17:I[462708,["/_next/static/chunks/3yo3kiro3bmlp.js","/_next/static/chunks/3vr2wvd8f2efb.js","/_next/static/chunks/2vtmb68_vu-9t.js","/_next/static/chunks/2s8mt6_8wrpfo.js","/_next/static/chunks/3vkulz2i3l61y.js","/_next/static/chunks/1cqw2i1silz0i.js","/_next/static/chunks/14dbm3lm_t629.js","/_next/static/chunks/335_v2mb569ld.js","/_next/static/chunks/3ykn5ops9bft5.js","/_next/static/chunks/3cmavum774kjt.js","/_next/static/chunks/3th-0-a2xf9qs.js","/_next/static/chunks/0p0xpwde6kzmv.js","/_next/static/chunks/401-sxxnzbtf_.js","/_next/static/chunks/0wywtv698a1v0.js","/_next/static/chunks/2botzqwpnrzyj.js"],"ArticleReader"] 18:T6d39,## Summary Metabolic dysfunction-associated steatotic liver disease (MASLD) is hepatic steatosis in a person with at least one defined cardiometabolic risk factor and without a more appropriate dominant steatotic-liver-disease category. Metabolic dysfunction-associated steatohepatitis (MASH) is the inflammatory phenotype characterized histologically by steatosis, lobular inflammation, and hepatocyte ballooning, with or without fibrosis. Fibrosis stage, rather than aminotransferase concentration or steatosis alone, is the strongest routinely available marker of liver-related risk.[1-3] Most patients have no liver-specific symptoms, and a normal ALT does not exclude advanced fibrosis. Patients with type 2 diabetes, obesity with additional metabolic risk, persistent liver-test abnormalities, or imaging-detected steatosis should undergo structured fibrosis assessment. A practical pathway begins with **FIB-4** in a clinically stable patient. In many adults, **FIB-4 <1.3** is low risk, **FIB-4 ≥1.3** triggers second-line fibrosis testing, and **FIB-4 >2.67** raises substantial concern for advanced fibrosis. For adults older than 65 years, a higher lower-risk threshold around **2.0** is used because age inflates FIB-4. FIB-4 is less accurate below age 35 and during acute illness.[2,3] Second-line testing usually uses vibration-controlled transient elastography (VCTE), an enhanced liver fibrosis blood test, or another validated elastography strategy. Discordant results, high clinical suspicion, or treatment-selection uncertainty warrant hepatology review. Liver biopsy is not required for every patient and is reserved for unresolved diagnostic uncertainty, competing disease, or situations in which histology will materially change care.[2,3] Treatment has three simultaneous targets: **cardiometabolic risk, liver fibrosis, and complications of advanced liver disease**. Sustained weight loss, physical activity, dietary quality, diabetes treatment, lipid management, blood-pressure control, smoking cessation, and minimizing alcohol exposure remain foundational. European guidance uses practical weight-loss targets of at least **5%** to reduce steatosis, **7–10%** to improve inflammatory liver injury, and approximately **10% or more** for the greatest likelihood of fibrosis improvement.[3] In the United States, two liver-directed pharmacologic options are now approved under accelerated pathways for selected adults with **noncirrhotic MASH and F2–F3 fibrosis**. **Resmetirom** is given orally once daily; the labeled dose is **80 mg daily for body weight <100 kg and 100 mg daily for body weight ≥100 kg**. **Semaglutide 2.4 mg subcutaneously once weekly** is also approved for noncirrhotic MASH with F2–F3 fibrosis. These indications do not extend to uncomplicated steatosis or established cirrhosis, and confirmatory clinical-outcome studies remain ongoing.[4-8] Patients with cirrhosis should move into a cirrhosis pathway for portal-hypertension assessment, hepatocellular carcinoma surveillance, decompensation prevention, and transplant evaluation when appropriate. Do not continue to manage advanced disease as if it were merely “fatty liver.”[2,3] > **Clinical pearl:** The key bedside question in MASLD is not “How much fat is present?” but “Is clinically important fibrosis present, and is it progressing?” --- ## Nomenclature and classification The 2023 multisociety nomenclature places **steatotic liver disease (SLD)** as the umbrella category. Major categories include MASLD, metabolic dysfunction with higher alcohol exposure (MetALD), alcohol-related liver disease, drug-induced SLD, specific-cause SLD, and cryptogenic SLD.[1] ### MASLD MASLD requires hepatic steatosis plus at least one cardiometabolic criterion. Adult criteria include dysglycemia, elevated blood pressure or treatment, hypertriglyceridemia or treatment, low HDL cholesterol or treatment, or excess adiposity defined by BMI or waist circumference using ethnicity-appropriate thresholds.[1] The diagnosis is positive rather than purely exclusionary, but clinicians must still identify competing or coexisting liver diseases because MASLD commonly coexists with viral hepatitis, alcohol-related injury, drug-induced injury, autoimmune disease, and hereditary conditions. ### MASH MASH is a histologic diagnosis within MASLD. The defining features are: - macrovesicular steatosis; - lobular inflammation; - hepatocyte ballooning; - fibrosis may be absent or present. Fibrosis is staged from F0 to F4; F4 represents cirrhosis. Clinical trials and current US liver-directed drug indications focus on noncirrhotic F2–F3 disease because this group has meaningful progression risk while retaining potential for fibrosis regression.[3-8] ### MetALD MetALD describes metabolic dysfunction plus alcohol exposure above the MASLD range but below the level used to categorize primarily alcohol-related liver disease. The 2023 consensus uses approximate weekly alcohol ranges of **140–350 g in women** and **210–420 g in men** for MetALD.[1] Record alcohol quantitatively in grams per week and document binge patterns. Terms such as “social drinking” are not sufficiently precise for liver-risk classification. ## Epidemiology and risk MASLD is closely associated with: - type 2 diabetes; - overweight and obesity; - dyslipidemia; - hypertension; - obstructive sleep apnea; - chronic kidney disease; - insulin resistance and metabolic syndrome. The main causes of adverse outcomes differ by stage. Cardiovascular disease is a dominant cause of morbidity and death across MASLD, whereas liver-related events rise markedly as fibrosis advances. Patients with F3 fibrosis and cirrhosis require particular attention because the risk of portal-hypertensive complications and hepatocellular carcinoma increases.[2,3] Features associated with higher probability of advanced fibrosis include: - type 2 diabetes, especially long-standing or poorly controlled disease; - severe or long-duration obesity; - multiple cardiometabolic risk factors; - thrombocytopenia; - persistently abnormal aminotransferases; - older age; - splenomegaly or other signs of portal hypertension; - imaging features of chronic liver disease; - family history of advanced liver disease. ## Pathophysiology MASLD arises from interacting metabolic, genetic, inflammatory, and environmental pathways. ### Metabolic substrate overload Insulin resistance increases adipose lipolysis and delivery of free fatty acids to the liver. Hyperinsulinemia and excess carbohydrate intake increase hepatic de novo lipogenesis. When fatty-acid delivery and synthesis exceed oxidation and export, hepatocytes accumulate lipid. Triglyceride storage alone does not account for progressive liver injury. Lipotoxic species, mitochondrial dysfunction, oxidative stress, endoplasmic-reticulum stress, altered autophagy, and inflammatory signaling contribute to hepatocyte injury and death.[2] ### Inflammation and fibrosis Injured hepatocytes activate resident macrophages and recruit inflammatory cells. Cytokines and cell-to-cell signaling activate hepatic stellate cells, leading to extracellular-matrix deposition. Repeated injury can progress from pericellular fibrosis to bridging fibrosis and cirrhosis. ### Genetic susceptibility Variants including **PNPLA3**, **TM6SF2**, and **MBOAT7** alter susceptibility to steatosis and fibrosis. Routine genetic testing is not required for most patients, but genetic variation helps explain severe disease in some patients without extreme obesity or severe metabolic disturbance.[2,3] ## Clinical presentation Most patients are identified through: - steatosis on ultrasound, CT, or MRI; - elevated ALT or AST; - evaluation of diabetes or obesity; - incidental hepatomegaly; - fibrosis case-finding in a high-risk metabolic population. Symptoms such as fatigue or vague right-upper-quadrant discomfort are nonspecific and do not reliably indicate fibrosis stage. Features suggesting advanced chronic liver disease include: - platelet decline; - splenomegaly; - nodular liver morphology; - varices or abdominal collaterals; - ascites; - hepatic encephalopathy; - jaundice; - sarcopenia. Cross-link: [Cirrhosis and Portal Hypertension](../gastroenterology/cirrhosis-and-portal-hypertension.md). ## Initial assessment ### History Document: - weight trajectory and central adiposity; - diabetes, prediabetes, hypertension, and dyslipidemia; - cardiovascular and kidney disease; - obstructive sleep apnea; - alcohol amount, frequency, binge pattern, and duration; - medications and supplements associated with steatosis or hepatotoxicity; - viral-hepatitis risk and prior testing; - family history of cirrhosis or liver cancer; - prior liver tests and imaging; - pregnancy status and pregnancy plans when medication therapy is considered. ### Baseline tests Common baseline studies include: - ALT, AST, alkaline phosphatase, and bilirubin; - albumin; - CBC with platelet count; - creatinine/eGFR; - HbA1c or fasting glucose; - fasting or nonfasting lipid profile according to the clinical setting; - hepatitis B and C testing according to national screening policy and prior results. If liver abnormalities are unexplained or disproportionate, investigate other causes such as autoimmune hepatitis, iron overload, Wilson disease in an appropriate age group, alpha-1 antitrypsin deficiency, celiac disease, or drug-induced liver injury according to the clinical context.[2,3] Cross-link: [Hereditary Hemochromatosis in Adults](hereditary-hemochromatosis-in-adults.md). ## Detecting steatosis ### Ultrasound Conventional ultrasound is accessible but has limited sensitivity for mild steatosis and performs less well in severe obesity. It cannot reliably distinguish MASH from uncomplicated steatosis and does not stage fibrosis accurately. ### VCTE and controlled attenuation parameter VCTE can provide liver-stiffness measurement and an estimate of steatosis through controlled attenuation. It is useful because fibrosis assessment can be performed during the same visit, but results are affected by obesity, hepatic inflammation, congestion, cholestasis, meal timing, and technical quality. ### MRI-based techniques MRI proton-density fat fraction provides accurate quantitative liver-fat measurement. MR elastography has high diagnostic accuracy for fibrosis but is less available and more expensive, so it is mainly used for unresolved cases, specialist pathways, or treatment selection.[2,3] ## Fibrosis risk stratification ### Initial blood-based triage with FIB-4 FIB-4 uses age, AST, ALT, and platelet count: ```text FIB-4 = (age × AST) / (platelet count × √ALT) ``` Use validated units and calculate the score when the patient is clinically stable. A practical adult interpretation used in major pathways is:[2,3] | FIB-4 result | Interpretation | Next action | |---|---|---| | <1.3 | Low probability of advanced fibrosis in many adults | Manage metabolic risk; repeat periodically | | 1.3–2.67 | Indeterminate/intermediate zone | Obtain VCTE, ELF, or another validated second-line test | | >2.67 | Higher probability of advanced fibrosis | Hepatology referral and second-line staging | | Age >65 years | Age raises the score independent of fibrosis | Use a higher lower-risk cutoff around 2.0 | | Age <35 years | Reduced accuracy | Use second-line testing when clinical risk is meaningful | Do not use FIB-4 during acute hepatitis, systemic acute illness, or another state that transiently changes AST, ALT, or platelets. ### Repeat interval after a low-risk result AASLD guidance suggests:[2] - approximately every **2–3 years** in patients without prediabetes or type 2 diabetes and with only one or two metabolic risk factors; - approximately every **1–2 years** in patients with prediabetes, type 2 diabetes, or multiple metabolic risk factors. Shorten the interval when liver tests, platelet count, metabolic status, or clinical findings worsen. ### Second-line fibrosis testing | Test | Main role | Important limitations | |---|---|---| | VCTE liver stiffness | Widely available noninvasive fibrosis stratification | Obesity, inflammation, congestion, fasting status, and technical quality affect results | | Enhanced liver fibrosis blood test | Blood-based second-line fibrosis assessment | Availability and thresholds vary by jurisdiction | | MR elastography | High diagnostic accuracy | Cost and access | | MRI composite methods | Specialist staging and selected treatment pathways | Not universally available | | Liver biopsy | Resolves uncertainty; provides histologic activity and fibrosis stage | Invasive, sampling variability, not required routinely | Elastography cutoffs differ across devices, populations, and intended uses. Use the threshold validated for the local pathway rather than transferring a cutoff from a different technology. > **Caution:** A single discordant noninvasive result should not overrule the clinical picture. Use sequential testing and hepatology review when fibrosis estimates conflict. ## When liver biopsy is useful Consider biopsy when: - noninvasive tests remain discordant or indeterminate; - another liver disease remains plausible; - persistent liver-test abnormalities are unexplained; - histologic confirmation would change treatment or trial eligibility; - a specialist needs to distinguish active MASH from an alternative injury pattern. Current US approvals for resmetirom and semaglutide do not require biopsy in every treated patient, but the clinician must establish a credible noncirrhotic F2–F3 phenotype using appropriate clinical and validated diagnostic information.[4,6] ## Differential diagnosis and coexisting disease | Condition | Clues | Targeted evaluation | |---|---|---| | Alcohol-related liver disease | Alcohol exposure above metabolic overlap range | Quantify grams/week and binge pattern | | Chronic hepatitis B or C | Exposure risk or prior positive test | Serology and viral testing as appropriate | | Drug-induced liver injury or steatosis | Temporal relation to medication | Medication/supplement review and cause-specific workup | | Autoimmune hepatitis | High aminotransferases, IgG elevation, autoimmune features | IgG, autoantibodies, biopsy when needed | | Iron overload | High transferrin saturation, compatible family history | Transferrin saturation, ferritin, genetic testing when indicated | | Wilson disease | Younger patient, neuropsychiatric features, hemolysis | Copper studies according to age and presentation | | Alpha-1 antitrypsin deficiency | Early emphysema or family history | A1AT phenotype/genotype testing | | Congestive hepatopathy | Right-sided heart failure, high venous pressure | Cardiac assessment and imaging | MASLD can coexist with any of these conditions. Treating one cause does not eliminate the need to manage metabolic risk. ## Management framework Management should address: 1. weight and metabolic drivers; 2. cardiovascular risk; 3. liver-directed treatment when F2–F3 MASH is established; 4. cirrhosis complications when F4 disease is present. ### Weight reduction Sustained weight loss has a dose-response relationship with liver improvement. European guidance supports these practical targets for adults with overweight or obesity:[3] | Sustained weight reduction | Expected liver effect | |---|---| | ≥5% | Reduces liver fat | | 7–10% | Improves inflammatory liver injury | | ≥10% | Greatest likelihood of fibrosis improvement | Avoid presenting 10% as an all-or-nothing target. A patient who achieves 5–7% has clinically meaningful metabolic and hepatic benefit even if further loss is not achieved. ### Dietary pattern Use a sustainable calorie deficit when weight loss is needed. Favor vegetables, legumes, whole grains, nuts, fish, unsaturated fats, and minimally processed foods. Reduce sugar-sweetened beverages, refined carbohydrate excess, saturated fat, and heavily processed foods. A Mediterranean-style pattern has supportive cardiometabolic and liver evidence.[2,3] ### Physical activity Aerobic and resistance activity improve insulin sensitivity and can reduce liver fat even without major weight loss. Tailor activity to cardiovascular disease, arthritis, neuropathy, frailty, and baseline fitness. Reduce sedentary time as well as prescribing structured activity.[2,3] ### Alcohol Alcohol can add to metabolic liver injury. Quantify intake and counsel toward minimization; abstinence is particularly appropriate in advanced fibrosis or cirrhosis and when alcohol itself is contributing to liver disease.[3] ## Cardiometabolic treatment ### Diabetes Treat type 2 diabetes according to cardiovascular, kidney, weight, and glycemic priorities. Agents that promote meaningful weight loss can also improve MASLD biology. Do not use liver disease as a reason to leave diabetes undertreated.[2,3] Cross-link: [Type 2 Diabetes Mellitus](../endocrinology/type-2-diabetes-mellitus.md). ### Dyslipidemia Statins are appropriate for cardiovascular-risk reduction in MASLD and are generally safe in compensated chronic liver disease. Mild stable aminotransferase elevation from MASLD is not, by itself, a reason to avoid statin therapy.[2] Cross-link: [Dyslipidemia in Adults](../cardiology/dyslipidemia-in-adults.md). ### Obesity For eligible patients, anti-obesity pharmacotherapy or metabolic/bariatric surgery can produce sustained weight loss and improve metabolic disease. Bariatric surgery is not a routine liver operation and requires individualized assessment in advanced fibrosis or cirrhosis because portal hypertension changes operative risk.[3] Cross-link: [Obesity in Adults](../endocrinology/obesity-in-adults.md). ## Liver-directed pharmacotherapy for noncirrhotic F2–F3 MASH ### Resmetirom Resmetirom is a liver-directed thyroid hormone receptor-beta agonist approved in the United States in 2024 under the accelerated approval pathway for adults with **noncirrhotic MASH and F2–F3 fibrosis**, in conjunction with diet and physical activity.[4,5] #### Dose Current US dosing is:[4,5] - **body weight <100 kg: 80 mg orally once daily**; - **body weight ≥100 kg: 100 mg orally once daily**. Dose modification is required with certain CYP2C8 inhibitors. Review the current prescribing information before starting therapy because drug interactions can materially alter exposure.[4] #### Evidence In the phase 3 MAESTRO-NASH trial, both 80-mg and 100-mg doses improved histologic MASH resolution without worsening fibrosis and improved fibrosis by at least one stage without worsening disease activity at 52 weeks compared with placebo.[5] #### Monitoring and cautions Monitor for: - liver-test abnormalities and suspected drug-induced liver injury; - gallbladder-related events; - gastrointestinal adverse effects, particularly diarrhea and nausea; - thyroid status when clinically indicated; - statin toxicity when relevant. Resmetirom increases exposure to several statins. Current US prescribing information limits daily doses of **atorvastatin to 40 mg, pravastatin to 40 mg, rosuvastatin to 20 mg, and simvastatin to 20 mg** when used together; monitor for myopathy, rhabdomyolysis, and liver-test abnormalities.[4] Do not extrapolate the noncirrhotic F2–F3 indication to cirrhosis. Avoid use in decompensated cirrhosis.[4] ### Semaglutide In August 2025, the FDA granted accelerated approval for **semaglutide 2.4 mg subcutaneously once weekly** for adults with **noncirrhotic MASH and F2–F3 fibrosis**.[6-8] In the ongoing ESSENCE phase 3 trial, semaglutide 2.4 mg weekly improved both prespecified histologic endpoints at 72 weeks: MASH resolution without worsening fibrosis and fibrosis improvement without worsening MASH. Gastrointestinal adverse effects were more frequent than with placebo.[7] Semaglutide also treats obesity and type 2 diabetes in appropriate patients, which can align liver therapy with broader cardiometabolic goals. However, the MASH indication remains specific: it is not a reason to treat every patient with hepatic steatosis. Important safety considerations include gastrointestinal adverse effects, gallbladder disease, pancreatitis risk, hypoglycemia when combined with glucose-lowering therapies that themselves cause hypoglycemia, and contraindication in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 under current US labeling.[6] ### Choosing between approved therapies No head-to-head outcome trial establishes one agent as universally superior. Selection should consider: - certainty of F2–F3 fibrosis staging; - obesity and diabetes phenotype; - cardiovascular and kidney comorbidity; - thyroid and gallbladder history; - concomitant statin therapy and drug interactions; - expected weight effect; - tolerability; - pregnancy potential; - local approval, access, and prescribing restrictions. Because both US indications are accelerated approvals, clinicians should distinguish established histologic efficacy from still-pending confirmation of long-term liver clinical outcomes.[4,6] > **Evidence note:** Histologic improvement is clinically important, but ongoing trials are still determining how current liver-directed therapies change rates of cirrhosis, decompensation, transplantation, and death over longer follow-up. ## Monitoring during treatment At follow-up, assess: - weight and waist trajectory; - blood pressure; - HbA1c/glucose and diabetes treatment; - lipid profile; - ALT, AST, alkaline phosphatase, bilirubin, and albumin; - CBC/platelets when fibrosis is clinically relevant; - medication adherence and adverse effects; - fibrosis markers or elastography at intervals appropriate to baseline risk and therapy. Do not use ALT normalization as the sole marker of treatment success. Fibrosis risk, metabolic status, and clinical outcomes are more important. ## Cirrhosis and decompensated disease Once cirrhosis is present, management changes substantially. Address: - portal-hypertension risk and variceal prevention; - hepatocellular carcinoma surveillance; - ascites and sodium balance; - hepatic encephalopathy; - nutrition and sarcopenia; - vaccination; - transplant eligibility when decompensation develops. Current resmetirom and semaglutide MASH indications do not include cirrhosis.[4,6] Cross-links: [Cirrhosis and Portal Hypertension](../gastroenterology/cirrhosis-and-portal-hypertension.md), [Hepatic Encephalopathy in Cirrhosis](hepatic-encephalopathy-in-cirrhosis.md), and [Hepatocellular Carcinoma in Adults](hepatocellular-carcinoma-in-adults.md). ## Hepatocellular carcinoma surveillance Patients with MASLD-related cirrhosis should undergo hepatocellular carcinoma surveillance according to cirrhosis guidance, commonly with liver ultrasound with or without alpha-fetoprotein every 6 months depending on the guideline and local pathway.[2,3] Routine population-wide surveillance is not recommended for all noncirrhotic MASLD. Patients with advanced fibrosis but not established cirrhosis require individualized hepatology assessment because recommendations vary by society and risk profile. ## Special populations ### Type 2 diabetes Type 2 diabetes is one of the strongest clinical markers of advanced MASLD risk. Use a lower threshold for fibrosis case-finding and repeat FIB-4 more frequently even when ALT is normal.[2,3] ### Older adults Age increases FIB-4 independently of fibrosis. In adults older than 65 years, use the age-adjusted lower-risk threshold around 2.0 and interpret frailty, sarcopenia, polypharmacy, and competing cardiovascular risk alongside liver disease.[2] ### Younger adults FIB-4 performs less reliably below age 35. A low score should not be falsely reassuring when severe obesity, type 2 diabetes, strong family history, or persistent liver abnormalities suggest substantial risk.[2] ### Pregnancy Pregnancy changes metabolic status and medication options. Do not initiate liver-directed pharmacotherapy without checking current reproductive safety information. Semaglutide should not be used during pregnancy, and resmetirom lacks an indication for pregnancy. Coordinate management with maternal-fetal medicine and hepatology when advanced disease is present. ## Prognosis Fibrosis stage is the strongest liver-specific prognostic marker. Patients with minimal fibrosis can remain stable for years, while those with F3 or F4 disease face much higher risks of liver-related events. Cardiovascular disease remains a major competing risk at every fibrosis stage.[2,3] Clinical improvement should therefore be judged across multiple domains: - fibrosis stability or regression; - prevention of cirrhosis and decompensation; - weight and metabolic improvement; - cardiovascular-risk reduction; - preservation of kidney function; - avoidance of treatment toxicity. ## Recent practice changes Three changes materially alter current care: 1. **New nomenclature:** the 2023 consensus introduced SLD, MASLD, MASH, and MetALD, replacing older exclusion-based terminology.[1] 2. **Fibrosis-first pathways:** contemporary AASLD and European guidance emphasizes systematic case-finding in high-risk metabolic populations and sequential noninvasive fibrosis testing rather than relying on ALT or ultrasound alone.[2,3] 3. **Liver-directed therapy:** resmetirom was approved in the United States in 2024 and semaglutide in 2025 for selected adults with noncirrhotic F2–F3 MASH under accelerated approval pathways.[4,6] ## References 1. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. *Hepatology*. 2023;78:1966-1986. doi:10.1097/HEP.0000000000000520. PMID: 37363821. https://pubmed.ncbi.nlm.nih.gov/37363821/ 2. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. *Hepatology*. 2023;77:1797-1835. doi:10.1097/HEP.0000000000000323. PMID: 36727674. https://pubmed.ncbi.nlm.nih.gov/36727674/ 3. European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease. *Journal of Hepatology*. 2024;81:492-542. doi:10.1016/j.jhep.2024.04.031. PMID: 38851997. https://pubmed.ncbi.nlm.nih.gov/38851997/ 4. U.S. Food and Drug Administration. Resmetirom approval and prescribing information for adults with noncirrhotic steatohepatitis and F2-F3 fibrosis. 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease 5. Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. *New England Journal of Medicine*. 2024;390:497-509. doi:10.1056/NEJMoa2309000. https://www.nejm.org/doi/10.1056/NEJMoa2309000 6. U.S. Food and Drug Administration. Semaglutide accelerated approval for adults with noncirrhotic MASH and moderate-to-advanced fibrosis. August 15, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-serious-liver-disease-known-mash 7. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. *New England Journal of Medicine*. 2025;392:2089-2099. doi:10.1056/NEJMoa2413258. https://www.nejm.org/doi/10.1056/NEJMoa2413258 8. U.S. Food and Drug Administration. Ongoing accelerated approvals: nonmalignant indications; semaglutide for noncirrhotic MASH with F2-F3 fibrosis. Updated 2026. https://www.fda.gov/drugs/accelerated-approval-program/ongoing-non-malignant-hematological-neurological-and-other-disorder-indications-accelerated19:T6d39,## Summary Metabolic dysfunction-associated steatotic liver disease (MASLD) is hepatic steatosis in a person with at least one defined cardiometabolic risk factor and without a more appropriate dominant steatotic-liver-disease category. Metabolic dysfunction-associated steatohepatitis (MASH) is the inflammatory phenotype characterized histologically by steatosis, lobular inflammation, and hepatocyte ballooning, with or without fibrosis. Fibrosis stage, rather than aminotransferase concentration or steatosis alone, is the strongest routinely available marker of liver-related risk.[1-3] Most patients have no liver-specific symptoms, and a normal ALT does not exclude advanced fibrosis. Patients with type 2 diabetes, obesity with additional metabolic risk, persistent liver-test abnormalities, or imaging-detected steatosis should undergo structured fibrosis assessment. A practical pathway begins with **FIB-4** in a clinically stable patient. In many adults, **FIB-4 <1.3** is low risk, **FIB-4 ≥1.3** triggers second-line fibrosis testing, and **FIB-4 >2.67** raises substantial concern for advanced fibrosis. For adults older than 65 years, a higher lower-risk threshold around **2.0** is used because age inflates FIB-4. FIB-4 is less accurate below age 35 and during acute illness.[2,3] Second-line testing usually uses vibration-controlled transient elastography (VCTE), an enhanced liver fibrosis blood test, or another validated elastography strategy. Discordant results, high clinical suspicion, or treatment-selection uncertainty warrant hepatology review. Liver biopsy is not required for every patient and is reserved for unresolved diagnostic uncertainty, competing disease, or situations in which histology will materially change care.[2,3] Treatment has three simultaneous targets: **cardiometabolic risk, liver fibrosis, and complications of advanced liver disease**. Sustained weight loss, physical activity, dietary quality, diabetes treatment, lipid management, blood-pressure control, smoking cessation, and minimizing alcohol exposure remain foundational. European guidance uses practical weight-loss targets of at least **5%** to reduce steatosis, **7–10%** to improve inflammatory liver injury, and approximately **10% or more** for the greatest likelihood of fibrosis improvement.[3] In the United States, two liver-directed pharmacologic options are now approved under accelerated pathways for selected adults with **noncirrhotic MASH and F2–F3 fibrosis**. **Resmetirom** is given orally once daily; the labeled dose is **80 mg daily for body weight <100 kg and 100 mg daily for body weight ≥100 kg**. **Semaglutide 2.4 mg subcutaneously once weekly** is also approved for noncirrhotic MASH with F2–F3 fibrosis. These indications do not extend to uncomplicated steatosis or established cirrhosis, and confirmatory clinical-outcome studies remain ongoing.[4-8] Patients with cirrhosis should move into a cirrhosis pathway for portal-hypertension assessment, hepatocellular carcinoma surveillance, decompensation prevention, and transplant evaluation when appropriate. Do not continue to manage advanced disease as if it were merely “fatty liver.”[2,3] > **Clinical pearl:** The key bedside question in MASLD is not “How much fat is present?” but “Is clinically important fibrosis present, and is it progressing?” --- ## Nomenclature and classification The 2023 multisociety nomenclature places **steatotic liver disease (SLD)** as the umbrella category. Major categories include MASLD, metabolic dysfunction with higher alcohol exposure (MetALD), alcohol-related liver disease, drug-induced SLD, specific-cause SLD, and cryptogenic SLD.[1] ### MASLD MASLD requires hepatic steatosis plus at least one cardiometabolic criterion. Adult criteria include dysglycemia, elevated blood pressure or treatment, hypertriglyceridemia or treatment, low HDL cholesterol or treatment, or excess adiposity defined by BMI or waist circumference using ethnicity-appropriate thresholds.[1] The diagnosis is positive rather than purely exclusionary, but clinicians must still identify competing or coexisting liver diseases because MASLD commonly coexists with viral hepatitis, alcohol-related injury, drug-induced injury, autoimmune disease, and hereditary conditions. ### MASH MASH is a histologic diagnosis within MASLD. The defining features are: - macrovesicular steatosis; - lobular inflammation; - hepatocyte ballooning; - fibrosis may be absent or present. Fibrosis is staged from F0 to F4; F4 represents cirrhosis. Clinical trials and current US liver-directed drug indications focus on noncirrhotic F2–F3 disease because this group has meaningful progression risk while retaining potential for fibrosis regression.[3-8] ### MetALD MetALD describes metabolic dysfunction plus alcohol exposure above the MASLD range but below the level used to categorize primarily alcohol-related liver disease. The 2023 consensus uses approximate weekly alcohol ranges of **140–350 g in women** and **210–420 g in men** for MetALD.[1] Record alcohol quantitatively in grams per week and document binge patterns. Terms such as “social drinking” are not sufficiently precise for liver-risk classification. ## Epidemiology and risk MASLD is closely associated with: - type 2 diabetes; - overweight and obesity; - dyslipidemia; - hypertension; - obstructive sleep apnea; - chronic kidney disease; - insulin resistance and metabolic syndrome. The main causes of adverse outcomes differ by stage. Cardiovascular disease is a dominant cause of morbidity and death across MASLD, whereas liver-related events rise markedly as fibrosis advances. Patients with F3 fibrosis and cirrhosis require particular attention because the risk of portal-hypertensive complications and hepatocellular carcinoma increases.[2,3] Features associated with higher probability of advanced fibrosis include: - type 2 diabetes, especially long-standing or poorly controlled disease; - severe or long-duration obesity; - multiple cardiometabolic risk factors; - thrombocytopenia; - persistently abnormal aminotransferases; - older age; - splenomegaly or other signs of portal hypertension; - imaging features of chronic liver disease; - family history of advanced liver disease. ## Pathophysiology MASLD arises from interacting metabolic, genetic, inflammatory, and environmental pathways. ### Metabolic substrate overload Insulin resistance increases adipose lipolysis and delivery of free fatty acids to the liver. Hyperinsulinemia and excess carbohydrate intake increase hepatic de novo lipogenesis. When fatty-acid delivery and synthesis exceed oxidation and export, hepatocytes accumulate lipid. Triglyceride storage alone does not account for progressive liver injury. Lipotoxic species, mitochondrial dysfunction, oxidative stress, endoplasmic-reticulum stress, altered autophagy, and inflammatory signaling contribute to hepatocyte injury and death.[2] ### Inflammation and fibrosis Injured hepatocytes activate resident macrophages and recruit inflammatory cells. Cytokines and cell-to-cell signaling activate hepatic stellate cells, leading to extracellular-matrix deposition. Repeated injury can progress from pericellular fibrosis to bridging fibrosis and cirrhosis. ### Genetic susceptibility Variants including **PNPLA3**, **TM6SF2**, and **MBOAT7** alter susceptibility to steatosis and fibrosis. Routine genetic testing is not required for most patients, but genetic variation helps explain severe disease in some patients without extreme obesity or severe metabolic disturbance.[2,3] ## Clinical presentation Most patients are identified through: - steatosis on ultrasound, CT, or MRI; - elevated ALT or AST; - evaluation of diabetes or obesity; - incidental hepatomegaly; - fibrosis case-finding in a high-risk metabolic population. Symptoms such as fatigue or vague right-upper-quadrant discomfort are nonspecific and do not reliably indicate fibrosis stage. Features suggesting advanced chronic liver disease include: - platelet decline; - splenomegaly; - nodular liver morphology; - varices or abdominal collaterals; - ascites; - hepatic encephalopathy; - jaundice; - sarcopenia. Cross-link: [Cirrhosis and Portal Hypertension](../gastroenterology/cirrhosis-and-portal-hypertension.md). ## Initial assessment ### History Document: - weight trajectory and central adiposity; - diabetes, prediabetes, hypertension, and dyslipidemia; - cardiovascular and kidney disease; - obstructive sleep apnea; - alcohol amount, frequency, binge pattern, and duration; - medications and supplements associated with steatosis or hepatotoxicity; - viral-hepatitis risk and prior testing; - family history of cirrhosis or liver cancer; - prior liver tests and imaging; - pregnancy status and pregnancy plans when medication therapy is considered. ### Baseline tests Common baseline studies include: - ALT, AST, alkaline phosphatase, and bilirubin; - albumin; - CBC with platelet count; - creatinine/eGFR; - HbA1c or fasting glucose; - fasting or nonfasting lipid profile according to the clinical setting; - hepatitis B and C testing according to national screening policy and prior results. If liver abnormalities are unexplained or disproportionate, investigate other causes such as autoimmune hepatitis, iron overload, Wilson disease in an appropriate age group, alpha-1 antitrypsin deficiency, celiac disease, or drug-induced liver injury according to the clinical context.[2,3] Cross-link: [Hereditary Hemochromatosis in Adults](hereditary-hemochromatosis-in-adults.md). ## Detecting steatosis ### Ultrasound Conventional ultrasound is accessible but has limited sensitivity for mild steatosis and performs less well in severe obesity. It cannot reliably distinguish MASH from uncomplicated steatosis and does not stage fibrosis accurately. ### VCTE and controlled attenuation parameter VCTE can provide liver-stiffness measurement and an estimate of steatosis through controlled attenuation. It is useful because fibrosis assessment can be performed during the same visit, but results are affected by obesity, hepatic inflammation, congestion, cholestasis, meal timing, and technical quality. ### MRI-based techniques MRI proton-density fat fraction provides accurate quantitative liver-fat measurement. MR elastography has high diagnostic accuracy for fibrosis but is less available and more expensive, so it is mainly used for unresolved cases, specialist pathways, or treatment selection.[2,3] ## Fibrosis risk stratification ### Initial blood-based triage with FIB-4 FIB-4 uses age, AST, ALT, and platelet count: ```text FIB-4 = (age × AST) / (platelet count × √ALT) ``` Use validated units and calculate the score when the patient is clinically stable. A practical adult interpretation used in major pathways is:[2,3] | FIB-4 result | Interpretation | Next action | |---|---|---| | <1.3 | Low probability of advanced fibrosis in many adults | Manage metabolic risk; repeat periodically | | 1.3–2.67 | Indeterminate/intermediate zone | Obtain VCTE, ELF, or another validated second-line test | | >2.67 | Higher probability of advanced fibrosis | Hepatology referral and second-line staging | | Age >65 years | Age raises the score independent of fibrosis | Use a higher lower-risk cutoff around 2.0 | | Age <35 years | Reduced accuracy | Use second-line testing when clinical risk is meaningful | Do not use FIB-4 during acute hepatitis, systemic acute illness, or another state that transiently changes AST, ALT, or platelets. ### Repeat interval after a low-risk result AASLD guidance suggests:[2] - approximately every **2–3 years** in patients without prediabetes or type 2 diabetes and with only one or two metabolic risk factors; - approximately every **1–2 years** in patients with prediabetes, type 2 diabetes, or multiple metabolic risk factors. Shorten the interval when liver tests, platelet count, metabolic status, or clinical findings worsen. ### Second-line fibrosis testing | Test | Main role | Important limitations | |---|---|---| | VCTE liver stiffness | Widely available noninvasive fibrosis stratification | Obesity, inflammation, congestion, fasting status, and technical quality affect results | | Enhanced liver fibrosis blood test | Blood-based second-line fibrosis assessment | Availability and thresholds vary by jurisdiction | | MR elastography | High diagnostic accuracy | Cost and access | | MRI composite methods | Specialist staging and selected treatment pathways | Not universally available | | Liver biopsy | Resolves uncertainty; provides histologic activity and fibrosis stage | Invasive, sampling variability, not required routinely | Elastography cutoffs differ across devices, populations, and intended uses. Use the threshold validated for the local pathway rather than transferring a cutoff from a different technology. > **Caution:** A single discordant noninvasive result should not overrule the clinical picture. Use sequential testing and hepatology review when fibrosis estimates conflict. ## When liver biopsy is useful Consider biopsy when: - noninvasive tests remain discordant or indeterminate; - another liver disease remains plausible; - persistent liver-test abnormalities are unexplained; - histologic confirmation would change treatment or trial eligibility; - a specialist needs to distinguish active MASH from an alternative injury pattern. Current US approvals for resmetirom and semaglutide do not require biopsy in every treated patient, but the clinician must establish a credible noncirrhotic F2–F3 phenotype using appropriate clinical and validated diagnostic information.[4,6] ## Differential diagnosis and coexisting disease | Condition | Clues | Targeted evaluation | |---|---|---| | Alcohol-related liver disease | Alcohol exposure above metabolic overlap range | Quantify grams/week and binge pattern | | Chronic hepatitis B or C | Exposure risk or prior positive test | Serology and viral testing as appropriate | | Drug-induced liver injury or steatosis | Temporal relation to medication | Medication/supplement review and cause-specific workup | | Autoimmune hepatitis | High aminotransferases, IgG elevation, autoimmune features | IgG, autoantibodies, biopsy when needed | | Iron overload | High transferrin saturation, compatible family history | Transferrin saturation, ferritin, genetic testing when indicated | | Wilson disease | Younger patient, neuropsychiatric features, hemolysis | Copper studies according to age and presentation | | Alpha-1 antitrypsin deficiency | Early emphysema or family history | A1AT phenotype/genotype testing | | Congestive hepatopathy | Right-sided heart failure, high venous pressure | Cardiac assessment and imaging | MASLD can coexist with any of these conditions. Treating one cause does not eliminate the need to manage metabolic risk. ## Management framework Management should address: 1. weight and metabolic drivers; 2. cardiovascular risk; 3. liver-directed treatment when F2–F3 MASH is established; 4. cirrhosis complications when F4 disease is present. ### Weight reduction Sustained weight loss has a dose-response relationship with liver improvement. European guidance supports these practical targets for adults with overweight or obesity:[3] | Sustained weight reduction | Expected liver effect | |---|---| | ≥5% | Reduces liver fat | | 7–10% | Improves inflammatory liver injury | | ≥10% | Greatest likelihood of fibrosis improvement | Avoid presenting 10% as an all-or-nothing target. A patient who achieves 5–7% has clinically meaningful metabolic and hepatic benefit even if further loss is not achieved. ### Dietary pattern Use a sustainable calorie deficit when weight loss is needed. Favor vegetables, legumes, whole grains, nuts, fish, unsaturated fats, and minimally processed foods. Reduce sugar-sweetened beverages, refined carbohydrate excess, saturated fat, and heavily processed foods. A Mediterranean-style pattern has supportive cardiometabolic and liver evidence.[2,3] ### Physical activity Aerobic and resistance activity improve insulin sensitivity and can reduce liver fat even without major weight loss. Tailor activity to cardiovascular disease, arthritis, neuropathy, frailty, and baseline fitness. Reduce sedentary time as well as prescribing structured activity.[2,3] ### Alcohol Alcohol can add to metabolic liver injury. Quantify intake and counsel toward minimization; abstinence is particularly appropriate in advanced fibrosis or cirrhosis and when alcohol itself is contributing to liver disease.[3] ## Cardiometabolic treatment ### Diabetes Treat type 2 diabetes according to cardiovascular, kidney, weight, and glycemic priorities. Agents that promote meaningful weight loss can also improve MASLD biology. Do not use liver disease as a reason to leave diabetes undertreated.[2,3] Cross-link: [Type 2 Diabetes Mellitus](../endocrinology/type-2-diabetes-mellitus.md). ### Dyslipidemia Statins are appropriate for cardiovascular-risk reduction in MASLD and are generally safe in compensated chronic liver disease. Mild stable aminotransferase elevation from MASLD is not, by itself, a reason to avoid statin therapy.[2] Cross-link: [Dyslipidemia in Adults](../cardiology/dyslipidemia-in-adults.md). ### Obesity For eligible patients, anti-obesity pharmacotherapy or metabolic/bariatric surgery can produce sustained weight loss and improve metabolic disease. Bariatric surgery is not a routine liver operation and requires individualized assessment in advanced fibrosis or cirrhosis because portal hypertension changes operative risk.[3] Cross-link: [Obesity in Adults](../endocrinology/obesity-in-adults.md). ## Liver-directed pharmacotherapy for noncirrhotic F2–F3 MASH ### Resmetirom Resmetirom is a liver-directed thyroid hormone receptor-beta agonist approved in the United States in 2024 under the accelerated approval pathway for adults with **noncirrhotic MASH and F2–F3 fibrosis**, in conjunction with diet and physical activity.[4,5] #### Dose Current US dosing is:[4,5] - **body weight <100 kg: 80 mg orally once daily**; - **body weight ≥100 kg: 100 mg orally once daily**. Dose modification is required with certain CYP2C8 inhibitors. Review the current prescribing information before starting therapy because drug interactions can materially alter exposure.[4] #### Evidence In the phase 3 MAESTRO-NASH trial, both 80-mg and 100-mg doses improved histologic MASH resolution without worsening fibrosis and improved fibrosis by at least one stage without worsening disease activity at 52 weeks compared with placebo.[5] #### Monitoring and cautions Monitor for: - liver-test abnormalities and suspected drug-induced liver injury; - gallbladder-related events; - gastrointestinal adverse effects, particularly diarrhea and nausea; - thyroid status when clinically indicated; - statin toxicity when relevant. Resmetirom increases exposure to several statins. Current US prescribing information limits daily doses of **atorvastatin to 40 mg, pravastatin to 40 mg, rosuvastatin to 20 mg, and simvastatin to 20 mg** when used together; monitor for myopathy, rhabdomyolysis, and liver-test abnormalities.[4] Do not extrapolate the noncirrhotic F2–F3 indication to cirrhosis. Avoid use in decompensated cirrhosis.[4] ### Semaglutide In August 2025, the FDA granted accelerated approval for **semaglutide 2.4 mg subcutaneously once weekly** for adults with **noncirrhotic MASH and F2–F3 fibrosis**.[6-8] In the ongoing ESSENCE phase 3 trial, semaglutide 2.4 mg weekly improved both prespecified histologic endpoints at 72 weeks: MASH resolution without worsening fibrosis and fibrosis improvement without worsening MASH. Gastrointestinal adverse effects were more frequent than with placebo.[7] Semaglutide also treats obesity and type 2 diabetes in appropriate patients, which can align liver therapy with broader cardiometabolic goals. However, the MASH indication remains specific: it is not a reason to treat every patient with hepatic steatosis. Important safety considerations include gastrointestinal adverse effects, gallbladder disease, pancreatitis risk, hypoglycemia when combined with glucose-lowering therapies that themselves cause hypoglycemia, and contraindication in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 under current US labeling.[6] ### Choosing between approved therapies No head-to-head outcome trial establishes one agent as universally superior. Selection should consider: - certainty of F2–F3 fibrosis staging; - obesity and diabetes phenotype; - cardiovascular and kidney comorbidity; - thyroid and gallbladder history; - concomitant statin therapy and drug interactions; - expected weight effect; - tolerability; - pregnancy potential; - local approval, access, and prescribing restrictions. Because both US indications are accelerated approvals, clinicians should distinguish established histologic efficacy from still-pending confirmation of long-term liver clinical outcomes.[4,6] > **Evidence note:** Histologic improvement is clinically important, but ongoing trials are still determining how current liver-directed therapies change rates of cirrhosis, decompensation, transplantation, and death over longer follow-up. ## Monitoring during treatment At follow-up, assess: - weight and waist trajectory; - blood pressure; - HbA1c/glucose and diabetes treatment; - lipid profile; - ALT, AST, alkaline phosphatase, bilirubin, and albumin; - CBC/platelets when fibrosis is clinically relevant; - medication adherence and adverse effects; - fibrosis markers or elastography at intervals appropriate to baseline risk and therapy. Do not use ALT normalization as the sole marker of treatment success. Fibrosis risk, metabolic status, and clinical outcomes are more important. ## Cirrhosis and decompensated disease Once cirrhosis is present, management changes substantially. Address: - portal-hypertension risk and variceal prevention; - hepatocellular carcinoma surveillance; - ascites and sodium balance; - hepatic encephalopathy; - nutrition and sarcopenia; - vaccination; - transplant eligibility when decompensation develops. Current resmetirom and semaglutide MASH indications do not include cirrhosis.[4,6] Cross-links: [Cirrhosis and Portal Hypertension](../gastroenterology/cirrhosis-and-portal-hypertension.md), [Hepatic Encephalopathy in Cirrhosis](hepatic-encephalopathy-in-cirrhosis.md), and [Hepatocellular Carcinoma in Adults](hepatocellular-carcinoma-in-adults.md). ## Hepatocellular carcinoma surveillance Patients with MASLD-related cirrhosis should undergo hepatocellular carcinoma surveillance according to cirrhosis guidance, commonly with liver ultrasound with or without alpha-fetoprotein every 6 months depending on the guideline and local pathway.[2,3] Routine population-wide surveillance is not recommended for all noncirrhotic MASLD. Patients with advanced fibrosis but not established cirrhosis require individualized hepatology assessment because recommendations vary by society and risk profile. ## Special populations ### Type 2 diabetes Type 2 diabetes is one of the strongest clinical markers of advanced MASLD risk. Use a lower threshold for fibrosis case-finding and repeat FIB-4 more frequently even when ALT is normal.[2,3] ### Older adults Age increases FIB-4 independently of fibrosis. In adults older than 65 years, use the age-adjusted lower-risk threshold around 2.0 and interpret frailty, sarcopenia, polypharmacy, and competing cardiovascular risk alongside liver disease.[2] ### Younger adults FIB-4 performs less reliably below age 35. A low score should not be falsely reassuring when severe obesity, type 2 diabetes, strong family history, or persistent liver abnormalities suggest substantial risk.[2] ### Pregnancy Pregnancy changes metabolic status and medication options. Do not initiate liver-directed pharmacotherapy without checking current reproductive safety information. Semaglutide should not be used during pregnancy, and resmetirom lacks an indication for pregnancy. Coordinate management with maternal-fetal medicine and hepatology when advanced disease is present. ## Prognosis Fibrosis stage is the strongest liver-specific prognostic marker. Patients with minimal fibrosis can remain stable for years, while those with F3 or F4 disease face much higher risks of liver-related events. Cardiovascular disease remains a major competing risk at every fibrosis stage.[2,3] Clinical improvement should therefore be judged across multiple domains: - fibrosis stability or regression; - prevention of cirrhosis and decompensation; - weight and metabolic improvement; - cardiovascular-risk reduction; - preservation of kidney function; - avoidance of treatment toxicity. ## Recent practice changes Three changes materially alter current care: 1. **New nomenclature:** the 2023 consensus introduced SLD, MASLD, MASH, and MetALD, replacing older exclusion-based terminology.[1] 2. **Fibrosis-first pathways:** contemporary AASLD and European guidance emphasizes systematic case-finding in high-risk metabolic populations and sequential noninvasive fibrosis testing rather than relying on ALT or ultrasound alone.[2,3] 3. **Liver-directed therapy:** resmetirom was approved in the United States in 2024 and semaglutide in 2025 for selected adults with noncirrhotic F2–F3 MASH under accelerated approval pathways.[4,6] ## References 1. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. *Hepatology*. 2023;78:1966-1986. doi:10.1097/HEP.0000000000000520. PMID: 37363821. https://pubmed.ncbi.nlm.nih.gov/37363821/ 2. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. *Hepatology*. 2023;77:1797-1835. doi:10.1097/HEP.0000000000000323. PMID: 36727674. https://pubmed.ncbi.nlm.nih.gov/36727674/ 3. European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease. *Journal of Hepatology*. 2024;81:492-542. doi:10.1016/j.jhep.2024.04.031. PMID: 38851997. https://pubmed.ncbi.nlm.nih.gov/38851997/ 4. U.S. Food and Drug Administration. Resmetirom approval and prescribing information for adults with noncirrhotic steatohepatitis and F2-F3 fibrosis. 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease 5. Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. *New England Journal of Medicine*. 2024;390:497-509. doi:10.1056/NEJMoa2309000. https://www.nejm.org/doi/10.1056/NEJMoa2309000 6. U.S. Food and Drug Administration. Semaglutide accelerated approval for adults with noncirrhotic MASH and moderate-to-advanced fibrosis. August 15, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-serious-liver-disease-known-mash 7. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. *New England Journal of Medicine*. 2025;392:2089-2099. doi:10.1056/NEJMoa2413258. https://www.nejm.org/doi/10.1056/NEJMoa2413258 8. U.S. Food and Drug Administration. Ongoing accelerated approvals: nonmalignant indications; semaglutide for noncirrhotic MASH with F2-F3 fibrosis. 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