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Review Article
a r t i c l e
i n f o
Article history:
Received 30 April 2014
Accepted 21 September 2014
Available online 18 November 2014
Keywords:
Dissociation
Insulin resistance
Natural history
Pathogenesis
a b s t r a c t
The conventional paradigm of nonalcoholic fatty liver disease representing the hepatic manifestation of
the metabolic syndrome is outdated. We identied and summarized longitudinal studies that, supporting the association of nonalcoholic fatty liver disease with either type 2 diabetes mellitus or metabolic
syndrome, suggest that nonalcoholic fatty liver disease precedes the development of both conditions.
Online Medical databases were searched, relevant articles were identied, their references were further
assessed and tabulated data were checked.
Although several cross-sectional studies linked nonalcoholic fatty liver disease to either diabetes and
other components of the metabolic syndrome, we focused on 28 longitudinal studies which provided
evidence for nonalcoholic fatty liver disease as a risk factor for the future development of diabetes.
Moreover, additional 19 longitudinal reported that nonalcoholic fatty liver disease precedes and is a risk
factor for the future development of the metabolic syndrome.
Finally, molecular and genetic studies are discussed supporting the view that aetiology of steatosis
and lipid intra-hepatocytic compartmentation are a major determinant of whether fatty liver is/is not
associated with insulin resistance and metabolic syndrome.
Data support the novel paradigm of nonalcoholic fatty liver disease as a strong determinant for the
development of the metabolic syndrome, which has potentially relevant clinical implications for diagnosing, preventing and treating metabolic syndrome.
2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.
Open access under CC BY-NC-ND license.
1. Introduction
Steatosis and steatohepatitis, in the absence of competing aetiologies such as high alcohol intake, hepatitis C virus (HCV) infection,
drugs and other endocrine disorders, are both part of the nonalcoholic fatty liver disease (NAFLD) spectrum [13]. NAFLD may either
occur in the absence of fatty changes and is often alluded to either
as cryptogenic or nonalcoholic steatohepatitis (NASH)-cirrhosis
[4,5] or encompass hepatic and extra-hepatic complications, from
hepatocellular carcinoma to atherosclerosis [6]. NAFLD is presently
recognized as one the most common causes of altered liver tests,
of end-stage liver disease requiring liver transplantation, and is
http://dx.doi.org/10.1016/j.dld.2014.09.020
1590-8658/ 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. Open access under CC BY-NC-ND license.
182
Table 1
Nonalcoholic fatty liver disease and metabolic syndrome the original spectrum of similarities.
Steatosis
Metabolic syndrome
Epidemiology
Prevalence in the general population
Prevalence grows with age
Males more affected
Up to 25% of adults
Yes
Yes (adults, children)
Anthropometry
Association with central obesity
Documented
In drinkers and non-drinkers
Yes
Yes
Circumstantial Evidence
Pathogenic mainstay
Yes
Yes
Yes
Yes
Clinical features
Systemic disease
Accelerated atherogenesis
Response to diet and/or exercise
Yes
Circumstantial Evidence
In the obese
Yes
Yes
Yes
Experimental pathology
Animal Models (rat)
additional components over time [17]. This, together with the possible progression to organ failure and of the development of some
cancer types, including primary liver cancer [9,11,18,19], makes
metabolic syndrome a relevant condition in clinical practice and a
major public health concern worldwide.
In 1999, European researchers [2022] provided biological, clinical and epidemiological evidence for the theory that NAFLD should
be regarded as the hepatic manifestation of the metabolic syndrome (Table 1) [20]. Since then, a chicken and egg scientic
debate has arisen, concerning the primacy of metabolic syndrome
(and insulin resistance) over NAFLD or, conversely, of NAFLD
over the metabolic syndrome [23]. Moreover, while most studies
acknowledge NAFLD to be a risk factor for T2D [24], the notion that
NAFLD anticipates the future development of components of the
metabolic syndrome other than T2D is far less accepted, although
it has been suggested by few authors [23,25,26] mainly based on
their expert opinion.
In our systematic review of the literature, we discuss all available data supporting the view that NAFLD, rather than being
a mere manifestation of the metabolic syndrome is indeed a
necessary precursor of the future development of metabolic syndrome in humans. To this end, further to identifying all relevant
cross-sectional studies, we specically address the evidence from
prospective studies showing that NAFLD is an independent risk factor for the future development of both T2D and other components
of the metabolic syndrome. Methodological limitations of such data
are briey analysed. Finally, we discuss how some examples of
dissociation of NAFLD from metabolic syndrome seemingly contradicting our thesis eventually conrm the general paradigm of
NAFLD being a precursor of the metabolic syndrome.
2. Research strategy
The PubMed data base was manually searched for the following terms: Metabolic syndrome; Type 2 Diabetes; Obesity;
Dyslipidemia Hyperlipidemia; Insulin resistance; Predictor;
Fatty liver; Follow-up; Association and Dissociation. The
research was updated at the 28th of April 2014. Further bibliographic updates were performed whenever needed during the
revision process.
All of the identied articles and their references were further
checked in duplicate in order to identify appropriate articles. Pertinent studies were identied as a result of the agreement two
183
Table 2
Nonalcoholic fatty liver disease and metabolic syndrome the expanded spectrum of similarities.
TSH
Bile acids
Caffeine
Smoking
Altered sleep physiology
NAFLD
Metabolic syndrome
Intestinal microbiota
Vitamin D deciency
List of abbreviations: BMI, body mass index; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcholic steatohepatitis; TGR5, membrane-type G-protein-coupled receptor for bile acids; TSH, thyroid stimulating hormone; UDCA, ursodeoxycholic acid.
from a pathophysiological point of view [8]] is independently associated with NAFLD, a few features (visceral obesity, dyslipidemia
and insulin resistance/T2D) are more closely related to NAFLD.
The association of NAFLD with the metabolic syndrome appears
to be stronger in lean than in obese individuals, especially in
women. NAFLD specically anticipates the presence of metabolic
disorders and independently predicts insulin resistance, identifying those individuals with insulin resistance who may be missed by
metabolic syndrome criteria in certain populations. The frequency
of metabolic syndrome signicantly increases with quintiles of ALT
and GGT, even within the normal range of these enzymes [51].
Moreover, T2D and hypertriglyceridemia are more commonly associated with raised hepato-biliary enzymes, and particularly GGT
[65], an association which appears to be independently mediated
by insulin resistance. In turn, the presence of metabolic syndrome
is associated with the development of brosis or NASH.
Again, association in cross-sectional studies does not provide
evidence as to which condition comes rst. In order to address this
issue, studies supporting the view that NAFLD precedes the development of metabolic syndrome are summarized in Supplementary
Table S-2.
184
Collectively, they suggest that NAFLD, either diagnosed via surrogate indices or by ultrasonography, antedates the presence of
several components of metabolic syndrome, not only of T2D. This
association is largely regulated by the presence of insulin resistance. However, in 13 out of 15 such studies, NAFLD was diagnosed
on surrogate laboratory indices, on ultrasonographic ndings in
two and in none by the gold standard liver biopsy technique. Moreover, the diagnostic criteria tended to be heterogeneous and given
that enlarged waist circumference is both a main pathogenic key
for NAFLD and is central for the diagnosis of metabolic syndrome, it
is virtually impossible to rule out the possibility that visceral obesity links the development of both NAFLD and metabolic syndrome.
Finally, no specic traits of the metabolic syndrome (dysglicemia,
dyslipidemia, high blood pressure and central obesity) are mandatory for the development of the full-blown metabolic syndrome
(Supplementary Table S-2).
185
Fig. 1. Primacy of nonalcoholic fatty liver disease over metabolic syndrome. Based on epidemiological and biological data discussed in the text, the cartoon schematically
illustrates the theory of nonalcoholic fatty liver disease being the precursor of metabolic syndrome. Although not included in current diagnostic criteria of metabolic
syndrome, uric acid is denitely a trait of the metabolic syndrome constellation from a pathophysiological point of view and a determinant of development and progression
of nonalcoholic fatty liver disease, as discussed in Table 2. The key-role of lipid droplets in potentially protecting fatty liver from developing insulin resistance is highlighted
based on recently published data [218,219].
a specic role of this protein in the four-step model of histogenetic events originally proposed by Wanless to account for NASH
pathogenesis and its progression to cirrhosis via hepatic venular
obstruction [226]. Perilipin has been conrmed by following studies as one of the most prominent upregulated genes in NAFLD [227].
In summary, alterations in the regulation of lipid droplets physiology and metabolism inuence the risk of developing metabolic
diseases such as T2D and NAFLD [227]. Fig. 1 illustrates the hypothesis that NAFLD is a precursor of the metabolic syndrome via insulin
resistance resulting from PKC activation which conceivably occurs
in most cases of NAFLD in humans.
If the general rule is that steatosis and insulin resistance are
associated, are there any examples of such two conditions being
dissociated from each other?
5. Dissociation of NAFLD from insulin resistance and the
metabolic syndrome
The rst clinical evidence for conditions where high-grade
steatosis occurs without insulin resistance or low-grade liver fat
content is nonetheless associated with insulin resistance was
reported in 2006. This conclusion was reached by comparing insulin
resistance (assessed by HOMA-IR) and steatosis grade in three naturally occurring different conditions displaying a variable extent
of steatosis: familial hypobetalipoprotenemia (FHBL), NAFLD and
steatosis (evaluated histologically) associated with HCV infection
[228]. In 2010 Amaro et al. measuring insulin resistance with the
hyperinsulinemic-euglycemic clamp procedure coupled with glucose tracer infusion and liver fat content with magnetic resonance
(MR) spectroscopy, conrmed the results in FHBL individuals [229].
Of interest, circumstantial evidence suggests that FHBL is associated with progressive liver disease only in those patients featuring
components of the metabolic syndrome [230].
Consistent with the potential occurrence of steatosis dissociated from insulin resistance, Kantartzis et al. reported that single
nucleotide polymorphisms in the diacylglycerol acyltransferase 2
186
T2D. Moreover, NAFLD is a strong determinant for the future development of the metabolic syndrome. This is likely to occur as a
result of its being a key factor associated with insulin resistance
in naturally occurring conditions in humans. Exceptions to such
a theory are found in some genetic polymorphisms where the
steatosis-insulin resistance-metabolic syndrome triad is dissociated in humans. The molecular biology of events dictating NAFLD
being associated with or dissociated from insulin resistance is
increasingly being elucidated.
On these grounds, the diagnostic importance of NAFLD as a criterion for the presence, as well as for risk of future development
of metabolic syndrome, needs to be emphasized. From a therapeutic point of view, those pathogenic-based interventions aimed
at reversing NAFLD are likely to be a rational approach in the
prevention and treatment of hepatic insulin resistance, metabolic
syndrome and related complications.
Conict of interest
None declared.
Acknowledgement
This article is devoted to the memory of late Professor Paola
Loria, M.D. The authors are grateful to Dr Leon Adams for invaluable
advice and thank Elisa Gibertini for kind assistance as a graphic
artist.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.dld.2014.09.020.
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