Diagnostic significance of alanine aminotransferase isoenzymes in alcoholic and non-alcoholic fatty liver cancers.

OBJECTIVES: Alanine aminotransferase (ALT) expression is highly elevated in the serum of patients with hepatocellular carcinoma. However, the role of ALT isoenzymes in the total ALT activity remains unclear. In the present study, we systematically investigated the role of ALT isoenzymes in alcoholic and non-alcoholic fatty liver cancer. MATERIALS AND METHODS: The expression of ALT1 and ALT2 at the mRNA and protein levels in 25 paired primary liver cancer tissues was detected by reverse transcription quantitative PCR (RT-qPCR), Western blotting, and immunohistochemistry. Serum ALT activity was determined using an automated biochemical analyzer. RESULTS: The mRNA and protein expression levels of ALT1 and ALT2 were lower in the tissues of alcoholic and non-alcoholic fatty liver cancers than in the paracancerous tissues. Notably, ALT2 was highly expressed in non-alcoholic fatty liver cancer tissues compared with alcoholic fatty liver cancer tissues. Total serum ALT activity was mainly contributed by ALT1 in alcoholic fatty liver cancer, whereas ALT1 contributed only marginally more to the total ALT activity than ALT2 in non-alcoholic fatty liver cancer. ALT2/ALT1 ratio can well discriminate normal control group, alcoholic liver cancer and non-alcoholic liver cancer. CONCLUSION: ALT1 contributed more to the total ALT activity than ALT2 in both alcoholic and non-alcoholic fatty liver cancer. Serum ALT2 to ALT activity was higher in non-alcoholic fatty liver cancer than that in alcoholic fatty liver cancer. ALT2/ALT1 ratio has some diagnostic significance for alcoholic and non-alcoholic liver cancer.

Adding Inflammatory Markers and Refining National Institute on Alcohol Abuse and Alcoholism Criteria Improve Diagnostic Accuracy for Alcohol-associated Hepatitis.

BACKGROUND & AIMS: Although histology is considered the gold standard for diagnosis of alcohol-associated hepatitis (AH), it is not required for entry into therapeutic studies if patients meet National Institute on Alcohol Abuse and Alcoholism (NIAAA) consensus criteria for probable AH. Our aim was to assess the diagnostic accuracy of NIAAA criteria against liver biopsy and to explore new criteria to enhance diagnostic accuracy for AH. METHODS: A total of 268 consecutive patients with alcohol-related liver disease with liver biopsy were prospectively included: 210 and 58 in the derivation and validation cohorts, respectively. NIAAA criteria and histological diagnosis of alcoholic steatohepatitis (ASH) were independently reviewed by clinical investigators and pathologists from Hospital Clínic and Mayo Clinic. Using biopsy-proven ASH as gold standard we determined diagnostic capability of NIAAA criteria and proposed the new improved criteria. RESULTS: In the derivation cohort, diagnostic accuracy of NIAAA for AH was modest (72%) due to low sensitivity (63%). Subjects who did not meet NIAAA with ASH at liver biopsy had lower 1-year survival compared with subjects without ASH (70% vs 90%; P < .001). NIAAAm-CRP criteria, created by adding C-reactive protein and modifying the variables of the original NIAAA, had higher sensitivity (70%), accuracy (78%), and specificity (83%). Accuracy was also higher in a sensitivity analysis in severe AH (74% vs 65%). In the validation cohort, NIAAAm-CRP and NIAAA criteria had a sensitivity of 56% vs 52% and an accuracy of 76% vs 69%, respectively. CONCLUSION: NIAAA criteria are suboptimal for the diagnosis of AH. The proposed NIAAAm-CRP criteria may improve accuracy for noninvasive diagnosis of AH in patients with alcohol-related liver disease.

Lipidomics and Redox Lipidomics Indicate Early Stage Alcohol-Induced Liver Damage.

Alcoholic fatty liver disease (AFLD) is characterized by lipid accumulation and inflammation and can progress to cirrhosis and cancer in the liver. AFLD diagnosis currently relies on histological analysis of liver biopsies. Early detection permits interventions that would prevent progression to cirrhosis or later stages of the disease. Herein, we have conducted the first comprehensive time-course study of lipids using novel state-of-the art lipidomics methods in plasma and liver in the early stages of a mouse model of AFLD, i.e., Lieber-DeCarli diet model. In ethanol-treated mice, changes in liver tissue included up-regulation of triglycerides (TGs) and oxidized TGs and down-regulation of phosphatidylcholine, lysophosphatidylcholine, and 20-22-carbon-containing lipid-mediator precursors. An increase in oxidized TGs preceded histological signs of early AFLD, i.e., steatosis, with these changes observed in both the liver and plasma. The major lipid classes dysregulated by ethanol play important roles in hepatic inflammation, steatosis, and oxidative damage. Conclusion: Alcohol consumption alters the liver lipidome before overt histological markers of early AFLD. This introduces the exciting possibility that specific lipids may serve as earlier biomarkers of AFLD than those currently being used.

Development of a Scoring System to Differentiate Amiodarone-Induced Liver Injury From Alcoholic Steatohepatitis.

OBJECTIVES: Amiodarone-induced liver injury (AILI) is histopathologically similar to alcoholic steatohepatitis (ASH). We sought to elucidate their histologic differences and develop a scoring system to differentiate these two entities. METHODS: A cohort of 17 AILI and 17 ASH cases was included in the initial study. Cases from three different institutions were included for further validation. RESULTS: Macrovesicular steatosis was usually below 10% of the liver parenchyma in AILI. Hepatocyte ballooning degeneration was more common in ASH than in AILI. "Balloon-like" hepatocyte was more common in AILI than in ASH. Lobular neutrophilic inflammation, satellitosis, and cholestasis were more common in ASH. Mallory-Denk bodies and pericellular fibrosis in AILI were mainly located in zone 1 compared with a panacinar or zone 3 distribution in ASH. A scoring system was developed in which points were assigned to different histologic features; a total sum of less than 5 suggests AILI, more than 5 is ASH, and 5 is equivocal. This scoring system was then evaluated on a test cohort comprising 14 AILI cases, in which 13 cases were correctly assigned with a score less than 5. The sensitivity, specificity, and accuracy for diagnosing AILI in the test cohort were 92.9%, 91.7%, and 92.3%, respectively. CONCLUSIONS: This scoring system can aid pathologists to differentiate AILI from ASH.

Clinical Presentation and Gene Expression of Acute Alcohol-Induced Microvesicular Steatosis Mimicking Alcoholic Hepatitis.

Acute alcoholic microvesicular steatosis (MIC) may complicate heavy alcohol intake and present as alcoholic hepatitis (AH) syndrome. However, detailed clinical, biological, and histologic data associated with MIC are scarce. We compared the clinical presentation, histologic features, and hepatic transcriptomic of patients presenting with AH due to either MIC or severe alcoholic steatohepatitis (ASH). In this case-control study, patients who drank heavily (>100 g/day) with the AH syndrome were included either in the MIC group (>50% severe microvesicular steatosis, no inflammation) or in the severe ASH group (polynuclear neutrophil infiltration, macrosteatosis, ballooned hepatocytes). All patients received standard supportive care plus steroids for those with severe ASH and were followed up for 3 months. Whole-liver transcriptome profiling was performed on liver snap-frozen biopsies. Compared to ASH (n = 24, mean age 49.3 years), patients in the MIC group (n = 12, mean age 49.1 years) had a higher reported alcohol intake (P < 0.01), lower Model for End-Stage Liver Disease score (P < 0.05), lower hepatic venous pressure gradient (P < 0.01), higher alanine aminotransferase (P < 0.02) and gamma-glutamyltransferase (P < 0.001), higher triglycerides (P < 0.001) and total cholesterol (P < 0.002), but similar bilirubin levels (P = 0.54). At histology, patients with MIC had a lower fibrotic stage compared to those with ASH (P < 0.001). A higher density of megamitochondria was seen in MIC compared to ASH (P < 0.05). During follow-up, death or transplantation occurred in 4/12 (33%) patients with MIC and 7/24 (29%) patients with severe ASH. Differential hepatic gene expression in MIC compared to ASH included down-regulation of genes related to inflammation and fibrosis and up-regulation of genes involved in lipid metabolism and mitochondrial function. Conclusion: MIC is an acute, noninflammatory, potentially severe alcoholic liver injury mimicking ASH, is associated with a lower fibrosis stage, and has a distinct gene expression profile.

The diagnostic and prognostic significance of liver histology in alcoholic hepatitis.

BACKGROUND: Liver biopsy may be of diagnostic and prognostic value but its role in alcoholic hepatitis (AH) has been controversial. AIM: To assess the utility of liver biopsy in the assessment of clinically severe AH METHODS: The histological features of alcoholic steatohepatitis (ASH) were recorded and scored in patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial who underwent liver biopsy. These features were then assessed relative to outcome and established clinical prognostic scores. RESULTS: The STOPAH trial recruited 1068 patients; biopsies were obtained in 182 (17%). One hundred and sixty-one biopsies were adequate for histological assessment and 140 (87%) were diagnostic for ASH. Only three biopsies (2%) did not have histological features of alcohol-related liver injury. In biopsies performed prior to randomisation, ASH was identified in 92.5% of patients meeting clinical trial definitions of severe AH. In biopsies with ASH, taken before or within 48 hours of randomisation, survival differences between Alcoholic Hepatitis Histological Score (AHHS) groups were not significant: comparison of mild / moderate (91%: 21 of 23 patients) with severe (78%: 29 of 37 patients) groups: P = 0.18. The AHHS was not superior to clinical scores of prognosis: area under the curve for 28-day mortality was 0.728, compared with 0.799 for the Glasgow alcoholic hepatitis score and 0.728 for the MELD score. CONCLUSION: Liver histology taken before treatment rarely changes the diagnosis in patients meeting strict criteria for a clinical diagnosis of AH. The AHHS is similar to clinical scores in determining prognosis. Clinical trial registration EudraCT reference number: 2009-013897-42. ISRCTN reference number: 88782125. MREC number: 09/MRE09/59. UKCRIN ID: 9143.

Novel reliability criteria for controlled attenuation parameter assessments for non-invasive evaluation of hepatic steatosis.

BACKGROUND: There is conflicting evidence regarding reliability criteria for the controlled attenuation parameter (CAP; a marker for hepatic steatosis [HS]). Thus, we assessed the diagnostic performance of CAP according to different reliability criteria based on real-world data from an academic centre. METHODS: Patients undergoing measurement of CAP and liver biopsy (±6 months) at the Medical University of Vienna were included. HS was assessed according to SAF score. RESULTS: In total 319 patients were included. The main aetiologies were non-alcoholic fatty liver disease (NAFLD, n = 177, 55.5%), viral hepatitis (n = 49, 15.4%), and alcoholic liver disease (ALD, n = 29, 9.1%). Histological steatosis and fibrosis stages were: S0: 93 (29.2%), S1: 100 (31.3%), S2: 67 (21.0%), and S3: 59 (18.5%); F0/F1: 150 (47.0%), F2: 47 (14.7%), and F3/F4: 122 (48.3%). In the overall cohort, the area under the receiver operating characteristic curve (AUC) of CAP was 0.843 (95% confidence interval [CI]: 0.798-0.887) for diagnosing HS ≥ S1), 0.789 (95%CI: 0.740-0.839) for ≥S2, and 0.767 (95%CI: 0.712-0.823) for S3. CAP corrections as suggested by Karlas et al. did not improve the diagnostic performance. Importantly, the AUC of CAP for HS ≥ S1 was numerically highest in patients with CAP-IQR/median<0.10 or <0.20 (obtained in 37.9% and 74.9%), in whom CAP also had better diagnostic performance, as compared with patients not meeting these criteria. Moreover, it was substantially higher in 288 (90.3%) patients with CAP-IQR/median<0.3: 0.856 (95%CI: 0.809-0.903) vs. patients not meeting this criterion (0.530 [95%CI: 0.309-0.751]). In contrast, the previously suggested reliability criterion of CAP-IQR<40 dB/m was not associated with an improved diagnostic performance for HS≥S1 (0.866 [95%CI: 0.812-0.920] vs. 0.799 [95%CI: 0.717-0.881]) and was only obtained in 199 (62.4%) patients. CONCLUSION: CAP-IQR/median<0.1, <0.2, and <0.3 identify reliable measurements for diagnosing any hepatic steatosis (≥S1). Importantly, CAP-IQR/median<0.3 has a considerably higher applicability in clinical practice, as compared with the previously suggested CAP-IQR<40 dB/m criterion.

Tributyrin Inhibits Ethanol-Induced Epigenetic Repression of CPT-1A and Attenuates Hepatic Steatosis and Injury.

Ethanol-mediated down-regulation of carnitine palmitoyltransferase-1 (CPT-1A) gene expression plays a major role in the development of hepatic steatosis; however, the underlying mechanisms are not completely elucidated. Tributyrin, a butyrate prodrug that can inhibit histone deacetylase (HDAC) activity, attenuates hepatic steatosis and injury. The present study examined the beneficial effect of tributyrin/butyrate in attenuating ethanol-induced pathogenic epigenetic mechanisms affecting CPT-1A promoter-histone modifications and gene expression and hepatic steatosis/injury. METHODS: Mice were fed a liquid Lieber-DeCarli diet (Research Diet Inc, New Brunswick, NJ) with or without ethanol for 4 weeks. In a subset of mice, tributyrin (2 g/kg) was administered orally by gavage. Primary rat hepatocytes were treated with 50 mmol/L ethanol and/or 2 mmol/L butyrate. Gene expression and epigenetic modifications at the CPT-1A promoter were analyzed by chromatin immunoprecipitation analysis. RESULTS: In vivo, ethanol induced hepatic CPT-1A promoter histone H3K9 deacetylation, which is indicative of a repressive chromatin state, and decreased CPT-1A gene expression. Our data identified HDAC1 as the predominant HDAC causing CPT-1A promoter histone H3K9 deacetylation and epigenetic down-regulation of gene expression. Significantly, Specificity Protein 1 (SP1) and Hepatocyte Nuclear Factor 4 Alpha (HNF4α) participated in the recruitment of HDAC1 to the proximal and distal regions of CPT-1A promoter, respectively, and mediated transcriptional repression. Importantly, butyrate, a dietary HDAC inhibitor, attenuated ethanol-induced recruitment of HDAC1 and facilitated p300-HAT binding by enabling SP1/p300 interaction at the proximal region and HNF4α/peroxisomal proliferator-activated receptor-γ coactivator-1α/p300 interactions at the distal region, leading to promoter histone acetylation and enhanced CPT-1A transcription. CONCLUSIONS: This study identifies HDAC1-mediated repressive epigenetic mechanisms that underlie an ethanol-mediated decrease in CPT-1A expression. Importantly, tributyrin/butyrate inhibits HDAC1, rescues CPT-1A expression, and attenuates ethanol-mediated hepatic steatosis and injury, suggesting its potential use in therapeutic strategies for alcoholic liver disease.

The roles of transmembrane 6 superfamily member 2 rs58542926 polymorphism in chronic liver disease: A meta-analysis of 24,147 subjects.

BACKGROUND: Some genetic association studies tried to investigate potential associations of transmembrane 6 superfamily member 2 (TM6SF2) polymorphisms with chronic liver disease. However, the results of these studies were not consistent. Thus, we performed the present meta-analysis to explore associations between TM6SF2 polymorphisms and chronic liver disease in a larger pooled population. METHODS: Systematic literature research of PubMed, Web of Science, Embase, and CNKI was performed to identify eligible studies for pooled analyses. I2 statistics were employed to assess between-study heterogeneities. If I2 was greater than 50%, random-effect models (REMs) would be used to pool the data. Otherwise, fixed-effect models (FEMs) would be applied for synthetic analyses. RESULTS: Totally 28 studies were included for analyses (13,137 cases and 11,010 controls). The pooled analyses showed that rs58542926 polymorphism was significantly associated with chronic liver disease in overall population (dominant model: p < 0.0001, OR = 0.70, 95% CI = 0.64-0.76, I2  = 47%; recessive model: p < 0.0001, OR = 2.94, 95% CI = 2.05-4.20, I2  = 0%; over-dominant model: p < 0.0001, OR = 1.34, 95% CI = 1.23-1.47, I2  = 0%; allele model: p < 0.0001, OR = 0.68, 95% CI = 0.63-0.73, I2  = 47%), and these significant findings were further confirmed in both Asians and Caucasians. Stratified analyses by type of disease revealed similar positive results in hepatocellular carcinoma (HCC), cirrhosis, alcoholic liver disease (ALD) and NAFLD (Nonalcoholic fatty liver disease), but not in chronic hepatitis B infection (CHB) and chronic hepatitis C infection (CHC). CONCLUSIONS: These results suggested that TM6SF2 rs58542926 could be used to identify individuals at higher susceptibility to chronic liver disease, especially for HCC, cirrhosis, ALD, and NAFLD.

Fatty liver disease in persons with HIV infection.

The leading cause of non-HIV-related mortality is liver disease. Fatty liver disease can be characterized as alcoholic or nonalcoholic in nature. Alcohol use is prevalent among individuals with HIV infection and can lead to medication nonadherence, lower CD4+ cell count, inadequate viral suppression, and disease progression. The pathogenesis of nonalcoholic fatty liver disease (NAFLD) in individuals with HIV infection includes metabolic syndrome, hyperuricemia, HIV-related lipodystrophy, genetic polymorphisms, medications, HIV itself, and the gut microbiome. The prevalence of NAFLD in persons with HIV infection ranges from 30% to 65% depending on the modality of diagnosis. Individuals with HIV infection and NAFLD are at higher risk of cardiovascular disease; however, there is a dearth of longitudinal outcomes studies on this topic. Current therapies for NAFLD, such as vitamin E and pioglitazone, have not been studied in persons with HIV infection. There are several drugs in phase II and III clinical trials that specifically target NAFLD in HIV, including CC chemokine receptor 5 inhibitors, growth hormone-releasing factor agonists, and stearoyl-CoA desaturase inhibitors. Persons with HIV should be screened for NAFLD while pursuing aggressive risk factor modification and lifestyle changes, given the increased risk of cardiovascular mortality.

The different expression of tumor suppressors, RASSF1A, RUNX3, and GSTP1, in patients with alcoholic steatohepatitis (ASH) vs non-alcoholic steatohepatitis (NASH).

As the fifth most common cancer and the second leading cause of cancer related deaths worldwide, hepatocellular carcinoma (HCC) causes up to one million deaths annually. Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) are becoming the two major risk factors because both may develop liver fibrosis and hepatocellular carcinoma (HCC) if left untreated. However, compared with 3-10% of patients with ASH may progress to HCC annually, about only 0.5% NASH patients may progress to HCC annually. The present study is to clarify the protein expression differences of tumor suppressor genes (TSGs) between ASH and NASH. In liver biopsied specimens from NASH and ASH patients, using an immunofluorescence method and morphometrically quantitating the fluorescence intensity, we studied the protein expression within hepatocytes cytoplasm of candidate TSGs including RUNX3, GSTP1, and RASSF1A. Compared with the control group of patients, the expression levels of all three proteins were upregulated in the ASH group of patients (p < .001 in all molecules). While RUNX3 was upregulated, GSTP1 and RASSF1 did not change in the NASH group of patients. The most important finding is that compared with the ASH group of patients, the expression levels of all three TSG proteins, RUNX3, GSTP1, and RASSF1, were significantly lower in the NASH group of patients (p < .001 in all three molecules). These results confirmed our previous finding that there are significant differences of many molecules including TSGs that changed in NASH compared to ASH. Thus, we conclude that there are significantly different TSGs and pathways involved during the pathogenesis of HCC development in NASH compared to ASH that may help to develop different strategies for prevention and treatment of NASH and ASH patients.

Alcoholic and non-alcoholic steatohepatitis: global perspective and emerging science.

Alcohol and high-fat diet are two major risk factors responsible for metabolic diseases, which are manifested as steatohepatitis and liver cancer in the liver, and chronic pancreatitis and pancreatic adenocarcinoma (PDAC) in the pancreas. These metabolic diseases are becoming increasingly prevalent around the globe, and more importantly, their two major etiologies commonly coexist to precipitate the disease processes. To highlight the importance of these metabolic diseases, Japanese Society of Gastroenterology (JSGE) and National Institute on Alcoholism and Alcohol Abuse of National Institute of Health cosponsored the JSGE's 7th International Forum jointly held with the 12th International Symposium on ALPD and Cirrhosis. Toward the main theme of "Frontiers in ASH, NASH, NBNC-HCC and PDAC", this platform showcased presentations by 12 invited international and Japanese speakers on brain-gut-liver interactions, emerging mechanisms of ASH and NASH, metabolic reprogramming, and new therapeutic targets for cirrhosis, HCC, and PDAC. This editorial discusses the most recent data on global statistics on how alcohol and obesity impact health and longevity as a prelude to a brief summary of the symposium presentations and discussions, primarily focusing on the first two session themes.

Association of thirty-year alcohol consumption typologies and fatty liver: Findings from a large population cohort study.

OBJECTIVE: To evaluate the longitudinal relationship between repeated measures of alcohol consumption and risk of developing fatty liver. PATIENTS AND METHODS: This study includes 5407 men and women from a British population-based cohort, the Whitehall II study of civil servants, who self-reported alcohol consumption by questionnaire over approximately 30 years (1985-1989 through to 2012-2013). Drinking typologies during midlife were linked to measures of fatty liver (the fatty liver index, FLI) when participants were in older age (age range 60-84 years) and adjusted for age, socio-economic position, ethnicity, and smoking. RESULTS: Those who consistently drank heavily had two-fold higher odds of increased FLI compared to stable low-risk moderate drinkers after adjustment for covariates (men: OR = 2.04, 95%CI = 1.53-2.74; women: OR = 2.24, 95%CI = 1.08-4.55). Former drinkers also had an increased FLI compared to low-risk drinkers (men: OR = 2.09, 95%CI = 1.55-2.85; women: OR = 1.68, 95%CI = 1.08-2.67). There were non-significant differences in FLI between non-drinkers and stable low-risk drinkers. Among women, there was no increased risk for current heavy drinkers in cross sectional analyses. CONCLUSION: Drinking habits among adults during midlife affect the development of fatty liver, and sustained heavy drinking is associated with an increased FLI compared to stable low-risk drinkers. After the exclusion of former drinkers, there was no difference between non-drinkers and low-risk drinkers, which does not support a protective effect on fatty liver from low-risk drinking. Cross-sectional analyses among women did not find an increased risk of heavy drinking compared to low-risk drinkers, thus highlighting the need to take a longitudinal approach.

Metabolic factors affecting hepatocellular carcinoma in steatohepatitis.

BACKGROUND & AIMS: With the rising prevalence of alcoholism, obesity and metabolic syndrome, steatohepatitis will become the leading cause of end-stage liver disease and hepatocellular carcinoma in the United States by 2025. Patients with non-alcoholic steatohepatitis and alcoholic liver disease have similar clinical and histopathological presentations, whether these similarities persist in non-alcoholic steatohepatitis and alcoholic liver disease patients with hepatocellular carcinoma remains unknown. METHODS: A retrospective analysis of the clinical features of adult patients from a large transplant center who underwent liver transplantation for steatohepatitis due to non-alcoholic steatohepatitis and alcoholic causes (alcoholic liver disease) between 1/1/02 and 1/1/12 was performed. Clinical features, explant histopathology, and clinical outcomes were compared. RESULTS: Hepatocellular carcinoma was present in 80 of 317 patients, who underwent liver transplantation for steatohepatitis with equivalent distribution in non-alcoholic steatohepatitis and alcoholic liver disease patients (24% vs 26%; P = 0.8). On multivariate analysis, significant predictors of hepatocellular carcinoma included age, ethnicity (Hispanic), and diabetes, but not BMI, hypertension or smoking. A lower risk of hepatocellular carcinoma was associated with a clinical history of hyperlipidemia. Clinical parameters were similar between patients with alcoholic liver disease - hepatocellular carcinoma and non-alcoholic steatohepatitis-hepatocellular carcinoma, except sex and presence of metabolic syndrome. non-alcoholic steatohepatitis-hepatocellular carcinoma livers retained histopathological features of non-alcoholic steatohepatitis such as ballooning and Mallory bodies, while alcoholic liver disease-hepatocellular carcinoma livers did not. There were no significant differences in hepatocellular carcinoma recurrence rates or post-transplant overall survival. CONCLUSIONS: We report the largest single-center study evaluating clinical, histopathological and outcome measures of patients undergoing liver transplantation for steatohepatitis. Older patients, diabetics, and Hispanics may warrant more frequent cancer screening due to increased risk of hepatocellular carcinoma.

Nonalcoholic Steatohepatitis: Histopathology Basics Within a Broader Context.

Nonalcoholic fatty liver disease (NAFLD) is a major health concern and the prevalence continues to increase in many industrialized and developing countries around the world. NAFLD affects adults and children. NAFLD-related cirrhosis is expected to become the top indication for liver transplantation in the near future, and the incidence of NAFLD-related hepatocellular carcinoma is also increasing. Nonalcoholic steatohepatitis is the more severe form of NAFLD. The pathogenesis of NALFD/nonalcoholic steatohepatitis is complex and new concepts continue to evolve. The diagnosis and categorization of nonalcoholic steatohepatitis currently rests on hepatopathologists. Accurate morphologic interpretation is important for therapeutic, prognostic, and investigational purposes.