Non-Alcoholic Fatty Liver Disease (NAFLD / MASLD): History and Discovery

Fat in the livers of people who did not drink had been noticed by pathologists for well over a century, but it was long dismissed as a harmless curiosity or a misdiagnosis of hidden drinking. The modern story begins in 1980, when Jurgen Ludwig and colleagues at the Mayo Clinic gave the condition its first durable name — nonalcoholic steatohepatitis (NASH) — after finding liver inflammation and damage that looked exactly like alcoholic hepatitis in twenty patients who were not heavy drinkers, most of them obese or diabetic. The umbrella term nonalcoholic fatty liver disease (NAFLD) followed in 1986. Over four decades, ideas about what drives the disease evolved from a simple “two-hit” model (1998) to a “multiple-hit” one (2010), and the name itself was overhauled twice more — MAFLD in 2020 and a multi-society consensus rename to MASLD in June 2023 — to put the metabolic cause front and centre and retire the stigmatising word “fatty.” What was once an overlooked footnote is now recognised as one of the most common liver diseases on Earth.

Table of Contents

  1. Before a Name: Fatty Liver in Non-Drinkers
  2. Jurgen Ludwig and the Coining of NASH (1980)
  3. NAFLD Becomes the Umbrella Term (1986)
  4. The Two-Hit Hypothesis (1998)
  5. The Multiple-Hit Hypothesis (2010)
  6. Obesity, Type 2 Diabetes, and the Metabolic Syndrome
  7. MAFLD: A New Name Is Proposed (2020)
  8. MASLD: The 2023 Consensus Rename
  9. A Global Disease and the Road Ahead
  10. Research Papers and References
  11. Connections

Before a Name: Fatty Liver in Non-Drinkers

Excess fat inside liver cells — medically called hepatic steatosis — is one of the oldest observations in liver pathology. Nineteenth- and early twentieth-century pathologists routinely saw fat-laden livers at autopsy, and the connection between heavy drinking and a fatty, inflamed liver was well established. The problem was that when the same fatty, inflamed liver turned up in someone who did not drink, it had nowhere to go conceptually. Because the microscopic picture was considered nearly diagnostic of alcohol injury, a non-drinker with that picture was often assumed to be a secret drinker, or the finding was written off as incidental.

Scattered reports through the mid-twentieth century described fatty liver in obese and diabetic patients, sometimes with inflammation and scarring, but these observations were not pulled together under a single coherent label. The condition lacked a name, and without a name it lacked an identity in medicine: it could not be studied as a distinct entity, taught to trainees as its own diagnosis, or counted in patients. That changed at the start of the 1980s, and the change came from a careful look down a microscope at the Mayo Clinic.

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Jurgen Ludwig and the Coining of NASH (1980)

In 1980, the pathologist Jurgen Ludwig and several gastroenterologist colleagues at the Mayo Clinic in Rochester, Minnesota published a short paper in Mayo Clinic Proceedings describing twenty patients whose liver biopsies showed striking fatty change together with lobular hepatitis, focal cell death (necrosis) with mixed inflammatory cells, and, in most cases, Mallory bodies and fibrosis — a microscopic picture that until then had been regarded as essentially specific for alcohol-related liver disease. The crucial point was that these patients did not have a significant history of alcohol consumption; many were obese, and several had diabetes.

Faced with a recognisable disease that did not fit the only category available for it, the Mayo team did something simple and consequential: they named it. They called it nonalcoholic steatohepatitis — “steato” for fat, “hepatitis” for liver inflammation, and “nonalcoholic” to mark the deliberate contrast with the alcoholic disease it mimicked — soon abbreviated to NASH. Ludwig himself later described it, with characteristic understatement, as a condition that had until then been “hitherto unnamed.”

The coining of NASH is widely treated as the founding moment of the modern field. Giving the disease a name made it real to clinicians and researchers: it could now be defined, looked for, debated, and investigated. In the decades since, NASH and its umbrella concept have generated an enormous research literature, and the 1980 Mayo Clinic Proceedings paper is routinely cited as the origin point. (Ludwig was the pathologist who introduced the term; the 1980 paper is the primary source for the coinage.)

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NAFLD Becomes the Umbrella Term (1986)

NASH named the inflamed, damaging end of the spectrum, but clinicians soon needed a broader term that also covered the much more common, quieter form — simple fat accumulation without significant inflammation (“simple steatosis” or non-alcoholic fatty liver) — and the whole range of severity from there through NASH to cirrhosis. In 1986, Schaffner and Thaler are credited with introducing the broader label nonalcoholic fatty liver disease (NAFLD) to encompass that full histological spectrum, from bland steatosis through steatohepatitis to its potential progression to cirrhosis and, in some cases, liver cancer.

This established the two-tier vocabulary that dominated the field for more than thirty years: NAFLD as the umbrella, with NASH as its aggressive, inflammatory subtype. The defining feature of NAFLD was a diagnosis of exclusion — fat in the liver in someone who does not drink heavily and who has no other identifiable cause such as certain medications, viral hepatitis, or inherited disorders. That “defined by what it is not” framing would, decades later, become one of the main arguments for changing the name.

It is worth being precise about the two dates, because they are easy to blur: NASH was coined in 1980 (Ludwig and colleagues), and the broader umbrella term NAFLD followed in 1986 (Schaffner and Thaler). The disease most people now call NAFLD therefore had its inflammatory core named first, and its full-spectrum umbrella name added six years later.

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The Two-Hit Hypothesis (1998)

Naming the disease was only the first step; the harder question was why a fatty liver tips over into an inflamed, scarring one in some people but not others. The first influential framework for this came in 1998, when Day and James proposed what became known as the “two-hit” hypothesis. It is presented here as a historically important model, not as settled fact — and indeed it has since been largely superseded.

In the two-hit model, the first hit is the accumulation of fat in the liver, driven by the now-familiar metabolic culprits: obesity, insulin resistance, and a diet high in fat and sugar. A fatty liver alone, the idea went, is relatively stable. The second hit — oxidative stress, inflammatory signals (cytokines), bacterial products from the gut, and mitochondrial dysfunction — is what then injures the fat-laden cells, igniting the inflammation and cell death that turn simple steatosis into steatohepatitis (NASH) and, over time, fibrosis.

The two-hit hypothesis was valuable because it gave researchers a clear, testable storyline and a way to think about progression rather than just the presence of fat. Its limitation, recognised over the following decade, was that real patients did not behave like a tidy two-step sequence; the biology was clearly more tangled than a single trigger acting on a stable fatty liver.

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The Multiple-Hit Hypothesis (2010)

By 2010 the field had accumulated enough mechanistic detail to outgrow the sequential picture. Tilg and Moschen proposed the “multiple parallel hits” hypothesis, which remains the dominant way of thinking about NAFLD/MASLD pathogenesis today. As with the two-hit model, it should be read as an evolving scientific framework rather than a closed case, but it captures the current consensus far better.

The core idea is that many insults act at the same time and in parallel, rather than in a strict order, and that the gut and adipose (fat) tissue are central players, not just the liver. The contributing “hits” include insulin resistance, an imbalance of fat-tissue hormones (adipokines such as too little adiponectin and too much inflammatory signalling), free fatty acid flux, oxidative and endoplasmic-reticulum stress, mitochondrial dysfunction, alterations in the gut microbiome and a leaky gut barrier, and genetic and epigenetic susceptibility — the best-known genetic example being variation in the PNPLA3 gene, which strongly influences who develops more severe disease.

This shift — from a single second hit to many parallel hits — mirrors a broader move in medicine toward seeing chronic disease as the product of many interacting systems. Practically, it reframed NAFLD as a whole-body, metabolic disorder that happens to show up in the liver, which is precisely the understanding that would soon reshape the disease’s very name.

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From Ludwig’s original twenty patients onward, one association was impossible to miss: this was a disease of metabolic ill-health. The patients were disproportionately obese and diabetic, and as the obesity and type 2 diabetes epidemics grew through the 1990s and 2000s, so did the prevalence of fatty liver. NAFLD came to be understood as the liver manifestation of the metabolic syndrome — the cluster of abdominal obesity, high blood sugar and insulin resistance, raised blood pressure, and abnormal blood lipids that together drive cardiovascular and metabolic disease.

The relationship runs in both directions and is tightly bound to insulin resistance, the common thread connecting the liver, fat tissue, and muscle. Insulin resistance promotes fat delivery to and synthesis within the liver; the fatty, inflamed liver in turn worsens whole-body insulin handling. People with type 2 diabetes are at especially high risk of the progressive, scarring forms of the disease, and fatty liver frequently travels together with cardiovascular disease — which is, in fact, the leading cause of death in people with NAFLD, more so than liver disease itself.

This deep entanglement with metabolic health is the single most important fact about the condition, and it became the central argument of the renaming debates that followed. If the disease is fundamentally about metabolic dysfunction, critics asked, why define it by the absence of alcohol and label it merely “fatty”? That question set the stage for the two name changes of the 2020s.

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MAFLD: A New Name Is Proposed (2020)

In 2020, an international group of experts — with leadership prominently from the Asia-Pacific region — proposed replacing “NAFLD” with MAFLD, short for metabolic dysfunction-associated fatty liver disease. The proposal (often associated with Eslam, Sanyal, George and colleagues) argued that the old name had two core flaws: it defined the disease negatively, by what the patient does not do (drink alcohol), and it relied on excluding other conditions rather than on the presence of the actual driver, metabolic dysfunction.

MAFLD was meant to fix this by being a positive, inclusion-based diagnosis: a patient would qualify on the basis of fatty liver plus evidence of metabolic dysfunction (such as overweight or obesity, type 2 diabetes, or specific metabolic risk markers), regardless of whether they also drank alcohol or had another liver condition. This was a genuine conceptual change, not just a relabelling, because it allowed metabolic fatty liver to coexist with other causes rather than requiring their absence.

The MAFLD proposal was influential and widely discussed, and it was adopted by some groups, but it did not achieve universal agreement. Debate over the criteria, the wording, and how it should relate to the established NAFLD definitions prompted the major liver societies to seek a broader, more formal consensus — the process that produced the 2023 nomenclature.

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MASLD: The 2023 Consensus Rename

In June 2023, a large, multi-society effort — led jointly by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Latin American Association for the Study of the Liver (ALEH), and involving a panel of well over a hundred experts — used a structured modified Delphi consensus process to agree on new names. The headline change: NAFLD became MASLD, metabolic dysfunction-associated steatotic liver disease.

Several deliberate choices are worth noting. The panel adopted “steatotic liver disease (SLD)” as a broad overarching umbrella for fat-related liver disease of any cause, with MASLD as the metabolic form sitting underneath it. NASH was renamed MASH (metabolic dysfunction-associated steatohepatitis) for the inflammatory subtype. A new in-between category, MetALD, was created for people who have MASLD and drink meaningful amounts of alcohol — acknowledging that metabolic and alcohol-related injury often overlap in the same patient rather than being mutually exclusive.

Two motivations were stated clearly. First, to centre the diagnosis on its true cause — metabolic dysfunction — defined by the presence of metabolic risk factors rather than by the exclusion of alcohol. Second, to remove language widely felt to be stigmatising: the words “fatty” (considered judgmental and imprecise) and “nonalcoholic” (which made alcohol the reference point for a metabolic disease) were both retired. The change was endorsed by numerous societies and journals and has been adopted rapidly, though, as with any major nomenclature shift, the older terms NAFLD and NASH remain widely understood and will appear in the literature for years to come.

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A Global Disease and the Road Ahead

From an unnamed curiosity at the start of the 1980s, MASLD (NAFLD) has become one of the most common chronic liver diseases in the world, affecting a large fraction of adults globally and rising in step with obesity and type 2 diabetes. It is now a leading reason for abnormal liver tests, a growing cause of cirrhosis and liver cancer, and an increasingly common indication for liver transplantation — a remarkable trajectory for a condition that medicine barely acknowledged half a century ago.

The history also reframes how the disease is managed. Because its roots are metabolic, the cornerstones of care are weight loss, physical activity, dietary change, and treatment of the accompanying diabetes, blood pressure, and lipid problems — the same levers that matter for the whole metabolic syndrome. After decades with no approved drug specifically for the liver disease itself, the field has more recently moved toward dedicated pharmacological treatments for MASH, reflecting how far understanding has advanced since the “two-hit” era.

The arc of this story — from a careful 1980 microscope reading, through competing hypotheses of cause, to a deliberate, consensus-driven renaming in 2023 — is a clear example of how medicine names, re-examines, and re-names a disease as understanding deepens. The condition did not change; our recognition of what it is, and how honestly to label it, did.

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Research Papers and References

The references below combine landmark peer-reviewed papers in the history of this disease with curated PubMed topic-search links into the broader literature. Where a specific seminal source is named in the article (Ludwig’s 1980 NASH paper; Schaffner and Thaler 1986; Day and James 1998; Tilg and Moschen 2010; the 2020 MAFLD and 2023 MASLD nomenclature statements), it is identified in the text. Each link opens at PubMed or the publisher (National Library of Medicine) in a new tab.

  1. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clinic Proceedings. 1980;55(7):434-438. — PubMed: Ludwig 1980, the coining of NASH
  2. Schaffner F, Thaler H. Nonalcoholic fatty liver disease. Progress in Liver Diseases. 1986;8:283-298. — PubMed: Schaffner & Thaler 1986, the NAFLD umbrella term
  3. Day CP, James OFW. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114(4):842-845. — doi:10.1016/S0016-5085(98)70599-2
  4. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836-1846. — doi:10.1002/hep.24001
  5. Eslam M, Sanyal AJ, George J, et al. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 2020;158(7):1999-2014. — doi:10.1053/j.gastro.2019.11.312
  6. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology / Journal of Hepatology. 2023. — doi:10.1097/HEP.0000000000000520
  7. From the origin of NASH to the future of metabolic fatty liver disease (historical review) — PMC: origin of NASH to metabolic fatty liver disease
  8. What’s Past Is Prologue: History of Nonalcoholic Fatty Liver Disease — PubMed: history of NAFLD review
  9. NAFLD / NASH terminology and the evolution to MASLD — PubMed: NAFLD to MASLD nomenclature history
  10. PNPLA3 and the genetics of NAFLD/MASLD susceptibility — PubMed: PNPLA3 and NAFLD genetics
  11. NAFLD, insulin resistance, and the metabolic syndrome — PubMed: NAFLD, insulin resistance, metabolic syndrome
  12. Global epidemiology and prevalence of NAFLD/MASLD — PubMed: global epidemiology of NAFLD/MASLD
  13. MetALD and steatotic liver disease (SLD) subclassification — PubMed: MetALD and steatotic liver disease classification
  14. NASH / MASH treatment and the move toward approved therapy — PubMed: NASH/MASH treatment and therapy

External Authoritative Resources

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Connections

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