Non alcoholic steato hepatitis (NASH)

NON-ALCOHOLIC STEATOHEPATITIS (NASH): A COMPREHENSIVE REVIEW

(≈1500–1800 words)

  1. INTRODUCTION
    Non-alcoholic fatty liver disease (NAFLD) comprises a histologic spectrum ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and, ultimately, cirrhosis. NASH is defined histologically by macrovesicular steatosis with hepatocyte ballooning and lobular inflammation in individuals who consume little or no alcohol. Because NASH can progress to advanced fibrosis, cirrhosis and hepatocellular carcinoma (HCC), it is now the fastest-growing indication for liver transplantation in many countries and a major public-health concern (Harrison’s Principles of Internal Medicine, 21st ed. [HPIM-21] Ch. 365).

  2. EPIDEMIOLOGY AND BURDEN
    • Prevalence: Global NAFLD prevalence is ~25 %; about 20–25 % of these patients meet criteria for NASH, yielding a worldwide NASH prevalence of 3–5 % (HPIM-21 Ch. 365; Younossi et al. Hepatology 2016).
    • Risk factors: central obesity, type 2 diabetes mellitus (T2DM), dyslipidaemia, metabolic syndrome, polycystic ovary syndrome, obstructive sleep apnoea and certain genetic variants (e.g., PNPLA3 I148M, TM6SF2 E167K).
    • Natural-history modelling predicts a 178 % rise in NASH-related liver deaths between 2020 and 2030 if trends remain unchecked (Harrington et al. J Hepatol 2022).
    • Economic impact: In the United States alone, direct annual medical costs attributable to NASH are estimated at $18–26 billion.

  3. PATHOGENESIS: THE MULTIPLE-HIT MODEL
    The classic “two-hit” hypothesis (steatosis → oxidative injury) has evolved into a “multiple-parallel-hit” paradigm incorporating genetic and environmental influences (HPIM-21 Chs. 365, 418).
    a) Insulin resistance and adipose tissue dysfunction stimulate hepatic de-novo lipogenesis (DNL) and inhibit β-oxidation, causing triglyceride accumulation.
    b) Lipotoxic species (free fatty acids, diacylglycerols, ceramides) drive mitochondrial dysfunction, oxidative stress and endoplasmic-reticulum stress, provoking hepatocellular injury and apoptosis.
    c) Inflammatory signalling: activation of Kupffer cells and recruited macrophages releases TNF-α, IL-1β and reactive oxygen species.
    d) Gut–liver axis: dysbiosis, increased intestinal permeability and translocated pathogen-associated molecular patterns (PAMPs) amplify hepatic inflammation via Toll-like receptors.
    e) Genetic / epigenetic factors: PNPLA3 and TM6SF2 variants modulate triglyceride export and oxidation; methylation patterns and micro-RNAs influence fibrosis progression.
    f) Stellate-cell activation and fibrogenesis: damaged hepatocytes release hedgehog ligands, platelet-derived growth factor and TGF-β, stimulating collagen deposition and architectural distortion (HPIM-21 Ch. 365; Friedman Nat Rev Gastroenterol Hepatol 2018).

  4. NATURAL HISTORY AND PROGNOSIS
    • Fibrosis stage is the single most powerful predictor of liver-related and all-cause mortality. Up to 20 % of NASH patients progress to cirrhosis within 10–15 years; once cirrhosis develops, annual risks are ~3–5 % for decompensation and 1 % for HCC (HPIM-21 Ch. 368).
    • Extra-hepatic disease: Cardiovascular disease is the leading cause of death, followed by malignancy (colorectal, breast) and liver complications. Chronic kidney disease, hypothyroidism and sarcopenia are more prevalent in NASH (HPIM-21 Ch. 422).

  5. CLINICAL PRESENTATION
    Most patients are asymptomatic; hepatomegaly or mild right-upper-quadrant discomfort may be noted. Laboratory abnormalities are non-specific: aminotransferases can be normal or mildly elevated (usually AST/ALT < 1 until advanced fibrosis). Thrombocytopenia, hypoalbuminaemia or hyperbilirubinaemia suggest cirrhosis (HPIM-21 Chs. 361, 362).

  6. DIAGNOSTIC APPROACH
    Step 1 Exclude significant alcohol use (women ≤ 20 g/d, men ≤ 30 g/d), viral hepatitis, autoimmune, hereditary and drug-induced causes.
    Step 2 Assess steatosis.
    • Conventional ultrasound is first-line (sensitivity ~80 % when liver fat > 20 %).
    • Controlled Attenuation Parameter (CAP) on vibration-controlled transient elastography (VCTE; “FibroScan”) quantifies steatosis; MRI-proton density fat fraction (PDFF) is the non-invasive gold standard in trials.
    Step 3 Evaluate fibrosis risk.
    • Simple scores (FIB-4, NAFLD Fibrosis Score) use age, AST, ALT, platelets, BMI and/or albumin to categorise low, indeterminate or high risk.
    • Elastography (VCTE stiffness, ARFI, MRE) refines fibrosis staging; MRE has the highest accuracy (AUROC ≈ 0.93 for ≥F2).
    Step 4 Consider liver biopsy.
    Indications: (i) indeterminate non-invasive tests, (ii) clinical trial inclusion, (iii) suspected steatohepatitis with advanced fibrosis or competing diagnoses. Histology remains the reference standard to confirm NASH (NAS ≥ 5 with ballooning and inflammation) and grade fibrosis (HPIM-21 Ch. 365).

  7. MANAGEMENT

7.1 Lifestyle Intervention (cornerstone)
Goal: 7–10 % body-weight reduction arrests steatohepatitis in ~90 % and regresses fibrosis in up to 45 %.
• Diet. Hypo-caloric Mediterranean or DASH diets reduce hepatic fat independent of weight change; limit fructose-sweetened beverages and ultra-processed food.
• Exercise. ≥150 min/week moderate-vigorous aerobic activity plus resistance training; HIIT may decrease intrahepatic fat by 32 % in 12 weeks.
• Behavioural therapy and structured programmes enhance adherence (HPIM-21 Ch. 418).

7.2 Pharmacotherapy (evidence-based options)
a) Vitamin E (800 IU/d RRR) – improves steatohepatitis in non-diabetic adults without cirrhosis (PIVENS trial); concerns: prostate cancer signal and haemorrhagic stroke in some studies.
b) Pioglitazone (30–45 mg/d) – beneficial for biopsy-proven NASH with or without T2DM; side-effects: weight gain, oedema, fracture risk.
c) GLP-1 receptor agonists (liraglutide, semaglutide). LEAN trial showed NASH resolution in 39 % vs 9 % (liraglutide). Semaglutide 0.4 mg daily led to 59 % NASH resolution with no fibrosis worsening (NEJM 2021).
d) SGLT-2 inhibitors (empagliflozin, dapagliflozin) improve steatosis and ALT; long-term histologic data pending.
e) Obeticholic acid (FXR agonist). In the REGENERATE interim analysis, 25 mg daily improved fibrosis by ≥1 stage in 23 % vs 12 % placebo but caused pruritus and LDL-C rise; regulatory review ongoing.
f) Emerging agents: resmetirom (THR-β agonist), lanifibranor (pan-PPAR agonist), aramchol (SCD-1 inhibitor), FGF-19/FGF-21 analogues, polyvalent incretin agonists; several have shown significant histologic endpoints in phase II/III trials.

7.3 Bariatric and Endoscopic Metabolic Therapies
• Bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy) resolves steatohepatitis in 80–90 % and regresses fibrosis in 50–70 % after 5 years; best evidence in BMI ≥ 35 kg/m².
• Endoscopic sleeve gastroplasty and intragastric balloon are options for moderate obesity when surgery is unacceptable.

7.4 Management of Cirrhosis and Complications
• Standard care: non-selective β-blockers for variceal bleeding prophylaxis, HCC surveillance q6 months, vaccination (HBV, HAV, pneumococcus), management of ascites/encephalopathy (HPIM-21 Ch. 368).
• Liver transplantation: indications mirror other aetiologies (MELD > 15, decompensation, HCC within criteria). Post-transplant, NASH recurs in 25–35 % and metabolic comorbidities require aggressive control.

  1. PREVENTION AND PUBLIC-HEALTH IMPLICATIONS
    Population strategies targeting obesity, dietary fructose, and promotion of physical activity are essential. Policies include taxation of sugar-sweetened beverages, urban design for active transport, and early childhood nutrition programmes. Primary-care screening of high-risk groups (T2DM, severe obesity) with FIB-4 followed by elastography is cost-effective for detecting advanced fibrosis (Chalasani et al. AASLD Practice Guidance 2023).

  2. FUTURE DIRECTIONS
    • Non-invasive biomarkers: composite panels (NIS4, ELF, Pro-C3) and multi-omics signatures aim to replace liver biopsy for regulatory endpoints.
    • Combination regimens (e.g., GLP-1 RA + FXR agonist) may exploit complementary mechanisms.
    • Gene editing and microbiome modulation (oral engineered Bacteroides, faecal transplant) are in early-phase trials.
    • Digital therapeutics, artificial-intelligence–enhanced imaging and remote monitoring could personalise lifestyle interventions.

  3. CONCLUSION
    NASH represents the hepatic nexus of the global metabolic syndrome epidemic. Accurate risk stratification hinges on non-invasive fibrosis assessment, while lifestyle intervention remains first-line therapy. Pharmacologic options are expanding rapidly; several agents have met histologic endpoints and may receive regulatory approval soon. A multipronged approach—clinical, pharmacologic and public-health—will be required to curb the projected surge in NASH-related morbidity and mortality.

SELECTED REFERENCES FOR FURTHER READING IN HARRISON’S PRINCIPLES OF INTERNAL MEDICINE, 21st EDITION
• Chapter 365 Non-Alcoholic Fatty Liver Disease and Steatohepatitis
• Chapter 361 Approach to the Patient with Liver Disease
• Chapter 362 Evaluation of Abnormal Liver Chemistry Tests
• Chapter 368 Cirrhosis and Its Complications
• Chapter 418 Obesity, Metabolic Syndrome, and Insulin Resistance
• Chapter 422 Type 2 Diabetes Mellitus