Please prepare a concise slide presentation on non‑alcoholic fatty liver disease (NAFLD) covering its definition, epidemiology, pathophysiology, risk factors, clinical presentation, diagnostic work‑up (laboratory tests, imaging, biopsy criteria), disease spectrum, risk stratification (FIB‑4, NAFLD Fibrosis Score, elastography), management (weight loss, Mediterranean‑type diet, exercise, GLP‑1 receptor agonists, vitamin E, pioglitazone, statins, emerging agents), and monitoring/surveillance (fibrosis reassessment, hepatocellular carcinoma screening).

Non-Alcoholic Fatty Liver Disease (NAFLD): Clinical Slide Presentation

Slide 1: Definition and Disease Spectrum

NAFLD is hepatic steatosis (≥5% fat accumulation) in the absence of significant alcohol consumption (<210 g/week in men, <140 g/week in women), steatogenic medications, or other secondary causes. 1

• NAFL (Simple Steatosis): Fat infiltration without hepatocyte ballooning or fibrosis—minimal progression risk 1
• NASH: Steatosis plus inflammation with hepatocyte ballooning ± fibrosis—can progress to cirrhosis, liver failure, and hepatocellular carcinoma 1
• NASH Cirrhosis: Cirrhosis with current or previous histological evidence of steatosis or steatohepatitis 1

Slide 2: Epidemiology

NAFLD affects approximately 25% of the global population, with the highest prevalence in the Middle East (31.79%) and South America (30.45%). 1

• United States prevalence: 30-40% have NAFL; 3-12% have NASH 1, 2
• Highest risk populations: Hispanic individuals have significantly higher prevalence; non-Hispanic blacks have lower prevalence compared to non-Hispanic whites 1
• Age and gender: Prevalence increases with age; male gender is a significant risk factor (31% in men vs 16% in women) 1
• Leading cause of death: Cardiovascular disease is the most common cause of mortality, followed by malignancy, then liver-related death 1, 2

Slide 3: Pathophysiology

NAFLD is a multisystem metabolic disease driven by insulin resistance, lipotoxicity, oxidative stress, and inflammatory pathways. 3, 4

• Metabolic dysfunction: Insulin resistance leads to hepatic fat accumulation and systemic metabolic derangements 1
• Lipotoxicity: Excess free fatty acids cause hepatocyte injury, oxidative DNA damage, and mitochondrial dysfunction 4
• Inflammatory cascade: Hepatocyte ballooning triggers lobular inflammation and activation of fibrogenic pathways 1
• Genetic susceptibility: PNPLA3, TM6SF2, GCKR, MBOAT7, and HSD17B13 polymorphisms increase disease risk and progression 4

Slide 4: Risk Factors and Comorbidities

Metabolic syndrome components are the primary drivers of NAFLD, with 66% of patients over 50 years with diabetes or obesity having NASH with advanced fibrosis. 2

Established associations: 1

• Obesity (especially visceral adiposity)
• Type 2 diabetes mellitus
• Dyslipidemia (low HDL, high triglycerides)
• Metabolic syndrome (≥3 criteria: waist circumference >102 cm men/>88 cm women, triglycerides ≥150 mg/dL, HDL <40 mg/dL men/<50 mg/dL women, blood pressure ≥130/85 mmHg, fasting glucose ≥100 mg/dL)

Emerging associations: 1

• Polycystic ovary syndrome
• Hypothyroidism
• Obstructive sleep apnea
• Hypopituitarism and hypogonadism

Slide 5: Clinical Presentation and Screening

Most NAFLD patients are asymptomatic; the disease is typically discovered incidentally through elevated liver enzymes or imaging findings. 1, 5

Who to screen: 5

• All patients with type 2 diabetes mellitus
• Patients with metabolic syndrome
• Overweight/obese patients (BMI >25 kg/m²)
• Incidental hepatic steatosis on imaging

Critical pitfall: Half of NAFLD patients have normal ALT levels—do not exclude NAFLD based on normal transaminases alone 5

Slide 6: Diagnostic Work-Up—Laboratory Tests

Initial comprehensive evaluation is essential to confirm NAFLD and exclude alternative diagnoses. 1

Required initial tests: 1, 5

• Comprehensive metabolic panel (AST, ALT, alkaline phosphatase, GGT, bilirubin, albumin)
• Complete blood count with platelets
• Fasting glucose or HbA1c
• Fasting lipid profile (total cholesterol, HDL, LDL, triglycerides)
• PT/INR

Extended evaluation to exclude other causes: 1

• Hepatitis B and C serology
• Ferritin and transferrin saturation (hemochromatosis)
• Autoimmune markers (ANA, ASMA, immunoglobulins)
• Alpha-1 antitrypsin level
• Thyroid function tests
• Celiac disease screening

Slide 7: Diagnostic Work-Up—Imaging

Ultrasound is the most economical and widely available first-line imaging modality for detecting steatosis, though it has limited sensitivity for mild steatosis (<33% fat). 5

• Ultrasound: Increased hepatic echogenicity indicates steatosis; cannot quantify fat or assess fibrosis 5
• CT: Can detect moderate-to-severe steatosis but involves radiation exposure 1
• MRI-PDFF (Proton Density Fat Fraction): Excellent for quantifying steatosis; primarily used in clinical trials 5
• Elastography for fibrosis assessment: Discussed in risk stratification section 5

Slide 8: Risk Stratification—Non-Invasive Fibrosis Assessment

Fibrosis stage is the strongest predictor of liver-related and all-cause mortality in NAFLD; non-invasive assessment is critical for risk stratification. 1, 6, 7

First-tier: FIB-4 Index (preferred initial test): 1, 5, 8

• Formula: Age (years) × AST (U/L) / [Platelet count (10⁹/L) × √ALT (U/L)]
• FIB-4 <1.3 (or <2.0 if age >65): Low risk—excludes advanced fibrosis with ≥90% NPV; repeat in 2-3 years 5, 8
• FIB-4 1.3-2.67: Indeterminate—requires second-tier testing 1, 5
• FIB-4 >2.67: High risk—refer to hepatology; 60-80% PPV for advanced fibrosis 1, 8

Alternative first-tier: NAFLD Fibrosis Score (NFS): 1

• Based on age, BMI, hyperglycemia, platelet count, albumin, AST/ALT ratio
• NFS <-1.455: Excludes advanced fibrosis (90% sensitivity, 60% specificity)
• NFS >0.676: Identifies advanced fibrosis (67% sensitivity, 97% specificity)

Slide 9: Risk Stratification—Second-Tier Testing

For patients with indeterminate FIB-4 (1.3-2.67), proceed to second-tier testing with elastography or serum biomarkers. 1, 5

Vibration-Controlled Transient Elastography (VCTE/FibroScan): 5

• <8 kPa: Rules out advanced fibrosis
• ≥12 kPa: Suggests advanced fibrosis—refer to hepatology

Enhanced Liver Fibrosis (ELF) Panel: 1, 5

• Measures hyaluronic acid, TIMP-1, and PIIINP
• ELF <9.8: Rules out advanced fibrosis (80% sensitivity, 90% specificity)
• ELF ≥9.8: Advanced fibrosis likely

Magnetic Resonance Elastography (MRE): 1, 5

• Most accurate non-invasive method (AUROC 0.92)
• More expensive; primarily used when other tests are discordant or in clinical trials

Slide 10: Liver Biopsy Indications

Liver biopsy remains the reference standard for diagnosing NASH and staging fibrosis, but is reserved for specific clinical scenarios due to invasiveness and sampling variability. 1, 6

Indications for liver biopsy: 1, 5

• Suspected NASH with advanced fibrosis (FIB-4 >2.67 or elastography ≥12 kPa)
• Indeterminate non-invasive test results with discordant findings
• Concurrent chronic liver disease cannot be excluded
• Treatment decisions require histologic confirmation (e.g., clinical trial enrollment)

Histopathological features of NASH: 1

• Macrovesicular steatosis (≥5% hepatocytes)
• Hepatocyte ballooning (cytoplasmic swelling)
• Lobular inflammation (mixed inflammatory infiltrate including neutrophils)
• Perisinusoidal/pericellular fibrosis (zone 3 pattern characteristic of NASH)

Slide 11: Disease Progression and Natural History

NASH with fibrosis progresses at variable rates, with fibrosis advancing approximately 1 stage every 7 years in NASH versus every 14 years in simple steatosis. 1

• Rapid progressors: 20% of NASH patients experience accelerated fibrosis progression 1
• Hypertension doubles progression rate: NASH patients with arterial hypertension have twice the rate of fibrosis progression 1
• NASH cirrhosis outcomes: 10-year survival is 81.5%, similar to hepatitis C cirrhosis; annual HCC incidence is 2-3% 1
• HCC in non-cirrhotic NAFLD: Up to 50% of NAFLD-related HCC occurs in the absence of cirrhosis, representing a major surveillance challenge 4, 2

Slide 12: Hepatocellular Carcinoma Surveillance

All patients with NASH cirrhosis require HCC surveillance with liver ultrasound ± AFP every 6 months, as NAFLD is projected to become the leading cause of HCC. 1, 4

• HCC risk in cirrhosis: 7-16% at 5 years, 29% at 10 years 9
• Non-cirrhotic HCC: NAFLD/NASH is a leading cause of HCC without cirrhosis—validated risk calculators for pre-cirrhotic patients are urgently needed 4
• Risk factors for HCC: Obesity, diabetes, Hispanic ethnicity, and genetic polymorphisms (PNPLA3, TM6SF2, GCKR, MBOAT7, HSD17B13) independently increase HCC risk 4

Slide 13: Management—Lifestyle Modifications (Foundation of Treatment)

Weight loss of 5-10% body weight through diet and exercise is the cornerstone of NAFLD treatment and can improve steatosis, inflammation, and fibrosis. 1, 8

Weight loss targets and outcomes: 1

• 5-7% weight loss: Improves steatosis and inflammation
• ≥10% weight loss: Required for fibrosis regression
• Mediterranean-type diet: Reduces hepatic steatosis independent of weight loss 1

Exercise recommendations: 1

• ≥150 minutes/week of moderate-intensity aerobic exercise (e.g., brisk walking)
• Resistance training 2-3 times per week
• Exercise improves insulin sensitivity and reduces hepatic fat even without weight loss

Alcohol consumption: 1

• Even moderate alcohol consumption (<210 g/week men, <140 g/week women) may accelerate fibrosis progression
• Complete abstinence is recommended for patients with advanced fibrosis or cirrhosis

Slide 14: Management—Pharmacotherapy for NASH

Vitamin E and pioglitazone have proven efficacy in select patients with biopsy-proven NASH; no medications are currently FDA-approved specifically for NASH. 1

Vitamin E (α-tocopherol): 1

• Dose: 800 IU daily
• Indication: Non-diabetic adults with biopsy-proven NASH without cirrhosis
• Efficacy: Improves steatosis, inflammation, and hepatocyte ballooning in <50% of patients
• Cautions: Potential increased risk of prostate cancer and hemorrhagic stroke at high doses; not recommended in diabetics or cirrhosis

Pioglitazone: 1, 3

• Dose: 30-45 mg daily
• Indication: Patients with biopsy-proven NASH (with or without diabetes)
• Efficacy: Improves steatosis, inflammation, and fibrosis; reduces cardiovascular risk
• Side effects: Weight gain (2-5 kg), fluid retention, bone loss, potential bladder cancer risk

GLP-1 Receptor Agonists (liraglutide, semaglutide): 8, 3

• Indication: Diabetic patients with NAFLD/NASH
• Efficacy: Proven benefit on liver histology (NASH resolution); reduces cardiovascular events
• Preferred over metformin for diabetic NAFLD patients

Slide 15: Management—Statins and Cardiovascular Risk

Statins are safe and effective in NAFLD patients and should be used for cardiovascular risk reduction; they do not treat NASH but are not contraindicated. 1, 3

• Cardiovascular disease is the leading cause of death in NAFLD—aggressive CVD risk factor management is essential 1, 3, 2
• Statins are well-tolerated in NAFLD and do not increase hepatotoxicity risk 1
• Metformin is not indicated for NASH treatment but is safe in diabetic NAFLD patients with other indications 1
• Antihypertensive therapy is well-tolerated and critical for reducing fibrosis progression 1, 3

Slide 16: Management—Emerging Therapies

Multiple novel agents targeting fibrosis, inflammation, and metabolic pathways are in late-stage clinical trials. 1

Promising therapeutic targets under investigation: 1

• Farnesoid X receptor (FXR) agonists (e.g., obeticholic acid): Target bile acid metabolism and fibrosis
• Thyroid hormone receptor-β agonists: Reduce hepatic lipid accumulation
• Acetyl-CoA carboxylase inhibitors: Block de novo lipogenesis
• Fibroblast growth factor 21 analogs: Improve insulin sensitivity and reduce steatosis
• Combination therapies: Targeting multiple pathways simultaneously

Current limitations: Effect size is modest (<50% response rate); long-term safety and cardiovascular outcomes remain unclear 1, 2

Slide 17: Management—Bariatric Surgery

Bariatric surgery is effective for weight loss and improving NASH histology in obese patients (BMI ≥35 kg/m² or ≥30 kg/m² with comorbidities) who fail lifestyle modification. 1

• Histological improvement: Reduces steatosis, inflammation, and fibrosis in the majority of patients 1
• Considerations: Perioperative risk is higher in cirrhotic patients; careful patient selection is essential 1
• Indications: Morbid obesity with NASH; metabolic comorbidities refractory to medical management 1

Slide 18: Monitoring and Surveillance

Monitoring frequency depends on disease severity; fibrosis reassessment guides prognosis and treatment decisions. 1, 5

NAFL without metabolic worsening: 1

• Repeat FIB-4 and metabolic panel every 2-3 years
• Only 12% show significant fibrosis progression over 3 years 5

NASH with fibrosis (F1-F2): 1

• Annual monitoring with FIB-4 or elastography
• Comprehensive metabolic assessment annually

NASH cirrhosis (F4): 1, 9

• Laboratory monitoring (CBC, CMP, PT/INR) every 6 months
• HCC surveillance (ultrasound ± AFP) every 6 months
• Upper endoscopy for variceal screening if not previously done (unless platelets >150,000/μL and liver stiffness <20 kPa)
• Consider liver transplant evaluation if MELD-Na ≥10 or decompensation occurs

Slide 19: Special Populations—Pediatric NAFLD

Pediatric NAFLD is of major concern due to potential for severe liver-related complications early in life; NASH-related cirrhosis has been reported as early as 8 years of age. 1

• Prevalence: Increasing in parallel with childhood obesity epidemic 1
• Genetic predisposition: Family history and PNPLA3 polymorphisms increase risk 1
• Screening: Target obese children (BMI ≥95th percentile) and those with metabolic risk factors 1
• Treatment: Lifestyle modification is the foundation; vitamin E and metformin have been studied but evidence is limited 1

Slide 20: Key Clinical Pitfalls to Avoid

Common errors in NAFLD management can lead to missed diagnoses and delayed treatment. 1, 5

• Do not exclude NAFLD based on normal ALT alone—50% of NAFLD patients have normal transaminases 5
• Do not assume AST:ALT >1 excludes NAFLD—this ratio reverses in advanced fibrosis/cirrhosis 5
• Do not rely on imaging alone to assess fibrosis—ultrasound cannot detect or stage fibrosis; use FIB-4 or elastography 5
• Do not withhold statins in NAFLD—they are safe and reduce cardiovascular mortality 1
• Do not delay hepatology referral for FIB-4 >2.67—these patients have high risk of advanced fibrosis and require specialist evaluation 8
• Do not forget HCC surveillance in cirrhosis—ultrasound every 6 months is mandatory regardless of etiology 9, 4