MASLD (Formerly NAFLD): Global Prevalence, FIB-4 Score, and Resmetirom

One Quarter of All Humans Carry This Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) — renamed from nonalcoholic fatty liver disease (NAFLD) in a 2023 multi-society nomenclature consensus — affects approximately 25% of the global adult population, making it the world's most prevalent chronic liver disease. In the United States, an estimated 80–100 million people have MASLD; in countries with high rates of obesity and type 2 diabetes — Saudi Arabia, Mexico, and China among them — prevalence approaches 35%. The disease exists on a spectrum: uncomplicated steatosis in most patients, but metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) in 20–30%, characterized by inflammation and hepatocyte ballooning that drives fibrosis progression. Approximately 10–20% of MASH patients develop cirrhosis over 10–20 years, and MASH has now surpassed hepatitis C as the leading indication for liver transplantation in the U.S.

The 2023 Nomenclature Change

The shift from NAFLD/NASH to MASLD/MASH was ratified at the International Liver Congress in June 2023. The change reflects two key insights: the term "nonalcoholic" defines the disease by what it is not, stigmatizing patients and obscuring its metabolic etiology; and the new criteria explicitly link diagnosis to at least one of five cardiometabolic risk factors (overweight/obesity, type 2 diabetes, hypertension, dyslipidemia, or metabolic syndrome).

• MASLD: Hepatic steatosis (>5% of hepatocytes with fat) plus at least one cardiometabolic risk factor, with alcohol consumption below threshold (men <30 g/day, women <20 g/day)
• MASH: MASLD with histological evidence of lobular inflammation and hepatocyte ballooning (steatohepatitis)
• MetALD: New category for patients with steatotic liver disease who drink more alcohol than MASLD thresholds but do not meet alcoholic liver disease criteria

FIB-4: Non-Invasive Fibrosis Assessment

Liver biopsy remains the histological gold standard for staging fibrosis, but its invasiveness, sampling error, and cost limit its use to high-risk patients. The FIB-4 index, originally validated in HIV-hepatitis C co-infected patients and subsequently validated across MASLD populations, offers non-invasive fibrosis stratification using four routinely available variables.

FIB-4 = (Age × AST) ÷ (Platelet count × √ALT)

Where age is in years, AST and ALT are in U/L, and platelet count is in 10⁹/L.

The AASLD 2023 MASLD Guidance recommends FIB-4 as the initial triage tool for all patients with MASLD identified in primary care. A low FIB-4 (<1.30) can confidently rule out advanced fibrosis in most patients under 65; the threshold is adjusted to <2.0 for patients over 65 to maintain specificity.

Resmetirom: The March 2024 FDA Approval

Resmetirom (Rezdiffra), developed by Madrigal Pharmaceuticals, received FDA approval on March 14, 2024 — making it the first pharmacological treatment ever approved specifically for MASH with moderate-to-advanced fibrosis (F2–F3). The approval was based on the MAESTRO-NASH phase 3 trial, which enrolled 966 adults with biopsy-confirmed MASH and fibrosis stages F1B through F3.

Results at 52 weeks were striking:

• MASH resolution (defined as NAS score improvement with no worsening of fibrosis) achieved in 25.9% (80 mg dose) and 29.9% (100 mg dose) vs. 9.7% for placebo
• Fibrosis improvement by ≥1 stage without MASH worsening achieved in 24.2% (80 mg) and 25.9% (100 mg) vs. 14.2% for placebo
• LDL-C reduction of 13–16% as a favorable metabolic side effect (resmetirom acts as a thyroid hormone receptor-beta agonist, selectively activating hepatic metabolism)

Resmetirom targets thyroid hormone receptor-beta (THR-β) in the liver selectively. THR-β activation in hepatocytes increases fatty acid oxidation, reduces lipogenesis, and promotes cholesterol conversion to bile acids. The hepatic selectivity (thyroid hormone receptor-alpha drives cardiac and systemic effects) avoids cardiovascular and thyroid side effects that doomed earlier non-selective thyromimetics.

Lifestyle Reversal: Quantifying the Benefit

Lifestyle intervention remains the cornerstone of MASLD treatment and the only proven approach for reversing disease at all stages. Weight loss produces dose-dependent histological improvements:

Bariatric surgery, which produces substantially greater weight loss, has demonstrated histological improvement in MASH and fibrosis at rates exceeding 85% in retrospective series. The NASHFIT trial (longitudinal cohort, 2022) reported fibrosis regression in 70% of bariatric surgery patients with paired liver biopsies at 5 years — though randomized trial evidence is still emerging. GLP-1 receptor agonists (semaglutide in particular) have shown MASH resolution rates of approximately 40–60% in phase 2 trials, with phase 3 ESSENCE results expected to further define their role alongside resmetirom.

This article is for informational purposes only. Consult a qualified healthcare professional.