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Non-Alcoholic Steatohepatitis (K75.81)

Advances in the mechanistic understanding of Nonalcoholic steatohepatitis (NASH) have reframed the disease from a passive fat‐accumulation disorder to a dynamic network of metabolic stress, lipotoxic signaling, immune activation, and fibrogenic remodeling. Beyond triglyceride storage, toxic lipid intermediates (ceramides, diacylglycerols, free cholesterol) induce mitochondrial dysfunction, oxidative stress, and ER stress, activating JNK, NF-κB, and the NLRP3 inflammasome, thereby linking hepatocellular injury to Kupffer cell–mediated inflammation and hepatic stellate cell activation. Key druggable nodes now include bile acid–FXR signaling, thyroid hormone receptor-β–mediated mitochondrial biogenesis, FGF19/FGF21 endocrine axes, PPAR-α/δ/γ–regulated lipid oxidation and insulin sensitivity, acetyl-CoA carboxylase (ACC)–driven de novo lipogenesis, and GLP-1–mediated metabolic modulation. The therapeutic landscape reflects this systems-level insight: Resmetirom (THR-β agonist) has achieved regulatory approval for NASH with fibrosis, while FGF21 analogs, dual/triple incretin agonists, pan-PPAR agonists, and combination regimens targeting both metabolic drivers and fibrogenesis (e.g., TGF-β, LOXL2 pathways) are advancing in late-stage development. Increasingly, patient stratification by fibrosis stage, transcriptomic signatures, and metabolic phenotype is guiding therapy selection, signaling a shift toward pathway-directed and potentially combinatorial metabolic reprogramming rather than single-axis intervention.

Causes

The etiology of Nonalcoholic steatohepatitis (NASH) is multifactorial and rooted in systemic metabolic dysfunction rather than primary hepatic pathology. The dominant driver is insulin resistance, which increases adipose tissue lipolysis and free fatty acid flux to the liver while simultaneously stimulating hepatic de novo lipogenesis via SREBP-1c and ChREBP. Obesity—particularly visceral adiposity—type 2 diabetes, dyslipidemia, and metabolic syndrome markedly increase risk. Genetic predisposition further modulates susceptibility, with variants in PNPLA3, TM6SF2, MBOAT7, and HSD17B13 influencing lipid handling and progression risk. Diet composition (high fructose intake, saturated fats), sedentary behavior, gut microbiome dysbiosis, and altered intestinal permeability contribute through endotoxin-mediated inflammatory signaling. Unlike alcohol-associated liver disease, NASH occurs in the absence of significant alcohol consumption, though environmental exposures, medications, and epigenetic regulation can modulate disease onset and severity. Thus, NASH emerges from the convergence of metabolic overload, genetic susceptibility, and inflammatory priming within a permissive systemic milieu.

Pathophysiology

The pathophysiology of Nonalcoholic steatohepatitis (NASH) reflects a transition from benign steatosis to hepatocellular injury, inflammation, and fibrosis driven by lipotoxic stress. Excess hepatic lipid flux leads not only to triglyceride accumulation but to generation of toxic intermediates such as ceramides, diacylglycerols, and free cholesterol, which impair mitochondrial β-oxidation and promote reactive oxygen species (ROS) production. Mitochondrial dysfunction and endoplasmic reticulum stress activate stress kinases (JNK), NF-κB signaling, and the NLRP3 inflammasome, triggering hepatocyte ballooning and release of damage-associated molecular patterns (DAMPs). These signals recruit and activate Kupffer cells and infiltrating monocyte-derived macrophages, amplifying cytokine production (TNF-α, IL-1β, TGF-β). TGF-β and platelet-derived growth factor (PDGF) drive hepatic stellate cell activation into collagen-producing myofibroblasts, initiating fibrogenesis. Progressive extracellular matrix deposition distorts sinusoidal architecture, impairs perfusion, and establishes a feed-forward cycle of hypoxia, oxidative stress, and further inflammation. Thus, NASH represents a systems-level failure of metabolic regulation coupled to innate immune activation and maladaptive wound-healing responses that culminate in fibrosis and, in advanced stages, cirrhosis.

Clinical features

The clinical features of Nonalcoholic steatohepatitis (NASH) are often subtle and nonspecific, particularly in early stages. Many patients are asymptomatic and identified incidentally through elevated aminotransferases (ALT > AST in earlier disease) or imaging showing hepatic steatosis. When symptoms occur, they may include fatigue, vague right upper quadrant discomfort, or malaise. NASH is strongly associated with components of metabolic syndrome—central obesity, type 2 diabetes, hypertension, and dyslipidemia—so clinical context is critical. As fibrosis advances, signs of chronic liver disease may emerge, including hepatomegaly, splenomegaly, thrombocytopenia from portal hypertension, and eventually stigmata of cirrhosis (ascites, varices, encephalopathy). Importantly, cardiovascular disease remains the leading cause of mortality in this population, often preceding liver-related complications. Thus, the clinical phenotype reflects both hepatic injury and systemic cardiometabolic risk, underscoring the need for integrated metabolic assessment.

Diagnosis

Diagnosis of Nonalcoholic steatohepatitis (NASH) requires establishing steatosis with hepatocellular injury and excluding competing etiologies, particularly significant alcohol use and other chronic liver diseases. Initial evaluation typically reveals mild to moderate elevation in aminotransferases (often ALT-predominant), though normal enzymes do not exclude disease. Imaging modalities such as ultrasound, CT, or MRI can detect steatosis, while MRI–proton density fat fraction (MRI-PDFF) and elastography (e.g., transient elastography/FibroScan) help quantify fat burden and assess fibrosis. Noninvasive fibrosis scores (FIB-4, NAFLD fibrosis score, ELF test) stratify risk and guide referral. However, definitive diagnosis of NASH—demonstrating steatosis, lobular inflammation, hepatocyte ballooning, and staging of fibrosis—historically requires liver biopsy. Increasingly, biomarker panels, circulating cytokeratin-18 fragments, and transcriptomic or proteomic signatures are being developed to reduce biopsy dependence and enable dynamic monitoring, aligning diagnostic strategy with fibrosis stage and therapeutic decision-making.

Mechanism of action videos

Biological pathways

  • CaM pathway
  • Lanosterol biosynthesis
  • Cam-PDE 1 activation
  • Type II diabetes mellitus
  • TNF signaling pathway
  • Regulation of necroptotic cell death
  • Protein processing in endoplasmic reticulum
  • Plasma lipoprotein assembly, remodeling, and clearance
  • Nuclear Receptor transcription pathway
  • PPAR signaling pathway
  • PI3K-Akt signaling pathway
  • Oxidative phosphorylation
  • Non-alcoholic fatty liver disease
  • Interleukin-4 and Interleukin-13 signaling
  • Fatty acid biosynthesis
  • Apoptosis
  • Adipocytokine signaling pathway
  • G alpha (s) signalling events
  • GPCR downstream signalling
  • Signaling by GPCR
  • cGMP effects
  • Nitric oxide stimulates guanylate cyclase
  • Activation of gene expression by SREBF (SREBP)
  • Signal Transduction
  • Regulation of cholesterol biosynthesis by SREBP (SREBF)
  • ChREBP activates metabolic gene expression
  • Opioid Signalling
  • SUMOylation of intracellular receptors
  • Transcriptional regulation of brown and beige adipocyte differentiation
  • Platelet homeostasis
  • DARPP-32 events
  • Metabolism of steroids
  • Intracellular signaling by second messengers
  • Adipogenesis
  • Activation of the phototransduction cascade
  • Constitutive Signaling by Aberrant PI3K in Cancer
  • PPARA activates gene expression
  • MECP2 regulates transcription factors
  • Calmodulin induced events
  • Regulation of lipid metabolism by PPARalpha

Clinical trials

  • "Constitution of a Biological Collection to Establish Preclinical Translational Models for the Study of Tumors and Chronic Liver Diseases".
  • Evaluation of XTYW007 in Healthy Subjects and Healthy Subjects With Elevated LDL-C:A Randomized, Double-Blind, Single-Center Phase I/IIa Study of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Food Effect Following Single and Multiple Doses
  • A Phase 3 Study to Evaluate the Efficacy and Safety of Pegozafermin in Subjects With Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Fibrosis
  • A Phase 3 Study to Evaluate the Efficacy and Safety of Pegozafermin in Subjects With Compensated Cirrhosis Due to Metabolic Dysfunction-Associated Steatohepatitis (MASH) (ENLIGHTEN-Cirrhosis)
  • Human Models of Selective Insulin Resistance: Diazoxide, Part I
  • A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Efruxifermin in Subjects With Non-Cirrhotic Nonalcoholic Steatohepatitis (NASH)/Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Fibrosis
  • A Phase 1, Open-Label Study Evaluating the Effect of Miricorilant on Hepatic Lipids in Patients With Presumed Metabolic Dysfunction-Associated Steatohepatitis (MASH)
  • A Multicenter, Double-blind, Placebo Randomized , Phase2b Study to Evaluate the Efficacy and Safety of HSK31679 in Chinese Patients With Non-Alcoholic Steatohepatitis (NASH).
  • A Randomized, Double-blind, Placebo-controlled, Single Ascending Dose, First-in-human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NNC4005-0001 in Adults
  • Stimulating Adipose Tissue Fatty Acid Disposal With Low-dose, Postprandial, Intermittent Niacin for the Treatment of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD).
  • A Master Protocol for a Randomized, Controlled, Clinical Trial of Multiple Pharmacologic Agents in Adult Participants With Metabolic Dysfunction-Associated Steatotic Liver Disease Who Are at Increased Risk of Developing Major Adverse Liver Outcomes
  • A Phase III Double-blind, Randomised, Placebo-controlled Trial to Evaluate Liver-related Clinical Outcomes and Safety of Once Weekly Injected Survodutide in Participants With Compensated Non-alcoholic Steatohepatitis/Metabolic Dysfunction Associated Steatohepatitis (NASH/MASH) Cirrhosis
  • A Randomised, Double-blind, Placebo-controlled, Multicentre, Phase III Trial Evaluating Long-term Efficacy and Safety of Survodutide Weekly Injections in Adult Participants With Noncirrhotic Non-alcoholic Steatohepatitis/Metabolic Dysfunction-associated Steatohepatitis (NASH/MASH) and (F2) - (F3) Stage of Liver Fibrosis
  • Tocotrienol Against the Progression of End Stage Liver Disease
  • Integrated Diagnostics for Early Diagnosis of Liver Disease
  • A Longitudinal Observational Study of Patients With Nonalcoholic Steatohepatitis (NASH) and Related Conditions Across the Entire Spectrum of Nonalcoholic Fatty Liver Disease (NAFLD)
  • Human Models of Selective Insulin Resistance: Pancreatic Clamp
  • Ketotifen in Non-Alcoholic Fatty Liver Disease Patients
  • A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Explore the Efficacy and Safety of Elobixibat in Adults With Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH)
  • A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Efficacy of MN-001 in Patients Diagnosed With Non-alcoholic Fatty Liver Disease, Type 2 Diabetes Mellitus, and Hypertriglyceridemia
  • Pathogenesis of Chronic Kidney Disease Associated With Metabolic Dysfunction- Associated Fatty Liver Disease (MAFLD) and Treatment Response of Oral Semaglutide - a Randomized Controlled Trial.
  • Mechanisms for Glucagon Resistance as Driver of Metabolic Associated Steatotic Liver Disease and Cardiovascular Disease in Humans With Type 2 Diabetes
  • A Comparative Study of the Effect of Dapagliflozin Versus Empagliflozin ,Added to Metformin, on NAFLD in Patients With Type 2 Diabetes
  • A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of siRNA Gene Silencing for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH) in Participants With Genetic Risk Factors
  • Effect of the Pharmacological Cessation of Menstruation With a GnRH Analog on Hepatic Steatosis in Women With Endometriosis
  • Quantification of Amino Acid and Glucose Metabolism in Healthy Controls and Patients With Non-alcoholic Fatty Liver Disease Using Total- Body PET
  • Phase 2a Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Efinopegdutide (MK-6024) in Adults With Compensated Cirrhosis Secondary to Metabolic Dysfunction-Associated Steatohepatitis
  • A Randomized, Double-blinded, Placebo-controlled, Multi-center Study to Investigate the Effect of L. Lactis CKDB001 Administration on Liver Aminotransferases in Subjects With Nonalcoholic Fatty Liver Disease
  • Effects of Empagliflozin on Preventing Fibrosis and Cirrhosis Progression in Nucleos(t)Ide Analogue-treated Chronic Hepatitis B Patients With F2-F4 Fibrosis: a Randomized, Double-blind Placebo-controlled Trial
  • A Randomized, Double-blind, Placebo-controlled Phase II Clinical Study Evaluating the Efficacy and Safety of DR10624 Injection in Subjects at High Risk of Liver Fibrosis With Metabolic Dysfunction-associated Steatotic Liver Disease and Metabolic Dysfunction and Alcohol Associated Steatotic Liver Disease
  • Duodenal Recellularization Via Electroporation Therapy as an Early Treatment for Type 2 Diabetes Mellitus (DREAM-1 Study)
  • A Phase 1, Open-label, Single-dose Study to Evaluate the Pharmacokinetics and Safety of Efimosfermin Alfa in Adults With Varying Degrees of Hepatic Impairment Due to Steatotic Liver Disease
  • Investigating the Link Between Type 2 Immunity and NAFLD in Human Obesity- AIM 1
  • Pilot Study of Milk Thistle for the Treatment of Pediatric Non-Alcoholic Fatty Liver Disease (NAFLD)
  • Pilot Study of On-Cart Liver Fat Quantification (LFQ) Feature to Assess Correlation With Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) Results in a Pediatric Population
  • Effects of Menopausal Hormone Therapy on Liver Function and Non-Alcoholic Fatty Liver Disease: A Prospective Study
  • Prevalence and Predictors of Hepatic Steatosis in Persons Living With HIV
  • Pilot Study of On-Cart Liver Fat Quantification (LFQ) Feature to Assess Correlation With Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) Results
  • Investigation of the Efficacy of a Probiotic Mixture in Subjects With Moderate Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Mechanistic Trial
  • Role of Lisinopril in Preventing The Progression of Non-Alcoholic Fatty Liver Disease (NAFLD): Relief-NAFLD

Therapeutic area: Metabolic

Non-Alcoholic Steatohepatitis (K75.81)