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Page 2 of 7 Byrne et al. Metab Target Organ Damage 2024;4:10 https://dx.doi.org/10.20517/mtod.2024.06

In 1980, Ludwig et al. described their findings in 20 patients with nonalcoholic steatohepatitis (NASH),
observing that many patients were overweight or had type 2 diabetes (T2DM), and concluding that they
[1]
knew of no treatment for this disease . More than 40 years later, it is prescient to reflect that while our
knowledge of the etiology and pathogenesis of NASH has improved considerably, the development of liver-
specific treatments for ameliorating NASH has not been so successful, and at the time of writing (at the
beginning of 2024), there are still no licensed pharmacotherapies for treating NASH and liver fibrosis.

In the last two decades, overwhelming evidence has shown that nonalcoholic fatty liver disease (NAFLD) is
a multisystem disease and is a risk factor for other extrahepatic diseases that require a holistic approach to
treatment . In support of that argument, there is now evidence that NAFLD is an independent risk factor
[2,3]
[7]
[6]
[5]
for T2DM , cardiovascular disease (CVD) , chronic kidney disease , congestive heart failure , and certain
[4]
extrahepatic cancers (principally gastrointestinal cancers, breast cancers, and gynecological cancers) .
[8]
Many of these extrahepatic diseases share common cardiometabolic risk factors, such as central obesity,
hypertension, glucose intolerance, insulin resistance and atherogenic dyslipidemia, and it has been known
for several years that many of these cardiometabolic risk factors tend to cluster together in affected patients
[2,9]
at risk of these extrahepatic disease complications .
The clustering of insulin resistance, glucose intolerance, atherogenic dyslipidemia, and hypertension was
[10]
first described by Reaven in his Banting lecture of 1988 . In 1991, De Fronzo and Ferrannini extended this
notion and elaborated on the syndrome being an important risk factor for T2DM and atherosclerotic
[11]
CVD . Over the following decade, there were further studies investigating cardiometabolic risk factors and
their links with T2DM and CVD, and in 2001, the National Cholesterol Education Program (NCEP)-ATP
III published a definition of these cardiometabolic risk factors and called this the metabolic syndrome
(MetS) . Importantly, this evolution from the Reaven’s work was proposed, because MetS was identified as
[12]
a practical tool for identifying a high-risk CVD phenotype. Subsequently, studies confirmed that MetS was
associated with the development of incident CVD [13,14] , even when body mass index (BMI) replaced waist
circumference as the central obesity component of the MetS . In the early 2000s, the concept of MetS
[15]
gained traction as an important risk factor for CVD, and between 2001 and 2009, there followed further
iterations of the original MetS diagnostic criteria from the international diabetes federation (IDF) and
[16]
from the NCEP-ATPIII . At the time, there was an argument regarding the validity and usefulness of the
[17]
MetS. The concern focussed on a fear that diagnosing MetS, based on a clustering of cardiometabolic risk
factors, implied that patients had a disease, thus "medicalizing" a variety of associated risk factors. There
were further arguments about the appropriate level of specific thresholds of the individual MetS
components and the numbers of these components that should be required to assign a diagnosis of MetS.
Having a threshold of at least three of five components to assign a diagnosis of MetS seemed strange when
there was evidence of increasing risk with increasing numbers (from one to five) of MetS components .
[18]
Additionally, (bearing in mind the original works of Reaven, De Fronzo, and Ferrannini focussing on the
pathogenic importance of insulin resistance), there was heated discussion about the centrality of abdominal
obesity as the key prerequisite for having MetS. The omission of a direct measure of insulin resistance that
was (and is) regarded as key to MetS, created insurmountable problems for many of us involved in this field
of research.

Eventually, in 2009, in an attempt to resolve some of this acrimonious debate, Alberti et al. published a
further iteration of the MetS criteria that included ethnic-specific thresholds for waist circumference .
[19]
Rather than placing central obesity at the core of the MetS, the authors stated that any three of five
characteristics from increased waist circumference, increased blood pressure, increased fasting triglyceride
or increased fasting glucose concentration, and decreased high-density (HDL) cholesterol concentration,