What does the liver do?
The liver performs several distinct jobs at once. It is the body's main site of macronutrient metabolism — converting, storing and releasing carbohydrates, fats and proteins as the body needs them. It produces bile, which is required to digest and absorb dietary fat. It synthesizes proteins the blood depends on, including clotting factors and albumin. And it filters the blood, breaking down and clearing medications, alcohol and metabolic byproducts.
Because so many systems route through it, liver function is closely tied to metabolic health more broadly — which is why conditions like insulin resistance, obesity and type 2 diabetes are now understood as central drivers of liver disease, rather than separate from it.
How does the liver process nutrients?
Nearly everything absorbed in the small intestine is routed directly to the liver before reaching general circulation, through a dedicated blood supply called the portal vein.
What is fatty liver disease?
"Fatty liver" describes fat accumulation inside liver cells. In 2023, the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL) and the Latin American Association for the Study of the Liver (ALEH) jointly adopted new terminology: metabolic dysfunction-associated steatotic liver disease (MASLD), replacing the older term "non-alcoholic fatty liver disease" (NAFLD). MASLD is diagnosed when liver fat is present alongside at least one cardiometabolic risk factor, such as elevated blood pressure, blood sugar or triglycerides.
Fat accumulation, inflammation and fibrosis are related but distinct concepts. Having fat in the liver does not automatically mean inflammation or scarring is present.
Steatosis → MASLD → MASH → fibrosis: what the progression actually looks like
Current estimates suggest MASLD affects roughly a third of adults worldwide, though prevalence varies by population and how it's measured. Most people with simple fat accumulation never progress further. In a subset, the liver develops active inflammation and cell injury — a stage called metabolic dysfunction-associated steatohepatitis (MASH). In a smaller subset of those, ongoing injury leads to fibrosis, and in a smaller subset still, advanced fibrosis or cirrhosis.
The narrowing at each stage is deliberate: progression is not inevitable, and most people do not move through every stage.
What causes liver fibrosis?
Fibrosis is the liver's wound-healing response to sustained injury. When liver cells are repeatedly damaged — by fat-driven inflammation, in the case of MASH — the liver lays down scar tissue as part of normal repair. With ongoing injury, that scar tissue can accumulate faster than it's cleared. Evidence indicates the pace and extent of fibrosis varies considerably between individuals with similar metabolic risk profiles, pointing to genetic and other factors researchers are still working to fully characterize.
How are liver diseases detected?
Current guidelines recommend a stepwise approach: blood-based markers and risk calculators to identify who needs further evaluation, followed by imaging — such as elastography, which estimates liver stiffness as a proxy for fibrosis — for those at higher risk. Liver biopsy remains the reference standard for directly staging inflammation and fibrosis, but is generally reserved for cases where non-invasive results are unclear or higher-stakes decisions are being made.
What does current research show?
Until recently, there was no approved medication specifically for MASH. That changed in 2024–2025, with two large randomized trials reporting meaningful histologic improvement from two different drug classes.
A thyroid-hormone-receptor agonist improved MASH and fibrosis in a Phase 3 trial
In the MAESTRO-NASH trial, resmetirom resolved steatohepatitis without worsening fibrosis in 25.9% (80mg) and 29.9% (100mg) of participants, versus 9.7% on placebo. Fibrosis improved by at least one stage in 24.2% and 25.9% of treated groups, versus 14.2% on placebo. It received FDA accelerated approval in March 2024 — the first approved MASH treatment.
Accelerated approval means confirmatory trials on hard clinical outcomes — like progression to cirrhosis or liver-related death — are still ongoing.
A GLP-1 receptor agonist showed histologic and metabolic benefit
In a planned interim analysis of the ESSENCE trial at 72 weeks, once-weekly semaglutide resolved steatohepatitis without worsening fibrosis in 62.9% of participants, versus 34.3% on placebo, alongside an average 10.5% body-weight reduction versus 2.0% on placebo.
This is an interim readout from a 240-week trial; the trial's longer-term clinical outcome data (part 2) have not yet reported.
What remains uncertain
- Why do two people with similar metabolic risk factors develop very different degrees of liver disease?
- Why do some people with MASH progress to fibrosis while others do not, even over long follow-up?
- How much of that variation is explained by genetics — such as known risk variants — versus diet, activity or other exposures?
- Will the histologic improvements seen with newer therapies translate into fewer cases of cirrhosis, liver cancer and liver-related death over the long term?
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References & Further Reading
- A multi-society Delphi consensus statement on new fatty liver disease nomenclature.
- AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease.
- A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
- Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis.
- Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD).