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Aim: Following the coronavirus disease outbreak, a state of public emergency was declared worldwide, which enforced lifestyle changes. This study therefore aimed to investigate the changes in lifestyle, body composition, hepatic steatosis, and fibrosis in patients with chronic liver disease (CLD) under lockdown. Methods: During the lockdown period, 1344 patients with CLD answered a lifestyle questionnaire. In 298 patients, body composition and liver stiffness measure (LSM)/controlled attenuation parameter (CAP) were analyzed by InBody and FibroScan, respectively, and serial data were obtained in 137 patients. Results: More than half of the CLD patients answered decreases in physical activity and frequency of outings during lockdown, while diet was less affected. Overall, 58% of patients showed elevations in CAP values, which were not different statistically over time. Women, but not men, were more likely to increase CAP values during lockdown. Neither LSM nor serum fibrosis markers were elevated chronologically during lockdown. In men, body mass index (BMI), body fat percentage, and visceral fat area (VFA) were significantly increased, whereas in women, lower‐limb muscle mass was significantly decreased. Patients with decreased SMI showed elevations in CAP and VFA values, and patients who exercised less showed increases in BMI. Conclusion: In response to lockdown, men tended to increase body fat but the degree of hepatic steatosis was less affected, while women were more likely to exacerbate hepatic steatosis with skeletal muscle loss among CLD patients. Gender‐specific approaches need to be established for management of CLD patients to avoid exacerbation or comorbidity of steatotic liver disease. [ABSTRACT FROM AUTHOR]

Despite pathophysiological similarities to alcoholic liver disease, susceptibility to acetaminophen hepatotoxicity in metabolic syndrome-related nonalcoholic steatohepatitis (NASH) has not been well elucidated. In this study, therefore, we investigated acetaminophen-induced liver injury in KK-[A.sup.y] mice, an animal model of metabolic syndrome. Twelve-week-old male KK-[A.sup.y] and C57B1/6 mice were injected intraperitoneally with 300 or 600 mg/kg acetaminophen, and euthanized 6 h later. Liver histology was assessed, and hepatic expression of 4-hydroxy-2-nonenal was detected by immunohistochemistry. Levels of reduced glutathione were determined spectrophotometrically. Phosphorylation of c-Jun N[H.sub.2]-terminal kinase (JNK) was analyzed by Western blotting. Hepatocytes were isolated from both strains by collagenase perfusion, and cell death and oxidative stress were measured fluorometrically by use of propidium iodide and 5-(and-6)-chloromethyl-2'7'-dichlorodihydrofluorescein diacetate acetyl ester, respectively. Acetaminophen induced more severe necrosis and apoptosis of hepatocytes in KK-[A.sup.y] mice than in C57B1/6 mice and significantly increased serum alanine aminotransferase levels in KK-[A.sup.y] mice. Acetaminophen-induction of 4-hydroxy-2-nonenal in the liver was potentiated, whereas the levels of reduced glutathione in liver were lower in KK-[A.sup.y] mice. Acetaminophen-induced phosphorylation of JNK in the liver was also enhanced in KK-[A.sup.y] mice. Exposure to 20 [micro]M tert-butyl hydroperoxide did not kill hepatocytes isolated from C57B1/6 mice but induced cell death and higher oxidative stress in hepatocytes from KK-[A.sup.y] mice. These results demonstrated that acetaminophen toxicity is increased in diabetic KK-[A.sup.y] mice mainly due to enhanced oxidative stress in hepatocytes, suggesting that metabolic syndrome-related steatohepatitis is an exacerbating factor for acetaminophen-induced liver injury. drug-induced liver injury; metabolic syndrome; steatohepatitis; oxidative stress; hepatotoxicity doi: 10.1152/ajpgi.00361.2009.

Aim: Despite its relevant clinical impact and high prevalence, covert hepatic encephalopathy (HE) still remains underdiagnosed. As patients with liver cirrhosis tend to be older in Japan, more suitable tests for the elderly and cut‐off values based on this attribute are needed. Recently, a Stroop test has been developed and validated for the screening and diagnosis of covert HE in the United States. The present study aims to establish the cut‐off values of the Stroop test to screen covert HE. Methods: This study was a prospective multicenter cross‐sectional endeavor. We undertook a survey of 311 cirrhotic patients, administering the number connection test (NCT)‐A and ‐B and the Stroop‐off and ‐on test. Results: We determined the cut‐off values of Stroop test results for cirrhotic patients in a variety of age ranges. The cut‐off value of the Stroop test was strongly correlated with age. There was a significant correlation between the results of NCT‐B and age, and Stroop‐on test results showed a correlation with serum albumin (Alb) levels. Serum Alb ≤3.2 g/dl could have the potential to be an objective biomarker of covert HE. In addition, stepwise logistic regression analysis revealed a relationship between the results of the Stroop‐on test and plasma ammonia levels. Conclusions: We established the cut‐off values of Stroop test results and confirmed the efficacy of the Stroop test as a simple tool for assessing cognitive alterations. The Stroop test could be suitable as a necessary minimum for the diagnosis of covert HE. [ABSTRACT FROM AUTHOR]

Background: Although type 2 diabetes mellitus (T2DM) is a known risk factor for hepatocellular carcinoma (HCC) development, the annual incidence in diabetes patients is far below the threshold of efficient surveillance. This study aimed to elucidate the risk factors for HCC in diabetic patients and to determine the best criteria to identify surveillance candidates. Methods: The study included 239 patients with T2DM who were diagnosed with non-viral HCC between 2010 and 2015, with ≥ 5 years of follow-up at diabetes clinics of 81 teaching hospitals in Japan before HCC diagnosis, and 3277 non-HCC T2DM patients from a prospective cohort study, as controls. Clinical data at the time of and 5 years before HCC diagnosis were collected. Results: The mean patient age at HCC diagnosis was approximately 73 years, and 80% of the patients were male. The proportion of patients with insulin use increased, whereas the body mass index (BMI), proportion of patients with fatty liver, fasting glucose levels, and hemoglobin A1c (HbA1c) levels decreased significantly in 5 years. In the cohort study, 18 patients developed HCC during the mean follow-up period of 4.7 years with an annual incidence of 0.11%. Multivariate logistic regression analyses showed that the FIB-4 index was an outstanding predictor of HCC development along with male sex, presence of hypertension, lower HbA1c and albumin levels, and higher BMI and gamma-glutamyl transpeptidase levels. Receiver-operating characteristic analyses showed that a FIB-4 cut-off value of 3.61 could help identify high-risk patients, with a corresponding annual HCC incidence rate of 1.1%. Conclusion: A simple calculation of the FIB-4 index in diabetes clinics can be the first step toward surveillance of HCC with a non-viral etiology. [ABSTRACT FROM AUTHOR]

Background and Aim: Aging is an independent risk factor for the progression of non‐alcoholic steatohepatitis. Here, we investigated the role of age‐related alterations in fatty acid metabolism in dietary steatohepatitis using lipidomics analysis. Methods: Male 8‐week and 55‐week‐old C57BL/6 J mice were fed a high‐fat diet (HFD) for 8 weeks. The quality and quantity of lipid molecular species in the liver were evaluated using the lipidomics approach. Results: Elder mice fed an HFD developed more severe steatohepatitis than young mice. Oxidative stress and inflammatory cytokines in the liver were exacerbated following HFD feeding in elder mice compared with young mice. In elder mice, de novo fatty acid synthesis was promoted, whereas β oxidation was blunted following HFD feeding, and lipid secretion from the liver was reduced. The expression of sirtuin 1 was not only reduced with age as expected but also significantly decreased due to intake of HFD. In the lipidomics analysis, the concentrations of diacylglycerol and TAG molecular species containing monounsaturated fatty acids were markedly increased following HFD feeding in elder mice compared with young mice. In contrast, the concentration of phosphatidylethanolamine and phosphatidylcholine molecular species containing polyunsaturated fatty acids were remarkably decreased following HFD feeding in elder mice compared with young mice, and the expression of fatty acid desaturase was blunted. Conclusions: Aging‐dependent alterations in lipid metabolism under excessive lipid supply most likely enhance hepatic lipotoxicity, thereby exacerbating metabolic steatohepatitis in elderly. [ABSTRACT FROM AUTHOR]

Background: Co‐occurrence of metabolic syndrome and chronic alcohol consumption is increasing worldwide. The present study investigated the effect of the chemical chaperone 4‐phenylbutyric acid (PBA)—which has been shown to alleviate dietary steatohepatitis caused by endoplasmic reticulum (ER) stress—on chronic‐plus‐binge ethanol (EtOH)–induced liver injury in a mouse model of obesity. Methods: Male KK‐Ay mice (8 weeks old) were fed a Lieber–DeCarli diet (5% EtOH) for 10 days. Some mice were given PBA intraperitoneally (120 mg/kg body weight, daily) during the experimental period. On day 11, mice were gavaged with a single dose of EtOH (4 g/kg body weight). Control mice were given a dextrin gavage after being pair‐fed a control diet. All mice were then serially euthanized before or at 9 hours after gavage. Results: Chronic‐plus‐binge EtOH intake induced massive hepatic steatosis along with hepatocyte apoptosis and inflammation, which was reversed by PBA treatment. Administration of PBA also suppressed chronic‐plus‐binge EtOH–induced up‐regulation of ER stress‐related genes including binding immunoglobulin protein (Bip), unspliced and spliced forms of X‐box‐binding protein‐1 (uXBP1 and sXBP1, respectively), inositol trisphosphate receptor (IP3R), and C/EBP homologous protein (CHOP). Further, it blocked chronic‐plus‐binge EtOH–induced expression of the oxidative stress marker heme oxygenase‐1 (HO‐1) and 4‐hydroxynonenal. Chronic EtOH alone (without binge) increased Bip and uXBP1, but it did not affect those of sXBP1, IP3R, CHOP, or HO‐1. PBA reversed the prebinge expression of these genes to control levels, but it did not affect chronic EtOH‐induced hepatic activity of cytochrome P450 2E1. Conclusions: Binge EtOH intake after chronic consumption induces massive ER stress‐related oxidative stress and liver injury in a mouse model of obesity through dysregulation of the unfolded protein response. PBA ameliorated chronic‐plus‐binge EtOH–induced liver injury by reducing ER and oxidative stress after an EtOH binge. Chronic‐plus‐binge ethanol (EtOH) feeding induced severe hepatic steatosis with hepatocyte apoptosis in obese KK‐Ay mice through dysregulation of the unfolded protein response. The treatment with 4‐phenylbutyrate (PBA) ameliorated chronic‐plus‐binge EtOH‐induced liver injury by reducing ER and oxidative stress after an EtOH binge (A: immunohistological staining for ccCK18, scale bar = 100 μm, B‐D: RT‐PCR for sXBP1, CHOP, or HO‐1). The components of ER stress pathway are potential therapeutic targets for the management and prevention of alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Aim: Hepatic inclusion composed of autophagy‐specific substrate p62 is one of the histological features of non‐alcoholic fatty liver disease (NAFLD) and can be a precursor to hepatic carcinogenesis. The expression of p62 was enhanced by not only autophagic dysfunction but also oxidative stress and inflammation. M1/M2 phenotypic balance of macrophages plays a pivotal role in the progression of NAFLD. We evaluated the correlation between macrophage polarization and the formation of p62 aggregation in NAFLD. Methods: Liver biopsy specimens from NAFLD patients were analyzed by immunohistochemical staining for M1 macrophage marker CD11c, M2 macrophage marker CD163, and p62/SQSTM1 (p62). The histological severity of NAFLD is assessed by a NAFLD activity score (NAS). The number of autophagic vesicles in hepatocytes was visualized and counted by using transmission electron microscopy. Results: The aggregation of p62 was undetectable in control, whereas hepatocytes with p62 aggregation were observed in approximately 88% of NAFLD specimens. The number of hepatocytes with p62 aggregation was positively correlated with the number of autophagic vesicles, serum alanine aminotransferase, NAS, fibrosis, and the number of CD11c‐positive cells, but not CD163‐positive cells. Assembly of CD11c‐positive cells was observed around hepatocytes with p62 aggregation. The ratio of CD11c/CD163‐positive macrophages was significantly associated with the formation of p62 aggregation. Conclusions: These findings indicate that chronic inflammation by M1‐polarization of macrophages contributes to the disease progression from simple steatosis to non‐alcoholic steatohepatitis in concert with autophagic dysfunction. [ABSTRACT FROM AUTHOR]