Fatty liver disease is a condition in which fat accumulates in the liver cells (hepatocytes) without being caused mainly by heavy alcohol use. Since 2023 the field has used the umbrella term steatotic liver disease (SLD), with metabolic dysfunction-associated steatotic liver disease (MASLD) replacing the older name nonalcoholic fatty liver disease (NAFLD), and metabolic dysfunction-associated steatohepatitis (MASH) replacing nonalcoholic steatohepatitis (NASH). The disease is closely tied to obesity, insulin resistance, type 2 diabetes and dyslipidemia, so it is best understood as the liver component of a systemic metabolic disorder. It is among the most common chronic liver conditions in the world, and a substantial share of affected people go on to develop inflammation, scarring and, in some cases, cirrhosis and liver cancer.
The subject matters for public-health and clinical medicine for three reasons. First, its prevalence rises with the spread of excess body weight and metabolic risk factors, so it affects a large fraction of adults and a growing number of children. Second, most patients have no symptoms until significant fibrosis develops, which makes diagnosis and risk stratification central. Third, the disease is linked to cardiovascular disease and chronic kidney disease, so the liver is often not the main cause of death. Recent drug approvals for MASH have made treatment decisions more pressing.
This entry covers the terminology and classification of the disease; the biology of hepatic fat handling and how steatosis progresses to inflammation and fibrosis; genetic and environmental risk factors; histological and non-invasive assessment; natural history and complications; epidemiology; lifestyle, pharmacological and surgical management; pediatric disease; the history of research; and the public-health debate over naming and unresolved questions.
Terminology and definitions
Steatosis is the accumulation of triglyceride-rich fat inside hepatocytes. The diagnosis requires fat in more than about 5% of hepatocytes on histology, or an equivalent fat fraction on imaging such as magnetic resonance imaging proton density fat fraction. Below this level, the finding is usually not considered steatosis for diagnostic purposes.
For decades the condition was called nonalcoholic fatty liver disease (NAFLD), and its inflammatory form nonalcoholic steatohepatitis (NASH). Both names defined the disease by what it was not, namely significant alcohol intake and other known causes. In 2023, multinational liver societies and patient advocacy groups convened a Delphi process to rename the disease, with the primary goal of establishing an affirmative, nonstigmatizing name and diagnosis. The resulting consensus was published in 2023 in Hepatology, volume 78, pages 1966–1986, with a parallel version in the Journal of Hepatology.
Under the new framework, steatotic liver disease (SLD) is the umbrella term for all causes of hepatic fat. NAFLD was renamed MASLD (metabolic dysfunction-associated steatotic liver disease), and NASH was renamed MASH (metabolic dysfunction-associated steatohepatitis). The panel kept the word steatohepatitis because it was regarded as an important pathophysiological concept, which is why the inflammatory form retains its own name.
MASLD is defined as hepatic steatosis together with at least one of five cardiometabolic risk factors and no other discernible cause. The five factors cover adiposity (body mass index or waist circumference, adjusted for ethnicity), dysglycemia or type 2 diabetes, raised blood pressure or antihypertensive treatment, raised triglycerides or lipid-lowering treatment, and low HDL cholesterol or its treatment. There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors. In the presence of hepatic steatosis, the finding of any CMRF would confer a diagnosis of MASLD if there are no other causes of hepatic steatosis.
The shift from NAFLD to MASLD is logically important because the old diagnosis was essentially a diagnosis of exclusion. The new definition asks for positive evidence of metabolic dysfunction, so the metabolic criteria are part of the diagnosis itself rather than a background description. Steatosis can be identified by histological (biopsy), imaging studies, or blood biomarkers indicating hepatic fat accumulation. Cases with steatosis but neither metabolic risk factors nor a known cause are placed in a separate group, cryptogenic SLD.
MetALD is a category for people who meet MASLD criteria but drink more alcohol than the MASLD range allows. MetALD was defined as female individuals with MASLD who drink 140–350 g of ethanol per week and male individuals with MASLD who drink 210–420 g of ethanol per week. Those who drink above these upper limits fall into alcohol-associated liver disease (ALD), while those below the lower limits remain in MASLD. The thresholds were set by expert consensus rather than from outcome data, and the panel acknowledged that the effect of a given intake varies between individuals. Within the MetALD range, the condition can be seen to be MASLD or ALD predominant. Some clinicians have argued that a single metabolic criterion should not be sufficient to diagnose MASLD in people who exceed the alcohol thresholds, because alcohol itself may be the main driver in that case.
Classification and differential causes
Since the 2023 multisociety Delphi consensus, <i>steatotic liver disease</i> (SLD) has been the umbrella term for any condition in which hepatic fat accumulates, whatever its cause. Within SLD, the main categories are metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and alcohol-related liver disease (MetALD), alcohol-associated liver disease (ALD), etiology-specific forms, and cryptogenic SLD, which is the residual group. MASLD requires steatosis together with at least one of five cardiometabolic risk factors: raised body mass index or waist circumference, impaired glucose metabolism, high blood pressure, elevated triglycerides, or low HDL cholesterol. Alcohol intake must stay below the MetALD threshold. Patients with steatosis but no cardiometabolic factor and no identifiable cause are classed as cryptogenic SLD. Where the picture is incomplete, clinicians may record "possible MASLD" and reassess periodically.
MASLD, MetALD and ALD
MetALD describes people who meet MASLD criteria but drink more than the MASLD ceiling: 140–350 g of alcohol per week for women and 210–420 g per week for men. ALD is defined by intake above 350 g per week for women and 420 g per week for men, and it is diagnosed irrespective of metabolic risk. The intermediate range is therefore a dual-etiology category in which both metabolic dysfunction and alcohol are considered meaningful contributors. The thresholds are expressed in grams per week, and the corresponding daily figures are roughly 20–50 g and 30–60 g for MetALD, and above 50 g and 60 g for ALD. Some clinical sources also state the MASLD ceiling as 20 g/day for women and 30 g/day for men. Proposed biomarker cut-offs for phosphatidylethanol (PEth), a marker of recent drinking, have been suggested for each category, but these remain provisional.
Other identifiable causes
Etiology-specific steatosis includes drug- and toxin-induced liver injury and monogenic metabolic diseases. Other conditions that can cause hepatic fat include viral hepatitis, rapid weight loss and parenteral nutrition, although these are assessed by exclusion rather than through the MASLD criteria. Among the monogenic disorders, lysosomal acid lipase deficiency (LALD) is a rare autosomal recessive disease caused by mutations in the LIPA gene. Complete loss of enzyme activity causes Wolman disease, which is fatal in infancy, whereas partial activity causes cholesteryl ester storage disease, which usually presents in childhood or early adulthood and can progress to fibrosis and cirrhosis. The steatosis in LALD is mainly microvesicular and reflects cholesteryl ester as well as triglyceride accumulation, while typical metabolic steatosis is macrovesicular and predominantly triglyceride. LALD is under-recognized and is often misdiagnosed as familial hypercholesterolemia, familial combined hyperlipidemia, or NAFLD. Other monogenic examples include Wilson disease, hypobetalipoproteinemia and inborn errors of metabolism, all of which can produce steatosis.
How clinicians distinguish the causes
Separation begins with history: quantity and pattern of alcohol consumption, medication and supplement use, recent weight loss or bariatric surgery, parenteral feeding, family history of early dyslipidemia, and signs such as hepatomegaly. Self-reported alcohol intake is often unreliable, so direct biomarkers such as PEth are increasingly used to support the MASLD/MetALD/ALD boundary. Serology for hepatitis B surface antigen and hepatitis C antibody or RNA excludes viral causes. Metabolic and genetic testing addresses rarer etiologies: LAL enzyme activity measured in leukocytes or dried blood spots is the standard test for LALD, and copper studies are used for Wilson disease. Histology can give clues, for example microvesicular steatosis with foamy macrophages suggests LALD and should prompt specific testing, but biopsy alone rarely settles the cause.
Coexistence and continuum
Several causes frequently coexist. A person with metabolic risk factors who drinks at a moderate level may have a combined etiology, and additional contributors to steatosis can be added to an existing diagnosis. Clinicians increasingly regard MASLD, MetALD and ALD as points on a continuum rather than discrete diseases, because the combined effect of alcohol and metabolic dysfunction on fibrosis, portal hypertension and hepatocellular carcinoma differs from either factor alone. The categories are therefore practical tools for classification and management, and their boundaries are approximate.
Hepatic lipid metabolism and fat accumulation
Under normal conditions the liver holds only a small amount of triglyceride, because it is a metabolic processing organ rather than a fat store. Because the liver does not act as a primary fat storage depot, the steady state concentration of hepatic TGs is low under normal physiological conditions. The steady state depends on a balance between lipid input, which comes from fatty acid uptake and de novo lipogenesis, and lipid removal, which comes from mitochondrial fatty acid oxidation and export in VLDL particles. This arises from an imbalance between lipid acquisition (i.e., fatty acid uptake and de novo lipogenesis) and removal (i.e., mitochondrial fatty acid oxidation and export as a component of VLDL particles).
Hepatocytes take up free fatty acids from the blood, and the largest share of this supply comes from adipose tissue lipolysis. In a stable-isotope study of people with NAFLD, DNL contributed about 26% of fatty acids in livers of NAFLD patients, free fatty acids from adipose tissue and from the diet contributed 59% of liver lipids, and dietary triglycerides associated with chylomicrons contributed 15% of liver fat. Estimates vary with the prandial state and the method used, but the principle holds that circulating fatty acids form the bulk of hepatic triglyceride, while de novo synthesis adds a substantial minority.
De novo lipogenesis converts carbohydrate substrates into fatty acids. The main drivers are the transcription factors SREBP-1c and ChREBP, which are regulated broadly by two key transcription factors: SREBP1c and ChREBP. In NAFLD, the enzymes they control, including acetyl-CoA carboxylase and fatty acid synthase, are expressed at higher levels. The newly made fatty acids are then esterified onto glycerol-3-phosphate, and an estimated 15–25% of these originate from DNL of the hepatic triglyceride pool, with the rest arising mainly from circulating fatty acids and dietary lipid.
Fatty acids leave the hepatocyte by two routes. The first is oxidation: fatty acid oxidation is controlled by PPARα and reduces intrahepatic fat levels by utilizing lipids as an energy source. Most oxidation occurs in mitochondria, but when lipid overload or mitochondrial impairment occurs, a larger share shifts to peroxisomes, which generates reactive oxygen species. The second route is export. Hepatocytes assemble triglycerides and cholesterol esters into very-low-density lipoprotein (VLDL) and release it into the circulation. Liver steatosis develops when hepatocyte triglyceride synthesis exceeds VLDL triglyceride secretion. Triglyceride that is not oxidized or exported is stored in cytoplasmic lipid droplets, which enlarge into the macrovesicular steatosis seen on biopsy.
Insulin resistance pushes this system toward accumulation through several parallel effects. Hyperinsulinemia stimulates lipogenic gene expression, and insulin resistance, a key feature of NAFLD, promotes DNL in a high insulin environment. Insulin-resistant adipose tissue releases more fatty acids, since it promotes peripheral lipolysis, which increases the delivery of nonesterified fatty acids to the liver. Hormonal changes also contribute. Together, hyperglucagonemia, hypercortisolemia and insulin resistance encourage VLDL hypersecretion in fatty liver disease. The overall pattern is that the liver often exports more VLDL in fatty liver disease, although the synthesis and disposal of triglyceride can still be unbalanced.
Diet, particularly sugar intake, modifies these pathways. Fructose is a potent lipogenic substrate because acutely, fructose increases de novo lipogenesis through the efficient and uninhibited action of ketohexokinase and aldolase B which yields substrates for fatty-acid synthesis. Over time it also amplifies the transcriptional program: chronic fructose consumption further enhances the capacity for hepatic fructose metabolism by activating several key transcription factors (i.e., SREBP1c and ChREBP) which augment the expression of lipogenic enzymes. Because the liver metabolizes most dietary fructose, dietary fructose is funneled into the liver and mostly metabolized to triglycerides by de novo lipogenesis (DNL). Fructose uptake also does not depend on insulin, so it can keep supplying lipogenic substrate when insulin signaling is impaired. Glucose and fructose each drive DNL in hepatocytes and can increase steatosis and affect insulin signaling.
Adipose tissue dysfunction links fat distribution to liver fat. Expanded visceral fat, in particular, appears to matter. Visceral adiposity contributes to hepatic triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance by increasing the portal delivery of free fatty acids to the liver. Dysfunctional adipocytes show enhanced lipolysis with release of free fatty acids, release of adipokines and inflammatory cytokines, which together with hepatocellular insulin resistance favors steatosis. Visceral fat drains directly into the portal circulation, so its free fatty acids reach the liver before they reach other tissues, which is one reason that central fat distribution is more closely linked to hepatic fat than total body weight alone.
Pathogenesis: from steatosis to steatohepatitis
Lipotoxicity
Fat stored in hepatocytes is not metabolically inert. When fatty acid influx and synthesis outpace esterification and oxidation, the cell accumulates lipid intermediates that are toxic in their own right. Saturated fatty acids, free cholesterol, ceramides, lactate and succinate act as paracrine signals that reinforce inflammatory and fibrotic responses across several liver cell types. Two intermediates are especially well studied. Diacylglycerol that builds up inside hepatocytes activates particular protein kinase C isoforms, notably PKCε, which interfere with insulin receptor signaling and Akt activation. Ceramides further weaken insulin action by blocking Akt phosphorylation, and they promote mitochondrial dysfunction and apoptosis. Sustained exposure to free fatty acids and lipotoxic metabolites engages JNK and NF-κB signaling, which increases cytokine and chemokine production and recruits immune cells.
The consequences depend on how far the cell's tolerance has been exceeded. In the early stage, impaired lipid processing is the dominant defect, producing substantial lipid accumulation, while hepatocytes can resist lipotoxic effects and cell death remains relatively rare. Secondary insults may later overwhelm this capacity, increasing hepatocyte death and triggering inflammation. This two-step view underlies the "multiple parallel hits" model, in which steatosis sensitizes the liver to oxidative stress, inflammation, endoplasmic reticulum stress and apoptosis, which then drive progression.
Oxidative stress and mitochondrial dysfunction
Insulin resistance and lipotoxicity together initiate a cascade of mitochondrial dysfunction in hepatocytes. Mitochondria normally consume fatty acids through β-oxidation, so their impairment shifts lipid flux toward toxic intermediates and leaves reactive oxygen species less controlled. Reviews describe impaired mitochondrial oxidation as one of the three drivers of the transition from steatosis to MASH, alongside increased hepatic fatty acid uptake and elevated de novo lipogenesis. The oxidative damage is self-amplifying: uncontrolled oxidative stress directly damages lipids through peroxidation, which activates hepatic stellate cells, recruits Kupffer cells and increases cytokine secretion. Oxidative stress is also one of the upstream activators of apoptosis, which in turn feeds inflammation and fibrogenesis.
Kupffer cells, inflammation and hepatocyte death
Kupffer cells, the resident macrophages of the liver, are among the first cells to respond when hepatocytes are injured. In a diet-induced mouse model, Kupffer cells responded first to hepatocyte injury, producing TNFα, inducing chemokines and promoting monocyte recruitment. Silencing TNFα in myeloid cells slowed disease progression in that model. Additional recruited monocytes and macrophages amplify the response, so inflammation becomes a self-sustaining loop rather than a simple reaction to fat.
Kupffer cells are not merely bystanders in hepatocyte injury. In a rat sucrose-fed MASH model, depleting Kupffer cells attenuated hepatic inflammation, oxidative stress, endoplasmic reticulum stress and apoptosis. Steatosis and insulin resistance in the same model were unchanged, which suggests that the inflammatory and metabolic arms of the disease can be separated experimentally. Cell death is the link between these processes. Apoptosis is a pivotal mechanism contributing to inflammation and fibrogenesis in MASH. Dying hepatocytes that are swollen and fragile take on the ballooned appearance that, together with lobular inflammation, defines MASH on histology.
Hepatic stellate cells and the step to fibrosis
In healthy liver, PPARγ activation keeps hepatic stellate cells quiescent, and these cells store vitamin A as retinyl esters within large lipid droplets. Stellate cells make up only about 5–10% of the total liver cell population, but they are the principal source of matrix deposition. In MASH, their activation is driven by metabolic stress, lipotoxicity and chronic inflammation. Ceramides and diacylglycerols, together with Kupffer cell signals, promote this transdifferentiation of stellate cells into contractile, fibrogenic myofibroblast-like cells. Activated cells lose their retinoid stores and gain a proliferative, inflammatory phenotype with enhanced extracellular matrix production.
This is the point at which inflammation becomes fibrosis. Deposition begins as early perisinusoidal collagen deposition, followed by portal and eventually bridging fibrosis. Because stellate cells sit in the space of Disse between sinusoidal endothelial cells and hepatocytes, matrix they lay down is in direct contact with the cells that are dying, which links the fibrotic and necroinflammatory processes in the same microenvironment. The rate at which this occurs varies between individuals, and the reasons for that variation are discussed in the sections on genetic and environmental risk.
Genetic and environmental risk factors
Common genetic variants
Fatty liver disease has a substantial heritable component. Genome-wide association studies have identified common risk variants in PNPLA3, TM6SF2, GCKR and MBOAT7, and protective variants in HSD17B13 and MARC1. The strongest of these is the PNPLA3 I148M substitution (rs738409). The change from isoleucine to methionine weakens the enzyme's lipase activity, so lipid droplets accumulate in hepatocytes. Its effect extends beyond fat: carriers of the G allele show higher rates of advanced fibrosis than non-carriers. In one biopsy cohort of 703 patients, the PNPLA3 G/G genotype carried an adjusted odds ratio of 3.48 for advanced fibrosis (aOR 3.48, p < 0.001).
The TM6SF2 E167K variant (rs58542926) replaces glutamate with lysine and impairs the assembly and secretion of very-low-density lipoprotein, so triglycerides are retained in the liver. Carriers have more hepatic fat but lower circulating triglycerides and cholesterol, and they appear to be protected from some cardiovascular complications (the variant causes VLDL retention in the liver and increases intrahepatic triglycerides, yet it protects against cardiovascular complications). The same variant nonetheless raises the risk of fibrosis, with an adjusted odds ratio near 2 in the cohort cited above.
MBOAT7 rs641738 reduces hepatic expression of the enzyme, which shifts phosphatidylinositol remodeling toward saturated species that feed triglyceride synthesis. Its association with fibrosis is weaker than that of PNPLA3, and not all populations replicate it. One Eastern European study found no link between the variant and fibrosis or cirrhosis, whether alcohol-related or hepatitis C-related.
Two common variants appear to be protective. An HSD17B13 splice variant (rs72613567) produces a truncated protein, and its carriers have lower aminotransferases, lower risk of NASH and nonalcoholic cirrhosis. Protective variants in HSD17B13 and MARC1 have been estimated to confer a 10–50% lower risk of cirrhosis. The HSD17B13 variant may also soften the risk conferred by PNPLA3 I148M. Because each variant contributes a modest effect, researchers have combined them into polygenic risk scores. These scores are being tested for predicting steatosis, cirrhosis and hepatocellular carcinoma.
Gene–environment interaction
Genetic background does not determine disease on its own. The disorder is widely described as multifactorial, resulting from a complex interaction of genetic and environmental factors. Two people with the same body weight and similar diets may therefore differ widely in liver fat and fibrosis, depending on which risk alleles they carry. Carriers of PNPLA3 risk alleles, for example, tend to accumulate more fat when their intake of refined carbohydrate and sugar is high, while protective variants can blunt the effect of an unhealthy diet. The reverse also holds: a favorable environment does not fully erase the risk of a high-risk genotype.
Diet, physical activity and sleep
Dietary patterns are among the most modifiable contributors. Sugar-sweetened beverages deliver a large fructose load in a form that the liver can convert rapidly to fat through de novo lipogenesis, and they are associated with higher liver fat in observational studies. Ultra-processed foods, which are typically rich in refined starch, added sugar and saturated fat while being low in fiber, are linked to steatosis and to the wider metabolic syndrome. Sedentary behavior reduces the muscle uptake of glucose and fat, which encourages insulin resistance and fat delivery to the liver. Short or disrupted sleep has been associated with higher liver fat in cohort studies, and sleep-disordered breathing, which is common in people with obesity, is itself linked to the disease.
Gut microbiota and the gut–liver axis
The liver receives blood from the intestine through the portal circulation, and the two organs are connected by the bile duct and by the systemic circulation. Under normal conditions, a small portion of the gut microbiota can reach the liver but will be eliminated by Kupffer cells. In people with fatty liver disease, the barrier between gut and bloodstream is often compromised. Studies have reported higher intestinal permeability, more small intestinal bacterial overgrowth and greater bacterial translocation in patients with liver injury. Children with steatohepatitis, for example, have been found to show higher intestinal permeability and higher blood lipopolysaccharide levels than children with simple steatosis. Lipopolysaccharide that reaches the liver can activate Toll-like receptor 4 on immune cells and trigger inflammatory signaling, which links gut events to the inflammation described in the pathogenesis section.
Microbial metabolites contribute in other ways. Some gut bacteria produce ethanol, and a larger endogenous ethanol output has been reported in patients with fatty liver disease. Other products affect the disease in the opposite direction. Short-chain fatty acids, produced when bacteria ferment dietary fiber, help maintain the intestinal barrier and reach the liver through the portal vein. Much of the evidence for these mechanisms comes from observational human studies and rodent models, and whether dysbiosis is a primary cause or a consequence of metabolic disease remains uncertain.
Histology and staging
Histological hallmarks of MASH
Liver biopsy assesses four interrelated features: fat within hepatocytes, lobular inflammation, injured hepatocytes that swell (ballooning), and fibrosis. Hepatocellular steatosis and ballooning, mixed acute and chronic lobular inflammation and fibrosis form the core of the diagnosis. Steatosis alone does not establish MASH; the diagnosis depends on the combination of injury and inflammation, while fibrosis is staged separately.
Activity scoring and grading
The NASH Clinical Research Network (NASH CRN) system, derived from the earlier Brunt system, is the most widely used scoring tool in trials. Brunt et al. first proposed a grading and staging system for NASH based on liver biopsies from 51 adult patients, and the NASH CRN version later became the reference. Each component is graded separately. Steatosis is scored 0 for under 5%, 1 for 5–33%, 2 for 34–66%, and 3 for over 66% of the parenchyma. Lobular inflammation is counted as foci per 20× field, with 0 for none, 1 for fewer than 2, 2 for 2–4, and 3 for more than 4. Ballooning is graded as 0 for none, 1 for few ballooned hepatocytes, and 2 for many.
The NAFLD activity score (NAS) adds these three components. The total is the sum of the steatosis, lobular inflammation and ballooning grades, giving a 0–8 scale in which higher scores indicate more severe disease. Fibrosis is excluded from the NAS, and a stage based upon the degree of fibrosis is reported alongside it. The NAS is mainly a research and trial tool. Its numerical logic does not map neatly onto diagnosis or prognosis. In one analysis, ballooning was classified as none in 41 of 473 biopsies (9%) with a NAS of 5 or more, and biopsies with definite steatohepatitis but a NAS of 4 or lower are clinically important because a low NAS could be interpreted as indicating absence of significant disease. In a cohort of patients with biopsy-confirmed disease, the mean NAS was 4.2 in patients with cirrhosis, 5.1 in those with bridging fibrosis and 4.0 in those with F0–F2 fibrosis, so the activity score does not track fibrosis closely.
Fibrosis staging
Fibrosis is staged on a scale from F0 to F4 using the NASH CRN system. Stage 0 is no fibrosis; stage 1 is mild, moderate or portal-only fibrosis; stage 2 combines perisinusoidal and portal/periportal fibrosis; stage 3 is bridging fibrosis; and stage 4 is cirrhosis. The stage carries the most prognostic weight. The recognition of liver fibrosis as the main predictor of major adverse liver outcomes is one of the central shifts in the field. Because of this, fibrosis stage, rather than steatosis or activity alone, largely determines risk estimates and trial eligibility.
The categorical scale has its own limitations. The NASH-CRN fibrosis scoring system defines only five categories, and it cannot distinguish a patient near the lower end of stage F3 from one near the upper end. Stages are therefore broad, and two patients in the same category may have different prognoses and treatment needs.
Limitations of histological scoring
Biopsy has several sources of error. Sampling variability is the first. Steatosis, inflammation and fibrosis are distributed unevenly across the liver, and observer-dependent interpretation adds further uncertainty, particularly for subjective features such as ballooning and lobular inflammation. A needle sample is tiny relative to the organ, and biopsy cores shorter than 1.5 cm are associated with reduced sensitivity for detecting MASH, which is why core length and portal tract count are increasingly reported.
Interobserver agreement is also imperfect. In one large trial dataset, inter-reader agreement was poor and intra-reader variability was modest, with kappa values for histologic endpoints generally 0.4 or less across paired biopsies, while intra-reader agreement ranged from 0.645 to 0.836. Among nine expert pathologists reviewing digitised slides, the kappa value for overall agreement on the presence or absence of ballooning was 0.197. For fibrosis, a comparison of four pathologists using the METAVIR system found that inter-observer agreement was moderate (mean k ± SD: 0.58 ± 0.26).
These problems affect trials and clinical care alike. Regulators have noted that conventional histological assessment requires staining of liver sections with subsequent review, which makes it complex, subjective, and prone to inter- and intra-reader variability and error. When baseline biopsies were re-read centrally in one MASH trial, 17 to 28% of enrolled patients were assessed as ineligible at baseline by central pathologist reading, largely because local and central readers examined different sections. Standardised central reading panels and digital pathology are now used to reduce this variability, but histology remains the reference standard against which noninvasive tests are validated.
Clinical course and complications
Natural history: uneven and often slow
Progression is uneven. Inflammation and fibrosis that advance toward cirrhosis affect only a subset of people with the condition, and cirrhosis develops in roughly 3–5% of patients, often over more than 20 years. Follow-up studies that used serial biopsies give a sense of the intermediate steps. Estimates suggest that 12–40 % of individuals with MASL progress to MASH within 8–13 years. Among people who already have MASH with early fibrosis, about 15% reach cirrhosis or decompensation in a similar period, and this percentage rises to 25 % among patients with advanced precirrhotic fibrosis at baseline. Fibrosis itself tends to advance gradually, and insulin resistance and other modifiable parameters can influence the pace of fibrosis progression. Among the available markers, fibrosis stage has proven to be the most accurate predictor of progression to cirrhosis, whether it is measured directly or estimated by imaging or biomarkers.
The share of cirrhosis attributable to this condition has grown considerably. Its contribution to new cirrhosis cases rose from 14% in 2000 to 36% in 2019, when it became the leading cause. Coexisting disease can also accelerate other liver conditions: MASLD may speed progression in people with alcohol-related liver disease or chronic hepatitis B and may synergistically promote cirrhosis or HCC.
Decompensated cirrhosis
Once cirrhosis is established, the liver's loss of function and portal hypertension produce decompensation. The main features are ascites (accumulation of fluid in the abdominal cavity), variceal bleeding from dilated veins in the esophagus or stomach, and hepatic encephalopathy, a neurological disturbance caused by toxins the liver can no longer clear. In one prospective cohort, a decompensation event, including variceal hemorrhage, ascites or encephalopathy, was linked to increased all-cause mortality after adjustment for age, sex, diabetes and baseline histology (adjusted HR 6.8).
Hepatocellular carcinoma
Cirrhosis remains the dominant setting for liver cancer. Roughly 80% of HCC cases occur in patients with cirrhosis, but incidence among people without cirrhosis has risen significantly in developed countries alongside the growth of this condition. The absolute risk differs sharply by fibrosis status. In one cohort, the annual incidence rate of HCC was 10.6 per 1000 person-years among individuals with cirrhosis, 0.08 per 1000 person-years among those with NAFLD without cirrhosis and 0.02 per 1000 person-years among controls. Nonetheless, cancer without cirrhosis is not rare. In NAFLD, up to 50% of patients with HCC had no clinical or histological evidence of cirrhosis. In a multicenter French series, 35% of HCC cases occurred in the absence of cirrhosis. Compared with people with cirrhosis, these patients were older and had larger tumors, but better preserved liver function. Fibrosis still shapes the risk: fibrosis is the main predictor of long-term liver-related morbidity in NAFLD, and cancer risk tracks the same gradient.
Mortality by fibrosis stage
Death risk rises with fibrosis stage, and the cause of death shifts with it. In a prospective multicenter study of 1,773 patients, all-cause mortality in those with fibrosis stages 0–2 was 0.32 per 100 person-years, compared with 0.89 per 100 person-years in those with bridging fibrosis and 1.76 per 100 person-years in those with cirrhosis. A meta-analysis of NAFLD cohorts reported that the risk of liver-related mortality increased exponentially with fibrosis stage from F2 onward (F2: HR, 4.1; F3: HR, 7.6; F4: HR, 15.1). Advanced fibrosis (F3–F4) was associated with a hazard ratio of about 3.3 for all-cause death and 10.4 for liver-related death, compared with F0–F2. Patients with cirrhosis have a 3-fold higher risk of death versus those with stage 3 fibrosis.
At earlier stages, the picture differs. Patients with advanced fibrosis or cirrhosis (F3 and above) carry the highest risk of liver-related death, while cardiovascular events and non-hepatic malignancies are the most common complications in early-stage disease. Excess deaths in early stages may stem mainly from systemic inflammation rather than from liver complications. Overall, although liver-related mortality is increased at fibrosis stages F3 and F4, cardiovascular disease remains the leading cause of death. Liver-related death is therefore concentrated in people with advanced fibrosis, while most deaths in the wider population with this condition are attributable to cardiometabolic disease.
Extrahepatic associations
Steatotic liver disease is connected to several conditions that share its metabolic roots. Some of these links are well documented, while others are still debated over whether the liver disease adds independent risk or simply marks shared cardiometabolic dysfunction.
Cardiovascular disease
Most deaths among people with MASLD are attributed to vascular and cardiac causes. Cardiovascular diseases are the leading cause of death in patients with MASLD. Imaging studies show higher rates of subclinical disease. In the Framingham Heart Study, MASLD was independently associated with coronary artery calcification, even in lean individuals. Cohort data from Japan and Australia report hazard ratios of roughly 1.2 to 1.5 for ischemic heart disease, independently of age and metabolic comorbidities. Within the disease spectrum, fibrosis stage being the strongest disease-specific risk factor for cardiovascular events.
The independence of this association is contested. A 2026 critical appraisal in the Journal of Hepatology concluded that MASLD cannot currently be considered an independent cardiovascular risk factor, though it identifies a higher-risk group. Its reasoning rests on Mendelian randomisation and large cohorts, which suggest that excess liver fat per se is not independently atherogenic; rather, accompanying abnormalities in lipid profiles mediate the observed risk. Some primary-care cohorts also found that the association between MASLD and myocardial infarction or stroke became nonsignificant after full adjustment for metabolic risk factors. Other large cohorts report an association that persists after adjustment, so the evidence remains mixed.
Type 2 diabetes, hypertension and chronic kidney disease
Type 2 diabetes is the most closely linked metabolic partner. This association is driven by insulin resistance (IR), a central feature of both MASLD and T2DM. In one set of Chinese studies cited in a review, among 1521 patients with type-2 DM, the prevalence of liver steatosis was 75.1%, while liver fibrosis was present in 28.0% of patients. Fibrosis severity also tracks with metabolic risk: the degree of liver fibrosis correlates with increased risk of T2DM and hypertension.
For kidney disease, a Korean national survey analysis found that MASLD was associated with CKD (adjusted OR, 2.47; 95% CI, 1.76–3.47; p<0.001). Within that group, hypertension and diabetes were consistently associated with CKD. A UK Biobank analysis reported that MetS (≥ 3 traits) increased prevalent CKD risk, and that advanced fibrosis further raised this risk. Because hypertension, diabetes and obesity are common confounders, MASLD has been shown to be independently associated with CKD even when adjusted for cardiometabolic covariates, although causation has not been established. In primary-care patients with type 2 diabetes, one study found no excess CKD, neuropathy or retinopathy overall, but participants with MASLD and a higher histopathological fibrosis stage had an increased risk of microvascular complications.
Polycystic ovary syndrome, sleep apnea and endocrine links
The association with polycystic ovary syndrome is among the best-described endocrine links. Women with PCOS have a 2-4 times higher risk of NAFLD independent of body mass index than healthy weight-matched controls. Insulin resistance and hyperandrogenemia together play a central role in the pathogenesis of NAFLD.
The relationship with obstructive sleep apnea runs in both directions. In one study of women with PCOS, the prevalence of NAFLD (83.3% vs. 26.9%; P<.001) were higher in patients with OSA than those without OSA. Conversely, in a large Korean cohort, the risk of OSA was significantly higher in the higher FLI groups, suggesting that fatty liver indices can help identify people at risk of sleep apnea. Proposed mechanisms include chronic intermittent hypoxia, which can trigger and increase the accumulation of triglycerides (TG), low-grade inflammation, tissue necrosis and liver fibrosis. Untreated apnea itself also contributes to metabolic harm, since left untreated, obstructive sleep apnea can precipitate or exacerbate insulin resistance, glucose intolerance, and hypertension.
Implications for care
These associations shape practice mainly through screening and coordinated management. Clinically, MASLD identifies individuals with higher than average cardiovascular risk who are frequently undertreated with preventive therapies. Current recommendations advise systematic screening for MASLD in individuals with T2DM, and assessment of glucose metabolism in those with hepatic steatosis. Proposed care pathways for patients with kidney disease combine non-invasive fibrosis assessment and cardiometabolic risk evaluation to guide risk stratification. Critics note that patients with MASLD, regardless of the number and type of MetS traits present, are managed the same way in a clinical setting despite substantial disease heterogeneity.
Noninvasive assessment: blood tests and scores
Routine liver enzymes are the usual starting point for suspected steatotic liver disease, but they are a poor guide to how much scarring is present. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) mainly reflect hepatocyte injury rather than fibrosis stage. Many people with advanced fibrosis have enzyme levels that fall within the reference range. One cited study found that 22–33% of people with MASLD and advanced fibrosis had ALT below 40 U/L, and that ALT correlates poorly with histological severity. Reference limits are also under revision. Recent healthy-population studies suggest lower upper limits, around 29–42 U/L in men and 19–30 U/L in women, and Japanese guidance uses 30 U/L as a referral trigger. AST can rise after alcohol, strenuous exercise or muscle injury, so an isolated value says little about the liver itself. Albumin, bilirubin and the INR usually stay normal until fibrosis is advanced, which limits their use for early detection.
Composite scores combine routine laboratory values with age and, in some cases, anthropometric data. The fibrosis-4 index (FIB-4) was developed in patients with hepatitis C and is calculated as . Its usual thresholds are below 1.30 for low risk, 1.30–2.67 for an indeterminate range, and above 2.67 for high risk. Many guidelines use a higher low-risk cut-off of about 2.0 in people over 65 to limit age-related false positives. In a 2026 bivariate meta-analysis of 14 studies, a cut-off below 1.3 had a pooled sensitivity of 0.73 and specificity of 0.69 for advanced fibrosis, while a cut-off below 1.0 gave higher specificity (0.83) at the cost of sensitivity (0.63). Its negative predictive value is the feature that makes it useful as a filter. Its performance drops in some groups. In people with diabetes or obesity, FIB-4 below 1.30 under-triages patients, so these individuals are often sent directly to elastography. Accuracy also falls in people with chronic hepatitis B and concurrent metabolic liver disease.
The NAFLD fibrosis score (NFS) uses age, BMI, impaired fasting glucose or diabetes, the AST/ALT ratio, platelet count and albumin. Using the original published cut-offs, a score below about −1.455 suggests low risk, a score above about 0.676 suggests high risk, and values in between remain indeterminate. The Enhanced Liver Fibrosis (ELF) test is a different kind of marker. It measures three extracellular matrix components, hyaluronic acid, amino-terminal propeptide of type III procollagen and TIMP-1, which are direct products of stellate-cell activity. Thresholds vary by source. The manufacturer's cut-off of 7.7 identifies the absence of fibrosis, 9.8 suggests severe fibrosis, and 11.3 or higher suggests cirrhosis. In the UK, NICE uses 10.51 as the threshold for advanced fibrosis and referral. The trade-off is clear in meta-analysis data. At 7.7, sensitivity exceeds 0.9, but specificity is only about 0.34. At 10.51, specificity rises to about 0.93, while sensitivity falls to about 0.51.
In primary care, these tools are normally used in sequence rather than all at once. FIB-4 is the cheapest step, and a low result can usually end further specialist assessment if other risks are absent. People with indeterminate or high scores are then referred for ELF, elastography or, in some pathways, specialist review. Sequential strategies can reduce costs, since ELF is proprietary and more expensive than FIB-4. The approach is not fully reliable, however. A large Danish screening study found that many people with low transient elastography readings also had low ELF values, but the correlation between the two tests was weak. Some people with significant fibrosis are therefore missed, which is why guidelines advise against treating a single low score as definitive when diabetes, obesity or other risk factors are present.
Research and specialist settings are testing additional blood-based markers. These include APRI, which relies on AST relative to the upper limit of normal and the platelet count, and proprietary panels such as FibroTest and FibroMeter, which combine bilirubin, macroglobulins, GGT, haptoglobin and apolipoproteins or matrix proteins. Such panels have shown good negative predictive value in some cohorts, but none has yet displaced FIB-4 as the first-line tool in most health systems. Their results cannot be compared directly across assays, and cut-offs derived in one population often perform differently in another. Transient elastography values in kilopascals likewise should not be treated as interchangeable with blood-score results, even though both are used to triage patients.
Imaging and liver biopsy
Ultrasonography
Ultrasonography is the usual first imaging test. It is also highly operator dependent, but it has advantages of being widely available, low cost, and no radiation exposure. Its accuracy depends strongly on how much fat is present. In a 2021 meta-analysis of observational studies, ultrasound detected steatosis of at least 5% of hepatocytes on histology with a pooled sensitivity of 82% and specificity of 80%, and detected moderate-to-severe steatosis (at least 30%) with 85% for both measures. Earlier studies reported high specificity (80%–100%) but low sensitivity (50%–70%) for fatty liver, and sensitivity was especially poor for mild steatosis. The discrepancy reflects differences in reference standards and in how the images were read. A 2022 reappraisal that used MRI proton density fat fraction as the reference reported a sensitivity of 83.4% for mild steatosis, which suggests that more standardized readings can improve performance. Its sensitivity is also reduced in people with severe obesity and in those with small amounts of fatty infiltration. Grading is semi-quantitative: it depends on echogenicity, attenuation of the acoustic beam, and how well the intrahepatic vessels and diaphragm can be seen. Computed tomography is generally not preferred, because of radiation exposure and limited accuracy for mild steatosis.
Transient elastography and controlled attenuation parameter
Transient elastography (FibroScan) combines two measurements. Stiffness is estimated from the speed of a mechanically generated shear wave through the liver, which is converted into a stiffness value. The controlled attenuation parameter (CAP) is derived from the attenuation of the ultrasound signal as it passes through the same volume, and it serves as a surrogate for hepatic fat. CAP is measured in decibels per meter (dB/m), with typical values ranging from 100 to 400 dB/m. Because the cutoffs depend on the probe and the population studied, published thresholds vary considerably. In a study of patients with chronic liver disease using the M probe, optimal cutoffs for steatosis grades S1, S2 and S3 were 206.5, 232.5, and 282.5 dB/m, respectively. Other probe-specific cutoffs placed the grade boundaries at different values. In potential living liver donors, a CAP above 259 dB/m identified macrovesicular steatosis greater than 10% with a sensitivity of 84.2% and a specificity of 92.4%. The technique is rapid and noninvasive, but it measures fat and stiffness separately, and it does not provide the histological information that distinguishes steatohepatitis from simple steatosis.
MRI proton density fat fraction and magnetic resonance elastography
Magnetic resonance imaging is the most accurate noninvasive approach for quantifying liver fat. Chemical shift–encoded MRI-based proton density fat fraction (PDFF) mapping has the best combination of accuracy, precision, and reproducibility among noninvasive methods for measuring liver fat content. In a prospective comparison with MR spectroscopy as the reference, there was excellent correlation between MRS and proton-density fat-fraction MRI (r2 = 0.992; slope, 0.974; intercept, −0.943). Its repeatability is also high, with an intraclass correlation of 0.99 in one study of people with NAFLD. Unlike MR spectroscopy and biopsy, which sample small regions of tissue, chemical shift–encoded MRI covers the entire liver and captures its spatial variability. In a study of explanted livers from people with advanced fibrosis, a PDFF threshold of 2.80% identified steatosis with an area under the curve of 0.83, a cutoff far below the 5% used in clinical definitions, which underlines that thresholds depend on the setting.
Magnetic resonance elastography (MRE) measures stiffness by applying low-frequency waves and imaging their propagation. Magnetic resonance elastography (MRE)-assessed liver stiffness has been demonstrated to be the most accurate noninvasive biomarker for staging fibrosis. A meta-analysis found a higher diagnostic accuracy in grading fibrosis for MRE than for TE, with an AUROC of 0.92 and 0.87 respectively, for diagnosing F2–4. In a head-to-head comparison, liver stiffness by MRE was the strongest predictor of at-risk NASH, while PDFF performed best for NASH with any degree of fibrosis. The main limitations of both MRI methods are cost, limited availability and the need for specialized equipment and analysis, which restrict their use to specialist centers and research.
Liver biopsy
Liver biopsy remains the reference standard for histological diagnosis. Although liver biopsy is still the gold standard for the diagnosis of NAFLD, especially for the diagnosis of NASH, imaging methods have been increasingly accepted as noninvasive alternatives. Biopsy is still needed in several situations: when the diagnosis of MASH is uncertain, when other liver diseases must be excluded, and when people are enrolled in clinical trials that use histological endpoints. Its drawbacks include invasiveness, procedure-related complications, and sampling error, since a small core may not represent the whole organ. Histology also depends on pathologist interpretation, a point discussed in the section on histological scoring. Because the reference standard itself is imperfect, noninvasive tests are validated against it, and MRI-PDFF has in some studies been shown to quantify steatosis more sensitively than histological grading.
Epidemiology and trends
Prevalence estimates for steatotic liver disease vary with the definition, the diagnostic test and the population studied, but most recent global figures place MASLD at roughly one in three adults. The global prevalence of MASLD among adults is around 30%, and up to 2019 it was estimated that there were approximately 1.66 billion prevalent cases worldwide. A 2021 systematic review that pooled 72 publications from 17 countries gave a figure of 32.4% (95% CI 29.9, 34.9). The Global Burden of Disease (GBD) 2021 analysis counted 1,267.9 million MASLD cases globally and reported that the age-standardized prevalence had risen by 24.3% since 1990. Trend estimates are not directly comparable across studies. One review gives a rise from 17.6% (1990) to 23.4% (2019), while another reports 25.3% (1990–2006) to 38.2% (2016–2019). Many earlier studies also relied on elevated ALT as a proxy for fat, which underestimates disease in people with normal enzyme levels.
Burden differs by sex and age. In one pooled analysis, the overall prevalence of MASLD in men (39.7%) is significantly higher than women (25.6%). The GBD 2021 data show that men aged 15–69 and 90–94 had higher DALY rates, while women aged 70–89 and 95+ had higher rates. Geographic patterns are also uneven. North Africa and the Middle East had the highest prevalence, while Andean and Central Latin America had the highest death and DALY rates. Regional disparities are pronounced, with Kuwait highest nationally and Finland lowest. Rapid increases are recorded in the Northern Africa and Middle East (MENA) region and Asia, and low- and middle-income countries are experiencing a rapid increase in MASLD attributed to urbanization and the westernization of diets. Among adults with type 2 diabetes, the pooled prevalence is much higher, with one meta-analysis estimating nearly 69% of patients affected.
In children and adolescents, the prevalence is lower overall but rising. Prevalence estimates are 13% in the general population and 47% among children with obesity, with higher rates observed in certain ethnic groups and in males. Childhood obesity itself has grown steeply: the rates of obesity in children have tripled since the 1960's from 5 % to close to 19 %. In US adolescents aged 12–17, from 1999 to 2020, the prevalence of MASLD rose significantly, paralleling the increasing rates of obesity. The pattern is not uniform across time: between the two survey cycles, the age-standardized prevalence of MASLD remained stable in a 2017–2023 NHANES analysis, with a non-significant decline in fibrosis, so short-term trends should be interpreted with caution.
Projections point to continued growth, but they depend heavily on assumptions about body weight and glycaemia. GBD-based estimates suggest that the global burden of metabolic dysfunction–associated steatotic liver disease (MASLD) is projected to grow by approximately 38% by 2050, equivalent to a rise from about 1.3 billion people in 2023 to 1.8 billion by 2050. Other models are more pessimistic about the proportion of adults affected. One review states that by 2040, its prevalence could exceed 55% of the global population, and a US model estimates that 36.8% of the United States adult population (101.2 million people) will have MASLD in 2030 and will further increase to 41.4% (121.9 million people) by 2050. Such models are typically built on the Bayesian Age-Period-Cohort model, so their results are sensitive to the trajectories assumed for obesity, diabetes and metabolic syndrome. Projected rises in cirrhosis and liver cancer are also linked to these trends, with the incidence of MASLD-related cirrhosis and MASH-associated liver cancer projected to rise in the coming decade.
Lifestyle and weight-loss management
Weight loss
Weight reduction is the lifestyle measure with the strongest histological evidence. Current evidence indicates that a 5–10% reduction in body weight is associated with meaningful histological improvement, including regression of steatosis, resolution of steatohepatitis, and, at higher degrees of weight loss, regression of fibrosis. The landmark Vilar-Gomez analysis followed 293 people with biopsy-proven disease through a year of lifestyle change and found that a loss of at least 5% of body weight was accompanied by histological improvement in steatosis. A 12-month trial with paired biopsies in 261 patients showed a graded response, and the 10% loss group improved all disease features, including portal inflammation and fibrosis.
Larger losses map onto larger benefits. A 2023 meta-analysis by Harrison and colleagues associated losses of at least 10% with MASH resolution, and losses of at least 5% with fibrosis improvement. In a network meta-analysis of randomised trials, each additional 1% of total body weight loss corresponded to a 7% higher probability of MASH resolution without worsening fibrosis. Drug-induced weight loss shows a similar pattern. In a prespecified analysis of the MAESTRO-NASH trial, achieving ≥5% weight loss enhanced resmetirom's efficacy in MASH resolution and fibrosis improvement, indicating a complementary mechanism.
The main obstacle is sustaining the loss. Weight loss is typically an unsustainable outcome of clinical intervention, with only 50% of individuals achieving the amount associated with histological improvement. Because of this, lifestyle programmes are usually judged by how many participants reach a clinically meaningful loss, not by average weight change alone.
Dietary approaches
Energy restriction is the common starting point, but composition appears to matter independently of calories. While caloric restriction is broadly effective, growing evidence suggests that dietary composition, beyond energy deficit alone, may influence MASLD outcomes. International practice guidance therefore advises limiting total calories, saturated and trans fats and fructose, while increasing lean protein, fibre and omega-3 fatty acids.
The Mediterranean pattern is the most widely recommended template. It is characterised by mainly plant-based foods and fish, with reduced meat and dairy products. Traditional versions also feature whole grains, legumes, nuts and vegetables, with high olive oil consumption and low saturated fatty acid intake. The evidence base remains uneven: the benefits for liver steatosis and metabolic dysfunction rest on observational studies and short-term trials with broadly consistent results.
Physical activity
Exercise lowers liver fat through mechanisms that do not depend on weight loss. Human data clearly demonstrate that regular exercise itself reduces liver fat and can do so in the absence of clinically significant weight loss. A 2023 systematic review and meta-analysis of 14 randomised trials, including 551 participants, found that those who participated in exercise training were 3.5 times more likely to achieve a 30% or more relative reduction in MRI-measured liver fat than those in the control condition. The threshold was modest: an exercise dose of 750 metabolic equivalents of task (MET)-minutes per week, or 150 minutes per week of brisk walking, was required to achieve a treatment response, independently of weight loss. In those trials the average weight loss was only about 2.8%, below the level linked to histological response. Both aerobic and resistance training reduced liver fat in human studies, although aerobic training may be more effective, and resistance training is more feasible for people with poor cardiorespiratory fitness. Evidence on histological benefit is thinner; a 2015 review noted the lack of evidence from clinical trials on the role of exercise in non-alcoholic steatohepatitis.
Alcohol avoidance and limitation
For people with steatotic liver disease, guidance generally advises avoiding alcohol or keeping intake low, because alcohol adds to hepatic fat and injury and can compound metabolic risk. The 2023 consensus created the MetALD category for people with metabolic risk factors who drink above defined weekly amounts, which are roughly 140–350 g of alcohol per week for women and 210–420 g per week for men. In this range, alcohol and metabolic factors interact, so cutting back on alcohol and treating obesity and insulin resistance are both relevant.
Adherence is difficult. Drinking is often tied to social routines, habit and, in some cases, dependence, and patients may not receive clear, consistent advice on safe limits. Some patients also find it hard to combine abstinence with other changes in diet and activity, which can lead to partial adherence in clinical practice.
Pharmacological treatment
Resmetirom
In March 2024 the US Food and Drug Administration (FDA) granted accelerated approval to resmetirom, a drug that became the first approved treatment for MASH. The approval covers noncirrhotic MASH with moderate to advanced fibrosis. The label is limited to MASH with F2–F3 fibrosis, and the FDA-approved label does not require liver biopsy to confirm the diagnosis of fibrotic MASH. Resmetirom is taken by mouth and is a thyroid hormone receptor-beta (THR-beta) agonist. Because the beta subtype of the receptor is concentrated in liver tissue, activating it there is expected to act locally rather than through the whole body. Receptor activation reduces hepatic lipogenesis, and by suppressing TGF-β signalling it may also interfere with fibrogenesis. They can also interfere with fibrogenesis by inhibiting TGF-β signalling. Thyromimetics that are selective for the β subtype (liver expressed) of the thyroid hormone receptor have been evaluated as a treatment for MASH.
The pivotal evidence comes from MAESTRO-NASH, a placebo-controlled phase 3 trial. Its histological endpoints showed broad treatment effects in patients with MASH with liver fibrosis, as well as reduced levels of low-density lipoprotein (LDL) cholesterol. Reported adverse effects are generally mild, with manageable side effects like diarrhea and nausea. The accelerated approval remains conditional. Final approval depends on verification and description of long-term clinical benefit in the ongoing MAESTRO-NASH trial, and as of the October 2024 guidance update these long-term data were not yet available.
Semaglutide 2.4 mg
Semaglutide 2.4 mg is a once-weekly subcutaneous glucagon-like peptide-1 (GLP-1) receptor agonist, and it is the second drug to be approved for MASH. On August 15, 2025 the FDA approved it for adults with MASH and moderate to advanced fibrosis who do not have cirrhosis, in conjunction with a reduced-calorie diet and increased physical activity. Approval was based on part 1 of the ESSENCE trial, with part 2 results expected in 2029. ESSENCE enrolled a total of 1197 individuals who were randomly assigned 2:1 to receive 2.4 mg of semaglutide or placebo, along with standard of care for 240 weeks. At the 72-week histological endpoint, about 63% of participants treated with semaglutide achieved resolution of steatohepatitis without worsening fibrosis, compared with 34% in the placebo arm.
Semaglutide acts systemically rather than in the liver alone. Its appetite-suppressing and gastric-emptying effects lead to weight loss, and the leading explanation for its hepatic benefit is that these weight-related and metabolic changes are indirect. The most robust explanation for the hepatoprotective effects of semaglutide in improving and/or potentially reversing liver histological outcomes, including hepatic fat accumulation, is linked to the so-called indirect effects of the drug. Histological analyses from the trial reported improvement in steatosis, necroinflammation, hepatocellular ballooning and fibrosis. Data from the ESSENCE trial demonstrated that subcutaneous semaglutide 2.4 mg/week not only improves steatosis but also reduces necroinflammation, hepatocellular ballooning and fibrosis.
Guideline recommendations
The 2024 joint EASL–EASD–EASO guideline recommended considering resmetirom, where approved locally, for non-cirrhotic adults with advanced fibrosis; (B) at-risk steatohepatitis with significant fibrosis (by liver biopsy, when available, or by non-invasive panels validated for that purpose); or (C) risk of adverse liver-related outcomes. For the cirrhotic stage, the same guideline states that no MASH-targeted pharmacotherapy can currently be recommended for adults with MASH at the cirrhotic stage. The guideline also addressed drugs used for other indications. It found insufficient evidence to recommend the use of sodium–glucose cotransporter-2 (SGLT2) inhibitors or metformin as MASH-targeted therapies, although these drugs are safe to use in MASLD. Incretin-based drugs are regarded differently: GLP1RAs are safe to use in MASH (including compensated cirrhosis) and should be used for their respective indications, namely type 2 diabetes and obesity.
A February 2026 amendment specifically addresses resmetirom and semaglutide. It recommends that pharmacotherapy with resmetirom or semaglutide should be considered in addition to – not instead of – lifestyle modification in non-cirrhotic adults with stage 2–3 fibrosis. It also notes that factors associated with the likelihood of treatment response within the currently approved indications are not established to select individuals for a specific drug option. The guidance treats selection as clinical, and the decision of which drug to use is not yet guided by biomarkers.
Pipeline and open questions
Other candidates in development span several mechanisms, including FGF21 analogues, pan-PPAR agonists and multi-receptor incretin agonists. Whether these agents will add to existing therapies is still unclear, and whether combining a MASH-specific drug with incretin therapy gives additive benefit has not been settled. Most approvals rest on histological endpoints measured at roughly 72 weeks, while the effect of treatment on cirrhosis, liver transplantation and cardiovascular outcomes requires longer follow-up. The long-term outcome data for both resmetirom and semaglutide are therefore central to deciding how long treatment should continue and who should stop.
Surgery and comorbidity management
Bariatric surgery and liver histology
Metabolic bariatric surgery is the most studied non-drug route to histological improvement in people with obesity. A 2024 review of MASH after surgery found that bariatric surgery has been found to be an effective treatment for MASH, with a 70% to 80% rate of resolution and a 30 to 50% reduction in fibrosis. Fibrosis regression in the literature generally falls approximately 50–70% of patients with baseline fibrosis, and the effect is usually progressive. In a Lille cohort, fibrosis began to decrease by 1 year after surgery and continued to decrease until 5 years, and resolution of steatohepatitis was maintained over that period.
Survival data are more limited. In a prospective Lille cohort of surgical candidates enrolled from 1994 to 2022, MASH resolution without fibrosis worsening at one year was associated with a better 15-year survival in univariate analysis (88.4% vs. 70.8%, p=0.009), and the association persisted after multivariable adjustment. Because the analysis was observational, the authors' own conclusions call for further studies... especially outside bariatric surgery. A pooled meta-analysis reported that histological worsening after surgery occurred in about 6% of patients, with a pooled mortality rate of 13% within a pooled follow-up time of 30.8 months, a figure that reflects surgical populations and not a causal effect of the procedure.
Cardiometabolic comorbidities
Because no liver-directed therapy has been widely adopted, management largely focus[es] on improving cardiometabolic risk factors, starting with regular cardiovascular risk stratification and lifestyle change. Lipid management is the most debated area. Currently 40%–50% of individuals in whom treatment is indicated do not receive statin therapy due to concerns over hepatotoxicity, yet mildly elevated transaminases should not prevent providers from prescribing or continuing statin therapy in people who meet guideline criteria. In cirrhosis the advice diverges: AASLD guidelines state that statins may be considered in decompensated cirrhosis with high cardiovascular risk, whereas AGA guidance recommends avoiding them. For people with Child–Pugh class B or C cirrhosis, primary prevention statins should not be initiated... without the guidance of the hepatologist. Where statins are not enough, non-statin therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors and bempedoic acid provide additional risk-reduction options.
Glucose-lowering treatment is shaped by the same logic. Several agents have no proven histological benefit, and one review states that metformin, acarbose, dipeptidyl peptidase IV inhibitors, insulin, ursodeoxycholic acid, statins, and silymarin should not be used as treatment for MASLD for liver purposes, although statins remain indicated for cardiovascular protection. Conversely, some of the anti-diabetic agents have demonstrated significant benefits in improving MASLD and MASH-related outcomes, and GLP-1 receptor agonists are regarded as a novel promising approach. Blood pressure treatment in cirrhosis requires particular care: guidance on non-selective beta-blockers for portal hypertension requires careful monitoring... to avoid hypotension, bradycardia, and worsening renal function, particularly in advanced cirrhosis.
Medication safety and avoiding hepatotoxic drugs
Most commonly used cardiometabolic drugs are considered safe in this population. Reviewers note that mild transaminase elevations may occur but are usually transient and resolve with dose adjustment or switching agents. The practical implication is that clinicians should check the full medication list, identify agents with known liver toxicity, and weigh their necessity against the liver risk, rather than discontinuing necessary cardiovascular treatment because of modest enzyme changes. Reviewing drugs is especially important in people with cirrhosis, where hepatic clearance is reduced and the margin for injury is narrower.
Multidisciplinary care in tertiary centers
Management of MASLD and MASH is widely described as a team task. Optimal care of patients with MASLD and MASH requires a multidisciplinary approach involving endocrinologists, gastroenterologists, hepatologists, cardiologists and nutritionists. Risk stratification determines who leads care: low-risk patients are still at high risk for metabolic complications, so they are managed by endocrinology, primary care and cardiology, while the intermediate- and especially high-risk patients must be managed by a multidisciplinary team including a hepatologist. Prescribing resmetirom, the first approved MASH drug, has likewise been framed as managed within a multidisciplinary framework, necessitating specialized hepatological care. Access remains uneven: one US analysis cited that only 30% of US academic medical centers offer this. Some programs have responded by co-locating several specialists in one clinic, as at Penn State Health, which runs a large program of seven specialists that are co-located in the same clinical space.
Pediatric fatty liver disease
Prevalence and early-life risk
Pooled estimates from a large meta-analysis place pediatric MASLD near 14% of children worldwide, and near 38% among children with obesity (14.3% overall and 38.0% in children with obesity). Other pooled analyses report somewhat higher figures for the general pediatric population and for children with obesity, so the estimates depend on the definition and the studies included (7.4% in the general population and 52.5% in the pediatric obesity population). Prevalence rises with body mass index, and among children with severe obesity it may reach up to 59%. Regional figures also differ, with the highest prevalence in North America (43.6%) and the lowest in Africa (31.1%).
Boys are affected more often than girls. Male sex is an independent risk factor and affects approximately 50% of boys and 35% of girls with obesity. The sharp rise during puberty is linked to physiological insulin resistance, which promotes hepatic de novo lipogenesis and reduces fatty acid oxidation (which facilitates lipid accumulation in hepatocytes). Perinatal exposures also matter: maternal obesity, gestational diabetes, preterm birth and suboptimal early nutrition increase risk, while breastfeeding for at least six months appears protective (risk is increased with maternal obesity, gestational diabetes, preterm birth, and suboptimal early nutrition—while breastfeeding for at least six months appears protective).
Histological features in children
Pediatric histology differs from adult disease. In children, periportal steatosis and fibrosis predominate, whereas adults more often show a centrilobular pattern (periportal steatosis and fibrosis is prevalent in children, while adults most often have the centrilobular pattern). Preadolescent children often lack hepatocyte ballooning, show portal rather than lobular inflammation, and tend to progress to cirrhosis less rapidly (lack of ballooning, predominant portal rather than lobular inflammation, and lesser rapid cirrhotic evolution). In one large series, about half of the children had this portal ("type 2") pattern, and these children tended to be younger, heavier, more often male and more often non-white (51% displayed type 2 NASH, and the children with type 2 portal NASH were younger, heavier, and more likely to be male and non-white). Portal inflammation is itself linked to more advanced disease, with an odds ratio of 3.7 for stage 2–3 fibrosis in one cohort (portal inflammation was associated with stage 2‐3 fibrosis on multivariable analysis, odds ratio = 3.7). Steatosis alone should not be regarded as harmless in children: simple steatosis, the most prevalent form of pediatric NAFLD, is not necessarily benign.
Natural history and outcomes
Pediatric MASLD is often silent in early stages but may progress to steatohepatitis, fibrosis, cirrhosis and liver failure in a subset of patients. Among children with biopsy-proven disease in tertiary care, approximately 20%–50% of them had MASH and 10%–20% had advanced fibrosis at the time of diagnosis, so referred cohorts are not representative of all affected children. Longitudinal data remain sparse. In a 2-year placebo arm of the TONIC trial, where all participants received lifestyle advice, 28% had resolution of NASH, 40% improved fibrosis, 40% improved steatosis, and 43% improved lobular inflammation. Progression occurred in 25% (Lavine et al., 2011). Long-term data are more concerning. A 20-year natural history study found that children with NAFLD had a much higher risk of severe liver disease or death than healthy controls (standardized mortality ratio = 13.6 [95% CI: 3.8, 34.8]). Follow-up of former pediatric patients also found a high rate of type 2 diabetes (30%) and the persistence of obesity into young adulthood. Such findings suggest that disease starting in childhood may carry cardiometabolic and hepatic consequences well into adult life, although the data are limited by small samples and short follow-up.
Screening, diagnosis and staging
Under-recognition is common. In one public-health cohort, MASLD was diagnosed clinically in 7.4%, while 14.5% met the criteria retrospectively, suggesting possible underdiagnosis. Guidance on who should be screened varies. The ESPGHAN position paper suggests ALT ≥ 30 IU/L is a suitable screening test for MASLD in children over 10 years of age with obesity (body mass index z‐score ≥+2), or in children of any age with additional risk factors. NASPGHAN uses sex-specific cutoffs, ≥50 U/L for boys and ≥44 U/L for girls, whereas another source cites sex-specific upper limits of 22 U/L for females and 26 U/L for males (22 U/L for females, 26 U/L for males), so thresholds are not yet harmonized. The AASLD practice statement advises screening from age 10 in children with overweight and cardiometabolic risk, and in all children with obesity, while universal screening of children younger than 10 years is not recommended. Overweight children without obesity are generally screened only when additional signs of insulin resistance or dyslipidaemia are present (should not be screened unless there are additional signs of insulin resistance, dyslipidaemia, or risk factors for MASLD). Guidelines differ on imaging, with ESPGHAN recommending ultrasound alongside ALT (recommends using US alongside ALT for diagnosing MASLD), and both adult elastography and blood-based fibrosis tests have significant limitations in children. Pediatric fibrosis tools are also less developed: adult scores may not be accurate to predict advanced fibrosis in children, which led to the pediatric NAFLD fibrosis score. Liver biopsy remains the gold standard for diagnosis and staging of MASLD, but should be reserved for diagnostic uncertainty, to guide treatment decisions, and risk stratification. Genetic risk scores are not routinely recommended in current pediatric guidelines, and polygenic risk stratification remains limited to research and specialized clinical contexts.
Treatment and lifestyle
Lifestyle change remains the foundation of care. Sedentary behavior and prolonged screen time reduce energy expenditure and worsen insulin resistance (thereby intensifying hepatic fat accumulation), and waist circumference tracks cardiometabolic risk and hepatic fat more closely than BMI alone (correlates more closely with cardiometabolic risk and hepatic fat accumulation than BMI alone). Family history is a recognized screening trigger (in children with severe obesity or a family history of MASLD). Pharmacological options are emerging: the pediatric guidance recommends considering GLP-1 receptor agonists and other approved antiobesity pharmacotherapies for the treatment of obesity in children with MASLD. Alcohol use is another issue, since MetALD is not consistently assessed for in most pediatric MASLD clinics and may be underappreciated.
History of research
Descriptions of fat in livers from people who drank little alcohol predate the modern labels. By the late 1800s, clinicians had linked fatty livers to fibrosis and cirrhosis, and in the early 1900s to diabetes. Fatty liver was associated with liver fibrosis and cirrhosis in the late 1800s, and with diabetes in the early 1900s. In 1958, Westwater and Feiner examined livers from people with obesity and found fat infiltration on histology, and several reports in the 1950s–1970s pathologically documented the occurrence of fatty liver disease in obese and diabetic subjects.
The diagnostic label came in 1980. Jurgen Ludwig and colleagues at the Mayo Clinic in Rochester, Minnesota, described the condition in a paper that published the first article to identify non-alcoholic steatohepatitis (NASH). Most of the patients were obese women, and many had diabetes. Their biopsies showed lobular inflammation, Mallory bodies and focal necrosis, with fibrosis in most specimens and cirrhosis in three patients. The authors had found these changes in people who denied any significant alcohol use, and the term was chosen because the histology resembled alcoholic steatohepatitis. The terminology, although cumbersome, was intended to differentiate these disorders from alcohol-related liver disorders, as they are histologically similar. Initial reception was muted. The medical community continued to accept that in people who were not alcoholics, a fatty liver was a benign condition, and the 1980 article had little impact at first. In 1983, Moran and colleagues extended the observations to obese children.
In 1986, Schaffner and Thaler proposed the broader term nonalcoholic fatty liver disease. NAFLD encompassed a histological broad spectrum that included steatosis, steatohepatitis (NASH), which can progress to cirrhosis, and even hepatocellular carcinoma. In 2002, an AASLD-sponsored conference discussed an alternative, metabolic steatohepatitis (MESH), but it was not uniformly accepted. Publication activity grew slowly at first, and the exponential rise in NAFLD publications was most notable from 2000 onwards.
Genetic research accelerated in the late 2000s. A genome-wide association study in the population-based Dallas Heart Study linked the PNPLA3 variant p.I148M to liver fat content measured by magnetic resonance spectroscopy. There was a stepwise increase of hepatic triglyceride content with the number of p.I148M risk alleles. Subsequent studies replicated these findings across populations, and the variant has since been described as the strongest known genetic determinant of MASLD to date. Parallel work on non-invasive tools for measuring liver fat and stiffness, which later shaped how clinical trials were designed, is covered in other sections.
The 2023 nomenclature consolidated these developments. A modified Delphi process was led by three pan-national liver associations and defined consensus as a supermajority of 67%. Consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. Before the vote, 74% of respondents from a multinational, multisociety Delphi process agreed that the term nonalcoholic fatty liver disease was "sufficiently flawed" and 89% preferred nomenclature that described the underlying cause of disease. Under the new scheme, steatotic liver disease serves as the umbrella category, and NAFLD was renamed MASLD; NASH was renamed MASH. The authors retained the concept of steatohepatitis because it was regarded as an important pathophysiological idea, and they stated that the new names do not change how fibrotic severity is characterized.
Public health, naming and stigma
Public health significance and the case for a priority NCD designation
Steatotic liver disease is among the most common chronic liver conditions. The American Association for the Study of Liver Diseases (AASLD) estimates that MASLD, formerly known as NAFLD, is the most common chronic liver disease around the world, affecting more than 30% of global population. Other estimates are lower: a 2025 trial registration describes it as affecting approximately 25% of the global adult population, a difference that reflects how prevalence is measured and which populations are sampled (see epidemiology and prevalence).
Advocates argue that the disease belongs among the noncommunicable diseases (NCDs) that the World Health Organization tracks as a global priority. One commentary argues that the WHO should formally recognise MASLD/MASH as a priority NCD spectrum, alongside other high prevalence diseases. The case rests partly on the mortality figures for NCDs in general, which the 2025 political declaration gives as more than 43 million deaths each year, and partly on the link between fibrosis and death. Fibrosis stage has been associated with an increased risk of overall, hepatic, and cardiovascular mortality, which is why proponents describe fibrosis screening as a public-health issue. A 2025 analysis of MASH in people with type 2 diabetes reached a similar conclusion, finding that systematic screening for MASLD and MASH is not well integrated in any health system as standard care for at-risk groups.
Naming, stigma and the older term
The 2023 renaming was driven partly by concerns about language. In the multisociety Delphi process, 74% of respondents agreed that the term nonalcoholic fatty liver disease was "sufficiently flawed" and 89% preferred nomenclature that described the underlying cause of disease. Specific words drew objections: 61% and 66% of respondents found the terms "nonalcoholic" and "fatty" potentially stigmatizing, respectively.
The objections to "nonalcoholic" have two parts. The first is that the word defines the disease by what it is not. Earlier discussions noted that the "nonalcoholic" component of NAFLD was considered inappropriate when this terminology was used to describe the disease if it occurs in children or in individuals from countries or cultures in which alcohol consumption is prohibited. The second is that the label could imply a moral distinction from alcohol-related liver disease, and the Delphi panel argued that the term could "create or exacerbate stigma, marginalize segments of the affected population and, ultimately, contribute to health inequalities."
Not all commentators accept this reasoning. A critical editorial in the Journal of Hepatology argued that the change in the nomenclature was motivated not by any scientific rationale but by the stigma associated with the terms 'alcoholic' and 'fat', and warned that frequent renaming makes the literature harder to search. The same editorial noted that stigma does not apply or reflect equally across different cultures or healthcare settings. Supporters respond that the new name is affirmative: it describes the metabolic cause of the disease rather than a negative exclusion, a point the AASLD and its partner societies have emphasized.
The 2025 United Nations meeting
The fourth UN High-Level Meeting on NCDs took place on 25 September 2025, and its resulting political declaration on NCDs was adopted by the UN in December 2025. The declaration's coverage of liver disease focused on hepatitis; its September 2025 revision text refers to hepatitis B and C prevention, diagnosis and treatment, and a draft from the same period also refers to screening and management for Non-Alcoholic Fatty Liver Disease (NAFLD).
Critics argue that the meeting did not give the condition adequate recognition. One commentary says that the outdated and stigmatising name non-alcoholic fatty liver disease (NAFLD) was used at the meeting and that MASLD/MASH was still not recognised as a priority NCD on par with other highly prevalent diseases. The authors describe this as sending the wrong signal to people living with MASLD/MASH. Supporters of the declaration would point to its general emphasis on NCDs and on hepatitis, but the debate has centered on whether the condition itself was named and prioritized.
Screening programs, health-system capacity and cost
The response to the disease depends heavily on how it can be detected at scale. Ultrasonography is widely available, but a 2025 economic analysis notes that performing abdominal ultrasound on all cases would place a significant social and economic burden on most societies, and that in many primary care clinics conducting abdominal ultrasound is often not feasible for various reasons, leading to the referral of patients to specialized centers or specialists. For this reason, many health economists favor sequential tests, usually combining a blood-based fibrosis score with a second-line measure.
Cost-effectiveness findings vary by setting. A US model of primary-care screening in high-risk patients found that screening reduced long-term costs for people with type 2 diabetes and obesity, even though it added upfront costs, and its authors concluded that screening for high-risk MASLD is cost-effective according to recent guidelines. A UK analysis reported that sequential strategies combining FIB-4 with ELF or TE, are cost-saving, reduce unnecessary hepatology referrals. Results are not uniform, however. A Korean-based model found that routine MASLD-associated fibrosis screening in the entire general population is not currently recommended, and cost-effectiveness depended on age and on assumptions about whether treatment also reduced cardiovascular events.
In low-resource settings, the cost question is one of prioritization. Researchers have suggested that low-cost, easy-to-use risk stratification tools could help decide who should be screened first, while acknowledging that the limited accuracy of imaging techniques like ultrasonography in isolation means composite scores are likely to be needed.
Unresolved questions and controversies
Diagnostic thresholds for metabolic risk and lean disease
The MASLD definition requires at least one cardiometabolic risk factor, but the BMI cut-offs used to judge body size were built largely on other populations. Lean MASLD is diagnosed in people with MASLD and a BMI below 25 kg/m² in non-Asian populations or below 23 kg/m² in Asian populations. Asian-specific thresholds have been adopted in regional guidance, and the 2025 APASL MASLD guidelines recommend the 23 kg/m² cut-off, but anthropometry itself is a rough proxy. Body mass index does not separate visceral from subcutaneous fat, so some lean people with excess central adiposity are missed. Global cohort data have therefore compared BMI with sex- and ethnicity-specific waist circumference thresholds, and the two definitions do not always agree.
Lean disease is also strikingly uneven across regions. One analysis reports prevalence as high as 22% in Asian registries compared with 9% in Western countries, while the Global MASLD biopsy cohort found lean MASLD most common in Asia and least common in North America. Whether these gaps reflect biology, body composition, or differences in how studies measure fat and define risk factors remains unsettled. Lean individuals are also not a uniformly low-risk group: they carry cardiovascular, hepatocellular carcinoma and liver-related mortality risks comparable to those of obesity-associated MASLD, yet standard lifestyle advice based on weight loss may be less relevant to them.
Long-term outcomes of drug therapy
Regulatory approval for MASH drugs rests mainly on histological endpoints. The semaglutide indication illustrates the point: it was granted under accelerated approval based on improvement in MASH and fibrosis, and continued approval may depend on verifying clinical benefit in a confirmatory trial. The phase 3 ESSENCE trial's 72-week results showed resolution of steatohepatitis without fibrosis worsening in a larger share of treated patients, but the outcome-oriented part of the programme is still running, with part 2 results expected in 2029. Biopsy changes at one to two years do not establish whether cirrhosis, decompensation, liver transplantation or death are reduced. Hepatology guidance also notes that data on long-term tolerability, treatment retention and clinical events are awaited in people with MASH fibrosis.
Other questions follow from this. Histological responses in short trials may not translate into equal benefit across drug classes, and the proportion of patients who stop treatment, regain weight, or lose the histological effect after discontinuation is not well characterized. Costs, access and the durability of benefit after long-term use all remain open.
Noninvasive tests and screening
No single noninvasive test has been accepted as the standard for all settings. Elastography, controlled attenuation parameter measurement, magnetic resonance methods and blood-based fibrosis scores each differ in accuracy, cost and availability, and their cut-offs have been derived in mixed populations. Guidance on which tests should be used at which step, and at what thresholds, continues to be revised. Confirmatory algorithms are still being compared in prospective studies.
Who should be screened, and how often, is equally unsettled. Population-level screening of adults with metabolic risk would detect many cases; a large US analysis of NHANES data found that lean disease in particular affects a substantial number of U.S. adults and is frequently underdiagnosed. Screening all people with obesity or diabetes would expand the number of patients needing follow-up, and the yield of testing in people without metabolic risk factors is low. Health-system capacity, the cost of follow-up imaging and specialist referral, and the lack of a clear threshold for treatment in early fibrosis all affect what can be recommended.
Mechanisms of progression and precision medicine
The reasons some people with steatosis progress to advanced fibrosis while others do not are incompletely understood. Genetic variants such as PNPLA3 and HSD17B13 explain part of the variation, and environmental exposures, insulin resistance, gut microbial composition and sex-related differences contribute as well, but their interactions have not been mapped in enough detail to predict an individual's course reliably. Most current risk stratification depends on fibrosis stage, which is a late marker of injury.
Precision medicine therefore aims to combine genetic, metabolic, microbial and clinical data to identify those at highest risk early, and to match treatments to patients most likely to respond. Attempts to define biomarker panels that track disease activity over time are in progress, but few have been validated prospectively, and it is not yet clear which subgroups will benefit most from particular drugs, or whether combination therapies will provide advantages that justify their cost and added complexity.
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- Semaglutide Receives FDA Approval for Treatment of MASHpharmacytimes.com
- Focus on Semaglutide 2.4 mg/week for the Treatment of Metabolic Dysfunction‐Associated Steatohepatitisncbi.nlm.nih.gov
- EASL–EASD–EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD): Executive Summarylink.springer.com
- EASL-EASD-EASO guidance on the use of resmetirom and semaglutide as MASH-targeted therapy - Journal of Hepatologyjournal-of-hepatology.eu
- Considerations for Resmetirom Use, Monitoring in Patients with MASH, Fibrosishcplive.com
- FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASHhcplive.com
- EQ-5D health utility gains with once-weekly semaglutide 2.4 mg in people with MASH and F2/F3 fibrosis: An analysis of ESSENCE - ScienceDirectsciencedirect.com
- Resolution of Metabolic Dysfunction-associated Steatohepatitis With No Worsening of Fibrosis After Bariatric Surgery Improves 15-year Survival: A Prospective Cohort Study - Clinical Gastroenterology and Hepatologycghjournal.org
- Impact of metabolic and bariatric surgery on MASLD: histological resolution and metabolic outcomes in a retrospective cohort - PMCpmc.ncbi.nlm.nih.gov
- Resolution of MASH with no worsening of fibrosis after bariatric surgery improves 15-year survival: a prospective cohort studyresearchgate.net
- MASH RESOLUTION WITHOUT FIBROSIS WORSENING AFTER BARIATRIC SURGERY IMPROVES LONG-TERM SURVIVALaasld.org
- Resolution of Metabolic Dysfunction-associated Steatohepatitis With No Worsening of Fibrosis After Bariatric Surgery Improves 15-year Survival: A Prospective Cohort Study - ScienceDirectsciencedirect.com
- Bariatric intervention improves metabolic dysfunction-associated steatohepatitis in patients with obesity: A systematic review and meta-analysis - PMCpmc.ncbi.nlm.nih.gov
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- Full article: Guideline-based management of metabolic dysfunction-associated steatotic liver disease in the primary care settingtandfonline.com
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- Cardiovascular-Liver-Metabolic Health: Recommendations in Screening, Diagnosis, and Management of Metabolic Dysfunction-Associated Steatotic Liver Disease in Cardiovascular Disease via Modified Delphi Approachahajournals.org
- Management of metabolic dysfunction and cardiovascular risk in patients with MASLDoaepublish.com
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- MASLD for Cardiologists - Page 7medscape.com
- ‘Future of treating MASH’ will combine GLP-1 drugs, liver-specific medicationshealio.com
- A turning point in hepatology? EASL reflects on the first approved drug for MASH - Journal of Hepatologyjournal-of-hepatology.eu
- Multidisciplinary clinic model enhances liver and metabolic health outcomes in adults with MASHncbi.nlm.nih.gov
- Focused Recommendations for the Management ofcorld.org
- Pediatric MASLD in Severe Obesity: Current Clinical Perspectives on Diagnosis and Treatmentncbi.nlm.nih.gov
- The evolving landscape of pediatric obesity and metabolic dysfunction-associated steatotic liver disease - PMCpmc.ncbi.nlm.nih.gov
- Pediatric MASLD in Severe Obesity: Current Clinical Perspectives on Diagnosis and Treatment - PMCpmc.ncbi.nlm.nih.gov
- MASLD In Children - A Distinct Phenotype? - PubMedpubmed.ncbi.nlm.nih.gov
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- The Histopathology of Pediatric Nonalcoholic Fatty Liver Disease*#journals.lww.com
- Portal inflammation is independently associated with fibrosis and metabolic syndrome in pediatric nonalcoholic fatty liver diseasejournals.lww.com
- Review Pediatric nonalcoholic fatty liver disease (NAFLD):journal-of-hepatology.eu
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- Non-invasive assessment of fibrosis and steatosis in pediatric non-alcoholic fatty liver disease - ScienceDirectsciencedirect.com
- Screening and diagnosis of metabolic dysfunction-associated steatotic liver disease in children within public healthcarenature.com
- European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) steatotic liver disease special interest group position paper on screening, diagnosis and investigation of paediatric metabolic dysfunction‐associated steatotic liver disease - PMCpmc.ncbi.nlm.nih.gov
- (PDF) Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in Children with Obesity: An Obesity Medicine Association (OMA) and Expert Joint Perspective 2025researchgate.net
- Highlights From the Recent AASLD Guidance on MASLD/MASH in Children - Gastroenterology & Hepatologygastroenterologyandhepatology.net
- The Development of the Pediatric NAFLD Fibrosis Score (PNFS) to Predict the Presence of Advanced Fibrosis in Children with Nonalcoholic Fatty Liver Diseasencbi.nlm.nih.gov
- European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) position paper on screening, diagnosis and investigation of paediatric metabolic dysfunction-associated steatotic liver disease - PubMedpubmed.ncbi.nlm.nih.gov
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- History of Nonalcoholic Fatty Liver Diseasencbi.nlm.nih.gov
- Fatty liver disease: turning the tidenature.com
- Nonalcoholic fatty liver disease: a review - PubMedpubmed.ncbi.nlm.nih.gov
- From Nonalcoholic Steatohepatits to Steatotic Liver Disease: A Long Wayncbi.nlm.nih.gov
- Toward Genetic Prediction of Nonalcoholic Fatty Liver Disease Trajectories: PNPLA3 and Beyond - Gastroenterologygastrojournal.org
- The fatty liver disease–causing protein PNPLA3-I148M alters lipid droplet–Golgi dynamicspnas.org
- New Name for NAFLD - MASLDnatap.org
- No patient left behind: MASLD rebranding provides ‘affirmative diagnosis’ without stigmahealio.com
- PNPLA3 and nonalcoholic fatty liver disease: towards personalized medicine for fatty liver - Yuan - HepatoBiliary Surgery and Nutritionhbsn.amegroups.org
- Screening for MASLD-related Advanced Fibrosis in Type 2 Diabetesclinicaltrials.gov
- Name MASLD/MASH — and act on itncbi.nlm.nih.gov
- Rev.4 Political declaration of the fourth high-level meeting ...healthpolicy-watch.news
- Cost-Effectiveness of MASH Diagnosis and Management Approaches Among Those With Type 2 Diabetesovid.com
- Understanding the Burden of Nonalcoholic Fatty Liver Disease: Time for Actiondiabetesjournals.org
- 10 Questions Answered About New Liver Disease Term 'MASLD'medscape.com
- Is the change from NAFLD to MASLD driven by political correctness? - Journal of Hepatologyjournal-of-hepatology.eu
- The UN HLM on NCDs - World Hepatitis Allianceworldhepatitisalliance.org
- Finalized PD on NCDs and Mental Health - REV4cdn.who.int
- Cost-effectiveness of advanced hepatic fibrosis screening in individuals with suspected MASLD identified by serologic noninvasive testsnature.com
- Pharmaco‐Economic Assessment of Screening Strategies for High‐Risk MASLD in Primary Care - Younossi - 2025 - Liver International - Wiley Online Libraryonlinelibrary.wiley.com
- Economic evaluation of non-invasive test pathways for high-risk metabolic dysfunction-associated steatotic liver disease (MASLD) in the United Kingdom (UK)elsevier.es
- Cost-effectiveness analysis of MASLD screening using FIB-4 based two-step algorithm in the medical check-upnature.com
- MASLD: time to optimise regional research prioritiesncbi.nlm.nih.gov
- United Nations A/80/L.34 General Assembly Distr.: Limited 8 December 2025documents.un.org
- World leaders adopt a historic global declaration on noncommunicable diseases and mental healthwho.int
- From Nonalcoholic Fatty Liver Disease to Metabolic Dysfunction-Associated Steatotic Liver Disease: Out with the Old, in with the Newncbi.nlm.nih.gov
- NAFLD Vs MASLD: What Changed In 2023?nirvanaclinics.com
- NAFLD to MASLD: What’s In A Name Change? — Clinical Research Philadelphiaphillyresearch.com
- Screening for MASLD is Cost-Effective for Patients, Study Suggestshcplive.com
- Lean metabolic dysfunction-associated steatotic liver disease: Current insights and knowledge gaps - ScienceDirectsciencedirect.com
- Non-lean versus lean MASLD: associations with advanced cardiovascular-kidney-metabolic syndrome in adults with type 2 diabetes mellitus, a cross-sectional study - PMCpmc.ncbi.nlm.nih.gov
- Lean MASLD Carries Similar Risk as Overweight, Obese Diseaseajmc.com
- Metabolic Signatures in Lean MASLD: Current Insights and Future Directions - PMCpmc.ncbi.nlm.nih.gov
- WEGOVY (semaglutide) injection, for subcutaneous useaccessdata.fda.gov
- Semaglutide therapy for metabolic dysfunction–associated... : Hepatologyjournals.lww.com
- Lean MASLD in U.S. Adults: Undiagnosed Burden and Metabolic Features from NHANES 2017–2020link.springer.com