Non-alcoholic Fatty Liver Disease and Longitudinal Cognitive Changes in Middle-Aged and Elderly Adults

Background and PurposeNon-alcoholic fatty liver disease (NAFLD) and cognitive impairment are common aging-related disorders. This study aims to explore the changes of cognitive function in middle-aged and elderly population with NAFLD from a Jidong impairment cohort.MethodsA total of 1,651 middle-aged and elderly participants (>40 years) without cognitive impairment were recruited into the current study in 2015 and were followed up until to 2019. Abdominal ultrasonography was used for diagnosis of NAFLD. Global cognitive function was assessed with the Mini-Mental State Examination (MMSE). Cognitive impairment was defined as a score <18 for illiterates, a score <21 for primary school graduates, and a score <25 for junior school graduates or above. Multivariable regression analysis was performed to evaluate the association between NAFLD and the four-year cognitive changes.ResultsOut of 1,651 participants, 795 (48.2%) of them had NAFLD in 2015. Cognitive impairment occurred in 241 (14.6%) participants in 2019. Patients with NAFLD had higher 4-year incidence of cognitive impairment than non-NAFLD patients did (17.7 vs. 11.7%, p < 0.001). Multivariable linear regression analysis showed significant association of baseline NAFLD with lower MMSE score in 2019 (β = −0.36, p < 0.05). Multivariable logistic analysis found that the adjusted odds ratio (OR) with 95% confidence interval (CI) of baseline NAFLD was 1.45 (1.00–2.11) for cognitive impairment in 2019 (p = 0.05). We also identified effects of baseline NAFLD on subsequent cognitive impairment as modified by age (interaction p < 0.01) and carotid stenosis (interaction p = 0.05) but not by gender.ConclusionsNAFLD is associated with cognitive decline, especially in middle-aged and with carotid stenosis population.

Role of Mitochondrial Cytochrome P450 2E1 in Healthy and Diseased Liver

Cytochrome P450 2E1 (CYP2E1) is pivotal in hepatotoxicity induced by alcohol abuse and different xenobiotics. In this setting, CYP2E1 generates reactive metabolites inducing oxidative stress, mitochondrial dysfunction and cell death. In addition, this enzyme appears to play a role in the progression of obesity-related fatty liver to nonalcoholic steatohepatitis. Indeed, increased CYP2E1 activity in nonalcoholic fatty liver disease (NAFLD) is deemed to induce reactive oxygen species overproduction, which in turn triggers oxidative stress, necroinflammation and fibrosis. In 1997, Avadhani’s group reported for the first time the presence of CYP2E1 in rat liver mitochondria, and subsequent investigations by other groups confirmed that mitochondrial CYP2E1 (mtCYP2E1) could be found in different experimental models. In this review, we first recall the main features of CYP2E1 including its role in the biotransformation of endogenous and exogenous molecules, the regulation of its expression and activity and its involvement in different liver diseases. Then, we present the current knowledge on the physiological role of mtCYP2E1, its contribution to xenobiotic biotransformation as well as the mechanism and regulation of CYP2E1 targeting to mitochondria. Finally, we discuss experimental investigations suggesting that mtCYP2E1 could have a role in alcohol-associated liver disease, xenobiotic-induced hepatotoxicity and NAFLD.

Association of Non-Alcoholic Fatty Liver Disease with Metabolic Syndrome: A Single Center Study

Background: NAFLD is a condition defined by excessive fat accumulation in the form of triglycerides (steatosis) in the liver (> 5% of hepatocytes histologically). Non-alcoholic fatty liver disease is increasingly being recognized as a major cause of liver-related morbidity and mortality among 15-40% of the general population. Aim of the study: To evaluate the clinical profile of patients with non-alcoholic fatty liver disease and its association with metabolic syndrome.Methods:The present cross-sectional, retro-spective study was conducted as outdoor patient basis in the Department of Medicine, Jashore medical college hospital & a private diagnostic centre, Jashore.. A total of 74 cases were included for the study. All patients in the study underwent routine investigations including complete blood counts, blood sugar, liver function tests, HBsAg, anti-HCV, lipid profile andUSG of whole abdomen. The data was collected during OPD treatment and was recorded in predesigned and pretested proforma and analyzed.Results:Mean age of the patient was 53.70±7.22 years. On physical examination findings showed the mean BMI was 27.6±4.39 kg/m2, mean waist circumference was 74.22±7.44 cm. Mean diastolic blood pressure (mm Hg) was 92.87±6.25 and mean systolic blood pressure (mm Hg) 132.0±18.17. Maximum 52% patients had triglycerides >150 mg/dl while low serum HDL level was seen in 37% patients and increased waist circumference was found in 32% patients. Altered ALT ≥41 IU was observed in 10 (62.50%) of Grade II of patients with NAFLD with metabolic syndrome. Central obesity was observed in 12 (75.00%) of Grade II patients with NAFLD with metabolic syndrome. While 14 (87.50%) Grade II of patients with NAFLD with metabolic syndrome showed impaired fasting glucose (>110 mg/dl). Hypertriglyceridemia (>150 mg/dl) in 12 (70.58%) seen in Grade I of patients with NAFLD without metabolic syndrome.Conclusion:Higher prevalence of all the components of metabolic syndrome in cases of NAFLD was observed. It can be concluded that symptoms and signs of NAFLD are non-specific and occur later in the course of the disease hence the physician should have a high index of suspicion in order to detect NAFLD early in the course of the disease.

Therapeutic potential of policosanol in the concurrent management of dyslipidemia and non-alcoholic fatty liver disease

Background High-fat diet (HFD) possesses a major cause of cardiovascular disease, and hepatosteatosis. Unfortunately, long-term use of statins has a theoretical possibility of worsening of hepatic histology in the patients with non-alcoholic fatty liver disease (NAFLD). The objective of the study was to explore hepatoprotective potential of policosanol as an alternative to statins in experimental NAFLD. For the same, young male Wistar rats were fed with HFD for 8 weeks to induce NAFLD. 48 adult Wistar rats were distributed into six investigational groups: normal control, HFD control, and four treatment groups, receiving policosanol (50 and 100 mg/kg/day), atorvastatin (30 mg/kg/day), and silymarin (100 mg/kg/day) for 8 weeks along with HFD. Result HFD consumption caused profound hepatotoxicity evident by hepatic oxidative stress, increased Serum glutamic oxaloacetic transaminase (SGOT), Serum glutamic pyruvic transaminase (SGPT), Alkaline phosphatase (ALP), and bilirubin content. Treatment with policosanol (100 mg/kg) markedly reduced the elevated SGOT, SGPT, and ALP levels in HFD-fed rats. Moreover, policosanol significantly reduced hepatic oxidative stress manifest by reduced malondialdehyde (MDA) and increased glutathione (GSH) level. The treatment with policosanol (100 mg/kg) was found to be more active in attenuating the HFD-induced hepatotoxicity as compared to policosanol (50 mg/kg) and atorvastatin (30 mg/kg). Moreover, we observed that the hepatoprotective potential of policosanol was comparable to the silymarin. Conclusions The results of the study clearly indicated that the policosanol could be considered an intriguing approach for the treatment of NAFLD.

Validation of a Quantification Method for Curcumin Derivatives and Their Hepatoprotective Effects on Nonalcoholic Fatty Liver Disease

Curcumin (CM), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are major curcumin derivatives found in the rhizome of turmeric (Curcuma longa L.), and have yielded impressive properties to halt various diseases. In the present study, we carried out a method validation for curcumin derivatives and analyzed the contents simultaneously using HPLC with UV detection. For validation, HPLC was used to estimate linearity, range, specificity, accuracy, precision, limit of detection (LOD), and limit of quantification (LOQ). Results showed a high linearity of the calibration curve, with a coefficient of correlation (R2) for CM, DMC, and BDMC of 0.9999, 0.9999, and 0.9997, respectively. The LOD values for CM, DMC, and BDMC were 1.16, 1.03, and 2.53 ng/μL and LOQ values were 3.50, 3.11, and 7.67 ng/μL, respectively. Moreover, to evaluate the ability of curcumin derivatives to reduce liver lipogenesis and compare curcumin derivatives’ therapeutic effects, a HepG2 cell model was established to analyze their hepatoprotective properties. Regarding the in vivo study, we investigated the effect of DMC, CM, and BDMC on nonalcoholic fatty liver disease (NAFLD) caused by a methionine choline deficient (MCD)-diet in the C57BL/6J mice model. From the in vitro and in vivo results, curcumin derivatives alleviated MCD-diet-induced lipid accumulation as well as high triglyceride (TG) and total cholesterol (TC) levels, and the protein and gene expression of the transcription factors related to liver adipogenesis were suppressed. Furthermore, in MCD-diet mice, curcumin derivatives suppressed the upregulation of toll-like receptors (TLRs) and the production of pro-inflammatory cytokines. In conclusion, our findings indicated that all of the three curcuminoids exerted a hepatoprotective effect in the HepG2 cell model and the MCD-diet-induced NAFLD model, suggesting a potential for curcuminoids derived from turmeric as novel therapeutic agents for NAFLD.

The Efficacy of Tofogliflozin on Metabolic Dysfunction-Associated Fatty Liver Disease

The increasing number of patients with fatty liver disease is a major health problem. Fatty liver disease with metabolic dysfunction has been recognized as nonalcoholic fatty liver disease (NAFLD). Although there is no standard therapy for NAFLD, previous reports support the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on NAFLD. Recently, fatty liver disease with metabolic dysfunction was proposed to be defined as a novel concept, “metabolic associated fatty liver disease (MAFLD)”, and it was proposed that new criteria for MAFLD diagnosis be established. To clarify the effect of SGLT2 inhibitors on MAFLD, we analyzed the efficacy of tofogliflozin in patients with MAFLD. We conducted a single-center, retrospective study to evaluate the efficacy of tofogliflozin in patients with MAFLD treated at Kyushu University Hospital between 2017 and 2019. Tofogliflozin was used to treat 18 patients with MAFLD. To determine the efficacy of tofogliflozin, we evaluated glucose metabolism, insulin resistance, liver injury, hepatic steatosis, and body composition three and six months after drug initiation. Although our study was a preliminary study because of some limitations (e.g., retrospective, observational, single-arm study, small sample size), we show that tofogliflozin could improve liver injury in patients with MAFLD by improving glucose metabolism and insulin resistance without causing muscle loss.

Genetic and Life Style Risk Factors for Recurrent Non-alcoholic Fatty Liver Disease Following Liver Transplantation

Recurrent or de novo non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) following liver transplantation (LT) is a frequent event being increasingly recognized over the last decade, but the influence of recurrent NASH on graft and patient outcomes is not yet established. Taking into consideration the long term survival of liver transplanted patients and long term complications with associated morbidity and mortality, it is important to define and minimize risk factors for recurrent NAFLD/NASH. Metabolic syndrome, obesity, dyslipidemia, diabetes mellitus are life style risk factors that can be potentially modified by various interventions and thus, decrease the risk of recurrent NAFLD/NASH. On the other hand, genetic factors like recipient and/or donor PNPLA3, TM6SF2, GCKR, MBOAT7 or ADIPOQ gene polymorphisms proved to be risk factors for recurrent NASH. Personalized interventions to influence the different metabolic disorders occurring after LT in order to minimize the risks, as well as genetic screening of donors and recipients should be performed pre-LT in order to achieve diagnosis and treatment as early as possible.