Increase, Steatohepatisis

Steatohepatitis is characterized by hepatic steatosis accompanied by hepatocellular injury and lobular inflammation. It represents a pathological progression beyond simple steatosis and is a defining feature of metabolic dysfunction–associated steatohepatitis (MASH).

Histologically, steatohepatitis includes:

• Macrovesicular steatosis

• Hepatocyte ballooning degeneration

• Lobular inflammatory cell infiltration

• Mallory–Denk bodies (in some cases)

• Variable degrees of perisinusoidal fibrosis

1. Histopathology (Primary Method)

• Hematoxylin and eosin (H&E) staining

• NAFLD Activity Score (NAS)

• Steatosis–Activity–Fibrosis (SAF) scoring system

• Assessment of:

  • Steatosis grade

  • Ballooning degeneration

  • Lobular inflammation

Histological scoring systems are considered the gold standard for detection.

2. Serum Biomarkers

• Elevated ALT (alanine aminotransferase)

• Elevated AST (aspartate aminotransferase)

• Inflammatory cytokines (TNF-α, IL-6)

Biochemical markers provide supportive but not definitive evidence.

3. Molecular Markers

• Increased expression of inflammatory genes (e.g., TNF-α, MCP-1)

• Markers of hepatocyte injury (e.g., cytokeratin-18 fragments)

4. Imaging (Clinical Context)

• MRI-PDFF (steatosis quantification)

• Elastography (for associated fibrosis)

However, histology remains required for definitive diagnosis of steatohepatitis.

Steatohepatitis is a well-defined pathological entity in humans and is reproducibly induced in rodent models of metabolic dysfunction and lipotoxic stress.

The KE is most applicable to:

• Mammalian species with comparable hepatic architecture

• Conditions involving chronic metabolic stress

• Adult or metabolically mature organisms

The weight of evidence for this KE is strong due to consistent clinical and experimental characterization.

Steatohepatitis represents a clinically recognized and pathologically defined stage of metabolic dysfunction–associated steatotic liver disease (MASLD), characterized by hepatic steatosis accompanied by hepatocellular injury and inflammation. It is a critical transition point between reversible metabolic steatosis and progressive, potentially irreversible liver pathology, including fibrosis, cirrhosis, and hepatocellular carcinoma. As such, an increase in steatohepatitis severity constitutes a biologically meaningful and adverse health outcome.

Human Health Relevance

Steatohepatitis (formerly NASH; now MASH under MASLD nomenclature) is associated with:

• Increased risk of liver fibrosis progression

• Elevated liver-related morbidity and mortality

• Increased risk of hepatocellular carcinoma

• Higher overall cardiometabolic mortality

Histologically confirmed steatohepatitis is a strong predictor of disease progression compared to simple steatosis. Therefore, regulatory concern is substantially higher once inflammatory and hepatocellular injury components are present.

Scientific Basis for Domain of Applicability

Taxonomic Applicability

The adverse outcome is highly relevant to mammals, particularly humans, due to conserved hepatic architecture, lipid metabolism, inflammatory signaling, and fibrogenic pathways. Rodent models (e.g., high-fat diet, Western diet, glucocorticoid exposure models) reliably reproduce key histopathological features of steatohepatitis, including:

• Steatosis with hepatocyte ballooning

• Lobular inflammation

• Early perisinusoidal fibrosis

This cross-species concordance supports high biological plausibility within Mammalia.

Life Stage Applicability

The adverse outcome is most relevant in adolescent and adult life stages, where metabolic systems are fully developed and chronic exposure conditions can lead to progressive disease. While pediatric MASLD exists, the majority of mechanistic and regulatory evidence derives from adult populations and adult rodent models.

Sex Applicability

Steatohepatitis occurs in both males and females. Sex differences in susceptibility and progression rate have been reported, likely reflecting hormonal influences on lipid metabolism and inflammation. However, the pathological entity and its progression mechanisms are conserved across sexes.

Weight of Evidence for Adversity

The weight of evidence supporting steatohepatitis as an adverse outcome is strong based on:

1. Clinical Evidence

   • Histologically confirmed steatohepatitis predicts fibrosis progression and mortality.

   • Longitudinal human studies demonstrate increased liver-related outcomes compared to simple steatosis.

2. Pathophysiological Evidence

   • Hepatocyte ballooning reflects cellular injury and cytoskeletal disruption.

   • Inflammatory infiltration drives sustained tissue damage and fibrogenesis.

   • Cytokine and TGF-β signaling link inflammation directly to fibrosis progression.

3. Consistency Across Models

   • Reproducible induction in multiple rodent models.

   • Mechanistic concordance between experimental systems and human disease.

4. Irreversibility Consideration

   • While early steatohepatitis may be partially reversible, sustained inflammation significantly increases the probability of irreversible fibrosis.

Regulatory Relevance

An increase in steatohepatitis severity represents:

• A clear adverse effect at the organ level

• A progression beyond adaptive metabolic perturbation

• A disease-defining pathological state recognized in clinical practice

From a regulatory perspective, this adverse outcome is relevant for:

• Hazard identification

• Chronic toxicity assessment

• Endocrine and metabolic disruptor evaluation

• Integration into adverse outcome pathways supporting chemical prioritization

Because steatohepatitis is a well-defined diagnostic and pathological entity with established clinical consequences, it provides a robust anchor for AOP-based risk assessment frameworks.