Residency · Residency · Gastroenterology

Non-Alcoholic Fatty Liver Disease and NASH

Nomenclature Update

MASLD/MASH (2023)

In 2023, a multi-society Delphi consensus process led to a fundamental reclassification of fatty liver disease terminology. Non-alcoholic fatty liver disease has been renamed to metabolic dysfunction-associated steatotic liver disease (MASLD), and non-alcoholic steatohepatitis is now designated metabolic dysfunction-associated steatohepatitis (MASH). This nomenclature change was driven by the recognition that the prior terminology was both stigmatizing (the "non-alcoholic" label defined a disease by what it was not) and imprecise (it failed to capture the metabolic underpinnings central to the disease).

The updated diagnostic criteria require the presence of hepatic steatosis plus at least one of five cardiometabolic risk factors: a body mass index of 25 or greater (or 23 or greater in individuals of Asian descent) or meeting waist circumference criteria; fasting glucose of 100 mg/dL or greater or a diagnosis of type 2 diabetes mellitus; blood pressure of 130/85 mmHg or greater or treatment for hypertension; triglycerides of 150 mg/dL or greater or treatment for hypertriglyceridemia; or HDL cholesterol below 40 mg/dL in males or below 50 mg/dL in females, or treatment for low HDL.

A new category termed MetALD has been introduced to describe patients who have metabolic risk factors and significant alcohol use (140 to 350 grams per week in women and 210 to 420 grams per week in men), acknowledging the frequent coexistence of metabolic and alcohol-related liver injury. Cryptogenic steatotic liver disease is reserved for patients with hepatic steatosis who do not meet the metabolic criteria and have no other identified cause.

Epidemiology

MASLD is the most common chronic liver disease globally, with a prevalence of 25 to 30% worldwide and 30 to 40% in the United States. The prevalence of MASH is estimated at 3 to 6% of the general population and 20 to 30% among patients with MASLD. The disease is rising in parallel with the global epidemics of obesity, type 2 diabetes mellitus, and metabolic syndrome.

MASLD has become the leading cause of liver transplantation in women and the second overall indication across all transplant centers, surpassing hepatitis C in many regions. MASLD-related hepatocellular carcinoma represents the fastest growing indication for liver transplantation and has the distinctive feature of occurring in the absence of cirrhosis in 10 to 20% of cases, posing a significant challenge for screening and surveillance strategies.

Pathogenesis -- Multiple-Hit Model

Key Pathways

The pathogenesis of MASLD and its progression to MASH is best understood through the multiple-hit model, which has supplanted the earlier two-hit hypothesis. This model recognizes that multiple parallel insults act synergistically on genetically susceptible individuals to drive hepatic steatosis, inflammation, and fibrosis.

Insulin resistance is the central driver of MASLD pathogenesis. Hepatic insulin resistance promotes de novo lipogenesis through upregulation of transcription factors such as SREBP-1c and ChREBP, while simultaneously impairing mitochondrial fatty acid oxidation. In adipose tissue, insulin resistance increases lipolysis, resulting in an increased flux of free fatty acids to the liver via the portal circulation. The net result is an overwhelming of the hepatocyte's capacity for lipid handling, leading to intracellular triglyceride accumulation.

Lipotoxicity extends beyond simple triglyceride storage. The accumulation of toxic lipid species including free cholesterol, diacylglycerols, ceramides, and lysophosphatidylcholines activates endoplasmic reticulum stress pathways, induces mitochondrial dysfunction with generation of reactive oxygen species, and triggers inflammasome activation. These lipotoxic intermediates, rather than triglycerides themselves, are the primary mediators of hepatocyte injury and inflammation.

Gut microbiome dysbiosis contributes to MASLD progression through multiple mechanisms including increased intestinal permeability with endotoxemia (LPS translocation), altered bile acid metabolism, and reduced activation of the farnesoid X receptor signaling pathway. Adipose tissue dysfunction, particularly visceral adiposity, produces an imbalance of adipokines (increased leptin, decreased adiponectin) and releases pro-inflammatory cytokines including TNF-alpha and interleukin-6, which perpetuate hepatic inflammation.

Genetic susceptibility plays a substantial role in determining individual risk. The PNPLA3 rs738409 polymorphism encoding the I148M variant is the strongest identified genetic risk factor for MASLD and impairs lipid droplet remodeling in hepatocytes, leading to increased intracellular lipid retention. Additional risk loci include TM6SF2, MBOAT7, and MARC1. Notably, the HSD17B13 loss-of-function variant appears to be protective against disease progression. Epigenetic modifiers including age, dietary composition, and physical activity influence DNA methylation patterns and disease expression.

Fibrosis Progression

Hepatic fibrosis in MASLD is driven by activation of hepatic stellate cells through TGF-beta signaling, hedgehog pathway activation, and NLRP3 inflammasome engagement. The fibrosis stage is the single strongest predictor of liver-related outcomes and all-cause mortality in MASLD, surpassing steatosis grade and inflammation severity in prognostic importance. The annual rate of fibrosis progression in MASH is approximately 1 stage per 7 to 14 years, which is slower than in hepatitis C or alcoholic liver disease. Over 10 to 20 years, approximately 20 to 30% of patients with MASH progress to advanced fibrosis or cirrhosis.

Clinical Presentation

Usually Asymptomatic

The majority of patients with MASLD are asymptomatic, and the diagnosis is typically made incidentally through imaging performed for unrelated indications or through detection of elevated aminotransferases on routine laboratory testing. When symptoms are present, fatigue is the most common complaint, followed by vague right upper quadrant discomfort. A critically important clinical point is that alanine aminotransferase may be normal in 50 to 75% of patients with MASH, even in the setting of advanced fibrosis. Therefore, normal transaminases should never be used to exclude significant liver disease in patients with metabolic risk factors.

Associated Conditions

Type 2 diabetes mellitus and MASLD are intimately linked, with MASLD prevalence reaching 55 to 70% among patients with type 2 diabetes. Obesity with a BMI of 30 or greater is present in 75 to 90% of MASLD patients, though lean MASLD (BMI below 25) occurs in 10 to 20% and should not be overlooked. Dyslipidemia, hypertension, and the full metabolic syndrome are commonly present.

Cardiovascular disease is the leading cause of death in patients with MASLD, exceeding liver-related mortality. This critical epidemiologic observation mandates aggressive cardiovascular risk factor management as a central component of MASLD care. Associated conditions also include chronic kidney disease, obstructive sleep apnea, polycystic ovary syndrome, and hypothyroidism, all of which should be screened for in appropriate clinical contexts.

Diagnosis

Steatosis Detection

Abdominal ultrasound is the first-line screening tool for hepatic steatosis, with a sensitivity of 60 to 94% for moderate to severe steatosis. However, it is operator-dependent, limited in obesity, and insensitive for mild steatosis. The controlled attenuation parameter, measured during FibroScan examination, provides a quantitative assessment of steatosis, with values exceeding 248 dB/m suggesting significant steatosis and values above 300 dB/m indicating severe steatosis.

Magnetic resonance imaging proton density fat fraction is the gold standard for steatosis quantification, with a threshold of 5% or greater defining steatosis. MRI-PDFF is highly accurate and reproducible, making it the preferred modality for clinical trials, though its expense limits routine clinical use.

Fibrosis Assessment -- Non-Invasive Tests (NITs)

The FIB-4 index, calculated as age multiplied by AST divided by the product of platelet count and the square root of ALT, is the recommended first-line triage tool for fibrosis assessment. A FIB-4 below 1.3 indicates low risk with a negative predictive value of 90 to 95% for advanced fibrosis, and these patients may defer further evaluation. A FIB-4 between 1.3 and 2.67 represents an indeterminate result that warrants second-line testing with elastography. A FIB-4 exceeding 2.67 indicates high risk with advanced fibrosis likely, and hepatology referral should be considered. The NAFLD Fibrosis Score, incorporating age, BMI, diabetes status, AST/ALT ratio, platelet count, and albumin, provides similar diagnostic accuracy.

Vibration-controlled transient elastography (FibroScan) measures liver stiffness, with values below 8 kPa corresponding to F0-F1 fibrosis (low risk), values between 8 and 12 kPa suggesting F2-F3 fibrosis (indeterminate, consider further evaluation), and values exceeding 12 kPa indicating likely F3-F4 disease (advanced fibrosis or cirrhosis). Important limitations include the need for an XL probe in patients with BMI above 30, and the potential for overestimation due to hepatic congestion, active inflammation, cholestasis, or recent food intake.

Magnetic resonance elastography is the most accurate non-invasive tool for fibrosis assessment, with values above 3.63 kPa indicating advanced fibrosis and less susceptibility to confounding by obesity. The Enhanced Liver Fibrosis test is a serum biomarker panel measuring hyaluronic acid, procollagen III N-terminal peptide, and tissue inhibitor of metalloproteinase 1, with a score exceeding 9.8 indicating advanced fibrosis. It is FDA-approved and offers the convenience of a simple blood test.

Liver Biopsy

Liver biopsy remains the gold standard for diagnosing MASH and staging fibrosis. The NAFLD Activity Score combines steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocyte ballooning (0 to 2); a NAS of 5 or greater generally correlates with MASH, though the NAS was designed for clinical trial use and is not itself a diagnostic criterion for MASH. The pathologic diagnosis of MASH requires the constellation of steatosis, hepatocyte ballooning, and lobular inflammation as determined by the pathologist. The SAF score (Steatosis, Activity, Fibrosis) is increasingly employed as it clearly separates activity from fibrosis staging.

Indications for liver biopsy include the presence of competing etiologies, discordant non-invasive test results, clinical trial enrollment, and diagnostic uncertainty. The role of liver biopsy is decreasing as non-invasive tests improve and as therapeutic agents are approved based on non-invasive endpoints.

<image>A non-invasive diagnostic pathway for MASLD/MASH assessment. Start with "Suspected MASLD (metabolic risk factors + hepatic steatosis on imaging)." First tier: "Exclude other liver disease (viral hepatitis, autoimmune, alcohol > thresholds, hemochromatosis, Wilson)." Second tier: "Assess fibrosis risk with FIB-4." Three pathways based on FIB-4: (1) FIB-4 < 1.3: "Low risk — reassess in 2-3 years; lifestyle modification; manage metabolic comorbidities." (2) FIB-4 1.3-2.67: "Indeterminate — proceed to second-line NIT: FibroScan/VCTE or ELF test." If VCTE < 8 kPa or ELF < 9.8: "Low risk, reassess in 2-3 years." If VCTE 8-12 kPa: "Consider liver biopsy or MRE for clarification." If VCTE > 12 kPa or ELF > 9.8: "Likely advanced fibrosis — refer to hepatology." (3) FIB-4 > 2.67: "High risk — refer to hepatology; consider biopsy; HCC screening if cirrhosis." Include a side panel showing FibroScan thresholds with corresponding fibrosis stages (F0-F4) and color gradient from green to red. Add MRI-PDFF for steatosis quantification as an optional pathway. Note: "FIB-4 is the recommended first-line triage tool for primary care and endocrinology screening."</image>

Management

Lifestyle Modification (Foundation of Therapy)

Lifestyle modification remains the foundation of MASLD/MASH management across all disease stages. Weight loss of 3 to 5% of body weight reduces hepatic steatosis, while weight loss of 7 to 10% or greater is required to improve steatohepatitis and may lead to fibrosis improvement. Weight loss exceeding 10% provides the most robust evidence for fibrosis regression.

Caloric restriction of 500 to 1000 kcal per day below maintenance requirements is recommended. The Mediterranean diet, characterized by high intake of olive oil, fish, nuts, and vegetables, is the preferred dietary pattern based on evidence of hepatic and cardiovascular benefit. Patients should be counseled to reduce fructose-sweetened beverages and ultra-processed foods.

Exercise at 150 to 300 minutes per week of moderate-intensity aerobic activity independently reduces hepatic fat content even in the absence of significant weight loss. Resistance training provides additional benefit and should be incorporated into the exercise prescription. Patients should be advised to avoid alcohol, as even moderate consumption may be harmful in the context of MASLD, though the optimal threshold remains debated. Observational data suggest that consumption of 3 or more cups of coffee daily is associated with reduced fibrosis progression.

Pharmacotherapy

Resmetirom (Rezdiffra) -- FDA-Approved 2024

Resmetirom is a thyroid hormone receptor beta-selective agonist and the first medication to receive FDA approval specifically for the treatment of MASH. In the MAESTRO-NASH phase 3 trial, resmetirom at doses of 80 mg or 100 mg daily for 52 weeks achieved MASH resolution without fibrosis worsening in 26 to 30% of patients compared with 10% receiving placebo. Fibrosis improvement by at least 1 stage occurred in 24 to 26% of treated patients versus 14% with placebo. The drug is approved for use in MASH with F2 to F3 fibrosis in conjunction with lifestyle modification. Common side effects include diarrhea and nausea, and monitoring of liver function tests and thyroid function is recommended. Resmetirom should not be used in decompensated cirrhosis.

GLP-1 Receptor Agonists

Semaglutide at a dose of 2.4 mg subcutaneously weekly demonstrated impressive results in the STEP-NASH trial, achieving MASH resolution in 59% of patients compared with 17% receiving placebo at 72 weeks. Fibrosis improvement occurred in 34% versus 26%, though this difference did not meet statistical significance for the primary fibrosis endpoint. The hepatic benefits of GLP-1 receptor agonists are both weight loss-dependent and weight loss-independent, with direct effects on reducing de novo lipogenesis and improving insulin sensitivity. While not FDA-approved specifically for MASH, semaglutide is widely used off-label in MASLD patients with concurrent type 2 diabetes or obesity.

Tirzepatide, a dual GIP and GLP-1 receptor agonist, demonstrated positive results in the SYNERGY-NASH trial, with MASH resolution rates of 44 to 62% compared with 10% for placebo, and fibrosis improvement was also demonstrated. These dual agonists represent a particularly promising therapeutic direction.

Pioglitazone

Pioglitazone is a thiazolidinedione that acts as a PPAR-gamma agonist. At doses of 30 to 45 mg daily, it was shown in the PIVENS trial to improve histologic steatohepatitis in non-diabetic patients with MASH and has also demonstrated efficacy in diabetic MASH. However, its use is limited by a side effect profile that includes weight gain of 3 to 5 kg, fluid retention, increased bone fracture risk in women, and a debated association with bladder cancer. Pioglitazone remains a reasonable therapeutic option, particularly in patients with concurrent type 2 diabetes and MASH.

Vitamin E

Alpha-tocopherol at 800 IU daily improved steatohepatitis in the PIVENS trial in non-diabetic, non-cirrhotic patients with MASH, with a number needed to treat of 4.4. Concerns about its long-term safety include a potential increase in all-cause mortality at high doses suggested by a meta-analysis (though this finding remains debated) and a modest increase in prostate cancer risk demonstrated in the SELECT trial. Vitamin E is not recommended for patients with diabetes (due to insufficient data), cirrhosis, or for long-term use without careful consideration of risks and benefits.

SGLT2 Inhibitors

Empagliflozin, dapagliflozin, and canagliflozin have been shown to reduce hepatic fat content as measured by MRI-PDFF in patients with type 2 diabetes. Histologic data remain limited. The cardiovascular and renal benefits of SGLT2 inhibitors in patients with type 2 diabetes and MASLD support their use in this population, though they are not FDA-approved for MASH.

Bariatric/Metabolic Surgery

Bariatric surgery is the most effective intervention for MASLD and MASH in patients with obesity meeting surgical criteria (BMI of 35 or greater with comorbidities or BMI of 40 or greater). MASH resolution occurs in 80 to 90% of patients, and fibrosis improvement is observed in 50 to 70% at 5 years. In patients with compensated cirrhosis, sleeve gastrectomy is the preferred procedure, avoiding Roux-en-Y gastric bypass due to concerns about nutrient absorption and portal hypertensive anatomy. Bariatric surgery is a relative contraindication in decompensated cirrhosis, though some select centers perform simultaneous liver transplantation and bariatric surgery.

<image>A therapeutic landscape overview for MASLD/MASH displayed as a pyramid of interventions. Base of pyramid (widest, all patients): "Lifestyle modification: weight loss >= 7-10%, Mediterranean diet, exercise 150-300 min/week, minimize alcohol, manage metabolic comorbidities." Second tier: "Pharmacotherapy for MASH with fibrosis (F2+): Resmetirom 80-100 mg daily (FDA-approved for F2-F3 MASH); GLP-1 RAs (semaglutide 2.4 mg/week, off-label); Pioglitazone 30-45 mg (especially with T2DM); Vitamin E 800 IU (non-diabetic, non-cirrhotic)." Third tier: "Bariatric/metabolic surgery for BMI >= 35: MASH resolution 80-90%, fibrosis improvement 50-70%." Apex: "Liver transplantation for decompensated MASLD cirrhosis or HCC." On the right side, show target outcomes for each tier: steatosis reduction, MASH resolution, fibrosis improvement, and survival benefit. Include percentages for each therapy's MASH resolution rate. Color code from green (base/lifestyle) to yellow (pharmacotherapy) to orange (surgery) to red (transplant). Add emerging therapies in a sidebar: tirzepatide, FXR agonists (obeticholic acid — withdrawn), combination approaches.</image>

Cardiovascular Risk in MASLD

Cardiovascular disease is the number one cause of death in patients with MASLD, not liver disease. MASLD is an independent cardiovascular risk factor with an odds ratio of 1.5 to 2.0 for major adverse cardiovascular events. This underscores the critical importance of aggressive management of cardiovascular risk factors in all MASLD patients.

Statins are safe in MASLD, MASH, and compensated cirrhosis, and clinicians should not withhold statin therapy due to mild transaminase elevations attributable to MASLD. Indeed, statin therapy may itself improve hepatic histology. Antihypertensive therapy with angiotensin receptor blockers may confer antifibrotic benefit beyond blood pressure control. Diabetes management should prioritize agents with cardiovascular benefit, including GLP-1 receptor agonists and SGLT2 inhibitors.

HCC Screening in MASLD

Patients with MASLD-related cirrhosis should undergo standard hepatocellular carcinoma screening with ultrasound with or without alpha-fetoprotein every 6 months. A unique challenge in MASLD is that 10 to 20% of MASLD-related hepatocellular carcinoma arises in non-cirrhotic patients, for whom no established screening protocol exists. Emerging biomarkers and risk stratification tools are under development for this population. Consideration should be given to screening patients with advanced fibrosis (F3) given the imperfect staging accuracy of non-invasive tools and the known hepatocellular carcinoma risk in this group.

Key Clinical Pearls

• Fibrosis stage is the strongest predictor of liver-related mortality in MASLD, not steatosis grade or inflammation severity.
• FIB-4 is the recommended first-line non-invasive triage tool for identifying patients who need further fibrosis evaluation.
• Resmetirom (Rezdiffra) is the first FDA-approved drug for MASH (2024), indicated for F2-F3 fibrosis with MASH.
• Weight loss of 7 to 10% or greater is the most effective non-pharmacologic intervention; 10% or greater is needed for fibrosis regression.
• GLP-1 receptor agonists (semaglutide, tirzepatide) show the most promising efficacy for MASH resolution but are not yet specifically approved for this indication.
• Cardiovascular disease is the leading cause of death in MASLD. Statins should not be withheld, and metabolic comorbidities must be aggressively managed.
• Up to 20% of MASLD-related hepatocellular carcinoma occurs in non-cirrhotic patients, representing a major surveillance challenge.
• MASLD has been renamed from NAFLD to reflect its metabolic-associated etiology and to remove the stigmatizing "non-alcoholic" terminology.

References

1. Rinella ME, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966-1986.
2. Harrison SA, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: MAESTRO-NASH phase 3 trial. N Engl J Med. 2024;390(6):497-509.
3. Newsome PN, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis (STEP-NASH). N Engl J Med. 2021;384(12):1113-1124.
4. Kanwal F, et al. Clinical Care Pathway for the Risk Stratification and Management of Patients with Nonalcoholic Fatty Liver Disease. Gastroenterology. 2021;161(5):1657-1669.
5. Sanyal AJ, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis (PIVENS). N Engl J Med. 2010;362(18):1675-1685.

Read this lecture as Markdown