Nonalcoholic Steatohepatitis Fibrosis Research Articles

Angiopoietin-like protein 4 deficiency augments liver fibrosis in liver diseases such as nonalcoholic steatohepatitis in mice through enhanced free cholesterol accumulation in hepatic stellate cells.

We recently reported that lipoprotein lipase (LPL)-mediated free cholesterol (FC) accumulation in hepatic stellate cells (HSCs) augmented liver fibrosis in non-alcoholic steatohepatitis (NASH). The aim of the present study was to explore the role of angiopoietin-like protein 4 (Angptl4), an LPL inhibitor, in the pathogenesis of liver fibrosis in NASH. Angptl4-deficient or wild-type mice were used to investigate the role of Angptl4 in the pathogenesis of NASH induced by feeding a methionine- and choline-deficient diet. We also examined the effect of Angptl4 on FC accumulation in HSCs, and the subsequent activation of HSCs, using Angptl4-deficient HSCs. In the NASH model, Angptl4-deficient mice had significantly aggravated liver fibrosis and activated HSCs without enhancement of hepatocellular injury, liver inflammation, or liver angiogenesis. FC levels were significantly higher in HSCs from Angptl4-deficient mice than in those from wild-type mice. Treatment with Angptl4 reversed low-density lipoprotein-induced FC accumulation in HSCs through the inhibition of LPL. The Angptl4 deficiency-induced FC accumulation in HSCs suppressed HSC expression of the transforming growth factor-β (TGF-ß) pseudoreceptor, bone morphogenetic protein, and activin membrane-bound inhibitor, and sensitized HSCs to TGF-β-induced activation in vivo and in vitro. Angptl4 plays an important role in the pathogenesis of FC accumulation in HSCs. In addition, regulation of FC levels in HSCs by Angptl4 plays a critical role in the pathogenesis of liver fibrosis in NASH. Thus, Angptl4 could represent a novel therapeutic option for NASH.

The clinical impact of cirrhosis on the postoperative outcomes of patients undergoing bariatric surgery: propensity score-matched analysis of 2011-2017 US hospitals

ABSTRACT Objectives: Since there is increasing number of patients with cirrhosis who require the bariatric procedure due to obesity and obesity-related nonalcoholic steatohepatitis fibrosis, we evaluate the effect of cirrhosis on post-bariatric surgery outcomes. Methods: 2011–2017 National Inpatient Sample was used to isolate bariatric cases, which were stratified by cirrhosis; controls were propensity-score matched to cases and compared to endpoints: mortality, length of stay (LOS), costs, and postoperative complications. Results: From 190,753 patients undergoing bariatric surgery, there were 957 with cirrhosis and 957 matched controls. There was no difference in mortality (0.94 vs 0.52% p = 0.42, OR 1.81 95%CI 0.60–5.41); however, cirrhosis patients had higher LOS (3.36 vs 2.89d p = 0.002), costs ($68,671 vs $61,301 p < 0.001), and bleeding (2.09 vs 0.72% p < 0.001, OR 2.95 95%CI 1.89–4.61). In multivariate, there was no difference in mortality (p = 0.330, aOR 1.73 95%CI 0.58–5.19). In subgroup comparison of cirrhosis patients, those with decompensated cirrhosis had higher mortality (7.69 vs 0.94% p < 0.001, OR 8.78 95%CI 3.41–22.59). Conclusion: The results of this study show compensated cirrhosis does not pose an increased risk toward post-bariatric surgery mortality; however, hepatic decompensation increases the postsurgical risks.

Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: Diagnosis and Treatment

The prevalence of non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is rapidly increasing in Korean populations and is estimated to reach 39% among Korean adults. NAFLD is one of the strongest risk factors of type 2 diabetes mellitus (T2DM), and the presence of NAFLD in T2DM patients is associated with a worse natural course of diabetic complications. The gold standard for diagnosing NAFLD is liver biopsy, which involves sampling error, high cost, and other disadvantages related to its invasive nature. We summarize non-invasive diagnostic NAFLD algorithms including biomarkers and four major imaging tools (ultrasonography, computed tomography, magnetic resonance imaging, and liver FibroScanⓇ) for diagnosing NAFLD including hepatic fibrosis. To prevent NASH (nonalcoholic steatohepatitis) or liver fibrosis, a combination of lifestyle modification with a low caloric diet and exercise, anti-diabetic agents, and non-anti-diabetic agents should be applied.

The role of bariatric surgery in the management of nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the United States and increasing globally. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), can lead to cirrhosis and complications of end-stage liver disease. No FDA-approved therapy for NAFLD/NASH exists. Treatment of NAFLD/NASH includes effective and sustained life-style modification and weight loss. This review reports on the recent findings of bariatric surgery in the management of NASH. NAFLD, at all stages, is common in those who meet indication for bariatric surgery. Bariatric surgery resolves NAFLD/NASH and reverses early stages of fibrosis. Although randomized controlled trials of bariatric surgery in NASH are infeasible, studies defining the metabolic changes induced by bariatric surgery, and their effect on NASH, provide insight for plausible pharmacologic targets for the nonsurgical treatment of NASH. Resolution of NASH and fibrosis regression can occur after bariatric surgery. Although the exact mechanism(s) underlying the improvement of NASH and hepatic fibrosis following bariatric surgery is not fully elucidated, emerging data on this topic is vitally important for lending insight into the pharmacotherapies for NASH for patients who are not otherwise suitable candidates for bariatric surgery.

Efficacy and safety of obeticholic acid in liver disease—A systematic review and meta-analysis

Background and aimsCurrently, there is no pharmacotherapy for non-alcoholic steatohepatitis (NASH), a common liver disorder. In contrast, primary biliary cholangitis (PBC) is a chronic cholestatic liver disease for which ursodeoxycholic acid (UDCA) is the drug of choice. However, 50% of PBC patients may not respond to UDCA. Obeticholic acid (OCA) is emerging as a vital pharmacotherapy for these chronic disorders. We aimed to analyse the safety and efficacy of OCA. MethodsWe performed an extensive search of electronic databases from 01/01/2000 to 31/03/2020. We included randomized controlled trials of OCA in patients with NASH, PBC, and primary sclerosing cholangitis (PSC). We assessed the histological improvement in NASH, reduction in alkaline phosphatase (≤1.67 ULN) in PBC, and the adverse effects of OCA. ResultsSeven RCTs (n = 2834) were included. Of the total RCTs, there were three on both NASH and PBC and one on PSC. OCA improved NASH fibrosis [OR: 1.95 (1.47–2.59; p < 0.001)]. With the 10 mg OCA dose, the odds of improvement was 1.61 (1.03–2.51; p = 0.03), while with the 25 mg dose, it was 2.23 (1.55−3.18; p < 0.001). However, 25 mg OCA led to significant adverse events and discontinuation of the drug [2.8 (1.42–3.02); p < 0.001)] compared with 10 mg OCA [0.95 (0.6–1.5); p = 0.84] in NASH patients. In PBC patients, the response to 5 mg OCA was better than with the higher doses [5 mg: 7.66 (3.12–18.81; p < 0.001), 10 mg: 5.18 (2–13.41; p = 0.001), 25 mg: 2.36 (0.94–5.93; p = 0.06), 50 mg: 4.08 (1.05–15.78; p = 0.04)]. The risk of pruritus was lowest with 5 mg OCA. ConclusionsLower doses of OCA are effective and safe in NASH and cholestatic liver disease. While 10 mg OCA is effective for NASH fibrosis regression, only 5 mg OCA is required for PBC.

Experimental and Investigational Targeted Therapies for the Management of Fibrosis in NASH: An Update.

There have been major advances in the treatment of HBV and HCV with anti-viral treatments, which is reducing the prevalence of fibrosis due to these viruses and obviating the need for anti-fibrotic therapies in these diseases. At the same time, however, the prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing, of which a substantial fraction of patients have non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis. Accordingly, NASH is emerging as the leading indication for liver transplantation in North America and Europe. Progress in uncovering pathogenic determinants of fibrosis in NASH include metabolic dysregulation in hepatocytes that induce inflammation and cytokine secretion leading to cell injury and apoptosis, among others. These pathogenic events converge upon hepatic stellate cells, which are the primary fibrogenic cell in liver, and represent a target of new therapeutic candidates that are currently being evaluated in animal models and clinical trials. This review highlights key experimental and investigational therapies for NASH fibrosis, whose evaluation will be accelerated as new non-invasive markers of fibrosis are established. While no drugs are approved yet for NASH fibrosis, there is growing optimism that new pharmacotherapies are likely to emerge within the next 3 years that will favorably alter the natural history of disease.

Deletion of TRPC3 or TRPC6 Fails to Attenuate the Formation of Inflammation and Fibrosis in Non-alcoholic Steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a disease that has progressed from non-alcoholic fatty liver disease (NAFLD) and is characterized by inflammation and fibrosis. Two transient receptor potential canonical (TRPC) subfamily members, TRPC3 and TRPC6 (TRPC3/6), reportedly participate in the development of fibrosis in cardiovascular and renal systems. We hypothesized that TRPC3/6 may also participate in NASH fibrosis. We evaluated the effects of TRPC3 or TRPC6 functional deficiency in a NASH mouse model using choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Wild-type (WT) and TRPC3 or TRPC6 gene-deficient (KO) mice were fed with CDAHFD or standard diet for 6 weeks. The CDAHFD-induced body weight loss in TRPC6 KO mice was significantly lower compared with WT mice with CDAHFD. CDAHFD treatment significantly increased TRPC3 mRNA expression level and tissue weight in WT liver, which were suppressed in TRPC3 KO mice. However, either systemic deletion of TRPC3 or TRPC6 failed to attenuate liver steatosis, inflammation and fibrosis. These results imply that TRPC3 and TRPC6 are unlikely to be involved in liver dysfunction and fibrosis of NASH model mice.

From the Editor's Desk...

From the Editor's Desk...

Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma.

Simple SummaryNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting a quarter of the global population and carries the risk of developing malignant liver cancer. Inflammation is considered paramount in the progression of the disease and many different immune cells and pathways have been implicated in the development of NAFLD. Novel techniques in basic immunology have substantially enhanced the possibilities to study inflammation and the heterogeneity of immune cells. Based on recent studies, we provide a review of novel paradigms emerging in steatohepatitis and the development of hepatocellular carcinoma and outline the multifaceted contributions of immunity to advancing NAFLD. End-stage NAFLD with liver cancer has an abysmal prognosis and effective medical therapies are lacking, therefore a better understanding of the disease mechanisms will ultimately help to improve patients’ care. Nonalcoholic fatty liver disease (NAFLD) is a rising chronic liver disease and comprises a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to end-stage cirrhosis and risk of hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is multifactorial, but inflammation is considered the key element of disease progression. The liver harbors an abundance of resident immune cells, that in concert with recruited immune cells, orchestrate steatohepatitis. While inflammatory processes drive fibrosis and disease progression in NASH, fueling the ground for HCC development, immunity also exerts antitumor activities. Furthermore, immunotherapy is a promising new treatment of HCC, warranting a more detailed understanding of inflammatory mechanisms underlying the progression of NASH and transition to HCC. Novel methodologies such as single-cell sequencing, genetic fate mapping, and intravital microscopy have unraveled complex mechanisms behind immune-mediated liver injury. In this review, we highlight some of the emerging paradigms, including macrophage heterogeneity, contributions of nonclassical immune cells, the role of the adaptive immune system, interorgan crosstalk with adipose tissue and gut microbiota. Furthermore, we summarize recent advances in preclinical and clinical studies aimed at modulating the inflammatory cascade and discuss how these novel therapeutic avenues may help in preventing or combating NAFLD-associated HCC.

Serum levels of endotrophin are associated with nonalcoholic steatohepatitis

Background and aims There are no currently available biomarkers that can accurately indicate the presence of non-alcoholic steatohepatitis (NASH). We investigated the association between endotrophin, a cleavage product of collagen type 6α3, and disease severity in patients with non-alcoholic fatty liver disease (NAFLD). Methods We measured serum endotrophin levels in 211 patients with NAFLD and nine healthy controls. Liver biopsy data was available for 141 (67%) of the patients. Associations between endotrophin and the presence of NASH and advanced fibrosis were investigated alone and in combination with standard clinical parameters using logistic regression. Results A total of 211 patients were enrolled in this study, consisting of 108 (51%) men and 103 (49%) women with a mean age of 55.6 years. 58 (27%) of the patients had advanced fibrosis. Of those with biopsy data, 87 (62%) had NASH. Serum levels of endotrophin were significantly higher in patients with NAFLD than those in healthy controls (37[±12] vs. 17[±7] ng/mL, p<.001). Serum levels of endotrophin were also significantly higher in patients with NASH than in those without NASH (40[±12] vs. 32[±13] ng/mL, p<.001). A model using age, sex, body mass index and levels of alanine aminotransferase (ALT), glucose and endotrophin effectively predicted the presence of NASH in a derivation (AUROC 0.83, 95%CI = 0.74–0.92) and validation cohort (AUROC 0.71, 95%CI = 0.54–0.88). There was no significant association between serum levels of endotrophin and advanced fibrosis. Conclusions These data suggest that serum endotrophin could be a valuable biomarker for diagnosing NASH, but not for detecting advanced fibrosis in NAFLD.

Relationship of ELF and PIIINP With Liver Histology and Response to Vitamin E or Pioglitazone in the PIVENS Trial.

Enhanced liver fibrosis score (ELF) and one of its components, amino‐terminal propeptide of type III procollagen (PIIINP) are promising noninvasive biomarkers of liver histology in patients with nonalcoholic steatohepatitis (NASH). We evaluated the association of ELF and PIIINP with fibrosis stages at baseline and end of treatment (EOT) with vitamin E or pioglitazone in the PIVENS trial (Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Nondiabetic Patients With NASH) and characterized ELF and PIIINP changes and their associations with changes in the histological endpoints. ELF and PIIINP were measured at baseline and weeks 16, 48, and 96 on sera from 243 PIVENS participants. Baseline and EOT ELF were significantly associated with fibrosis stage (P < 0.001). The area under the curve for ELF’s detection of clinically significant and advanced fibrosis in baseline biopsies was 0.74 and 0.79, respectively (P < 0.001). There was a significant drop in ELF score at weeks 48 and 96 in patients who achieved the NAFLD activity score (NAS)–based primary end point (P = 0.007) but not in those who experienced NASH resolution (P = 0.24) or fibrosis improvement (P = 0.50). Change in PIIINP was significantly associated with NASH resolution and improvement in NAS‐based histological endpoint and fibrosis (P < 0.05 for all). Over the study period, both ELF and PIIINP significantly decreased with vitamin E (P < 0.05), but only PIIINP decreased with pioglitazone (P < 0.001). Conclusion: ELF is significantly associated with clinically significant and advanced fibrosis in patients with NASH, but its longitudinal changes were not associated with improvement in fibrosis or NASH resolution. PIIINP, one of its components, appears promising for identifying longitudinal histologic changes in patients with NASH and is worthy of further investigation.

Dietary lycopene attenuates cigarette smoke-promoted nonalcoholic steatohepatitis by preventing suppression of antioxidant enzymes in ferrets

Cigarette smoke (CS) is an independent risk factor in development of nonalcoholic steatohepatitis (NASH) and fibrosis. Lycopene, a carotenoid naturally occurring in tomatoes, has been shown to be a protective agent against tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced NASH. In the present study using a ferret model we investigated whether CS promotes NASH and whether dietary lycopene can inhibit CS-promoted NASH development, and if so, what potential mechanisms were involved. Ferrets were divided into 4 groups (n=12−16/group): control, NNK/CS exposed, NNK/CS plus low-dose lycopene (2.2 mg/kg BW/day), and NNK/CS plus high-dose lycopene (6.6 mg/kg BW/day) groups, for 26 weeks. Results showed that hepatic steatosis, infiltrates of inflammatory cells, and the number and size of inflammatory foci in liver, together with key genes involved in hepatic fibrogenesis were higher in the NNK/CS group compared to the control group; a lycopene diet reversed these changes to the levels of the control group. Interestingly, a major lycopene cleavage enzyme, beta-carotene 9’,10’-oxygenase (BCO2), which recently has been recognized to play metabolic roles beyond cleavage function, was down-regulated by NNK/CS exposure, but this decrease was prevented by lycopene feeding. NNK/CS exposure also downregulated liver expression of antioxidant enzymes and upregulated oxidative stress marker, which were all prevented by lycopene. In conclusion, our results suggest that CS can promote development of NASH and liver fibrosis in ferrets, which is associated with downregulation of BCO2 and impairment of antioxidant system in liver; dietary lycopene may inhibit CS-promoted NASH by preventing suppression of BCO2 and decline in antioxidant network.

The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model.

Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1 (−37%) and pdgfr-β (−36%), as well as desmin area (−42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (−28%) but also mean arterial pressure (−25%) and heart rate (−37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion.

Iron-rich Kupffer cells exhibit phenotypic changes during the development of liver fibrosis in NASH

SummaryAlthough recent evidence suggests the involvement of iron accumulation in the pathogenesis of nonalcoholic steatohepatitis (NASH), the underlying mechanisms remain poorly understood. Previously, we reported a unique histological structure termed “crown-like structure (CLS),” where liver-resident macrophages (Kupffer cells) surround dead hepatocytes, scavenge their debris, and induce inflammation and fibrosis in NASH. In this study, using magnetic column separation, we show that iron-rich Kupffer cells exhibit proinflammatory and profibrotic phenotypic changes during the development of NASH, at least partly, through activation of MiT/TFE transcription factors. Activation of MiT/TFE transcription factors is observed in Kupffer cells forming CLSs in murine and human NASH. Iron chelation effectively attenuates liver fibrosis in a murine NASH model. This study provides insight into the pathophysiologic role of iron in NASH. Our data also shed light on a unique macrophage subset rich in iron that contributes to CLS formation and serves as a driver of liver fibrosis.

Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH

IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.

The roles of gap junctional intercellular communication in non-alcoholic steatohepatitis (NASH) and liver fibrosis

Non-alcoholic steatohepatitis (NASH) is a common risk factor for fibrosis, cirrhosis, and a predisposing factor for the development of hepatocellular carcinoma. Recently, incidence of NASH has increased due to an increase in metabolic syndrome. Connexin (Cx)32, a hepatocyte gap-junction protein, plays an important role in liver tissue homeostasis; Cx32 dominant-negative transgenic rat (Cx32ΔTg) has much decreased gap-junctional intercellular communication, and high susceptibility to carcinogens. We found for the first time that Cx32 has play suppressive roles in inflammation and fibrosis of NASH using Cx32ΔTg received methionine-choline deficient diet (MCDD). Elevation of reactive oxygen species (ROS) play important roles in progression of NASH and elimination of ROS by antioxidant luteolin inhibited NASH in the Cx32ΔTg-MCDD model. This model had histological changes similar to those of human NASH, but was not accompanied by the metabolic syndrome such as obesity and insulin resistance. Therefore, we further established an improved NASH model. Cx32ΔTg rats and wild-type rats were fed a high-fat diet (HFD) and dimethylnitrosamine to induce NASH with metabolic syndrome. The HFD and DMN increased body, liver, and visceral fat weights in both genotypes. Serum insulin level and HOMA-IR score in Cx32ΔTg rats were higher than those in wild-type rats. Elevation of serum hepatic enzymes (AST, ALT), inflammatory cytokine expressions, α-smooth muscle actin expression, progression of steatohepatitis and fibrosis were induced by HFD and dimethylnitrosamine especially in Cx32ΔTg rats. These results indicate Cx32 dysfunction promoted the development of NASH and fibrosis accompanied by metabolic syndrome through accumulation of oxidative stress.

Effect of Obeticholic Acid on Hepatic Artery Blood Flow in Non-Cirrhotic Porcine Livers: Possible Mechanism of OCA Action in NASH

The progression of fibrosis in non-alcoholic steatohepatitis, NASH has been linked to intermittent hypoxia and improves with oxygenation. Obeticholic acid, OCA has demonstrated efficacy in the treatment of NASH fibrosis. We studied the dose-responsive effects of OCA on HA, portal vein and hepatic vein flow in porcine liver perfused ex vivo with a cardio-emulation pump, the CaVESWave® system. Increased flow in the HA, which provides over 50 percent of tissue oxygenation to the liver, might explain the beneficial effect of OCA in NASH Funding: The study was supported by an Investigator Initiated grant from Intercept Pharmaceutical Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Ethical Committee – Centura Health Research Committee

Application of artificial intelligence in non-alcoholic fatty liver disease and liver fibrosis: a systematic review and meta-analysis.

Background:The global prevalence of non-alcoholic fatty liver disease (NAFLD) continues to rise. Non-invasive diagnostic modalities including ultrasonography and clinical scoring systems have been proposed as alternatives to liver biopsy but with limited performance. Artificial intelligence (AI) is currently being integrated with conventional diagnostic methods in the hopes of performance improvements. We aimed to estimate the performance of AI-assisted systems for diagnosing NAFLD, non-alcoholic steatohepatitis (NASH), and liver fibrosis.Methods:A systematic review was performed to identify studies integrating AI in the diagnosis of NAFLD, NASH, and liver fibrosis. Pooled sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and summary receiver operating characteristic curves were calculated.Results:Twenty-five studies were included in the systematic review. Meta-analysis of 13 studies showed that AI significantly improved the diagnosis of NAFLD, NASH and liver fibrosis. AI-assisted ultrasonography had excellent performance for diagnosing NAFLD, with a sensitivity, specificity, PPV, NPV of 0.97 (95% confidence interval (CI): 0.91–0.99), 0.98 (95% CI: 0.89–1.00), 0.98 (95% CI: 0.93–1.00), and 0.95 (95% CI: 0.88–0.98), respectively. The performance of AI-assisted ultrasonography was better than AI-assisted clinical data sets for the identification of NAFLD, which provided a sensitivity, specificity, PPV, NPV of 0.75 (95% CI: 0.66–0.82), 0.82 (95% CI: 0.74–0.88), 0.75 (95% CI: 0.60–0.86), and 0.82 (0.74–0.87), respectively. The area under the curves were 0.98 and 0.85 for AI-assisted ultrasonography and AI-assisted clinical data sets, respectively. AI-integrated clinical data sets had a pooled sensitivity, specificity of 0.80 (95%CI: 0.75–0.85), 0.69 (95%CI: 0.53–0.82) for identifying NASH, as well as 0.99–1.00 and 0.76–1.00 for diagnosing liver fibrosis stage F1–F4, respectively.Conclusion:AI-supported systems provide promising performance improvements for diagnosing NAFLD, NASH, and identifying liver fibrosis among NAFLD patients. Prospective trials with direct comparisons between AI-assisted modalities and conventional methods are warranted before real-world implementation.Protocol registration:PROSPERO (CRD42021230391)

Severity of metabolic syndrome is greater among nonalcoholic adults with elevated ALT and advanced fibrosis

The obesity epidemic has increased risk for nonalcoholic fatty-liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. We hypothesized that metabolic syndrome (MetS) severity would correlate with markers of NAFLD and NASH fibrosis. We evaluated cross-sectional data from 5463 participants of the National Health and Nutrition Examination Survey 1999-2012, age 20 to 64 years with and without diabetes, excluding those with heavy drinking and infectious liver serologies. We used linear and logistic regression to evaluate links between MetS-severity (using a race/ethnicity-specific MetS-severity-Z-score, MetS-Z) and apparent NALFD sequelae, using elevated alanine aminotransferase (ALT) to determine presence of NAFLD and elevated NAFLD Fibrosis Score to identify advanced fibrosis (NASH Clinical Research Network scoring stage 3-4). The prevalence of unexplained ALT elevations and advanced fibrosis were 11.4% and 1.37%, respectively. MetS-Z-scores were higher among those with elevated ALT (0.7, 95% confidence interval [CI]: 0.6, 0.8) and advanced fibrosis (1.7, CI: 1.5,1.9), compared to those without liver abnormalities (0.2, CI:0.2, 0.3). For every 1-standard-deviation unit increase in MetS-Z, there were higher odds of elevated ALT (OR = 1.58, CI: 1.44, 1.72) and advanced fibrosis (OR = 1.96, CI: 1.77, 2.18), with some attenuation after adjustment for age, sex, race/ethnicity, and diabetes status. Significant differences were noted by race/ethnicity, with stronger links among whites versus blacks. The degree of MetS-severity was associated with progressive increase in apparent NAFLD and advanced fibrosis; as MetS-severity has also been linked to future cardiovascular disease, diabetes, and chronic kidney disease, this provides support for use of a MetS-severity score to screen for general health, with high levels triggering further assessment for liver abnormalities.

The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension.

Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comparing HFC-induced hepatic fibrogenesis between spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto counterpart. Compared to the counterpart, the HFC diet led to stronger aggregation of CD68-positive macrophages in SHRs. HFC feeding also resulted in significantly higher upregulation of the fibrosis-related gene alpha-smooth muscle actin in SHR. The HFC diet induced higher overexpression of serum tissue inhibitor of metalloproteinase-1 (TIMP1) and greater suppression of matrix metalloproteinase-2 (MMP2):TIMP1, MMP8:TIMP1, and MMP9:TIMP1 ratios, as a proxy of the activities of these MMPs in SHR. Administration of the antihypertensive agent hydralazine to SHRs significantly ameliorated HFC-induced liver fibrosis; it suppressed the aggregation of CD68-positive macrophages and the upregulation of platelet-derived growth factor receptor beta, and collagen, type 1, alpha-1 chain. In conclusion, a hypertensive environment exacerbated the hepatic fibrogenetic effects of the HFC diet; while the effects were partially reversed by the antihypertensive agent hydralazine. Our data suggest that antihypertensive drugs hold promise for treating NASH exacerbated by hypertension.