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Metabolic DysfunctionAssociated Steatotic Liver Disease and Steatohepatitis¶

Chapter 354 | Part 10: Disorders of the Gastrointestinal System · Part 10 – Gastrointestinal Disorders · Chapter 354

Key Clinical Points¶

MASLD/MASH replaces NAFLD/NASH; diagnosis requires hepatic steatosis, metabolic dysfunction (e.g., obesity, T2DM), and low alcohol intake (<20 g/d for women, <30 g/d for men).
MetALD is a specific category for patients with both metabolic dysfunction and hazardous alcohol consumption (≥50 g/d for women, ≥60 g/d for men).
FIB-4 ≥ 2.67 or persistent elevated AST/ALT indicates high risk for advanced fibrosis and requires specialist referral.
T2DM is the strongest risk factor for MASL acquisition, fibrosis progression, and hepatocellular carcinoma (HCC).
VCTE ≥ 12 kPa or ELF >9.8 are indicators of advanced fibrosis or suspected cirrhosis.
Lean MASLD (BMI <25) is common in Asian populations and involves visceral adiposity and insulin resistance despite lower BMI.
Fibrosis progresses significantly faster in MASH (one stage every 7 years) compared to simple steatosis (one stage every 14 years).
Genetic factors like PNPLA3 I148M increase the heritability of MASLD; HSD17B13 loss-of-function variants are protective against MASH and fibrosis.
Steatohepatitis (MASH) is defined by lipotoxicity, resulting in inflammatory cell accumulation and injured/dying hepatocytes.
Management focuses on weight loss, metabolic control, and cardiovascular risk reduction.

DEFINITION & OVERVIEW¶

• Steatotic Liver Disease (SLD): Umbrella term for liver disease characterized by fat accumulation. • MASLD: Metabolic dysfunction-associated steatotic liver disease; replaces NAFLD.

Definition (Harrison's 22e): People who fulfill the new diagnostic criteria for MASLD/MASH have hepatic steatosis, drink little alcohol (<20 g/d for women and <30 g/d for men) and have one or more cardiometabolic risk factors (e.g., overweight/obesity, hypertension, dyslipidemia, insulin resistance/type 2 diabetes).

• MASH: Metabolic dysfunction-associated steatohepatitis; represents the inflammatory and lipotoxic stage of MASLD.

• MetALD: A specific subcategory for patients with metabolic dysfunction AND hazardous alcohol consumption.

Definition (Harrison's 22e): Hazardous alcohol consumption (≥50 g/d for women; ≥60 g/d for men) is defined as ALD irrespective of the presence of hepatic steatosis and/or metabolic syndrome.

Disease Spectrum & Pathology¶

• Steatosis: Accumulation of triglycerides in hepatocytes; considered a clinically benign extreme but serves as a biomarker of metabolic dysfunction. • Lipotoxicity: Result of dysregulated processing of fatty acids leading to accumulation of toxic intermediates and/or by-products. • MASH: Distinguished from steatosis by lipotoxicity → leads to inflammatory cell accumulation and injured/dying hepatocytes. • Fibrosis: A biomarker for defective liver regeneration; progression from F0 (no fibrosis) to F4 (severe fibrosis/cirrhosis). • Cirrhosis: Final stage of fibrosis; can regress but increases risk of hepatic decompensation and HCC.

EPIDEMIOLOGY¶

• Prevalence: SLD is the most common cause of chronic liver disease worldwide. • Growth: Prevalence of MASH is increasing with an aging population; 14% of asymptomatic patients ≥50 years old undergoing colon cancer screening had MASH. • Fibrosis Trends: Cases of clinically significant hepatic fibrosis (fibrosis ≥ stage 2 [F2]) have more than doubled in the past two decades.

• Lean MASLD: ◦ Occurs in individuals with BMI <25 kg/m² (or <23 kg/m²). ◦ Common in Asian ethnicity; involves visceral adiposity and insulin resistance despite lower BMI. Prevalence varies geographically (e.g., 4% in US to 19% in Asia).

ETIOLOGY & PATHOPHYSIOLOGY¶

• Energy Imbalance: Excessive intake + reduced expenditure → visceral adiposity and insulin resistance. • Lipid Dynamics: ◦ DNL (De novo lipogenesis) driven by dietary sugars (e.g., fructose) and saturated fats. ◦ Lipolysis of fatty acids from adipose depots due to insulin resistance. • Genetic Factors: ◦ PNPLA3 I148M: Impairs lipolysis of triglyceride lipid droplets → increases heritability of MASLD and fibrosis. ◦ TM6SF2 & MBOAT7: Influence cholesterol and phospholipid metabolism. ◦ HSD17B13: Loss-of-function variants are protective against MASH, progressive fibrosis, and liver cancer. • Gut Microbiota: Alterations in obesity enhance energy harvest and increase intestinal permeability → increased exposure to gut-derived products → inflammatory mediators.

Disease Modifiers & Risk Factors¶

• Alcohol: Thresholds for "little alcohol" are <20 g/d (women) and <30 g/d (men). • T2DM: Strongest risk factor for MASLD acquisition, fibrosis progression, and HCC. Prevalence in T2DM patients is 30–75%. • Hypertension & Dyslipidemia: Associated with MASH; lipid subfractions in MASLD are more atherogenic. • Endocrine Disorders: Higher rates in hypothyroidism, hypogonadism, GH deficiency, and PCOS.

CLINICAL FEATURES¶

• Presentation: Most patients are asymptomatic; diagnosis often made via abnormal aminotransferases or during workup for other reasons. • Physical Signs: 50–90% of subjects have obesity; some show signs of chronic liver disease (spider angiomata, palmer erythema, splenomegaly). • Associated Conditions: Chronic fatigue, mood alterations, OSA, thyroid dysfunction, and PCOS.

Clinical Presentation & Signs¶

• Asymptomatic Nature: Liver may not be enlarged; other liver tests (ALP, bilirubin, albumin) may be normal. • Diagnostic Confidence: Based on identification of metabolic risk factors (BMI, T2DM, hypertension, dyslipidemia) in the context of hepatic steatosis.

DIFFERENTIAL DIAGNOSIS¶

• General Rule: Must exclude viral hepatitis, autoimmune liver disease, iron/copper overload, and α-antitrypsin deficiency. • Aminotransferase Levels: True normal ALT is 29–33 U/L (men) and 19–25 U/L (women).

• Table 354-1: Alternative Causes of Hepatic Steatosis ◦ Includes: Alcohol-related liver disease, Hepatitis C (particularly genotype 3), Inborn errors of metabolism (e.g., Galactosemia, Glycogen storage disease, Homocystinuria, Tyrosinemia), Wilson’s disease, Wolman’s disease, and various surgical/procedural causes (e.g., Bilopancreatic diversion, Gastric bypass).

• Table 354-2: Medications Associated with Hepatic Steatosis and Steatohepatitis ◦ Macrovesicular: 5-Fluorouracil, Amiodarone (causes fibrosis/steatohepatitis), Fluoxetine, Irinotecan, Tamoxifen. ◦ Microvesicular: Cocaine (via n-oxidation), L-Asparaginase, NRTIs (zidovudine, didanosine).

Medication-Associated Steatosis¶

• Amiodarone: Decreases β-oxidation; increases lipid peroxidation and ROS. • Cocaine: Inhibits β-oxidation via n-oxidation of products. • NRTIs: Cause mitochondrial dysfunction by mtDNA depletion.

DIAGNOSTIC APPROACH¶

Initial Screening (Primary Care): \bullet FIB-4 Assessment: → If FIB-4 < 1.3 → Low risk → Reassess in 2–3 years (or 1–2 years if pre-DM or T2DM).
Advanced Fibrosis Screening: \bullet Risk Identification: → If FIB-4 ≥ 2.67 OR persistent elevated AST and ALT → Refer to Gastroenterology/Hepatology for advanced assessment.
Specialist Assessment (Gastroenterology): \bullet Advanced Noninvasive Tests (NITs): → VCTE: <8.0 (Low), 8–12 (Intermediate), >12 (High). → ELF: <7.7 (Low), 7.7–9.8 (Intermediate), >9.8 (High/Suspect Cirrhosis).
Biopsy Decision: \bullet Criteria for Biopsy: → If "Indeterminate NITs" OR "Diagnostic uncertainty" OR "Chronic hepatitis" → Consider liver biopsy.

Flowchart 354-2 (Decision Logic): • Primary Care Pathway: → Start → FIB-4 <1.3 → Reassess in 1–2 or 2–3 years based on metabolic profile. → Start → FIB-4 ≥ 1.3 → FIB-4 <2.67 AND normal AST/ALT → Referred to Gastroenterology as "Low risk" → PCP follow-up. • Specialist Pathway: → Start → FIB-4 ≥ 1.3 → FIB-4 ≥ 2.67 OR persistent AST/ALT → Gastroenterology assessment → "Intermediate" or "High risk" based on VCTE/ELF → Liver biopsy (if indicated) → Stage 2–3 or Stage 4 management. • Cirrhosis Pathway: → Start → FIB-4 ≥ 1.3 → Referral to Gastroenterology → ELF >9.8 → "Suspect cirrhosis" (clinical, radiologic, and ELF).

Key Thresholds for Decision Making¶

• FIB-4: <1.3 (Low risk); ≥ 2.67 (Advanced fibrosis indicator). • VCTE: >12 kPa (High risk/Advanced fibrosis). • ELF: >9.8 (High risk/Suspect cirrhosis).

MANAGEMENT & TREATMENT¶

General Management (All Patients): \bullet Cardiovascular risk reduction. \bullet Treatment of metabolic dysfunction. \bullet Reduction of alcohol intake. \bullet Lifestyle modification. \bullet Weight loss (if appropriate/dose).
Specialist Management: \bullet Stage 2–3 → Consider pharmacotherapy. \bullet Stage 4 → Cirrhosis-based management. \bullet Follow-up: Reassess in 1–3 years for Stage 0–2.

Monitoring¶

• Follow-up Frequency: → Pre-DM or T2DM → reassess every 1–2 years. → Other metabolic risk factors → reassess every 2–3 years.

COMPLICATIONS & PROGNOSIS¶

• Fibrosis Progression Rates: → Steatosis: average one stage every 14 years. → MASH: average one stage every 7 years. • Cirrhosis Consequences: → Increased risk of hepatic decompensation, HCC, and liver-related morbidity/mortality. • Premalignancy: → MASLD may be a premalignant condition for both primary liver cancers and extrahepatic malignancies, even in noncirrhotic livers.

SPECIAL POPULATIONS¶

• Pediatric MASLD: → Linked to weight gain and insulin resistance. → Driven by rising incidence of childhood obesity. • Endocrine & Metabolic Comorbidities: → Higher rates in hypothyroidism, hypogonadism, growth hormone (GH) deficiency, and polycystic ovarian syndrome (PCOS).

Reproductive Factors¶

• Postmenopausal Women: Higher prevalence of MASLD compared to premenopausal women. → Potential role of higher free testosterone levels and/or lower estradiol level.

KEY PEARLS & HIGH-YIELD POINTS¶

• Terminology: MASLD/MASH are the current standard; MetALD identifies those with both metabolic issues and high alcohol intake. • Risk Factors: T2DM is the strongest predictor for progression to fibrosis and HCC. • Diagnostic Tools: FIB-4 is the primary screening tool; VCTE and ELF provide advanced risk stratification in specialist settings. • Progression: MASH progresses to fibrosis twice as fast as simple steatosis. • Clinical Rule: Normal liver enzymes do not exclude MASLD/MASH.

Reference Tables¶

Harrison's 22e, p.2703

• Alcohol-related liver disease
• Hepatitis C (particularly genotype 3)
• Inborn errors of metabolism
• Abetalipoproteinemia
• Cholesterol ester storage disease
• Galactosemia
• Glycogen storage disease
• Hereditary fructose intolerance
• Homocystinuria
• Systemic carnitine deficiency
• Tyrosinemia
• Weber-Christian syndrome
• Wilson’s disease
• Wolman’s disease
• Medications (see Table 354-2)
• Miscellaneous
• Industrial exposure to petrochemical
• Inflammatory bowel disease
• Lipodystrophy
• Bacterial overgrowth
• Starvation
• Parenteral nutrition
• Surgical procedures
• Bilopancreatic diversion
• Extensive small-bowel resection
• Gastric bypass
• Jejunoileal bypass
• Reye’s syndrome
• Acute fatty liver of pregnancy
• HELLP syndrome (hemolytic anemia, elevated liver enzymes, low platelet
count)

TABLE 354-2 Medications Associated with Hepatic Steatosis and Steatohepatitis 5-Fluorouracil Androgens Amiodarone…¶