Etiology Of Nonalcoholic Steatohepatitis Research Articles

Comparative effects of thymol and vitamin E on nonalcoholic fatty liver disease in male Wistar rats.

Following the obesity epidemics, nonalcoholic fatty liver disease (NAFLD) has grown in prevalence and become a main cause of morbidity and death, intimately linked to cardiovascular disease, cancer, and cirrhosis. The key factor in the evolution of NAFLD is thought to be oxidative stress. Because most patients cannot change their lifestyle or dietary habits, a pharmaceutical strategy is now required to treat NAFLD. Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis, is treated with vitamin E. (NASH). Vitamin E is also a powerful antioxidant that has been demonstrated to lower oxidative stress in people with NAFLD. Thymol is a monoterpene phenol with a variety of pharmacological effects, however its anti-fatty liver properties have yet to be investigated. Despite the fact that oxidative stress is thought to have a role in the etiology of nonalcoholic steatohepatitis, antioxidant therapies have not been well studied in the treatment of nonalcoholic steatohepatitis. The goal was to learn more about vitamin E and thymol's biological activities, with a particular emphasis on their therapeutic effectiveness in NAFLD. Four groups of thirty-two adult male rats were formed (healthy control, thymol, Vit E, and fatty liver). For 28 days, rats were given either oral vitamin E (200 mg/kg) or thymol (50 mg/kg) randomly. The levels of ALT, AST, TNF- α, Ferritin, CK-MB enzymes, and MAPK gene expression were then determined in the serum. Based on a random effect model analysis, at the end of 28 days of therapy, ALT (41.43 U/L), AST (47.91 U/L), Ferritin (1.13 pg/dl), CK-MB (251.22 IU/L), TNF-α (95.39 pg/mL) (p≤0.001), and MAPK gene expression levels (p≤0.05) significantly reduced in both experimental groups compared with the fatty liver group. Vitamin E and thymol therapy is a safe, affordable, and effective therapeutic option in the fatty liver group. Patients with fatty liver disease should be encouraged to take vitamin E and Thymol supplements, which are both safe and affordable, because more effective new therapeutic options are lacking.

Pharmacological inhibition of CFTR attenuates nonalcoholic steatohepatitis (NASH) progression in mice

Nonalcoholic steatohepatitis (NASH) is considered a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression and increases the risk of end-stage liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The etiology of NASH is multifactorial and identifying reliable molecular players has proven difficult. Presently, there are no approved drugs for NASH treatment, which has become a leading cause of liver transplants worldwide. Here, using public human transcriptomic NAFLD dataset, we uncover Cystic fibrosis transmembrane conductance receptor (CFTR) as a differentially expressed gene in the livers of human NASH patients. Similarly, murine Cftr expression was also found to be upregulated in two mouse models of diet-induced NASH. Furthermore, the pharmacological inhibition of CFTR significantly reduced NASH progression in mice and its overexpression aggravated lipotoxicity in human hepatic cells. These results, thus, underscore the involvement of murine Cftr in the pathogenesis of NASH and raise the intriguing possibility of its pharmacological inhibition in human NASH.

MiR-690 treatment causes decreased fibrosis and steatosis and restores specific Kupffer cell functions in NASH

Nonalcoholic steatohepatitis (NASH) is a liver disease associated with significant morbidity. Kupffer cells (KCs) produce endogenous miR-690 and, via exosome secretion, shuttle this miRNA to other liver cells, such as hepatocytes, recruited hepatic macrophages (RHMs), and hepatic stellate cells (HSCs). miR-690 directly inhibits fibrogenesis in HSCs, inflammation in RHMs, and de novo lipogenesis in hepatocytes. When an miR-690 mimic is administered to NASH mice invivo, all the features of the NASH phenotype are robustly inhibited. During the development of NASH, KCs become miR-690 deficient, and miR-690 levels are markedly lower in mouse and human NASH livers than in controls. KC-specific KO of miR-690 promotes NASH pathogenesis. A primary target of miR-690 is NADK mRNA, and NADK levels are inversely proportional to the cellular miR-690 content. These studies show that KCs play a central role in the etiology of NASH and raise the possibility that miR-690 could emerge as a therapeutic for this condition.

Sex-based Disparities in Hepatocellular Carcinoma Recurrence After Liver Transplantation.

Women with chronic liver disease have lower rates of hepatocellular carcinoma (HCC) as compared to men; it is unknown if there are sex-based differences in HCC recurrence postliver transplant. We conducted an analysis of patients who underwent liver transplant for HCC in the United Network for Organ Sharing/Organ Procurement and Transplantation Network from January 1, 2012 through December 31, 2017. A total of 12 711 patients underwent liver transplant for HCC: 2909 (23%) women and 9802 (73%) men. Women had significantly lower rates of postliver transplant HCC recurrence than men (4.0% versus 5.4%, P = 0.002). A cox-regression analysis for postliver transplant HCC recurrence highlighted that even after accounting for etiology of cirrhosis, alpha-fetoprotein at liver transplant, tumor diameter, tumor pathology, and vascular invasion, female sex was associated with a 25% lower risk of postliver transplant HCC recurrence (95% confidence interval: 0.57-0.99). There were no interactions between female sex and the following variables: age, type of locoregional therapy, alpha-fetoprotein, donor sex, body mass index, or nonalcoholic steatohepatitis etiology (P > 0.05 for each). This study demonstrates an independent effect of sex on risk for HCC recurrence postliver transplant. Our data highlight an opportunity to better understand HCC tumor biology by investigating the drivers of this sex-based difference in HCC recurrence.

A non-obese, diet-induced animal model of nonalcoholic steatohepatitis in Wistar/ST rats compared to Sprague-Dawley rats

Summary Background Non-alcoholic steatohepatitis (NASH), a subtype of non-alcoholic fatty liver disease (NAFLD), is a potentially progressive liver disease that can lead to cirrhosis. Obesity increases the risk of NAFLD/NASH, but this disease can also be observed in non-obese individuals. Methods We investigated the metabolic and histopathological changes in 13 obesity-resistant Slc:Wistar/ST rats fed a high-fat and high-cholesterol (HFC) diet for 9 weeks, and also retrospectively compared the results of 41 Sprague-Dawley (SD) rats that were previously fed with the same protocol to the results of the Slc:Wistar/ST rats. Results Of the 13 Slc:Wistar/ST rats fed an HFC diet containing 1.25% or 2.5% cholesterol, 11 (84.6%) developed histologically proven NASH without obesity, an increased visceral fat volume, insulin resistance, histopatological severe lobular inflammation and severe hepatic fibrosis. The HFC diets significantly increased the levels of mRNA encoding collagen type I alpha 1 (COL1A1), transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1). The SD rats also developed NASH without obesity, an increased visceral fat volume and insulin resistance, but the metabolic and histopathological effects, such as lower serum adiponectin levels, higher serum leptin levels, histopatological severe lobular inflammation and hepatic fibrosis, seemed to be more pronounced in the SD rats than in the Slc:Wistar/ST rats. Conclusions These two rat models may reflect the human etiology of NASH that is influenced by dietary factors, and the obesity-resistant Slc:Wistar/ST rat model may be particularly useful for elucidating the pathophysiological mechanism of the so-called lean NASH.

Abstract No. 646 Natural history of transjugular intrahepatic portosystemic shunts: long-term analysis of survival and protective factors

To evaluate long-term survival in patients with portal hypertension treated with transjugular intrahepatic portosystemic shunts (TIPS) and to identify patient characteristics associated with improved survival. This is a multicenter retrospective cohort study. Patients who received TIPS between January 1, 2008 and December 31, 2014 were included in this study. Patient data was collected between the time of procedure and September 1, 2019. Statistical analysis was performed using SPSS (IBM, New York). 129 patients are included in this study, 84 males and 45 females, with a median age of 61. 32% of patients had chronic hepatitis C, 33% had a history of alcohol use disorder, and 19% of patients had nonalcoholic steatohepatitis (NASH). The remainder of patients had miscellaneous etiologies of cirrhosis including autoimmune biliary cirrhosis, hepatitis B, and cystic fibrosis. 77% of patients had variceal bleeding and 34% of patients had refractory ascites prior to their procedures. 14% of patients had a history of hepatic encephalopathy. The technical success rate was 91% and overall complication rate was 30%. 1-, 3-, 5-, 7-, and 10-year survival rates are as follows: 93%, 74%, 58%, 38%, and 15%. 19% of patients had at least one episode of ascites requiring therapeutic paracentesis and 16% of patients experienced variceal hemorrhage during the follow-up period. 28% of patients required revision to expand their TIPS and 4% of patients required revision to constrain their TIPS. 56% of patients had episodes of hepatic encephalopathy during the follow-up period requiring hospitalization. 25% of patients experienced a decline in renal function of at least one stage. 21% of patients underwent subsequent liver transplantation. Female sex, preprocedural variceal bleeding rather than ascites, and NASH etiology of cirrhosis were associated with higher rates of overall survival. TIPS are crucial for many patients with symptomatic portal hypertension. Female sex, preprocedural variceal bleeding rather than ascites, and NASH as etiology of cirrhosis are associated with increased rates of long-term survival.

Weight Gain and De Novo Metabolic Disorders after Liver Transplantation.

The development of nutritional and metabolic abnormalities represents an important burden in patients after liver transplantation (LT). Our study aimed at evaluating the incidence, time of onset, and risk factors for nutritional and metabolic abnormalities in patients after LT. The study was a single-center retrospective study. Consecutive patients undergoing elective LT from 2000 to 2016 were enrolled. The presence of at least two among arterial hypertension (AH), diabetes mellitus (DM), dyslipidemia, and obesity (BMI ≥ 30 Kg/m2) was utilized to define patients with the metabolic disorder (MD). Three hundred and fifteen patients were enrolled; the median age was 56 years (68% males). Non-alcoholic steatohepatitis (NASH) was the origin of liver disease in 10% of patients. During follow-up, 39% of patients developed AH, 18% DM, and 17% dyslipidemia. Metabolic disorders were observed in 32% of patients. The NASH etiology (OR: 6.2; CI 95% 0.5–3; p = 0.003) and a longer follow-up (OR: 1.2; CI 95% 0.004–0.02; p = 0.002) were associated with de novo MD. In conclusion, nutritional and metabolic disorders are a frequent complication after LT, being present in up to one-third of patients. The NASH etiology and a longer distance from LT are associated with de novo MD after LT.

Liver Transplantation and Bariatric Surgery: Timing and Outcomes.

Nonalcoholic steatohepatitis (NASH) is projected to become the leading indication for liver transplantation (LT) in the next decade in the United States. Strategies to treat the underlying etiology of NASH, which is almost always obesity, are being pursued. One such strategy is the utilization of bariatric surgery (BS) in the peritransplant period. The use of BS prior to LT could prevent the progression of NASH and abrogate the need for LT. BS at the time of LT or postoperatively has the potential to not only improve obesity-associated conditions such as diabetes, but also the potential to influence the incidence of NASH in the post-LT setting. However, there continues to be no consensus on the use and timing of BS in this patient population. This review aims to discuss the current literature and possible future action.

Stage of fibrosis and portal pressure correlation in nonalcoholic steatohepatitis.

Hepatic venous pressure gradient (HVPG) measurement correlates with staging of liver fibrosis. Patients with nonalcoholic steatohepatitis (NASH) have a different pattern of fibrosis compared with hepatitis C virus (HCV) with possible alterations in pressures. The aim of this study was to compare portal pressures with the stage of fibrosis in NASH in comparison with other liver diseases. Records of all patients who had undergone transjugular liver biopsy with pressure measurements between January 2001 and June 2013 were reviewed. Wedge hepatic venous pressure (WHVP) and HVPG were compared with stages of fibrosis in liver diseases of different etiologies. Among 142 patients included in this study, the liver disease etiology was as follows: HCV (26.6%) and NASH (24.6%), with the remaining (38.7%) grouped under other categories. The mean age of the patients was 51.2±11.5 years, with more men with HCV (73.1%) compared with NASH (51.4%) in terms of etiology (P=0.046). There were strong correlations between the stage of fibrosis with both the HVPG (r=0.64; P<0.0001) and the WHVP (r=0.63; P<0.0001) in NASH patients. Compared with HCV patients, NASH patients had a lower HVPG (3.4±2.4 vs. 7.5±11 mmHg/stage; P=0.01) with a coefficient estimate of -0.24 (P=0.017) and WHVP (9.6±5.5 vs. 14.6±15.2 mmHg/stage; P=0.03) for the stage of fibrosis. HVPG and WHVP measurements were strongly correlated with stages of fibrosis in NASH. Patients with NASH had lower HVPG and WHVP for each stage of fibrosis compared with HCV patients. This raises the concern of underestimation of pressures by HVPG in NASH etiology for the stage of disease or increased fibrosis despite lower pressures in them.

Nonalcoholic steatohepatitis recurrence and rate of fibrosis progression following liver transplantation.

Nonalcoholic steatohepatitis (NASH) is known to recur following liver transplantation (LT). Metabolic risk factors increase with immunosuppression. However, the rate of fibrosis progression following LT for NASH while on immunosuppression is less clear. The incidences of steatosis, NASH, and fibrosis following LT for NASH were quantified and compared with those transplanted for alcoholic liver disease (ALD). Records of all NASH patients and 1 : 2 match with ALD transplant recipients between 2001 and 2006 were reviewed retrospectively. Patients without liver biopsies beyond 2 months following LT were excluded. NASH patients (n=77) were older (P=0.0006) and less likely male (P<0.001) than ALD patients (n=108). The incidence of steatosis, NASH, and fibrosis stage increased at 1, 3, and 5 years in both groups. Although steatosis and nonalcoholic fatty liver disease activity scores were higher, fibrosis was lower in NASH compared with ALD (0.43 vs. 1.0 stage/year; P=0.0045). The incremental increase in the rate of fibrosis was faster in the first year compared with 4-5 years (0.8 vs. 0.04 stage/year) following LT. The rate of fibrosis progression during 4-5 years was decreased in NASH compared with ALD recipients (0.04 vs. 0.33 stage/year; P=0.015). NASH etiology was associated with reduced rate of fibrosis progression (odds ratio=0.67) on multivariate analysis. Despite having more steatosis and inflammation, progression of fibrosis was slower in NASH compared with ALD recipients. Fibrosis progression slows with time following LT on immunosuppression and approximates the pretransplant progression rate by year 5.

Mosapride citrate improves nonalcoholic steatohepatitis with increased fecal lactic acid bacteria and plasma glucagon-like peptide-1 level in a rodent model.

Several lines of evidence have suggested a role of gut microbiota in the etiology of nonalcoholic steatohepatitis (NASH). NASH subjects reportedly showed a prolonged orocecal transit time coexistent with small intestinal bacterial overgrowth. We considered the possibility that enhanced gastrointestinal motility would influence gut microbiota and thus investigated the effects of the gastroprokinetic agent mosapride citrate (MC) on gut microbiota and the development of NASH using a methionine-choline deficient (MCD) diet-fed rodent model. Mice were divided into three groups, given the normal chow diet (NCD), the MCD diet, or the MCD diet containing 10 mg·kg(-1)·day(-1) of MC (MCD plus MC) for 6 wk. NASH development was evaluated based on hepatic histochemical findings, serum parameters and various mRNA and/or protein expression levels. MC treatment suppressed MCD diet-induced NASH development, with reduced serum lipopolysaccharide and increased plasma glucagon-like peptide-1 (GLP-1) concentrations. Calculation of the relative abundance of each strain based on gut microbiota analyses indicated lactic acid bacteria specifically, such as Bifidobacterium and Lactobacillus, in feces to be decreased in the MCD, compared with the NCD group. Interestingly, the reduction in lactic acid bacteria in the MCD diet group was reversed in the MCD plus MC group. In addition, colon inflammation observed in the MCD diet group was reduced in the MCD plus MC group. Therefore, MC showed a protective effect against MCD diet-induced NASH development in our rodent model, with possible involvements of increased fecal lactic acid bacteria, protection against colon inflammation and elevated plasma GLP-1.

Inhibiting Monoacylglycerol Acyltransferase 1 Ameliorates Hepatic Metabolic Abnormalities but Not Inflammation and Injury in Mice

Abnormalities in hepatic lipid metabolism and insulin action are believed to play a critical role in the etiology of nonalcoholic steatohepatitis. Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis, and knocking down Mogat1 improves glucose metabolism and hepatic insulin signaling, but whether increased MGAT activity plays a role in the etiology of nonalcoholic steatohepatitis is unclear. To examine this issue, mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were injected with antisense oligonucleotides (ASOs) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. The HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver and adipose tissue, attenuated weight gain, improved glucose tolerance, improved hepatic insulin signaling, and decreased hepatic triacylglycerol content compared with control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic diacylglycerol, cholesterol, or free fatty acid content; improve histologic measures of liver injury; or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves hepatic metabolic abnormalities without attenuating liver inflammation and injury.

Pediatric Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the pediatric population. Increased recognition of this form of liver disease parallels the dramatic rise in childhood and adolescent obesity over the past 2 decades. Like adults, most children with NAFLD are obese, and comorbidities include insulin resistance, hypertension, and dyslipidemia. Unfortunately, pediatric NAFLD is not always a benign condition, with some children progressing to hepatic fibrosis and even cirrhosis in severe cases. The etiology of nonalcoholic steatohepatitis is not yet fully understood; however, hepatic steatosis in the context of insulin resistance and increased oxidative stress may lead to progressive disease. Although physical examination, laboratory evaluation, and radiographic findings provide clues to the potential presence of fatty liver disease, liver biopsy remains the gold standard for diagnosis. Lifestyle modification, including slow and steady weight loss, improved dietary habits, and increased daily, aerobic physical activity, remains the first-line approach in treating pediatric fatty liver disease. Antioxidant pharmacologic therapy such as use of vitamin E has shown some benefit in patients with biopsy-proven steatohepatitis. Nutrition plays an essential role not only in the development of fatty liver disease but also potentially in the treatment and prevention of progression to more severe disease.

Liver Fibrogenesis in Non-Alcoholic Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common chronic liver diseases in developed western countries. Non-alcoholic steatohepatitis (NASH) is the most severe form of NAFLD, and can progress to more severe forms of liver disease, including fibrosis, cirrhosis, and even hepatocellular carcinoma. The activation of hepatic stellate cells plays a critical role in NASH-related fibrogenesis. Multiple factors, such as insulin resistance, oxidative stress, pro-inflammatory cytokines and adipokines, and innate immune responses, are known to contribute to the development of NASH-related fibrogenesis. Furthermore, these factors may share synergistic interactions, which could contribute to the process of liver fibrosis. Given the complex etiology of NASH, combined treatment regimes that target these different factors provide potential treatment strategies for NASH-related liver fibrosis.

Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis.

The aim of this study was to determine if a relationship exists between nonalcoholic steatohepatitis (NASH) and serum levels of free fatty acids, choline deficiency, or celiac disease. Forty-seven patients with liver biopsy proven NASH were enrolled. Total serum free fatty acids and anti-endomysial antibodies were determined in all patients, while plasma free and phospholipid-bound choline were determined in 29 patients. Total serum free fatty acid concentration correlated significantly with female gender and serum albumin concentration. Patients with severe fibrosis on liver biopsy had significantly greater serum concentration of free fatty acids than patients without severe fibrosis. Plasma free and phospholipid-bound choline levels were normal and no significant correlation was found between the concentration of plasma free or phospholipid bound choline, and the severity of liver damage. Only one of the 47 patients with NASH had a positive titer for the anti-endomysial antibody. In conclusion, increased serum concentrations of free fatty acids were found in NASH and were associated with development of more severe liver disease. Neither choline deficiency nor celiac sprue by anti-endomysial antibody testing was associated with NASH.