results: Of 73 consecutive patients studied, macrovesicular steatosis of any severity on biopsy was found in 46 (63%) and micro vesicular fat found in 51 (69.9%). The overall impression of the sonographer for the presence of macrovesicular hepatic steatosis of any degree had a sensitivity of 60.9% and a specificity of 100%. The sensitivity increased to 100% and the specificity to 90% when there was > or =20% of fat. The zonular distribution of the fat did not alter the diagnostic accuracy of ultrasound. Ultrasound had a poor yield in the diagnosis of microvesicular fat with an overall sensitivity of 43% and a specificity of 73%. The combination of increased echogenicity and portal vein blurring on ultrasound had the greatest sensitivity in the diagnosis of hepatic steatosis., Conclusion: Real time ultrasound using a combination of sonographic findings has a high specificity but underestimates the prevalence of hepatic steatosis when there is<20% fat.

Non-alcoholic fatty liver disease is the most common cause of chronic liver disease in the United States. The development of non-alcoholic steatohepatitis increases the risk for cirrhosis and its complications. The gold standard for diagnosis is liver biopsy, the costs and risks of which make it impractical. Some demographic factors, blood tests, and imaging studies can be used to predict a higher risk of steatohepatitis or advanced fibrosis, but are of limited sensitivity and specificity. More accurate predictors and scoring systems would allow identifying who would benefit most from liver biopsy and monitor disease progression and response to therapy.

Unlabelled: Nonalcoholic fatty liver disease (NAFLD) may have distinct histological features in children and adults, but to date limited data are available on the spectrum and significance of histological lesions in pediatric patients. We conducted a multicenter study of children with well-characterized, biopsy-proven NAFLD to (1) assess the presence and significance of a constellation of histological lesions and (2) identify clinical and laboratory predictors of disease severity. One hundred thirty children with NAFLD seen from 1995 to 2007 in five centers in the United States and Canada were studied. Clinical and laboratory data were collected. Slides stained with hematoxylin-eosin and trichrome were evaluated by two liver pathologists. The NAFLD activity score (NAS) and the pattern of liver injury (type 1 or adult versus type 2 or pediatric nonalcoholic steatohepatitis [NASH]) were recorded. Fibrosis was staged using a published 7-point scale. The median age was 12 years (range, 4-18 years); 63% were boys, and 52% were Caucasian. Fibrosis was present in 87% of patients; of these, stage 3 (bridging fibrosis) was present in 20%. No patient had cirrhosis. The median NAS was 4. Overlapping features of both type 1 (adult pattern) and type 2 (pediatric pattern) NASH were found in 82% of patients. Compared with patients with no or mild fibrosis, those with significant fibrosis were more likely to have higher lobular and portal inflammation scores (P < 0.01), perisinusoidal fibrosis (P < 0.001), and NAS > or =5 (P < 0.005). Serum aspartate aminotransferase levels were the only clinical or laboratory data that independently predicted severity of fibrosis (P = 0.003)., Conclusion: Our results highlight the limitations of published proposals to classify pediatric NAFLD, and identified histological lesions associated with progressive disease.

Unlabelled: Liver biopsy remains the gold standard for diagnosing nonalcoholic steatohepatitis (NASH). We have recently demonstrated that plasma cytokeratin 18 (CK-18) fragment levels correlate with the magnitude of hepatocyte apoptosis and independently predict the presence of NASH. The goal of this study was to validate the use of this biomarker for NASH diagnosis. The study was an ancillary study of the NASH Clinical Research Network (NASH CRN). Our cohort consisted of 139 patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) from eight CRN participant centers across the United States and 150 age-matched healthy controls. CK-18 fragments were measured using a specific enzyme-linked immunosorbent assay. Histology was assessed centrally by study pathologists. CK-18 fragments were markedly increased in patients with NASH versus those without NASH and borderline diagnosis (median [25th, 75th percentile], 335 [196, 511], 194 [151, 270], 200 [148, 284], respectively; P < 0.001). Moreover, the odds of having fibrosis on liver biopsy increased with increasing plasma CK-18 fragment levels (P < 0.001). On multivariate regression analysis, CK-18 fragments remained an independent predictor of NASH after adjusting for variables associated with CK-18 fragments or NASH on univariate analysis (fibrosis, alanine aminotransferase, aspartate aminotransferase, age, biopsy length). The area under the receiver operating characteristic curve for NASH diagnosis was estimated to be 0.83 (0.75, 0.91)., Conclusion: Determination of CK-18 fragments in the blood predicts histological NASH and severity of disease in a large, diverse population of patients with biopsy-proven NAFLD, supporting the potential usefulness of this test in clinical practice.

The rates of oxidation of glycine and ureagenesis were quantified in the basal state and in response to an intravenous infusion of intralipid with heparin (IL) in healthy subjects (n = 8) and in subjects with nonalcoholic steatohepatitis (NASH) (n = 6). During fasting, no significant difference in weight-specific rate of appearance (R(a)) of glycine, glycine oxidation, and urea synthesis was observed. Intralipid infusion resulted in a significant increase in plasma beta-hydroxybutyrate in both groups. The correlation between free fatty acids and beta-hydroxybutyrate concentration in plasma was 0.94 in NASH compared with 0.4 in controls, indicating greater hepatic fatty acid oxidation in NASH. Intralipid infusion resulted in a significant decrease in urea synthesis and glycine R(a) in both groups and did not impact glycine oxidation. The fractional contribution of glycine carbon to serine was lower in subjects with NASH before and after IL infusion. In contrast, the fractional contribution of serine carbon to cystathionine was higher in NASH before and following IL infusion. These results suggest that hepatic fatty acid oxidation is higher in NASH compared with controls and that glycine oxidation and urea synthesis are not altered. An increase in oxidative stress, induced by a higher rate of fatty acid oxidation in NASH, may have caused an increase in the contribution of serine to cystathionine to meet the higher demands for glutathione.

Non-alcoholic fatty liver disease (NAFLD), a spectrum of liver disease ranging from simple steatosis to non-alcoholic steatohepatitis, is increasingly recognized as the hepatic manifestation of metabolic syndrome and is an important cause of liver-related morbidity and mortality. It is among the most common forms of liver disease. NAFLD reflects abnormal partitioning of fat, such that fat deposition is increased in the liver, and provides a link between NAFLD and the metabolic syndrome, a constellation of metabolic disorders that can also be associated with visceral fat or central adiposity. Together, the features of the metabolic syndrome presage overt diabetes and increase cardiovascular risk. Hepatitis C virus (HCV) appears to exacerbate the metabolic syndrome by eliciting increased insulin resistance (IR) and promoting truncal obesity. Moreover, the concomitant presence of HCV and NAFLD is associated with an increased likelihood of diabetes, hypertension and/or hypertriglyceridaemia. Metabolic abnormalities have been shown to influence response to treatment such that the presence of IR or obesity reduces the likelihood of a sustained virological response (SVR); conversely, SVR has been demonstrated to ameliorate IR and improve beta-cell function. Clinically, these data suggest that attention must be paid not only to optimizing antiviral response but also to screening for and treatment of the various components of the metabolic syndrome.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of conditions ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) convincingly. NASH is the only subtype of NAFLD that has been shown to progress relatively, although these findings were reported from studies with short follow-up periods. We assessed the long-term outcomes of a NAFLD cohort., Methods: Patients with NAFLD established by biopsy were identified in databases and categorized as NASH or non-NASH. Mortality data and causes of death were obtained from National Death Index Plus. The nonparametric Kaplan-Meier method with log-rank test and multivariate analyses with a Cox proportional hazard model were used to compare different NAFLD subtypes and to identify independent predictors of overall and liver-related mortality., Results: Of 173 NAFLD patients (age at biopsy, 50.2 +/- 14.5 y; 39.9% male; 80.8% Caucasian; 28.9% with type II diabetes), 72 (41.6%) had NASH and 101 (58.4%) had non-NASH NAFLD. Over the follow-up period, the most common causes of death were coronary artery disease, malignancy, and liver-related death. Although overall mortality did not differ between the NAFLD subtypes, liver-related mortality was higher in patients with NASH (P < .05). Independent predictors of liver-related mortality included histologic NASH, type II diabetes, older age at biopsy, lower albumin levels, and increased levels of alkaline phosphatase (P < .05)., Conclusions: This long-term follow-up evaluation of NAFLD patients confirms that NASH patients have increased liver-related mortality compared with non-NASH patients. In addition, patients with NAFLD and type II diabetes are especially at risk for liver-related mortality.

Nonalcoholic steatohepatitis (NASH), which is the most severe histological form of nonalcoholic fatty liver disease, is emerging as the most common clinically important form of liver disease in developed countries. Although its prevalence is 3% in the general population, this increases to 20-40% in obese patients. Since NASH is associated with obesity, its prevalence has been predicted to increase along with the growing epidemic of obesity and type 2 diabetes mellitus. The importance of this observation comes from the fact that NASH is a progressive fibrotic disease in which cirrhosis and liver-related death occur in 25 and 10% in these patients, respectively, over a 10-year period. This is of particular concern given the increasing recognition of NASH in the developing world. Treatment consists of treating obesity and its comorbidities: diabetes and hyperlipidemia. Nascent studies suggest that a number of pharmacological therapies may be effective, but all remain unproven at present. Histological and laboratory improvement occurs with a 10% decrease in bodyweight. Bariatric surgery is indicated in selected patients. A greater understanding of the pathophysiological progression of NASH in obese patients must be obtained in order to develop more focused and improved therapy., (Copyright (c) 2009 S. Karger AG, Basel.)

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, and its prevalence is increasing worldwide. It currently affects approximately 30% of adults and 10% of children in the United States. NAFLD represents a wide spectrum of conditions ranging from simple fatty liver which in general follows a benign nonprogressive clinical course, to nonalcoholic steatohepatitis (NASH), which is a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. At present, a liver biopsy remains the only reliable way to diagnose NASH and establish the presence of fibrosis. Current noninvasive clinically available tests lack accuracy and reliability. In light of the dramatic increase in the prevalence of NAFLD in conjunction with the significant research effort in developing novel therapies for patients with NASH, noninvasive, simple, reproducible, and reliable biomarkers are greatly needed. They will not only help in the diagnosis of NASH, but also be useful for assessment of treatment response and prognosis and remain a research priority in the NAFLD field.

Non-alcoholic fatty liver disease (NAFLD) has moved rapidly to the forefront of clinical disease, with a prevalence of 30% in the adult United States population and a definite but yet uncertain rate of progression to cirrhosis and end-stage liver disease. This disease has an impact on all areas of clinical medicine, with increasing prevalence and adversity. It is essential to understand the pathophysiologic mechanisms involved in NAFLD, so that therapeutic strategies can be developed. Although fatty liver may be caused by other factors, this review concentrates on fatty liver associated with insulin resistance, sometimes referred to as the primary form.

In patients with nonalcoholic fatty liver disease (NAFLD), a liver biopsy remains the only reliable way to differentiate simple steatosis from nonalcoholic steatohepatitis (NASH). Noninvasive methods are urgently needed. Increasing evidence suggests hepatocyte apoptosis is a key mediator of liver injury in NAFLD. The aim of this study was to quantify hepatocyte apoptosis in plasma from patients with NAFLD and correlate it with histological severity. Plasma was obtained from 44 consecutive patients with suspected NAFLD at the time of liver biopsy. Histology was assessed blindly. Caspase-3-generated cytokeratin-18 fragments were measured in situ via immunohistochemistry and in vivo using a novel enzyme-linked immunosorbent assay. Plasma cytokeratin-18 fragments were markedly increased in patients with NASH compared with patients with simple steatosis or normal biopsies (median [interquartile range]: 765.7 U/L [479.6-991.1], 202.4 U/L [160.4-258.2], 215.5 U/L [150.2-296.2], respectively; P < .001). Cytokeratin-18 fragment levels independently predicted NASH (OR 1.95; 95% CI 1.18-3.22; P = .009 for every 50 U/L increase). A cutoff value of 395 U/L calculated using the receiver operating characteristic curve approach showed a specificity of 99.9%, a sensitivity of 85.7%, and positive and negative predictive values of 99.9% and 85.7%, respectively, for the diagnosis of NASH. In conclusion, these findings strongly suggest that determination of hepatocyte caspase activation in the blood is a strong and independent predictor of NASH in human subjects. These data highlight the potential usefulness of this test as a noninvasive diagnostic means of determining histological disease severity in patients with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) affects approximately 30% of adults and 20% of children in the United States. Nonalcoholic steatohepatitis (NASH) is its most severe histologic form and progresses to cirrhosis in 20% of these patients. Once developed, 30% to 40% of patients with NASH cirrhosis will experience a liver-related death. Consequently, it has become extremely important to understand the pathophysiology of NASH to develop sound therapeutic interventions. It is now recognized that nonhepatic mechanisms are largely responsible for the development of insulin resistance, which causes hepatic steatosis. Once developed, oxidative stress and diminished antioxidants within the liver initiate the progression from steatosis alone to NASH and ultimately to cirrhosis. However, not all patients progress to cirrhosis. As is the case for other common complex metabolic diseases, it is the interaction between the environment and genetics that will determine the phenotypic expression of NAFLD and NASH in each individual patient. Which of the pathophysiologic factors (which are discussed in this review), either alone or in combination, will eventually provide the basis for the most effective therapy has yet to be determined.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."

Background: Superimposed non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) may affect HCV-related fibrosis. We performed a study to determine the relationship between NAFLD and chronic hepatitis C., Methods: One hundred and twenty patients with chronic hepatitis C and available liver biopsies were included. Baseline liver biopsies were read by 1 hepatopathologist using Metavir, as well as a fatty liver pathology protocol. Patients' baseline clinical, demographic, and virologic data were associated with the extent of steatosis (>33% vs. < or =33%), the type of fatty liver (no steatosis vs. steatosis only vs. NASH), and the stage of fibrosis seen on the liver biopsy., Results: Seventy percent of patients were men and 80% were white. The mean age was 47.48+/-5.70 years, mean BMI was 29.01 +/-5.01 kg/m, and mean waist to hip ratio (W/H) was 0.90+/-0.08. Patients with higher grade of steatosis had higher BMI (32.83+/-6.26 vs. 28.49+/-4.62, P = 0.034), more likely to have genotype 3 (21.4% vs. 5.7%, P = 0.037) and advanced fibrosis (92.9% vs. 62.3%, P = 0.033) than those with lower grade of steatosis. Of these, only HCV-genotype 3 remained independently associated with higher grade of steatosis. When patients with superimposed NASH (n = 22) were compared with those with only steatosis (n = 49) and those without steatosis (n = 49), patients with superimposed NASH had more evidence of obesity (BMI: 30.64+/-5.23 vs. 29.90+/-5.35 vs. 27.33+/-4.07, P = 0.008; W/H: 0.97+/-0.06 vs. 0.91+/-0.08 vs. 0.87+/-0.07, P < 0.001), more commonly infected with HCV genotype 3 (14% vs. 12% vs. 0%, P = 0.036) and had more advanced fibrosis (95.5% vs. 75.5% vs. 42.9%, P < 0.001). Race, gender, and age did not affect extent of steatosis or presence of superimposed NASH., Conclusion: In conclusion, markers of obesity (BMI and W/H) and HCV genotype 3 are associated with the extent of steatosis and type of fatty liver. Higher grade of steatosis and presence of superimposed NASH are both associated with advanced hepatic fibrosis.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease in the United States. The histologic spectrum of NAFLD ranges from steatosis liver alone to nonalcoholic steatohepatitis (NASH), which is the most serious form of NAFLD. NASH is a progressive fibrotic disease, in which cirrhosis and liver-related death occur in up to 20% and 12%, respectively, over a 10-year period. NASH-associated cirrhosis also can develop into subacute liver failure, progress to hepatocellular carcinoma, and reoccur post-transplantation. In contrast, steatosis alone has a more benign clinical course, although progression to cirrhosis has occurred in 3% of these patients. The major risk factors for fibrosis include diabetes or obesity, an aspartate aminotransferase/alanine aminotransferase ratio of greater than 1, age older than 50, and hepatic histology.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is reported commonly in patients with type 2 diabetes mellitus (DM), which has been suggested as a risk factor for the progressive form of NAFLD, or nonalcoholic steatohepatitis. The aim of this study was to assess the outcome of patients with NAFLD and DM., Methods: A cohort of patients with NAFLD was identified, and patients with other causes of liver disease (alcohol, medication, etc.) were excluded. Clinical, pathological, and mortality data were available for this cohort. Patients were categorized and compared according to the presence or absence of DM., Results: Of 132 patients with NAFLD, 44 patients (33%) had an established diagnosis of DM. Patients with DM were older and had greater serum glucose and triglyceride levels and a greater aspartate aminotransferase-alanine aminotransferase ratio. Liver biopsy specimens from patients with DM showed more vacuolated nuclei and acidophilic bodies. Cirrhosis (histological or clinical) occurred in 25% of patients with DM (11 of 44 patients) and NAFLD compared with only 10.2% (9 of 88 patients) of patients without DM with NAFLD (P = 0.04). After adjusting for potential confounders (age, body mass index, and the presence of cirrhosis), both overall mortality (risk ratio [RR], 3.30; 95% confidence interval [CI], 1.76-6.18; P = 0.002) and mortality related to liver disease (RR, 22.83; 95% CI, 2.97-175.03; P = 0.003) were greater in diabetic patients with NAFLD. Markers of hepatic dysfunction (low albumin level, high total bilirubin level, and prolonged prothrombin time) were the only independent predictors of increased mortality., Conclusions: Patients with NAFLD and DM are at risk for the development of an aggressive outcome, such as cirrhosis and mortality. This study supports the potential role of insulin resistance in the development of poor clinical outcomes in patients with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of clinicopatholologic conditions ranging from steatosis alone to nonalcoholic steatohepatitis (NASH), with varying risks for progression to cirrhosis. Although steatosis alone seems to be nonprogressive, some patients with NASH can progress. This study focuses on the clinical and pathological characteristics of patients with NAFLD associated with the development of histological fibrosis. Patients with an established diagnosis of nonalcoholic fatty liver were identified through our NAFLD database containing extensive clinical, demographic, and laboratory data. Liver biopsy specimens were read blindly by one hepatopathologist using a 19-item pathological protocol and by another hepatopathologist using a second pathological protocol. Clinical and pathological data were matched to the presence of different types of histological fibrosis. Univariate and multivariate analyses helped determine all of the variables independently associated with histological fibrosis. Of 132 NAFLD patients, 21.2% had advanced fibrosis (septal/bridging fibrosis or well-established cirrhosis). Sinusoidal fibrosis was present in 20.3% of patients, whereas perivenular fibrosis was seen in 17.2%. Ballooning degeneration and Mallory bodies were independently associated with both sinusoidal fibrosis and perivenular fibrosis. Aspartate aminotransferase/alanine aminotransferase ratio and ballooning degeneration were also independently associated with periportal-portal fibrosis. We conclude that the presence of hepatocyte injury in NAFLD is associated with fibrosis. These pathological features can be used to establish the pathological criteria for diagnosis of the progressive form of NAFLD or NASH.

Nonalcoholic steatohepatitis (NASH), which is the most severe histological form of nonalcoholic fatty liver disease (NAFLD), is emerging as the most common clinically important form of liver disease in developed countries. Although its prevalence is 3% in the general population, this increases to 20-40% in obese patients. Since NASH is associated with obesity, prevalence has been predicted to increase along with the arsent epidemic of obesity and type II diabetes mellitus. The importance of this observation comes from the fact that NASH is a progressive fibrotic disease, in which cirrhosis and liver-related death occur in 25% and 10% in these patients respectively over a 10-year period. This is of particular concern given the increasing recognition of NASH in children. Treatment consists of treating obesity and its co-morbidities; diabetes and hyperlipidemia. Nascent studies suggest that a number of pharmacological therapies may be effective, but all remain unproven at present. Histological and laboratory improvement occurs with a 10% decrease in body weight. Bariatric surgery is indicated in selected patients.A greater understanding of the pathophysiological progression of NASH in obese patients must be obtained in order to develop more focused and improved therapy.

Nonalcoholic fatty liver disease is now recognized as the most common liver disease in the United States, with a prevalence of approximately 5% in the general population and up to 25% to 75% in patients with obesity and type II diabetes mellitus. Nonalcoholic fatty liver disease is a clinicopathologic syndrome with a wide spectrum of histologic abnormalities and clinical outcomes. Hepatic steatosis has a benign clinical course. In contrast, nonalcoholic steatohepatitis (NASH) may progress to cirrhosis and liver-related death in 25% and 10% of patients, respectively. Cases occur most commonly in obese, middle-aged women with diabetes. However, NASH may also occur in children and normal-weight men with normal glucose and lipid metabolism. The pathophysiology involves two steps. The first is insulin resistance, which causes steatosis. The second is oxidative stress, which produces lipid peroxidation and activates inflammatory cytokines resulting in NASH. Liver biopsy provides prognostic information and identifies NASH patients who may benefit from therapy. Treatment consists of managing the comorbidities: obesity, diabetes, and hyperlipidemia. Although antioxidant therapy with vitamin E is often used, ursodeoxycholic acid is the only drug that has shown benefit and is the most promising of the drugs currently being investigated. Future therapies will depend on a greater understanding of the pathophysiology and should focus on diminishing fibrosis.

Nonalcoholic fatty liver disease is emerging as the most common liver disease in North America. The histological spectrum of nonalcoholic fatty liver disease ranges from fatty liver alone to steatohepatitis and to the most serious form--nonalcoholic steatohepatitis (NASH). An increasing body of evidence suggests that NASH is associated with the development of progressive fibrosis and eventually cirrhosis in approximately 20% of cases. These data emphasize the need to develop effective therapy for the treatment of NASH. Cases occur most commonly in obese middle age women with diabetes. However, NASH may also occur in children and normal weight men with normal glucose and lipid metabolism. The pathophysiology involves 2 steps. The first is insulin resistance, which causes steatosis. The second is oxidative stress, which produces lipid peroxidation and activates inflammatory cytokines resulting in NASH. Liver biopsy provides prognostic information and identifies NASH patients who may benefit from therapy. Treatment consists of managing the comorbidities: obesity, diabetes, and hyperlipidemia. Nascent clinical trials suggest that a number of therapies may be beneficial. These include anti-oxidants such as vitamin E and betaine, bile acid therapy with ursodeoxycholic acid, and improved insulin sensitivity with metformin. Another potential therapeutic strategy is the reduction of inflammatory cytokines.

Background: Chronic inflammation in IBD is postulated to drive NAFLD progression from steatosis to fibrosis. Aims: To study the histopathological spectrum of NAFLD in Crohn disease (CD) and Ulcerative colitis (UC). Methods: Patients with biopsy proven NAFLD at a quaternary center from 2008 to 2018 were included in this retrospective analysis. Inflammatory bowel disease (IBD) diagnosed either clinically and/or endoscopically at the time of liver biopsy. Multivariable regression and propensity score (PS) weighted analysis were conducted. Statistical analysis were performed using SAS statistical software. Results: Among 1009 patients with NAFLD a diagnosis of IBD was identified in 50 cases (34 CD and 16 UC). On multivariable analysis; CD was independently associated with significantly higher odds of advanced fibrosis (AF) on liver biopsy (adjusted OR = 4.09, 95% CI = 1.40–11.94) compared to NAFLD patients without IBD. Similar results were obtained with both the overlap PS weighted model (OR = 3.17, 95% CI = 1.55–6.49) and the PS matched model (OR = 3.49, 95% CI = 1.50–8.13). Conclusion: In a large cohort of patients with histologically well characterized NAFLD, AF was more common in CD patients than NAFLD patients without IBD. These findings must be confirmed in a larger cohort, but suggest CD patients with NAFLD could be at greater risk for liver fibrosis. [ABSTRACT FROM AUTHOR]

Importance: No therapy has been shown to reduce the risk of serious adverse outcomes in patients with nonalcoholic steatohepatitis (NASH).Objective: To investigate the long-term relationship between bariatric surgery and incident major adverse liver outcomes and major adverse cardiovascular events (MACE) in patients with obesity and biopsy-proven fibrotic NASH without cirrhosis.Design, Setting, and Participants: In the SPLENDOR (Surgical Procedures and Long-term Effectiveness in NASH Disease and Obesity Risk) study, of 25 828 liver biopsies performed at a US health system between 2004 and 2016, 1158 adult patients with obesity were identified who fulfilled enrollment criteria, including confirmed histological diagnosis of NASH and presence of liver fibrosis (histological stages 1-3). Baseline clinical characteristics, histological disease activity, and fibrosis stage of patients who underwent simultaneous liver biopsy at the time of bariatric surgery were balanced with a nonsurgical control group using overlap weighting methods. Follow-up ended in March 2021.Exposures: Bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy) vs nonsurgical care.Main Outcomes and Measures: The primary outcomes were the incidence of major adverse liver outcomes (progression to clinical or histological cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related mortality) and MACE (a composite of coronary artery events, cerebrovascular events, heart failure, or cardiovascular death), estimated using the Firth penalized method in a multivariable-adjusted Cox regression analysis framework.Results: A total of 1158 patients (740 [63.9%] women; median age, 49.8 years [IQR, 40.9-57.9 years], median body mass index, 44.1 [IQR, 39.4-51.4]), including 650 patients who underwent bariatric surgery and 508 patients in the nonsurgical control group, with a median follow-up of 7 years (IQR, 4-10 years) were analyzed. Distribution of baseline covariates, including histological severity of liver injury, was well-balanced after overlap weighting. At the end of the study period in the unweighted data set, 5 patients in the bariatric surgery group and 40 patients in the nonsurgical control group experienced major adverse liver outcomes, and 39 patients in the bariatric surgery group and 60 patients in the nonsurgical group experienced MACE. Among the patients analyzed with overlap weighting methods, the cumulative incidence of major adverse liver outcomes at 10 years was 2.3% (95% CI, 0%-4.6%) in the bariatric surgery group and 9.6% (95% CI, 6.1%-12.9%) in the nonsurgical group (adjusted absolute risk difference, 12.4% [95% CI, 5.7%-19.7%]; adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01). The cumulative incidence of MACE at 10 years was 8.5% (95% CI, 5.5%-11.4%) in the bariatric surgery group and 15.7% (95% CI, 11.3%-19.8%) in the nonsurgical group (adjusted absolute risk difference, 13.9% [95% CI, 5.9%-21.9%]; adjusted hazard ratio, 0.30 [95% CI, 0.12-0.72]; P = .007). Within the first year after bariatric surgery, 4 patients (0.6%) died from surgical complications, including gastrointestinal leak (n = 2) and respiratory failure (n = 2).Conclusions and Relevance: Among patients with NASH and obesity, bariatric surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident major adverse liver outcomes and MACE. [ABSTRACT FROM AUTHOR]

Background and Aims: Obesity and diabetes are risk factors for advanced alcoholic liver disease, and both are components of the metabolic syndrome. We aimed to assess the prevalence of metabolic syndrome and its components in a contemporary US cohort of adults with alcoholic liver disease and compare it to a historic cohort to assess changes over time.Method: Individuals 18 years or older who participated in the National Health and Nutrition Examination Survey during 2009-2014 and 1999-2001 were used as the contemporary and historic cohort, respectively. Alcoholic liver disease was defined as excessive alcohol consumption (men: ≥ 3 drinks/day; women: ≥ 2 drinks/day) and elevated alanine aminotransferase. Metabolic syndrome definition was based on the updated International Diabetes Federation criteria. Data are presented as mean ± standard error or unweighted frequency. A logistic regression analysis was performed to assess differences in metabolic syndrome components between the two period cohorts while adjusting for central obesity.Results: The mean age for our contemporary cohort was 41.9, 66.1% being male. Central obesity was present in 66.3%, type 2 diabetes in 18.7%, low high-density lipoprotein in 28.3%, hypertriglyceridemia in 44.8%, and hypertension in 54.7%. 36.9% met the criteria for metabolic syndrome. Compared to the historic cohort, patients in the contemporary cohort were more likely to have central obesity (50% vs. 66%, p = 0.002), metabolic syndrome (26% vs. 37%, p = 0.044), and type 2 diabetes (12% vs. 19%, p = 0.099).Conclusions: Prevalence of both obesity and metabolic syndrome is increasing in alcoholic liver disease patients. Further studies are required to investigate effective interventions to avoid disease progression in these high-risk patients. [ABSTRACT FROM AUTHOR]

Background and Aims: Sarcopenia or skeletal muscle loss adversely affects outcomes in cirrhosis. The impact of aetiology of liver disease on the severity or the rate of muscle loss is not known. Methods: Consecutive, well‐characterized adult patients with cirrhosis due to viral hepatitis (VH), alcoholic liver disease (ALD) or non‐alcoholic fatty liver disease (NAFLD) and non‐diseased controls with at least two temporally distinct abdominal CT (computed tomography) scans were evaluated. Psoas, paraspinal and abdominal wall muscle areas at the L3 vertebra level were quantified on the CT scans. Standardized rate of change in muscle area was expressed as change in area/100 days. Univariate and multivariable analyses were performed to identify contributors to rate of muscle loss and survival. Results: Among 83 cirrhotics (NAFLD n = 26, ALD n = 39, VH n = 18), there were 20 (24.1%) deaths over 62.7 ± 41.3 months. The mean percentage change in psoas area was −0.03 ± 0.05/100d in controls and −3.52 ± 0.45/100d in cirrhosis (P <.001). The mean percentage change in psoas area was −1.72 ± 0.27/100d in NAFLD, −5.28 ± 0.86/100d in ALD and −2.29 ± 0.28/100d in VH. Among cirrhotics, patients with ALD had the lowest initial muscle area and most rapid rate of reduction in muscle area. Aetiology of liver disease, model for end‐stage liver disease (MELD) and the rate of loss of muscle area were independent risk factors for survival. Conclusions: Aetiology of liver disease is an independent risk factor for sarcopenia with the greatest rate of muscle loss noted in ALD. Survival in cirrhosis was dependent on initial muscle mass, rate of muscle loss and MELD score. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome. Our aim was to study the long-term effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on NAFLD/NASH.Methods: Between 2008 and 2015, 3813 patients had an intraoperative liver biopsy performed at the time of primary RYGB and SG at a single academic center. Utilizing strict inclusion criteria, 487 patients with biopsy-proven NAFLD who had abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values (≥ 40 IU/L) at baseline were identified. Matching of SG to RYGB patients (1:4) was performed via logistic regression and propensity scores adjusting for clinical and liver histological characteristics. Changes in liver function tests (LFTs) at least 1 year after surgery were compared to baseline values and between the surgical groups.Results: A total of 310 (weighted) patients (SG n = 62, and RYGB n = 248) with a median follow-up time of 4 years (range, 1-10) were included in the analysis. The distribution of covariates was well-balanced after propensity matching. In 84% of patients, LFT values normalized after bariatric surgery at the last follow-up time. The proportions of patients having normalized LFT values did not differ significantly between the SG and RYGB groups (82% vs. 84%, p = 0.66). The AST decreased from (SG: 49.1 ± 21.5 vs. RYGB: 49.3 ± 22.0, p = 0.93) at baseline to (SG: 28.0 ± 16.5 vs. RYGB: 26.5 ± 15.5, p = 0.33) at the last follow-up. Similarly, a significant reduction in ALT values from (SG: 61.7 ± 30.0 vs. RYGB 59.4 ± 24.9, p = 0.75) at baseline to (SG: 27.2 ± 21.5 vs. RYGB: 26.1 ± 19.2, p = 0.52) at the last follow-up was observed.Conclusions: In patients with biopsy-proven NAFLD/NASH, abnormal LFTs are normalized in most SG and RYGB patients by the end of the first postoperative year and remain normal until the last follow-up. This study also suggests that both bariatric procedures are similarly effective in improving liver function. [ABSTRACT FROM AUTHOR]