Association between sleep duration and a new onset of nonalcoholic fatty liver disease.

Objective A short sleep duration is associated with non-alcoholic fatty liver disease (NAFLD). However, the causal relationship between a short sleep duration and the onset of NAFLD remains unknown because of the lack of any longitudinal studies. Therefore, we evaluated the association between sleep duration and the onset of NAFLD. Methods We evaluated health checkup data for 1,862 NAFLD-free Japanese adults aged 33-86 years at baseline and followed those individuals for a median of 41 months. Hepatic steatosis was examined using ultrasonography (US). The Cox proportional hazards model was used to evaluate the association between sleep duration and NAFLD onset. Results Among the 1,862 participants, 483 (25.9%) developed NAFLD. The proportion of women who developed NAFLD was the highest in the group with a sleep duration of <6 hours and lowest in the group with a sleep duration of 7 to <8 hours. The multivariable-adjusted hazard ratio (95% confidence interval) for the onset of NAFLD in women with a sleep duration <6 hours compared with those with a sleep duration of 7 to <8 hours was 1.55 (1.09-2.20; p=0.02). Conclusions In women, a short sleep duration was independently associated with the onset of NAFLD, thus suggesting that an adequate sleep duration can be a promising preventive factor for the onset of NAFLD in women.

Association between equol and non-alcoholic fatty liver disease in Japanese women in their 50s and 60s.

BACKGROUND AND AIM: Equol is a metabolite of soy isoflavone and has estrogenic activity. The incidence of non-alcoholic fatty liver disease (NAFLD) increases after menopause in women, which is thought to result in a decrease in estrogen. This study aimed to evaluate the association between equol and NAFLD. METHODS: We evaluated 1185 women aged 50-69 years who underwent health check-ups at four health centers in Fukushima, Japan. Equol producers were defined by a urinary equol concentration of 1.0 µM or more. In addition to comparison between equol producers and non-producers, the association between equol and NAFLD was estimated using logistic regression analysis adjusting for fast walking and eating habits. RESULTS: Of the 1185 participants, 345 (29.1%) women were equol producers. The proportions of women who had NAFLD (34.8% vs 45.2%) were significantly lower in the equol-producing group than in the non-producing group. Multivariable logistic regression analysis showed that equol production was significantly associated with NAFLD (odds ratio = 0.66, 95% confidence interval: 0.51-0.86). CONCLUSIONS: Equol production was significantly associated with NAFLD in women in their 50s and 60s.

Association between equol production and metabolic syndrome in Japanese women in their 50s-60s.

OBJECTIVE: Equol is an active metabolite of soy isoflavone. As a phytoestrogen, equol has the potential to prevent metabolic disorders such as hyperglycemia, hyperlipidemia, and obesity. This study aimed to determine the association between equol production and metabolic syndrome (METS) in postmenopausal women. METHODS: This cross-sectional study included 1,345 women aged 50 to 69 years who underwent health checkups from February 2018 to November 2021 at four health centers in Fukushima, Japan. Equol producers were defined as those with a urinary equol concentration of 1.0 µM or more. METS was defined based on Japanese diagnostic criteria including abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and glucose intolerance. The association between equol production and METS was estimated by logistic regression analysis, with adjustments for age, exercise, physical activity, and fast walking. RESULTS: Of the 1,345 women, 378 (28.1%) were equol producers. The proportion of women who had METS (6.6% vs 10.9%) was significantly lower in the equol-producing group than in the nonproducing group. Multivariable logistic regression analysis revealed that equol production was significantly associated with METS (odds ratio, 0.60; 95% CI, 0.38-0.95). CONCLUSIONS: Equol production was associated with a lower prevalence of METS among women aged 50 to 69 years.

Association of equol with obesity in postmenopausal women.

OBJECTIVE: Equol, which is an active metabolite of isoflavone, has a beneficial impact on metabolic diseases such as dyslipidemia and hyperglycemia. However, the effect of equol on obesity remains uncertain. This study was performed to determine the association between equol and obesity in postmenopausal women. METHODS: We evaluated 386 women in their 50s-60s who underwent health check-ups from February 2018 to January 2019 at Watari Hospital Health Center in Fukushima, Japan. Overweight and visceral obesity were defined as a body mass index ≥25 kg/m2 and waist circumference ≥ 90 cm, respectively. Participants were asked to complete a questionnaire about their ordinary lifestyle. Participants were defined as equol producers when urinary equol level was 1.0 µM or more. The proportion of individuals with obesity (overweight and visceral obesity) and lifestyle factors were compared between equol producers and nonproducers. In addition, the association between equol and obesity was examined using logistic regression analysis with adjustment for lifestyle factors. RESULTS: Of the 386 participants, 106 (27.5%) women were equol producers. The proportions of women who were overweight (13.2% vs 25.7%) and had visceral obesity (6.6% vs 20.7%) were significantly lower in the equol-producing group than in the nonproducing group. Multivariable logistic regression analysis showed that equol production was significantly associated with overweight (odds ratio =0.47, 95% confidence interval: 0.25-0.88) and visceral obesity (odds ratio =0.30, 95% confidence interval: 0.13-0.68). CONCLUSIONS: Equol is significantly associated with obesity in postmenopausal women.

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Effects of sleep quality on non-alcoholic fatty liver disease: a cross-sectional survey.

BACKGROUND: The effects of sleep quality on the risk of developing non-alcoholic fatty liver disease (NAFLD) remain uncertain. The purpose of this study was to clarify the association between sleep quality and NAFLD. METHODS: The data of 4828 participants who underwent health check-ups at four hospitals were analysed. Sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI), which comprised seven elements scored from 0 to 3. The global PSQI score and the score for each element were compared between NAFLD and non-NAFLD groups separately by sex. Logistic regression analysis was performed to determine the association between NAFLD and each PSQI score. RESULTS: In both men and women, the mean PSQI score for sleep medication use was significantly higher in non-NAFLD than in NAFLD. With regard to sleep medication use in men, the OR (95% CI) for NAFLD was lower with a score of 3 (OR 0.60, 95% CI 0.38-0.95) than with a score of 0 on multivariate logistic regression analysis adjusted for age, smoking habits and physical activity. The OR for NAFLD based on daytime dysfunction was also higher with a score of 3 than with a score of 0 in both men (OR 2.82, 95% CI 1.39-5.75) and women (OR 2.08, 95% CI 1.10-3.92). After adjustment for body mass index, the sleep latency scores in men and daytime dysfunction in women were associated with NAFLD. CONCLUSION: Sleep quality was associated with NAFLD, and there were sex differences.

Sigmoid Colon Varices due to Massive Thrombosis of a Noncirrhotic Extrahepatic Portosystemic Shunt.

A 33-year-old man presented with hepatic encephalopathy and was diagnosed to have a noncirrhotic extrahepatic portosystemic shunt (NCPSS). He presented with abdominal pain 16 months after the NCPSS diagnosis. Computed tomography revealed thrombosis between the intrahepatic portal vein and the left internal iliac vein, including the NCPSS, and varices of the sigmoid colon. Thrombosis was treated with danaparoid sodium and antithrombin III followed by edoxaban. After treatment, the thrombosis disappeared from the intrahepatic portal vein, but it remained in the NCPSS. The sigmoid colon varices were followed up without any treatment. Follow-up is needed in NCPSS patients in order to make an early detection of complications.

Endogenous Endophthalmitis Associated with Pyogenic Liver Abscess Caused by Klebsiella pneumoniae.

We report 2 cases of endogenous endophthalmitis associated with pyogenic liver abscess caused by Klebsiella pneumoniae. Case 1 involved a 70-year-old woman and case 2 involved a 50-year-old man who were admitted to our hospital with diagnoses of liver abscess and endogenous endophthalmitis, respectively. The liver abscess resolved with antibiotics and percutaneous transhepatic drainage in case 1 and with antibiotics alone in case 2. Even though both cases underwent ophthalmic surgery, they were discharged from our hospital without the recovery of their eyesight. An earlier diagnosis and treatment are needed to improve the prognosis of endophthalmitis.

Dysbiosis of oral microbiota and its association with salivary immunological biomarkers in autoimmune liver disease.

The gut microbiota has recently been recognized to play a role in the pathogenesis of autoimmune liver disease (AILD), mainly primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). This study aimed to analyze and compare the composition of the oral microbiota of 56 patients with AILD and 15 healthy controls (HCs) and to evaluate its association with salivary immunological biomarkers and gut microbiota. The subjects included 39 patients with PBC and 17 patients with AIH diagnosed at our hospital. The control population comprised 15 matched HCs. Salivary and fecal samples were collected for analysis of the microbiome by terminal restriction fragment length polymorphism of 16S rDNA. Correlations between immunological biomarkers measured by Bio-Plex assay (Bio-Rad) and the oral microbiomes of patients with PBC and AIH were assessed. Patients with AIH showed a significant increase in Veillonella with a concurrent decrease in Streptococcus in the oral microbiota compared with the HCs. Patients with PBC showed significant increases in Eubacterium and Veillonella and a significant decrease in Fusobacterium in the oral microbiota compared with the HCs. Immunological biomarker analysis showed elevated levels of inflammatory cytokines (IL-1ß, IFN-γ, TNF-α, IL-8) and immunoglobulin A in the saliva of patients with AILD. The relative abundance of Veillonella was positively correlated with the levels of IL-1ß, IL-8 and immunoglobulin A in saliva and the relative abundance of Lactobacillales in feces. Dysbiosis of the oral microbiota is associated with inflammatory responses and reflects changes in the gut microbiota of patients with AILD. Dysbiosis may play an important role in the pathogenesis of AILD.

Utility of magnetic resonance elastography for predicting ascites in patients with chronic liver disease.

OBJECTIVE: This study aimed to evaluate the utility of magnetic resonance elastography (MRE) as a non-invasive method for predicting ascites in patients with chronic liver disease (CLD). METHODS: A total of 208 CLD patients underwent MRE to measure liver stiffness (LS) at our institution from March 2013 to June 2015. We evaluated the diagnostic performance of MRE for predicting the presence of ascites using receiver-operating characteristic (ROC) curve analysis and compared the performance with that of serum fibrosis markers. Multivariate logistic regression analysis was performed to identify factors associated with the presence of ascites. The cumulative incidence of ascites was examined in patients without ascites at baseline. The pathological stage of liver fibrosis was evaluated in 81 CLD patients using histopathologic diagnosis. RESULTS: Of the 208 patients, 41 had ascites. The optimal cut-off LS value for the presence of ascites was 6.0 kPa (area under the ROC curve = 0.87). The area under the ROC curve for the presence of ascites was significantly higher for MRE than that for fibrosis markers. Multivariate analysis revealed that LS >6.0 kPa is an independent risk factor for the presence of ascites. The cumulative incidence of ascites was significantly higher among those with LS values >6.0 kPa. There was significantly greater diagnostic accuracy for liver fibrosis stage ≥4 with MRE than that with fibrosis markers. CONCLUSIONS: Compared with serum fibrosis markers, MRE has higher diagnostic performance in predicting the presence of ascites. MRE-based LS has the potential to predict the presence of ascites in CLD patients.

Reduced brain activity in female patients with non-alcoholic fatty liver disease as measured by near-infrared spectroscopy.

Patients with non-alcoholic fatty liver disease (NAFLD) have impaired health-related quality of life including physical and mental state. Near-infrared spectroscopy (NIRS) is a useful tool for evaluation of brain activity and depressive state. This study aimed to determine the brain activity of female NAFLD patients using NIRS. Cerebral oxygenated hemoglobin (oxy-Hb) concentration during a verbal fluency task (VFT) was measured using NIRS in 24 female NAFLD patients and 15 female healthy controls. The Center for Epidemiologic Studies Depression Scale (CES-D) questionnaire was administered to both groups before NIRS. There was no significant difference in CES-D score between groups. However, the oxy-Hb concentration and number of words during the VFT were less in NAFLD compared to healthy controls. The mean value of oxy-Hb concentration during 0-60 s VFT in the frontal lobe was also smaller in NAFLD patients compared to healthy controls (0.082 ± 0.126 vs. 0.183 ± 0.145, P < 0.001). Cerebral oxygen concentration is poorly reactive in response to VFT in female NAFLD patients. This may indicate an association between decreased brain activity and NAFLD regardless of depression.

Reduced frontal activation during verbal fluency task in chronic hepatitis C patients with interferon-based therapy as measured by near-infrared spectroscopy.

AIM: Psychiatric side-effects are the main reason for discontinuation of interferon (IFN)-based therapy. Recent developments in near-infrared spectroscopy (NIRS) have enabled non-invasive clarification of brain functions in psychiatric disorders. We prospectively evaluated brain activation in 20 chronic hepatitis C patients with or without IFN-based therapy by using NIRS during a verbal fluency task (VFT). METHODS: The relative concentrations of oxygenated hemoglobin were measured while patients completed a questionnaire survey at the start of treatment and at 4 and 12 weeks during treatment, using NIRS. RESULTS: The VFT performance did not change among the two groups. Patients with IFN-based therapy showed significantly lower activation during VFT in frontal channels at 12 weeks than those at the start of treatment and control (P < 0.05). Their Center for Epidemiologic Studies Depression Scale scores were significantly higher at 12 weeks than those at the start of treatment, although major depressive symptoms were not found (8.3 ± 7.9 vs. 13.2 ± 6.0, P < 0.001). CONCLUSION: The decrease in oxygenated hemoglobin concentrations of the frontal lobe detected using NIRS in this study reflects hypofunction of the frontal lobe. This functional decline that was caused by IFN-based therapy may be associated with the prodromal phase of depression.

Simple Resistance Exercise for 24 Weeks Decreases Alanine Aminotransferase Levels in Patients with Non-Alcoholic Fatty Liver Disease.

BACKGROUND: Exercise therapy is effective and recommended for non-alcoholic fatty liver disease (NAFLD) based on the efficacy of hepatic fat reduction. However, the efficacies of exercise therapy are based on short-term intervention. Moreover, no reports have examined whether significant reductions in serum levels of alanine aminotransferase (ALT) are achieved with exercise therapy in patients with NAFLD. The aim of this study is to assess the effects of simple resistance exercise for 24 weeks in NAFLD. METHODS: 59 patients with NAFLD were assigned to a resistance exercise group ( n =28) or a control group ( n =31). The resistance exercise group performed 2 exercises (push-ups and squats) 3 times a week on nonconsecutive days for a trial periods of 24 weeks. Patients in the control group proceeded with regular physical activities under a restricted diet throughout the study. The effects of exercise were compared between groups after 24 weeks. RESULTS: Mean ALT level, homeostasis model assessment-estimated insulin resistance index and hepatic steatosis grade were all decreased in the resistance exercise group. Changes in ALT levels correlated negatively with changes in muscle:body weight ratio in the exercise group. CONCLUSION: These data demonstrate that 24 weeks of simple resistance exercise comprising squats and push-ups represents an effective treatment for NAFLD.

Interleukin-21 plays a critical role in the pathogenesis and severity of type I autoimmune hepatitis.

BACKGROUND AND AIMS: Recently, the number of follicular helper T (Tfh) cells expressing interleukin (IL)-21 was found to increase in peripheral blood of human and murine models of autoimmune hepatitis (AIH). IL-21, the most recently discovered member of the type-I cytokine family, exerts various effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. We aimed to assess the relationship of serum IL-21 levels in patients with type I AIH with clinical and laboratory parameters and histology. METHODS: Ninety-two Japanese patients with liver disease (22 AIH, 20 primary biliary cholangitis, 19 drug-induced liver injury, 8 acute hepatitis B, 8 chronic hepatitis C, 10 non-alcoholic steatohepatitis, 5 viral hepatitis) and 10 healthy volunteers were recruited. Serum IL-21 levels were detected by enzyme-linked immunosorbent assay. Real-time polymerase chain reaction measured mRNA levels of Bcl-6, IL-21, and CXCR5 (Tfh-related factors) in peripheral mononuclear cells. RESULTS: Mean age at diagnosis of AIH was 58.6 years, male-to-female ratio was 4:18, 18.2 % of participants had cirrhosis, and 22.7 % had severe disease. IL-21 levels were significantly increased in the serum of patients with AIH compared to those with other liver diseases and controls (p < 0.0001). Particularly, serum IL-21 levels were significantly increased in severe AIH cases compared to non-severe cases (p < 0.05). Serum IL-21 levels correlated positively with total serum bilirubin levels (r = 0.46, p < 0.05), grading of necroinflammatory activity (r = 0.68, p < 0.005) and negatively with serum albumin levels in patients with AIH (r = -0.49, p < 0.05). In patients with biochemical remission of AIH, serum IL-21 levels remained elevated and correlated positively with serum IgG levels (r = 0.84, p < 0.01). Expression of Tfh-related factors, such as Bcl-6 and IL-21, in peripheral blood mononuclear cells of patients with AIH was significantly higher than that in healthy volunteers. CONCLUSIONS: IL-21 may play an important role in the pathogenesis and severity of AIH, and may present a promising target for AIH therapy.

A case of liver abscess with systemic infection caused by Fusobacterium.

A 43-year-old man was admitted to our hospital because of an abnormal shadow on chest X-ray. Blood testing showed elevated levels of C-reactive protein and white blood cells. Computed tomography revealed multilocular masses of the right hepatic lobe, reticulonodular shadowing on both lungs, left kidney masses, and aortic arch aneurysm. Fusobacterium nucleatum was isolated from the hepatic abscess after percutaneous transhepatic drainage. Because of severe dental caries, he was diagnosed with liver abscess caused by dental infection with F. nucleatum. Administration of cefmetazole and meropenem was not effective; however, he showed remarkable improvement after treatment with metronidazole and continuous drainage.

Drug-induced liver injury with autoimmune features complicated with hemophagocytic syndrome.

A 60-year-old woman was admitted to our hospital with non-coma acute liver failure. Based on a 1-month history of supplement use, negative viral hepatitis markers, positive antinuclear antibody test, high IgG level, positive HLA-DR4, liver biopsy findings of centrizonal necrosis, and inflammatory cell infiltration in the portal area, she was diagnosed with drug-induced liver injury (DILI) with autoimmune features or the acute hepatitis phase of autoimmune hepatitis (AIH). Although her liver disorder was ameliorated by administration of prednisolone and plasma exchange, anemia and thrombocytopenia were observed during the course of treatment. A bone marrow examination showed hemophagocytosis. Therefore, with no other evidence suggesting infection or malignancy, we determined that the patient had DILI complicated by hemophagocytic syndrome (HPS). Although HPS is very rarely seen in patients with DILI with autoimmune features or the acute hepatitis phase of AIH, this condition should be considered if cytopenia is observed in a patient with DILI.

Paralytic Ileus due to Superior Mesenteric Venous Thrombosis after Transarterial Injection for Hepatocellular Carcinoma.

A 69-year-old man was admitted to hospital with abdominal pain. In the four years prior to his presentation, he had undergone repeated transarterial chemoembolizations and injections for hepatocellular carcinoma. He underwent his 8th transcatheter arterial therapy one month prior to admission. Abdominal X-rays and contrast-enhanced computed tomography showed large amounts of small intestinal gas and venous thrombosis from the portal vein to the superior mesenteric vein, respectively. The thrombosis was reduced after anticoagulation therapy (heparin, antithrombin III, danaparoid sodium and warfarin). This is the first case report of paralytic ileus due to superior mesenteric venous thrombosis after transcatheter arterial therapy for hepatocellular carcinoma with an arterioportal shunt.

The Association between Sleep Duration and Non-Alcoholic Fatty Liver Disease among Japanese Men and Women.

OBJECTIVE: To examine the relationship between sleep duration and non-alcoholic fatty liver disease (NAFLD). METHODS: We evaluated 3,968 subjects who underwent health check-ups from June 2012 to May 2013 at the Watari Hospital Health Center in Fukushima Prefecture in Japan. Fatty liver was detected by ultrasonography. Sleep duration and lifestyle factors were estimated using a questionnaire. Sleep duration was categorized into the following groups: ≤ 6, 6 to ≤ 7, >7 to ≤ 8, and >8 h. The four sleep duration groups were compared using the χ(2) test and Kruskal-Wallis test. RESULTS: In total, 2,172 subjects were enrolled. The overall prevalence of NAFLD was 29.6% (men, 38.0%; women, 25.3%). The proportion of NAFLD tended to decrease as sleep duration increased in men. The proportion with NAFLD was lowest in the group with a sleep duration of 6 to ≤ 7 h and highest in the groups with sleep durations of ≤ 6 and >8 h in women. The distribution showed a U-shaped curve. The age-adjusted odds ratio (OR) (95% confidence interval (CI)) for subjects with NAFLD with a sleep duration ≤ 6 h compared to the reference (6 to ≤ 7 h) was 1.44 (1.06-1.96) in women. CONCLUSION: Sleep shortage tends to be associated with NAFLD in women and may be mediated by body adiposity.

Drug-induced Liver Injury with HHV-6 Reactivation.

Liver dysfunction was identified in a 16-year-old boy hospitalized with high fever and abdominal pain and fullness. He had received pharmacotherapy for a headache 2 months previously and other drugs for a high fever 4 days prior to being admitted to our hospital. The patient's liver dysfunction was consistent with and fulfilled the criteria for drug induced liver injury, but the laboratory findings showed elevated procalcitonin levels, hyponatremia and leukocytosis. Moreover, we confirmed the presence of human herpesvirus 6 (HHV-6) DNA. The patient exhibited symptoms of high fever and abdominal pain and fullness but no exanthema. The clinical and laboratory findings did not satisfy the criteria for drug-induced hypersensitivity syndrome, and we speculate that the diversity of clinical and laboratory findings may have resulted from HHV-6 reactivation. To the best of our knowledge, this is the first case report on drug-induced liver injury with various findings due to HHV-6 reactivation. HHV-6 reactivation should be considered in patients with drug induced liver injury even in the absence of exanthema.

The utility of IgG, IgM, and CD138 immunohistochemistry in the evaluation of autoimmune liver diseases.

Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) present with distinct clinical features. The term "PBC-AIH overlap syndrome (OS)" has been adopted to describe the condition characterized by occurrence of both PBC and AIH, although this clinical entity is difficult to define. This study aimed to assess the utility of IgG, IgM, and CD138 immunohistochemistry in the evaluation of AIH, PBC, and OS. Immunohistochemistry was performed with anti-human IgG, IgM, and CD138 to detect specific plasma cells in the liver. Predominant IgG staining was observed in AIH (85.7 %), while equivocal (46.1 %) or predominant (38.5 %) IgM staining was observed in PBC. In OS, equivocal (20 %) or predominant (80 %) IgG staining was observed. The IgM/IgG ratio was significantly higher in PBC than in AIH or OS (P < 0.005). Histological findings revealed significantly higher IgM expression in PBC at cholangitis activity grades 2-3 compared to those at cholangitis activity grades 0-1. In contrast, a significantly higher IgG expression was observed in PBC at hepatitis activity and fibrosis grades 2-3 compared to those at hepatitis activity and fibrosis grades 0-1. Taken together, periportal plasmacytic infiltrates with variable immunohistochemistry patterns of IgG and IgM expression characterized different autoimmune liver diseases.