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Aims: A multi-stakeholder consensus has proposed MASLD (metabolic dysfunction-associated steatotic liver disease). We aimed to investigate the pathological findings related to the mid-term mortality of patients with biopsy-proven MASLD in Japan., Methods: We enrolled 1349 patients with biopsy-proven MASLD. The observational period was 8010 person years. We evaluated independent factors associated with mortality in patients with MASLD by Cox regression analysis. We also investigated pathological profiles related to mortality in patients with MASLD using data-mining analysis., Results: The prevalence of MASH and stage 3/4 fibrosis was observed in 65.6% and 17.4%, respectively. Forty-five patients with MASLD died. Of these, liver-related events were the most common cause at 40% (n = 18), followed by extrahepatic malignancies at 26.7% (n = 12). Grade 2/3 lobular inflammation and stage 3/4 fibrosis had a 1.9-fold and 1.8-fold risk of mortality, respectively. In the decision-tree analysis, the profiles with the worst prognosis were characterised by Grade 2/3 hepatic inflammation, along with advanced ballooning (grade 1/2) and fibrosis (stage 3/4). This profile showed a mortality at 8.3%. Furthermore, the random forest analysis identified that hepatic fibrosis and inflammation were the first and second responsible factors for the mid-term prognosis of patients with MASLD., Conclusions: In patients with biopsy-proven MASLD, the prevalence of MASH and advanced fibrosis was approximately 65% and 20%, respectively. The leading cause of mortality was liver-related events. Hepatic inflammation and fibrosis were significant factors influencing mid-term mortality. These findings highlight the importance of targeting inflammation and fibrosis in the management of patients with MASLD., (© 2024 John Wiley & Sons Ltd.)

In Japan, liver biopsies were previously crucial in evaluating the severity of hepatitis caused by the hepatitis C virus (HCV) and diagnosing HCV-related hepatocellular carcinoma (HCC). However, due to the development of effective antiviral treatments and advanced imaging, the necessity for biopsies has significantly decreased. This change has resulted in fewer chances for diagnosing liver disease, causing many general pathologists to feel less confident in making liver biopsy diagnoses. This article provides a comprehensive overview of the challenges and potential solutions related to liver biopsies in Japan. First, it highlights the importance of considering steatotic liver diseases as independent conditions that can coexist with other liver diseases due to their increasing prevalence. Second, it emphasizes the need to avoid hasty assumptions of HCC in nodular lesions, because clinically diagnosable HCCs are not targets for biopsy. Third, the importance of diagnosing hepatic immune-related adverse events caused by immune checkpoint inhibitors is increasing due to the anticipated widespread use of these drugs. In conclusion, pathologists should be attuned to the changing landscape of liver diseases and approach liver biopsies with care and attention to detail., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest related to this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Case History: A 3-month-old infant was found dead in his bed. A postmortem computed tomography (CT) scan suggested fatty attenuation in the liver parenchyma, but no other potentially fatal changes were found. To clarify the cause of death, a medicolegal autopsy was carried out., Autopsy Findings: Internal examination confirmed the presence of liver steatosis as well as hepatomegaly. There were no other significant findings including encephalitis or brain edema., Mass Spectrometry Analysis: To clarify the mechanism underlying lipid accumulation in the liver, matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) analysis was conducted. This indicated a significant accumulation of C14:1 acylcarnitine in the liver of the deceased, suggesting very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency., Genetic Analysis: To find the cause of the VLCAD deficiency, genetic analysis of the responsible gene, acyl-CoA dehydrogenase, very long chain (ACADVL), was performed. This revealed two novel mutations that may have accounted for the disease., Conclusion: A combination of these data revealed that the liver steatosis in this case might have been caused by VLCAD deficiency based on genetic mutations of ACADVL. Thus, the deceased might have been vulnerable to energy crisis and sudden infant death. The present findings show that MALDI-IMS analysis as well as genetic analysis can be useful for elucidating the cause of death., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Aims: The aim of this study was to investigate the clinicopathological significance of steatohepatitic features in hepatocellular carcinomas (HCCs) using a large-scale analysis., Methods and Results: Retrospective clinicopathological analysis was performed on HCCs treated surgically at the University of Tokyo Hospital between 2005 and 2010. The diagnosis of HCC with steatohepatitic features (SH-HCC) was made if the tumour fulfilled four of the following five criteria: steatosis (>5% tumour cells), ballooning or Mallory-Denk body formation, interstitial fibrosis and inflammatory infiltrates. There were 120 HCCs (31.4%) from 106 patients (36.3%) that met the criteria of SH-HCC. Patients with SH-HCC were characterized by a higher frequency of diabetes mellitus and hypertension, along with higher serum levels of cholesterol and triglycerides, than those with conventional HCC (P < 0.01). The background liver of SH-HCC patients showed steatosis and steatohepatitis more frequently (P < 0.01). SH-HCCs were smaller, relatively more differentiated and had a higher frequency of bile duct invasion (P < 0.05). Multivariate analysis failed to show prognostic significance of steatohepatitic features in HCCs., Conclusions: SH-HCC is a subcategory of HCC associated with the patient's metabolic condition and the presence of steatosis or steatohepatitis in the background liver. Steatohepatitic features were not a significant prognostic factor for HCCs., (© 2013 John Wiley & Sons Ltd.)

We examined the genetic background of nonalcoholic fatty liver disease (NAFLD) in the Japanese population, by performing a genome-wide association study (GWAS). For GWAS, 392 Japanese NAFLD subjects and 934 control individuals were analyzed. For replication studies, 172 NAFLD and 1,012 control subjects were monitored. After quality control, 261,540 single-nucleotide polymorphisms (SNPs) in autosomal chromosomes were analyzed using a trend test. Association analysis was also performed using multiple logistic regression analysis using genotypes, age, gender and body mass index (BMI) as independent variables. Multiple linear regression analyses were performed to evaluate allelic effect of significant SNPs on biochemical traits and histological parameters adjusted by age, gender, and BMI. Rs738409 in the PNPLA3 gene was most strongly associated with NAFLD after adjustment (P = 6.8 × 10(-14), OR = 2.05). Rs2896019, and rs381062 in the PNPLA3 gene, rs738491, rs3761472, and rs2143571 in the SAMM50 gene, rs6006473, rs5764455, and rs6006611 in the PARVB gene had also significant P values (<2.0 × 10(-10)) and high odds ratios (1.84-2.02). These SNPs were found to be in the same linkage disequilibrium block and were associated with decreased serum triglycerides and increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in NAFLD patients. These SNPs were associated with steatosis grade and NAFLD activity score (NAS). Rs738409, rs2896019, rs738491, rs6006473, rs5764455, and rs6006611 were associated with fibrosis. Polymorphisms in the SAMM50 and PARVB genes in addition to those in the PNPLA3 gene were observed to be associated with the development and progression of NAFLD.

Background: The Japan Society of Diabetes Mellitus reported that the leading cause of death in patients with diabetes mellitus (DM) was chronic liver disease; however, there are limited studies investigating the cause of liver injury in these patients. Our study aimed to clarify the clinicopathological features of liver injury and the characteristics of nonalcoholic fatty liver disease (NAFLD) in DM patients., Methods: In total, 5,642 DM patients and 365 histologically proven NAFLD patients were enrolled. Clinical and laboratory parameters and liver biopsy results were, respectively, recorded and analyzed for the two sets of patients., Results: Positivity rates for Hepatitis B surface antigens (HBsAg) and anti-hepatitis C virus antibodies (anti-HCV Ab) were 1.7 and 5.1 %, respectively. The proportion of drinkers consuming 20-59 g and ≥60 g alcohol daily was 14.9 and 4.3 %, respectively. The percentage of DM patients with elevated serum alanine aminotransferase (ALT) levels (≥31 IU/L) was 28.6 %. Alcohol consumption had no significant effect on serum ALT levels. Seventy-two percent of HBsAg-positive patients were serum hepatitis B virus (HBV)-DNA negative, whereas 10 % exhibited high levels of the same (>4.0 log copies/ml). Thirty-eight percent of anti-HCV Ab-positive patients were serum HCV-RNA negative. Among the NAFLD patients, the frequencies of NASH and advanced stage NASH were significantly higher in male DM patients than in male patients without DM., Conclusions: Although HBsAg- and anti-HCV Ab-positivity rates were high in our Japanese DM patients, a majority of liver injuries could be associated with NAFLD/nonalcoholic steatohepatitis.

Background/aims: The degree of hepatic fibrosis is an important factor for prognosis and management of patients with chronic liver disease; however, liver biopsy is an invasive method of measuring fibrosis. Here, we investigated the diagnostic utility of liver stiffness, as measured by transient elastography in assessing hepatic fibrosis of viral chronic liver disease and nonalcoholic fatty liver disease (NAFLD)., Methodology: Four hundred and nine eligible patients underwent transient elastography to measure liver stiffness. Liver biopsy for histopathological assessment of fibrosis (F0-F4) was performed in 71 of these patients. Serum levels of hyaluronic acid were determined in 110 patients. We assessed liver stiffness in several chronic liver diseases and compared correlations among liver stiffness, hepatic fibrosis stage and serum hyaluronic acid levels., Results: A steady stepwise increase in liver stiffness was observed with progressing severity of hepatic fibrosis (p<0.0001) in 71 patients who underwent liver biopsy. In 32 chronic viral hepatitis patients, measuring liver stiffness was useful for differentiating between F1, or F2, or F3 and F4, while in 32 NAFLD liver stiffness can differentiate between F0 and F1, F2, or F3, F1 and F3 or F4 and F2 and F4. There was no significant correlation between liver fibrotic stages and serum hyaluronic levels., Conclusions: The present data advocates measuring liver stiffness for assessing hepatic fibrosis is more sensitive in NAFLD than viral chronic diseases, and liver stiffness is useful compared to serum hyaluronic acid level in estimating hepatic fibrosis.

Objectives: The aim of this study was to determine the incidence and risk factors of hepatocellular carcinoma (HCC), and to elucidate the utility of two non-invasive predictive procedures for liver fibrosis: the aspartate aminotransferase (AST) to platelet ratio index (APRI) and the BARD score (which includes the following three variables: body mass index, AST/alanine aminotransferase ratio, and diabetes) in the prediction of HCC in a large population of Japanese patients with non-alcoholic fatty liver disease (NAFLD)., Methods: This was a retrospective cohort study conducted at a public hospital. Study subjects included 6,508 patients with NAFLD diagnosed by ultrasonography. The median follow-up period was 5.6 years. The primary end point was the onset of HCC. Evaluation was performed using Kaplan-Meier methodology and Cox's proportional hazards analysis., Results: In all, 16 (0.25%) new cases with HCC were diagnosed during the study. The cumulative rates of NAFLD-related HCC were 0.02% at year 4, 0.19% at year 8, and 0.51% at year 12. The annual rate of new HCC was 0.043%. Multivariate analysis identified serum AST level ≥40 IU/L (hazard ratio (HR): 8.20; 95% confidence interval (95% CI): 2.56-26.26; P<0.001), platelet count <150 × 10(3)/μl (HR: 7.19; 95% CI: 2.26-23.26; P=0.001), age ≥60 years (HR: 4.27; 95% CI: 1.30-14.01; P=0.017), and diabetes (HR: 3.21; 95% CI: 1.09-9.50; P=0.035) as independent risk factors for HCC. With regard to the APRI, 184 patients (2.83%) were considered to have significant fibrosis (equivalent to non-alcoholic steatohepatitis (NASH) stage 3-4). The cumulative rate of HCC was significantly higher in this group (HR: 25.03; 95% CI: 9.02-69.52; P<0.001). In contrast, regarding the BARD score, 3,841 (59%) patients were considered to have advanced fibrosis (NASH stage 3-4). However, no significant associations between the BARD score and the incidence of HCC were observed (HR: 1.16; 95% CI: 0.40-3.37; P=0.780)., Conclusions: This retrospective study indicates that the annual incidence rate of HCC among Japanese NAFLD patients is low. Elderly NAFLD patients with diabetes, elevated serum AST, and especially thrombocytopenia (suggested to be associated with advanced liver fibrosis) should be monitored carefully during follow-up that includes using the APRI to ensure early diagnosis and treatment of HCC.

Objective: To clarify the clinical characteristics of type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD) and to assess whether NAFLD is related to angiopathy., Methods: The study included 388 Japanese type 2 diabetic outpatients without viral hepatitis. The main outcome measures were angiopathy and NAFLD., Results: The 388 subjects were divided into two subgroups based on alcohol consumption. Fatty liver was recognized in 36 of the 142 drinking patients (25%). There was no association of fatty liver disease with diabetic macro- or microangiopathy in these patients. Fatty liver disease (namely, NAFLD) was recognized in 77 of the 246 non-drinking patients (31%). Type 2 diabetic patients with NAFLD had a significantly younger age, higher body mass index level, higher levels of HbA1c, total cholesterol and triglyceride, lower HDL-C level, higher prevalence rates of hypercholesterolemia and obesity than counterparts without NAFLD. In addition, individuals in the elderly (≥65 years) non-drinking group with NAFLD had a significantly higher prevalence rates of diabetic macroangiopathy, coronary heart disease and thicker intima-media thickness level than their counterparts without NAFLD. The logistic regression analysis showed that NAFLD is an independent predictor of diabetic macroangiopathy., Conclusion: NAFLD was associated with an increased prevalence of diabetic macroangiopathy and coronary heart disease in elderly patients. In addition, NAFLD is an independent predictor for diabetic macroangiopathy. These findings suggest that type 2 diabetic patients with NAFLD should be considered as a high risk group for developing macroangiopathy, even if macroangiopathy is not clinically detected.

Background: Nonalcoholic fatty liver disease (NAFLD) includes a broad range of liver pathologies from simple steatosis to cirrhosis and fibrosis, in which a subtype accompanying hepatocyte degeneration and fibrosis is classified as nonalcoholic steatohepatitis (NASH). NASH accounts for approximately 10-30% of NAFLD and causes a higher frequency of liver-related death, and its progression of NASH has been considered to be complex involving multiple genetic factors interacting with the environment and lifestyle., Principal Findings: To identify genetic factors related to NAFLD in the Japanese, we performed a genome-wide association study recruiting 529 histologically diagnosed NAFLD patients and 932 population controls. A significant association was observed for a cluster of SNPs in PNPLA3 on chromosome 22q13 with the strongest p-value of 1.4 × 10(-10) (OR = 1.66, 95%CI: 1.43-1.94) for rs738409. Rs738409 also showed the strongest association (p = 3.6 × 10(-6)) with the histological classifications proposed by Matteoni and colleagues based on the degree of inflammation, ballooning degeneration, fibrosis and Mallory-Denk body. In addition, there were marked differences in rs738409 genotype distributions between type4 subgroup corresponding to NASH and the other three subgroups (p = 4.8 × 10(-6), OR = 1.96, 95%CI: 1.47-2.62). Moreover, a subgroup analysis of NAFLD patients against controls showed a significant association of rs738409 with type4 (p = 1.7 × 10(-16), OR = 2.18, 95%CI: 1.81-2.63) whereas no association was obtained for type1 to type3 (p = 0.41). Rs738409 also showed strong associations with three clinical traits related to the prognosis of NAFLD, namely, levels of hyaluronic acid (p = 4.6 × 10(-4)), HbA1c (p = 0.0011) and iron deposition in the liver (p = 5.6 × 10(-4))., Conclusions: With these results we clearly demonstrated that Matteoni type4 NAFLD is both a genetically and clinically different subset from the other spectrums of the disease and that the PNPLA3 gene is strongly associated with the progression of NASH in Japanese population.

Background & Aims: Nonalcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to characterize the clinical features of NASH patients with HCC., Methods: In a cross-sectional multicenter study in Japan, we examined 87 patients (median age, 72 years; 62% male) with histologically proven NASH who developed HCC. The clinical data were collected at the time HCC was diagnosed., Results: Obesity (body mass index ≥25 kg/m(2)), diabetes, dyslipidemia, and hypertension were present in 54 (62%), 51 (59%), 24 (28%), and 47 (55%) patients, respectively. In nontumor liver tissues, the degree of fibrosis was stage 1 in 10 patients (11%), stage 2 in 15 (17%), stage 3 in 18 (21%), and stage 4 (ie, liver cirrhosis) in 44 (51%). The prevalence of cirrhosis was significantly lower among male patients (21 of 54, 39%) compared with female patients (23 of 33, 70%) (P = .008)., Conclusions: Most patients with NASH who develop HCC are men; the patients have high rates of obesity, diabetes, and hypertension. Male patients appear to develop HCC at a less advanced stage of liver fibrosis than female patients., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Insulin resistance and diabetes mellitus (DM) are known to contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, the relationship between glucose metabolism and NAFLD is not well known. In this study, we investigated whether secretion patterns of glucose and insulin could influence the histological severity in NAFLD patients without prior known type 2 DM., Methods: A 75-g glucose tolerance test was performed on 173 biopsy-proven NAFLD patients without prior known type 2 DM. Plasma glucose and insulin levels were analyzed periodically for 3 h after oral glucose loading., Results: Of the 173 NAFLD patients, 168 had non-alcoholic steatohepatitis, whereas no patient had cirrhosis. Irrespective of the hemoglobin A1c levels, impaired glucose tolerance, including DM, was detected in 60% of the NAFLD patients. While the secretion pattern of glucose after glucose loading was similar among the NAFLD patients, postprandial insulin levels increased and delayed insulin secretion increased in severity in parallel with the aggravation of histological findings (fibrosis stages). Factors associated with advanced fibrosis were higher insulin levels at 120 min after oral glucose loading (P = 0.0001; odds ratio [OR], 3.56; 95% confidence interval [CI], 1.61-7.86), aspartate aminotransferase (P = 0.003; OR, 2.70; 95% CI: 1.19-6.12), and age (P = 0.02; OR, 2.49; 95% CI: 1.15-5.37) as determined by multivariate analysis., Conclusions: Postprandial hyperinsulinemia (but not glucose levels) was associated with advanced fibrosis. The oral glucose tolerance test should be considered in NAFLD patients without prior known type 2 DM in order to facilitate early therapeutic intervention., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background: Liver histology is the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH). Noninvasive, simple, reproducible, and reliable biomarkers are greatly needed to differentiate NASH from nonalcoholic fatty liver disease (NAFLD)., Methods: To construct a scoring system for predicting NASH, 177 Japanese patients with biopsy-proven NAFLD were enrolled. To validate the scoring system, 442 biopsy-proven NAFLD patients from eight hepatology centers in Japan were also enrolled., Results: In the estimation group, 98 (55%) patients had NASH. Serum ferritin [≥200 ng/ml (female) or ≥300 ng/ml (male)], fasting insulin (≥10 μU/ml), and type IV collagen 7S (≥5.0 ng/ml) were selected as independent variables associated with NASH, by multilogistic regression analysis. These three variables were combined in a weighted sum [serum ferritin ≥200 ng/ml (female) or ≥300 ng/ml (male) = 1 point, fasting insulin ≥10 μU/ml = 1 point, and type IV collagen 7S ≥5.0 ng/ml = 2 points] to form an easily calculated composite score for predicting NASH, called the NAFIC score. The area under the receiver operating characteristic (AUROC) curve for predicting NASH was 0.851 in the estimation group and 0.782 in the validation group. The NAFIC AUROC was the greatest among several previously established scoring systems for detecting NASH, but also for predicting severe fibrosis., Conclusions: NAFIC score can predict NASH in Japanese NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use.

Background and Goals: Reliable noninvasive biomarkers to assess the histologic activity of nonalcoholic fatty liver disease (NAFLD) have not been established. As the frequency of Mallory bodies is known to be closely associated with the disease severity, we hypothesized that serum levels of Mallory body-related proteins were correlated with NAFLD histologic activity and evaluated this possibility., Study: Serum levels of total and fragmented cytokeratin (CK) 18, heat shock protein (Hsp) 70, Hsp90alpha, ubiquitin+1, and p38alpha at the time of liver biopsy were measured in 118 NAFLD patients and their association with histologic findings and NAFLD histologic activity score (NAS) was investigated., Results: Serum levels of both forms of CK18 and Hsp90alpha were markedly higher in patients having nonalcoholic steatohepatitis (NASH) compared with non-NASH ones. Both forms of CK18 significantly correlated with degree of steatosis, lobular inflammation, and ballooning, and showed stronger positive correlations with NAS than serum aspartate and alanine aminotransferase (AST and ALT). Multiple regression analysis further revealed that fragmented CK18 and AST were effective predictors of NAS, with the former being the more definitive of the two (P<0.001 vs. 0.005). In 20 NAFLD patients who received a follow-up biopsy, changes in fragmented CK18 levels, but not AST or ALT levels, closely paralleled those in NAS., Conclusions: These results establish the usefulness of fragmented CK18 measurement for assessing and monitoring the histologic activity of NAFLD.

Objective: We evaluated the efficacy of malabsorptive bariatric surgery on daily blood glucose fluctuations and oxidative stress in type 2 diabetic obese patients., Research Design and Methods: The 48-h continuous subcutaneous glucose monitoring was assessed in type 2 diabetic patients before and 1 month after biliopancreatic diversion (BPD) (n = 36), or after diet-induced equivalent weight loss (n = 20). The mean amplitude of glycemic excursions and oxidative stress (nitrotyrosine) were evaluated during continuous subcutaneous glucose monitoring. During a standardized meal, glucagon-like peptide (GLP)-1, glucagon, and insulin were measured., Results: Fasting and postprandial glucose decreased equally in surgical and diet groups. A marked increase in GLP-1 occurred during the interprandial period in surgical patients toward the diet group (P < 0.01). Glucagon was more suppressed during the interprandial period in surgical patients compared with the diet group (P < 0.01). Mean amplitude of glycemic excursions and nitrotyrosine levels decreased more after BPD than after diet (P < 0.01)., Conclusions: Oxidative stress reduction after biliopancreatic diversion seems to be related to the regulation of glucose fluctuations resulting from intestinal bypass.

Background: Patients with hepatitis C virus (HCV) frequently show glucose intolerance. Diabetes mellitus (DM) has been proposed to be a risk factor for hepatocellular carcinoma (HCC)., Aims: The aim of this study is to clarify the influence of glucose intolerance as evaluated by the 75 g oral glucose tolerance test (OGTT) on hepatocarcinogenesis in patients with HCV., Methods: This study was carried out in a cohort of 197 patients with HCV who had not been previously diagnosed as having DM. All patients underwent the 75 g OGTT at entry. They were also screened for HCC and, thereafter, the rate of hepatocarcinogenesis was compared between the patients with and without glucose intolerance., Results: Based on the results of the 75 g OGTT, 125 (63%) had normal glucose tolerance (NGT), 49 (25%) had impaired glucose tolerance (IGT) and 23 (12%) had the DM pattern. HCC occurred more frequently in patients with the DM pattern than in patients with either NGT or IGT. Even in patients without advanced liver fibrosis, HCC was more frequently observed in patients with DM than in patients with NGT. A multiple logistic regression analysis showed advanced liver fibrosis, the DM pattern on the 75 g OGTT, an older age and gamma-glutamyltransferase to all be independent risk factors related to hepatocarcinogenesis., Conclusions: A DM pattern on the 75 g OGTT was thus found to be associated with hepatocarcinogenesis and the 75 g OGTT is considered to be useful for identifying this risk factor for HCC in patients with HCV.

Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver injury in many countries. Genetic factors are important for the development of NAFLD, as well as environmental factors. Recently an angiotensin II type 1 receptor (AGTR1) has been recognized as important in the aetiology of fibrosis in the liver., Objective: In this study we investigated the association between angiotensin II type 1 receptor gene polymorphism (ATGR1) and NAFLD., Methods: One hundred and sixty-seven NAFLD patients [106 with nonalcoholic steatohepatitis (NASH) and 61 with simple steatosis] with a positive diagnosis by liver biopsy and 435 healthy control subjects were recruited in this study., Results: We investigated 12 single nucleotide polymorphisms (SNPs) of the ATGR1 gene, among which rs3772622 showed the lowest P-value of allele frequency model (P=0.0000012) with an odds ratio (95% confidence interval) of 1.95 (1.49-2.55). Five SNPs (rs3772622, rs3772633, rs2276736, rs3772630 and rs3772627) were significantly associated with NAFLD, even when the most conservative Bonferroni's correction was applied. Linkage disequilibrium analysis revealed that SNP rs3772622 and another four SNPs (rs3772633, rs2276736, rs3772630 and rs3772627) were in the same block. We investigated the association between rs3772622 genotypes and the fibrosis index. The results of the analysis revealed an additive increase of the fibrosis index in the patients with the A allele of rs3772622., Conclusions: This is the first report to demonstrate the genetic variations in ATGR1 that may influence the risk of NAFLD and liver fibrosis in NAFLD.

Background and Aim: Ethnic differences in non-alcoholic steatohepatitis (NASH) are well-documented, but there has been no study on the prognosis of Japanese NASH patients with cirrhosis. Accordingly, we compared cirrhotic NASH with liver cirrhosis caused by chronic hepatitis C (LC-C) to clarify its clinical features and define the risk factors for death., Methods: A prospective evaluation of the outcomes of NASH patients with severe fibrosis was started in 1990. Data on age- and sex-matched patients with biopsy-proven LC-C were collected retrospectively and used as the control., Results: There were 68 patients with cirrhotic NASH and 69 with LC-C. The Child-Turcotte-Pugh (CTP) class was similar in these two groups. Although the outcome of the NASH group was better than that of the LC-C group, cirrhotic NASH followed a similar course to that of LC-C; that is, complications of cirrhosis developed, including hepatocellular carcinoma (HCC; the 5-year HCC rate was 11.3% for NASH and 30.5% for HCV) and death (the 5-year survival rates were 75.2% and 73.8%, respectively). HCC was the leading cause of death in both groups (NASH, 47%; HCV, 68%). The occurrence of HCC and the CTP class were significant risk factors for mortality in NASH patients according to a multivariate analysis (HCC: hazard ratio [HR] 7.96, 95% confidence interval [CI] 2.45-25.88, CTP class A: HR 0.17, 95% CI 0.06-0.50)., Conclusion: In conclusion, the present study confirmed that cirrhotic NASH has a similar course to LC-C. The occurrence of HCC was the strongest predictor of mortality in the NASH groups. These findings may be helpful when deciding on therapeutic interventions for NASH and also for the daily management of these patients.

Background/aims: We evaluated patients with nonalcoholic fatty liver disease (NAFLD) and compared the clinical and pathological features to identify the risk factors for NAFLD with severe fibrosis., Methods: One hundred and eighty-two patients with biopsy-confirmed NAFLD from various medical centres were recruited into this study., Results: The variables that were significantly associated with severe steatosis were male gender (mild:severe=36%:53%, P=0.02), younger age (mild:severe=57%:82%, P>0.001) and absence of type 2 diabetes (mild:severe=43%:71%, P>0.001). There was no significant difference in the degree of inflammation among the clinical groups. The variables that were significantly associated with severe fibrosis were female gender (mild:severe=54%:84%, P=0.002), older age (> or = 60 years old) (mild:severe=29%:53%, P=0.020), type 2 diabetes (mild:severe=42%:71%, P=0.020) and hypertension (mild:severe=24%:53%, P=0.002). Although there were more obese patients in the group with severe fibrosis, the association was not statistically significant (mild:severe=67%:78%, P=0.229). The prevalence of high serum triglyceride levels was similar between the two groups. The N (Nippon) score (total number of risk factor) could significantly predict severe fibrosis in NAFLD patients (1.48 +/- 1.14 vs. 2.66 +/- 0.94, P<0.001)., Conclusions: The N score can be used to predict severe fibrosis in cases of NAFLD.

Background: In 2003, we encountered the first donor death for living donor liver transplantation in Japan, which was related to nonalcoholic steatohepatitis (NASH). The aim of this study was to retrospectively investigate the prevalence of NASH among a living donor liver transplantation donor population and to analyze the postoperative course for both donors and recipients of NASH grafts to minimize risk for donors., Methods: The study population comprised 263 donors who donated the right lobe of the liver between February 1998 and April 2003. Their zero-hour biopsy specimens were screened retrospectively. Regarding severe steatosis or NASH, long-term follow-up results for laboratory data from donors were investigated along with changes in graft histologic findings in recipients., Results: NASH was diagnosed histopathologically in three cases (1.1%). Pathologic examination showed that a donor who died in 2003 had the most severe NASH among the three cases. The remaining two NASH donors had uneventful postoperative courses without complications. All grafts showed improvement with respect to the steatosis and histologic findings of NASH., Conclusions: Donor safety is a top priority in living donor liver transplantation. To exclude patients with NASH from potential donor lists, careful evaluation, including selective preoperative liver biopsy, should be carried out.

Background and Aim: Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver disease from simple steatosis to cirrhosis. Therefore, markers for predicting NAFLD with advanced fibrosis are needed. The aim of this study was to establish non-invasive predictive markers of liver fibrosis in NAFLD., Methods: One hundred and forty-eight patients were diagnosed as having biopsy-proven NAFLD. In order to separately identify severe fibrosis (bridging fibrosis plus cirrhosis) and cirrhosis, the patients were analyzed twice: first, as mild fibrosis versus severe fibrosis; and second, as non-cirrhosis versus cirrhosis. Univariate and multivariate analyses were conducted. The diagnostic ability to detect severe fibrosis and cirrhosis was assessed by the area under the receiver operating characteristic curve. The cut-off values of serum markers to detect severe fibrosis and cirrhosis were determined., Results: Hyaluronic acid was selected as a predictive marker for severe fibrosis. A cut-off value of 42 ng/mL of hyaluronic acid had a 100% predictive value for patients free of severe fibrosis and was associated with an optimal combination of sensitivity (100%, 95% confidence interval [CI] 90-100%) and specificity (89%, 95%CI 80-94%). The platelet count was found to be an independent predictor of cirrhosis. A cut-off value of 16 x 10(4)/microL for the platelet count was associated with an optimal combination of sensitivity (100%, 95%CI 82-100%) and specificity (95%, 95%CI 90-98%)., Conclusions: Hyaluronic acid levels can accurately identify NAFLD patients with severe fibrosis, and the platelet count can identify NAFLD patients with cirrhosis. Thus, these markers offer a good guideline for the assessment of hepatic fibrosis in the many patients with NAFLD.

From April 1989 to December 2004, we performed liver biopsy on 475 patients and obtained biopsy proven 35 cases of non-alcoholic fatty liver. Among them, 18 cases were diagnosed as non-alcoholic steatohepatitis (NASH). During the last three years, we have tried to detect NASH using ultrasonography and elevated value of serum ferritin (> 300 ng/ml). All of the eligible 7 cases biopsied during the course were diagnosed as NASH. In these 7 cases, ALT levels improved after the body weight loss accompanied by the parallel decrease of serum ferritin levels. Measurement of serum ferritin is useful in the detection of NASH but the normal value of ferritin cannot rule out the possibility of NASH.

Background: This study compared the liver histology of patients with NASH and patients with ASH., Methods: Subjects consisted of 79 patients (41 in the NASH group and 38 in the ASH group). We performed physical and laboratory examinations as well as liver biopsy in all subjects, and we evaluated the differences between the NASH and ASH groups. In addition, we compared the liver histology of patients with obesity, diabetes or hyperlipidemia within the NASH group., Results and Conclusions: BMI was significantly higher in the NASH group than in the ASH group. Steatosis and nuclear vacuoles were more prevalent in the NASH group than in the ASH group. On the other hand, ballooning hepatocytes, lipogranuloma, focal necrosis, acidophilic bodies and fibrosis were more remarkable in the ASH group than in the NASH group. The degrees of steatosis and lipogranuloma gradually decreased as the stage of liver fibrosis progressed. Necro-inflammation and fibrosis tended to be more remarkable in the ASH group than in the NASH group. In the NASH group, ballooning hepatocytes and acidophilic bodies were significantly higher in the group with diabetes than in that without diabetes. Perivenular fibrosis, pericellular fibrosis and portal fibrosis were also higher in the NASH group with diabetes than in the NASH group without diabetes. These findings suggested that diabetes is deeply involved in the development and progression of NASH.

We describe a 12-year-old patient with focal fatty liver change (FFLC). The lesion was incidentally detected by ultrasonography which showed a circumscribed hyperechoic lesion measuring approximately 6 x 4 cm. The lesion was also examined by CT and MRI. Histologically, the lesion corresponded to a focal area of lipid-laden hepatocytes. FFLC has been delineated as a disease entity in adults. As shown by this report, it may also occur in children. There was no associated clinical morbidity and the lesion was incidentally detected by modern imaging techniques. The aetiology and pathogenesis are unknown. The significance of focal fatty lesions is their differentiation from other focal lesions such as hepatic cell carcinomas, metastatic tumours, abscess and benign tumours including lipoma, haemangioma and angiomyolipoma.

Alcohol-like liver injury (ALLI) in non-alcoholics has not been elucidated in Japan. The present study attempted to characterize the clinicopathologic features of ALLI in routine liver biopsies. ALLI was found in 1% of 561 biopsy cases obtained from 1988 to May, 1991 at Kanazawa University Hospital. Laboratory data characteristically showed only a mild to moderate degree of dysfunction, and none of the cases exhibited jaundice. Hepatic histology showed a mild to moderate degree of perivenular, pericellular and/or portal stellate fibrosis with a varying degree of fatty change and inflammatory cell infiltration. Portal stellate fibrosis with a varying degree of cell infiltration was more severe than the centrilobular or pericellular fibrosis in all cases. Intralobular inflammatory cell infiltration was associated with spotty or single hepatocyte necrosis, but extensive hepatocyte necrosis was not observed. Neutrophil infiltration was absent or minimal, and lymphocytes predominated in all cases. Mallory bodies were rare and were found in a few hepatocytes of only one of the 7 cases. The above histologic findings in ALLI were very similar to those seen in liver disease in Japanese alcoholics, and were somewhat different from ALLI reported in Western countries. In cases in which hepatic fibrosis, characterized by pericellular, perivenular or portal stellate fibrosis dominated without apparent hepatic necrosis and inflammation, the term "non-alcoholic steatofibrosis" is more suitable to depict its liver histology, being very similar to the alcoholic fibrosis frequently seen in Japanese alcoholics.

Recently, fatty liver of unknown etiology has been increasing in number among relatively younger persons in Japan. The tendency is very likely related to drastic reformation of the standard of living with the height of economic prosperity due to industrial advances in Japan at present. On the basis of our own 392 patients with fatty liver of unknown etiology, in whom fatty liver could be confirmed laparoscopically and bioptically, clinical and pathophysiological aspects of fatty liver of unknown etiology have been into consideration. The clinical outline of the disease was stated in this paper.