MASLD (Formerly NAFLD): Diagnosis, Staging, and Treatment in 2025

What MASLD Means and Why the Name Changed From NAFLD

The term NAFLD (nonalcoholic fatty liver disease) was replaced by MASLD in 2023 because the old label defined the disease by what it was not, rather than by what it actually is. A Delphi consensus involving 236 panelists from 56 liver societies worldwide agreed that the new terminology should reflect the positive cardiometabolic criteria that underlie the condition [1]. The change was published simultaneously in Hepatology, Journal of Hepatology, and several other journals in June 2023.

Under the 2023 framework, MASLD is diagnosed when hepatic steatosis affecting at least 5% of hepatocytes coexists with at least one of five cardiometabolic risk factors: BMI above 25 kg/m² (or above 23 kg/m² in Asian populations), fasting glucose at or above 100 mg/dL or a diabetes diagnosis, blood pressure at or above 130/85 mmHg or antihypertensive therapy, fasting triglycerides at or above 150 mg/dL or lipid-lowering treatment, or HDL cholesterol below 40 mg/dL in men and below 50 mg/dL in women [1]. Patients who have hepatic steatosis with excessive alcohol use are now classified separately under MetALD, a new category covering those with both metabolic risk factors and moderate alcohol consumption.

The practical implication for clinicians: a patient who previously carried an NAFLD diagnosis retains that diagnosis under MASLD terminology with no re-evaluation required, provided the cardiometabolic criteria are met. The American Association for the Study of Liver Diseases (AASLD) has endorsed this nomenclature change and updated its practice guidance accordingly [2].

MASH (Formerly NASH): The Inflammatory Subtype That Drives Fibrosis

MASH is the subtype of MASLD characterized by hepatocyte ballooning, lobular inflammation, and steatosis on biopsy, a combination that carries meaningful risk of progression to cirrhosis. Simple steatosis without inflammation (called MASLD without MASH) rarely progresses to advanced fibrosis, but MASH does so in a clinically significant proportion of patients.

A paired-biopsy study by Singh et al. published in Clinical Gastroenterology and Hepatology (N=411) found that patients with MASH progressed by at least one fibrosis stage in 40.8% of cases over a median of 5.9 years, compared with 21.7% for those without MASH [3]. Patients with fibrosis stage F3 progressed to cirrhosis (F4) at a rate of 10.3% per year. These are not trivial numbers given the estimated 25 million Americans who may have MASH [4].

The histologic diagnosis of MASH relies on the NASH Clinical Research Network (CRN) scoring system. The NAS (NAFLD Activity Score) grades steatosis (0-3), lobular inflammation (0-3), and hepatocyte ballooning (0-2) for a maximum of 8. A score of 5 or higher generally correlates with MASH on biopsy, though fibrosis stage is scored separately using the Kleiner system (F0-F4) [5].

Serum aminotransferases (ALT, AST) may be normal in up to 79% of patients with biopsy-proven MASH, making them unreliable screening tools on their own [6]. The AST/ALT ratio above 1.0 suggests advanced fibrosis or cirrhosis rather than simple steatohepatitis, because AST rises disproportionately as fibrosis progresses.

Hepatic Steatosis: How Fat Accumulates and What Quantifies It

Hepatic steatosis, the defining feature of MASLD, occurs when triglyceride-rich lipid droplets accumulate in hepatocytes beyond the 5% threshold. The main mechanisms are increased free fatty acid delivery from adipose tissue (lipolysis-driven), de novo lipogenesis stimulated by hyperinsulinemia, and impaired hepatic fatty acid oxidation [7].

Imaging can confirm and quantify steatosis without biopsy. MRI-proton density fat fraction (MRI-PDFF) is the most accurate non-invasive method, with a sensitivity of 90% and specificity of 91% for detecting steatosis grade S1 or higher (at least 5% hepatic fat) [8]. Controlled attenuation parameter (CAP), measured during transient elastography (FibroScan), offers a less expensive point-of-care alternative; CAP values above 275 dB/m suggest at least 11% hepatic fat content [9].

Routine ultrasound is widely available but insensitive below 20-30% hepatic fat fraction and cannot grade steatosis quantitatively [10]. A negative ultrasound does not exclude MASLD.

Fibrosis Staging: From F0 to Cirrhosis

Fibrosis stage is the single strongest predictor of liver-related mortality and overall mortality in MASLD. A 2015 meta-analysis by Angulo et al. (N=619) in Gastroenterology confirmed that each one-stage increase in fibrosis was independently associated with a 2.16-fold increase in liver-related events and a 1.41-fold increase in all-cause mortality [11].

Liver biopsy remains the gold standard for staging. Non-invasive strategies are appropriate for initial triage. The FIB-4 index, calculated from age, AST, ALT, and platelet count, is recommended by the AASLD and American College of Gastroenterology (ACG) as a first-line tool [2]. A FIB-4 score below 1.30 has a negative predictive value exceeding 90% for advanced fibrosis (F3-F4) in the general MASLD population. A score above 2.67 warrants referral to hepatology and likely biopsy.

Transient elastography (liver stiffness measurement, LSM) adds incremental accuracy. An LSM above 8 kPa suggests at least F2 fibrosis, while values above 12 kPa raise concern for cirrhosis [9]. Combining FIB-4 with LSM in a sequential algorithm reduces unnecessary biopsies by approximately 60% without meaningfully increasing missed advanced fibrosis cases [12].

Cirrhosis and MASLD: Clinical Features and the Cryptogenic Cirrhosis Connection

MASLD-related cirrhosis (F4 fibrosis) may be clinically silent for years. When decompensation occurs, patients develop ascites, variceal hemorrhage, hepatic encephalopathy, or jaundice. The Model for End-Stage Liver Disease (MELD) score guides transplant listing, and MASLD is now the second leading indication for liver transplantation in the United States, behind alcohol-related liver disease [4].

Cryptogenic cirrhosis, defined historically as cirrhosis with no identifiable cause after standard workup, is now understood to represent largely burned-out MASLD. As MASH-related inflammation burns out in late-stage fibrosis, steatosis and ballooning may disappear on biopsy, leaving only the cirrhotic architecture. Studies estimate that between 60% and 75% of cryptogenic cirrhosis cases are attributable to MASLD when metabolic risk factors and body composition data are examined systematically [13]. This has significant implications for transplant centers, because recurrence of MASLD in the graft occurs in up to 40% of recipients within five years if cardiometabolic risk is not managed post-transplant [4].

Hepatocellular carcinoma (HCC) can develop in MASLD-related cirrhosis and, importantly, in a subset of patients with advanced fibrosis but pre-cirrhotic disease. The AASLD recommends biannual ultrasound surveillance with AFP in all patients with MASLD-related cirrhosis [2].

FDA-Approved Treatment: Resmetirom (Rezdiffra) for MASH F2-F3

Resmetirom is the first and, as of mid-2025, only FDA-approved pharmacotherapy specifically for MASH with liver fibrosis. The FDA granted approval in March 2024 based on the MAESTRO-NASH trial. MAESTRO-NASH (N=966) was a Phase 3, randomized, double-blind, placebo-controlled trial. Resmetirom 100 mg daily achieved MASH resolution without worsening of fibrosis in 29.9% of patients versus 9.7% on placebo (P<0.001). Fibrosis improvement of at least one stage without MASH worsening occurred in 25.9% on resmetirom 100 mg versus 14.2% on placebo (P<0.001) [14]. These were histologic endpoints from paired liver biopsies at 52 weeks.

Resmetirom is a liver-directed thyroid hormone receptor-beta (THR-beta) agonist. It reduces hepatic fat by activating fatty acid oxidation and reducing de novo lipogenesis in hepatocytes without the cardiac and bone effects associated with non-selective thyroid hormone agonism. The approved indication is adults with MASH and moderate-to-severe liver fibrosis (F2-F3), used alongside diet and exercise.

The AASLD Practice Guidance statement notes: "Resmetirom is the only pharmacological agent with FDA approval for MASH with fibrosis, and its use should be considered in patients with biopsy-confirmed or non-invasively diagnosed F2-F3 MASH after lifestyle modification alone has been insufficient" [2].

Common adverse effects in MAESTRO-NASH included nausea (26.9% vs. 16.7% placebo) and diarrhea (29.5% vs. 17.8% placebo), most of which were mild-to-moderate and occurred early in treatment [14].

Lifestyle and Weight-Loss Interventions: What the Evidence Actually Shows

Weight loss remains the most effective single intervention for MASH. A landmark analysis by Vilar-Gomez et al. in Gastroenterology (N=261, biopsy-proven NASH) showed that patients achieving at least 10% body weight loss had NASH resolution in 90% of cases and fibrosis regression in 45% [15]. Even 7% weight loss produced NASH resolution in 64% of patients. These thresholds are now embedded in AASLD guidance [2].

GLP-1 receptor agonists have shown histologic benefit in clinical trials. The LEAN trial (liraglutide 1.8 mg daily, N=52 to 48 weeks) found NASH resolution in 39% on liraglutide versus 9% on placebo (P=0.019) [16]. Semaglutide 2.4 mg weekly data from a 72-week Phase 2 trial (N=320) demonstrated NASH resolution in 59% on the highest dose versus 17% on placebo, though fibrosis improvement did not reach statistical significance in that study [17]. Phase 3 semaglutide data specific to MASH outcomes are anticipated through the ESSENCE trial, which completed enrollment in 2024.

Vitamin E 800 IU/day improved NASH resolution versus placebo in the PIVENS trial (N=247) at 96 weeks (43% vs. 19%, P<0.001) in non-diabetic adults, but had no effect on fibrosis and is not recommended in patients with diabetes or cirrhosis [18].

Pioglitazone (a thiazolidinedione) improved steatosis, ballooning, and inflammation in the PIVENS trial among diabetic participants and in separate analyses, though long-term use carries risks of weight gain, fluid retention, and possible bladder cancer with duration above two years [18]. The AASLD considers pioglitazone an option for MASH in patients with type 2 diabetes [2].

Screening: Who Should Be Tested for MASLD

The AASLD recommends case-finding in patients with at least one cardiometabolic risk factor who have unexplained elevations in liver enzymes or incidentally discovered hepatic steatosis on imaging [2]. Routine population screening is not currently recommended, though this position is evolving given the 38% global prevalence estimate [1].

Patients with type 2 diabetes carry an estimated MASLD prevalence of 55-70% and have a three- to fivefold higher rate of advanced fibrosis compared to the general MASLD population [19]. The American Diabetes Association (ADA) 2024 Standards of Care recommend that clinicians consider screening for MASLD with FIB-4 in all patients with type 2 diabetes at initial evaluation and periodically thereafter [20].

Children with obesity are also at risk. Pediatric MASLD affects approximately 13% of children overall and up to 34% of children with obesity, with MASH confirmed on biopsy in a subset [21]. Pediatric MASLD has distinct histologic features, including portal-predominant inflammation, and standard NAS scoring criteria may underestimate disease severity in this age group.

Cardiovascular Risk in MASLD: The Leading Cause of Death

Liver disease is not the primary cause of death in most MASLD patients, at least in the early stages. Cardiovascular disease accounts for 38-40% of mortality in cohort studies of MASLD, compared with liver-related deaths at approximately 9% [11]. The metabolic risk factors defining MASLD overlap substantially with those driving atherosclerosis, and MASLD itself appears to independently increase cardiovascular risk beyond traditional risk factors.

A meta-analysis by Targher et al. covering 34 studies found that MASLD was associated with a 64% increased risk of fatal or non-fatal cardiovascular events (hazard ratio 1.64 to 95% CI 1.26-2.13) after adjustment for conventional cardiovascular risk factors [22]. This association was stronger in patients with MASH or advanced fibrosis.

Statin therapy is safe in MASLD and reduces cardiovascular events without worsening liver histology. The AASLD explicitly states that MASLD is not a contraindication to statin use and that elevated baseline transaminases alone should not preclude statin initiation [2]. Statin-induced liver injury is rare (estimated at 1-3 per 10,000 patient-years) and not specifically linked to MASLD [23].

Non-Invasive Biomarkers and Emerging Blood Tests

The Enhanced Liver Fibrosis (ELF) test measures three extracellular matrix proteins (hyaluronic acid, PIIINP, TIMP-1) and has an AUROC of 0.87 for advanced fibrosis in MASLD [24]. The Pro-C3 assay, measuring type III collagen synthesis, shows promise for detecting fibrosis progression and was used as an endpoint in several recent clinical trials.

The NIS4 score, combining microRNA-34a-5p, alpha-2-macroglobulin, YKL-40, and ALT, was validated in a cohort of 793 MASLD patients and achieved an AUROC of 0.82 for identifying at-risk MASH (NAS at least 4 with at least F2 fibrosis) [25]. NIS4 is commercially available in some markets as the NASHnext assay.

These tests support a non-invasive pathway for diagnosis and monitoring, particularly for patients who decline biopsy or in whom biopsy carries elevated procedural risk.