UNEB - Bahia State University Review

NONALCOHOLIC STEATOHEPATITIS (NASH) AND THE METABOLIC

SYNDROME: A SYSTEMATIC REVIEW

Laura Costa MENEZES1

Naiara Brunelle Oliveira NEIVA1
Edilene Maria Queiroz ARAUJO2

They graduated in Nutrition and they are currently postgraduate students in “Clinical
Nutrition in Obesity and Aesthetics” at Bahia State University, Life Sciences Department.
Campus I, 2555, Cabula, CEP:41.150-000, Salvador, Bahia, Brazil. Contacts:
lc.nut@gmail.com; naiarabrunellenut@gmail.com.
2
Currently, she is a doctor’s degree student in Biotechnology – Genetics at
UEFS/FioCruz-Bahia. Further, she has been working for Bahia State University as
Assistant Professor in Life Sciences Department. Campus I, 2555, Cabula, CEP:41.150-
000, Salvador, Bahia, Brazil. Contact: emaraujo@uneb.br.

ABSTRACT
Recent researches has been working to clarify the correlation between Metabolic
Syndrome (MS) and Nonalcoholic Steatohepatitis (NASH) because of increasing number
of people with both diseases. NASH is a necroinflammatory situation of liver and it is a
Nonalcoholic Natty Liver Disease (NAFLD). The increasing of NASH in Western
countries has followed the obesity epidemic, maybe for this reason both MS and NASH
etiopathogenesis are connected. Thus, this paper verified if there were some researches
that prove the correlation between MS and NASH, its similar mechanisms and the risks
for MS cofactors. In other words, it carried out a bibliographic review based on data from
Lilacs, SciELO and PubMed-NCBI. The data included original studies published in the
last 5 years, which approached patients with MS as well as bibliographic reviews
published between 2006 and 2016. This review found 9 original articles and it assessed
the MS cofactors. The NAFLD prevalence in articles was from 23,8% to 100%, however,
the NASH prevalence was from 18% to 94% and SM prevalence from 17,6% to 95,8%
as well. The heterogeneity of studied populations and the different diagnosis criteria can
be the justification for remarkable variation in NAFLD, NASH and MS prevalence. It
found out significant relations between MS and NASH in 3 articles. However, most of
them assessed the NAFLD. Moreover, it noticed relations between NASH and MS
cofactors featured for WC, HDL-C and TG. Nevertheless, in majority of articles, the
studies only approached the prevalence analysis, while ones found relations among MS
cofactors and NASH and/or NAFLD without the pathophysiological mechanisms
descriptions.
KEYWORDS: NASH; Steatohepatitis; Metabolic Syndrome; Relations.

1. Introduction

The Metabolic Syndrome has defined as complex disorder with a set of cardiovascular
risk factors. These factors include Obesity, Systemic Arterial Hypertension (SAH),
Diabetes mellitus Type 2 (DM2) and dyslipidemias1. The SM etiology is multifactorial
origin, however, there is a consensus regarding central fat deposition protagonism and
Insulin Resistance (IR) in its development2,3,4.
The MS prevalence has been increasing worldwide in recent decades, what implies that
it is an important public health issue1,5,6. This has motivated a great interesting concerning
in pathophysiological mechanisms comprehension which involves the syndrome as well
as some potential targets in therapeutic intervention.
In diagnosis scope, several Institutions such as World Health Organization (OMS, 1998)7
, the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP-ATP
III, 2005)7 and the International Diabetes Federation (IDF, 2006)8 characterize it as a
combination at least three of following factors: the central obesity, Systemic Blood
Pressure (SBP), triglycerides (TG) or high Fasting Blood Glucose (FBG), low levels of
HDL cholesterol (HDL-c) or the medication usage to treat these abnormalities.
Nevertheless, some parameters have showed significant relations with MS, such as
Nonalcoholic Natty Liver Disease. Although it is not part of definition criteria, the SM
hepatic manifestation has been considered due to its relations with cardiometabolic2,4,9,10
risk factors.
According to some studies worldwide, the NAFLD is the more common cause for chronic
liver disease. The current estimates show that it is the most prevalent liver disease around
the world, with variation about 20% and 30%2. In addition, some patients with NAFLD
have the greatest rate of MS than ones without hepatic abnormalities11,12,13. Others
describe NAFLD as an independent risk factor for subclinical atherosclerosis,
cardiovascular disease (CVD) and MS as well as a way to increase mortality risk13.
Whereas the growing number of people with MS related to NAFLD, recent researches
have been working to clarify the correlation between them2,5,12,13. The involved
mechanism in this relation might have a connection, mostly, with glucose
homeostasis2,6,9,12 imbalance. The hypothesis which declares that IR leads to MS and
NAFLD é bidirectional, but it is limited since the both pathogenesis can be multifactorial.
Both, MS and NAFLD, involve adipokines interactions, cytokines, inflammatory factors
and insulin resistance4,13.
The NAFLD spectrum varies between simple steatosis and NASH. For the first, there is
only hepatocellular fat accumulation and that is why it is benign and reversible3. In
NASH, there is a necroinflammatory situation related to an increased risk in cirrhosis
development and hepatocellular carcinoma (HCC)10. The NASH diagnosis involves
steatosis, lobular inflammation, hepatic ballooning and, in some cases4, fibrosis can
appear. The estimate of patients with hepatic steatosis develop NASH is about 10%-20%.
This data is relevant because the inflammation rate and/or fibrosis in steatosis determine
the disease prognosis.
The NASH constitutes an important progression risk factor for NAFLD in final stage4.
Its growing in Western countries has followed the obesity epidemic with mean prevalence
of 33% in obese patients15,16. In other words, an estimate shows that 2,8% to 24% world
population have NASH14. In children, the prevalence varies between 13% and 80% with
significant obesity15 correlation. In adults, the NASH can progress to cirrhosis in about
20% of patients and 30% to 40% of cases, the cirrhosis is related to HCC4,17.
Once there is a clue about relations2,12,13 between MS and NASH etiopathogeny,
therapeutic strategies are emerging and some investigations reveal its triggering factors.
Thus, this paper verifies if there are studies that proves the relation between NASH and
MS, the similar mechanisms to its etiopathogenesis and risks related to MS cofactors.

2. Methodology
It carried out a bibliographic review based on data from Lilacs, SciELO and PubMed-
NCBI with keywords: NASH; Steatohepatitis; Metabolic Syndrome; Relations. It
preselected some articles through reading from articles in Portuguese and English. It
included original studies (controlled and randomized) published in the last 5 years which
approached patients with MS regardless of diagnosis criteria and bibliographic reviews
published between 2006 and 2016. As for the NASH diagnosis, it included studies that
used hepatic biopsy, Computed Tomography (CT), Magnetic Resonance Imaging (MRI)
or ultrasonography. It excluded articles that approached alcoholic steatohepatitis and
others chronic liver disease such as viral hepatitis, autoimmune liver disease, drug
induced, hereditary hemochromatosis and Wilson's disease.

3. Results
According to the search with keywords, it found 9 original articles which approached
methodological requirements, whose data are present in table 1 (Relations Study between
NAFLD or NASH and MS) and 2 (the MS cofactors: SAH, FBG, WC, HDL, TG and
NASH/NAFLD). It focused on searching for relations between NASH and MS and its
risk factors even as the similar etiopathogenic mechanisms. The studies assessed as main
marks the MS cofactors, namely: Waist Circumference (CC), Fasting Blood Glucose
(FBG), HDL-c, TG, Systemic Blood Pressure (SBP) or Systemic Arterial Hypertension
(SAH). One of the article reported a group with Alcoholic Hepatic Steatosis (AHS)14 and
it is not part of this paper.
Since the relations between NAFLD and MS as well as among their constituent
components have been recognized increasingly, such findings have also motivated the
interest regarding the influence of liver diseases in increased cardiometabolic risk. In
2012, for example, researchers investigated the relations between NAFLD and injury
markers as well as liver function and MS components. It kept up with 144 Brazilian
patients (Obese Class III) between January and December (2006). The prevalence of
patients with NAFLD diagnosis was 71%. On the other hand, for patients with SM was
49%. In addition, it showed that 81,4% of patients with NAFLD were syndromic – it was
statistically significant (p = 0,01). However, this study did not assess NASH. In individual
analysis concerning MS components, it registered significant relation between HDL-c
(p=0,05), WC (p<0,05), SAH (p=0,041) and NAFLD. FBG and TG did not show any
relation liver disease (p>0,05)3.
Some authors assessed 33 children 2-13 years old with overweight in order to study the
MS, NAFLD and IR prevalence. The selection criteria demanded the presence at least
one hepatic abnormality (clinical hepatomegaly or high level of ALT) to justify the liver
biopsy in patients. The authors found a prevalence of MS and IR about 60,6% and 48,4%,
respectively. In addition, patients with syndrome were susceptible to have NAFLD (p=
0,001). The children with NAFLD were 45,5%, which 24,2% showed simple steatosis
and 21,2% with NASH. There was a significant relation between NAFLD and the higher
values of TG (p=0,001), WC (p=0,001), and lower HDL-c (p=0,01), comparing to
patients with normal hepatic histology. However, there was not a significant relation
between FBG and NAFLD (p>0,05). This study did not assess the Blood Pressure or
SAH. It found out almost the double of MS prevalence in children with NAFLS regarding
healthy children (80% versus 44%, p = 0,05). The IR was also higher in this group (48,4%,
p=0,001)9.
 Table 1: Relation Studies between NAFLD ou NASH and MS
Search Year Kind of N MS NAFLD, Relation Relation Authors
Location Study Classification NASH and between between
Criteria MS NAFLD NASH
Prevalence and MS and MS
(Pvalue) (Pvalue)
Brazil 2012 Transverse 144 Obese Class III NCEP/ATP III 71% 0,01 Not CHAVES et
(19-64 years old) Not applied applied al3
49%
Cairo 2012 Transverse 33 with NCEP/ATP III 45,5% 21,2% 0,05 Not EL-KOOFY
Overweight/Obesity 60,6% applied et al9
(2-13 years old)
Spain 2014 Transverse 139 (Obese Class NCEP/ATP III 89,9% <0,001 0,000 RODRÍGUEZ
III) 18% 50,4% et al16
Spain 2015 Transverse 145 (18-67 years NCEP/ATP III 50% Not 0,05 ALLER et al10
old) 27,5% applied
75%
Brazil 2015 Transverse 50 Obese Class III NCEP/ATP III 100% p = 0,254 Not CORDEIRO
(20-60 years old) 30% applied et al2
56%
Brazil 2015 Prospective 137 women NCEP/ATP III 23,8% p<0,01 Not ROMANOWS
(≥ 18 years old) and IDF Not applied applied KI et al18
with PCOS PCOS +
NAFLD:
75% and
95,8%
Peru 2015 Retrospective 32 (average: 49 No information 100% Not Not MATOS et
years old) 94% applied applied al14
19%
Iran 2016 Cohort 3415 NCEP/ATP III M: 33,1%; Not Not FATAHI et
(≥ 18 years old) and CCDMIA W: 27,4% applied applied al19
Not applied
M:
65,9%/30,1%
W:
64,6%/73,7%
China 2016 Transverse 614 (average: 42,6 NCEP/ATP III 53,7% - p<0,0001 Not YANG et al13
years old) 17,6% applied

M: Men; W: Women. NS: No Significance (pvalue > 0,05).

NCEP-ATP III: National Cholesterol Education Program’s Adult Treatment Panel III;
IDF: International Diabetes Federation; CCDMIA: Criteria for Clinical Diagnosis of
Metabolic Syndrome in Iranian Adults.
In 2014, researchers studied 139 Spanish patients with severe obesity who had to undergo
bariatric surgery between 2008 and 2011 in order to verify the relation between visceral
adiposity and NAFLD in addition to describe the factors related to MS. This study used
the histological scoring system known as NAFLD Activity Score (NAS). The NAS scale
varies from 0 to 8, according to hepatic histology: steatosis, lobular inflammation,
hepatocellular balloon and fibrosis. It considered NASH when it was ≥ 5. The diagnosis
registered 89,9% of patients with NAFLD and 18% with NASH. Moreover, half of
patients (50,4%) met the MS criteria. There was significant relation between NASH and
TG (p = 0,002) and HDL (p = 0,014). There was not analysis for FBG and SAH. In genre
 context, the NASH showed relation with WC both men (p=0,001) and women (p=0,024).
A total of 76% of patients with NASH had MS against 27,3% who had normal hepatic
biopsy. Thus, it found out a significant relation between NASH and the syndrome (p =0,000)16.

In this same way, in 2015, a research recruited 145 Spanish patients in order to assess the
relation between IR, MS and BMI and hepatic histology. This study also used NAS to
diagnose liver disease, which determined NASH with scoring from 5 to 8. The authors
found that 50% of patients had NAFLD diagnosis, 27,5% with NASH and 75% with MS.
In univariate analysis, it showed that the predictor factors of NASH were MS and
BMI>3010. In same year, researchers assessed 50 people, men and women, with obesity
Class III and 20-60 years old. The gradation of liver disease considered macro vesicular
steatosis (simple), NASH and presence of fibrosis and cirrhosis. In addition, 100% of
patients showed NAFLD, who 70% had steatosis and 30% NASH. In turn, 56% of
patients had MS but there was significant relation between MS and NAFLD (p>0,05). It
did consider the relation analysis between NASH and MS but it only considered its
individual parameters. The patients with NASH and fibrosis had the higher TG and lower
HDL than who had simple steatosis (p=0,001 and p=0,038, respectively). Nevertheless,
there was no relation when it studied the relation between NASH group with fibrosis and
NASH group without fibrosis (p>0,05)2 . There was not significant relation between
NASH and WC, FBG and SAH (p>0,05).
Table 2: MS cofactors: SAH, FBG, WC, HDL-c, TG and NASH/NAFLD
Search Year Relation Relation between Relation Relation Relation Authors
Location between NASH*/NAFLD between between between
NASH*/ and SAH(Pvalue) NASH*/NAFLD NASH*/NAFLD NASH*/NAFLD
NAFLD and and and TG(Pvalue) and
SAH(Pvalue) WC(Pvalue) HDL(Pvalue)
Brazil 2012 0,041 NS 0,05 NS 0,05 CHAVES et al3
Cairo 2012 Not applied NS 0,001 0,001 0,01 EL-KOOFY et
al9
Spain 2014 Not applied Not applied M = 0,001 0,002 0,014 *RODRÍGUEZ
W = 0,024 et al16
Spain 2015 0,001 Not applied 0,007 Not applied NS *ALLER et
al10
Brazil 2015 NS NS NS 0,001 0,038 *CORDEIRO
et al2
Brazil 2015 Not applied <0,01 <0,01 <0,01 NS ROMANOWS
KI et al18
Peru 2015 Not applied Not applied Not applied Not applied Not applied *MATOS et
al14
Iran 2016 NS Not applied NS NS NS FATAHI et al19
China 2016 <0,0001 0,0001 <0,0001 <0,0001 <0,0001 YANG et al13

* Studies assessed specifically NASH.

Still in 2015, Brazilian researchers determined the prevalence of NAFLD and MS in
women are 18 years old or over, carriers of Polycystic Ovary Syndrome (PCOS), in order
to verify the existence of relation between them. It showed that in a group with 137
patients, 103 had PCOS and 34 formed the control group. They used two main diagnosis
criteria of MS: NCEP ATP III7 and IDF8. In group with PCOS, it registered 23,8% of
women with NAFLD, comparing to 3,3% in control group (p=0,01). There was not
significant difference between group with PCOS and control group (p>0,05) and it
showed the following results: in control group, the MS prevalence was 26,6% by NCEP
ATP III and 36,6% by IDF; and MS prevalence by PCOS was 32,7% by NCEP ATP III
and 44,6% by IDF. The patients with PCOS were youngest than who in control group
showed higher WC (p=0,05) and lower level of HDL (p=0,05). A comparison declared
that in PCOS group there was the lower prevalence of MS (p<0,01), 28,6% by NCEP
ATP III and 19,5% by IDF; the last group showed the higher prevalence of MS (p<0,01):
75% by NCEP ATP III and 95,8% by IDF. The group “PCOS + NAFLD” also showed
the higher relation with WC (p<0,01), FBG (p<0,01) and TG (p<0,01) without relation
with HDL (p>0,05). It did not assess SAH18. In the same year, another study assessed
clinical and biochemical characteristics of 32 patients with histology compatible with
steatohepatitis (2010-2012) and it verified the relation between histological diagnosis of
NASH and MS presence. The authors found a prevalence of 94% of NASH, which 19%
of patients had MS. Nevertheless, this study did not make either relation analysis with
MS or with its individual components. In histological findings, 66% of patients had mild
steatohepatitis, 31% moderate and 3% severe14.
In 2016, some researchers assessed from Cohort study in Iran 1069 men (31,3%) and
2346 women (68,7%) (≥18 years old). It studied the prevalence of NAFLD and MS as
well as the function of each component in NAFLD syndrome existence. The prevalence
of NAFLD was 33,1% and 27,4% in men and women, respectively. It characterized MS
according to two criteria: o NCEP/ATP III7 and CCDMIA (Criteria for Clinical Diagnosis
of Metabolic Syndrome in Iranian Adults). The CCDMIA is a specific Iranian criterion
and it advocates the following cut points: WC ≥ 95cm for both, TG ≥ 150mg/dL, HDL <
40mg/dL for men and <50mg/dL for women, SBP ≥ 130/85mmHg and blood glucose ≥
100mg/dL. For men, the prevalence of MS was 65,9% and 30,1% by NCEP/ATPIII and
CCDMIA, respectively. For women, the prevalence of MS was 64,6% and 73,7% by
NCEP/ATPIII and CCDMIA, respectively. There was not significant difference between
genre regarding MS cofactor (p>0,05)19(the study did not consider FBG), concerning the
relation between NAFLD and isolated MS components. Another investigation, in 2016,
investigated the relation between NAFLD, MS, IR and obesity in 614 Chinese patients.
This study used an ultrasound technique known as Ultrasonographic Fatty Liver Indicator
(US-FLI) to mirror the severity of histological hepatic changes in NAFLD. The general
prevalence of MS was 17,6% and NAFLD 53,7%, which 28,8% had mild steatosis and
17,1% moderate to severe steatosis. Comparing to individuals without NAFLD, those
with the higher disease score had the higher percentage of MS (p<0,0001), TG
(p<0,0001), SAH (p<0,0001), WC (p<0,0001), FBG (p<0,00001) and HDL-c (p<0,0001).
The MS was higher in individuals with moderate to severe steatosis, comparing to mild
steatosis (p<0,0001). The author reported that the score US-FLI < 4 regarding NASH, put
away its diagnosis, thus, the NASH would be in group of moderate to severe steatosis13.
Although, it cannot predict the quantitative of individuals with NASH and score > 4.

4. Discussion
This systematic research review assessed the relation between NASH and MS, its
etiopathogeny and connection with MS cofactors. However, it noticed a shortage of
article regarding relations between steatohepatitis and syndrome. Thus, 4 articles reported
this relation2,10,14,16. Others articles listed MS with NAFLD, including both steatosis and
NASH.
The prevalence of NAFLD in selected article varied from 23,8% to 100%, NASH from
18% to 94% and MS, from 17,6% to 95,8%. The methodological difference in researches
and ethnic heterogeneity in studied population are reasons for the remarkable variation.
The factors such as genre, age and ethnicity can have a great impact in prevalence of
NAFLD. Sayiner et al (2014)20 showed distinct prevalence in different ethnic groups, for
example, Hispanic (28% to 45%), African American (11% to 24%) and White (15% to
33%)20. In this review, there was only one study about children9. Ued et al (2015)21
described that the prevalence of NAFLD in obese children was in variable border, from
3% to 60,3%. This makes the comparison somewhat hard, even studies approach the same
age group21. For adults, there was an important variation, as showed in Table 1. On the
other hand, there are conflicting data about prevalence of NAFLD in genre context.
According to Sayiner et al (2014)20, while some authors suggest the higher prevalence on
male genre (risk factor assumption), ones found that NAFLD was more common among
women20.
Some studies used NAS scale to classify the disease activity and to determine its severity
regarding NAFLD diagnosis10,16. One study used the US-FLI13 model, but others used
hepatic biopsy2,9,14, NMR3 and ultrasonography18,19. In NAS, the scoring follows this
scope: 0-3 for steatosis degree and lobular inflammation, according to number of
inflammatory foci, 0-2 for hepatic ballooning and 0-4 for fibrosis stages. The main goal
of NAS is to assess histological changes during the time and it does not give any diagnosis
criteria for NASH7. However, the threshold of NAS ≥ 5 was the substitute for the
differential histological diagnosis of NASH4,17. In US-FLI method, the scale varies from
0 to 8, according to ultrasound impressions, as the presence of liver contrast, gallbladder
wall view, diaphragm view and focal preservation areas. The US-FLI classifies NAFLD
differently of NAS, namely: normal (0-1), mild hepatic steatosis (2-4) and moderate to
severe (>4). These methods still vary regarding hepatic biopsy – it is the “golden-pattern”
for disease diagnosis – and NMR22. Therefore, this could be a problem concerning
variation range for prevalence of NAFLD and NASH. In addition, the variation present
in MS prevalence could be connection to several diagnosis criteria, such as: WHO, NCEP,
IDF, and so on. It is reasonable to think that its cut points can lead different results.
The diversity in concepts and criteria, inevitably, leads some misunderstanding and this
can spoil the comparability between studies and standardization in diagnoses. The MS
components also have variations according to ethnicity, genre, eating habits, life styles,
phenotypes and geographic location. Thus, it is complicated to establish a general
classification23. For example, Junqueira et al23 quotes a study known as INTERHEART,
in United States, which compared the risk of heart attack by isolated risk factors and in
MS presence, according to WHO and IDF. It found a prevalence of MS in 10,1% of
patients by WHO and 17,7% by IDF. However, if this study applied the NCEPATPIII
criteria, the prevalence would be about 34%. This indicates a greater proportion of
patients who met MS criteria23. Maybe, this explains the preference of this criteria in all
articles.
According to main goal in this study, it verified that only two article assessed the relation
between MS and NASH, effectively10,16. In general, it can verify the studies assessed
more the relation between MS and NAFLD, steatosis and steatohepatitis. Maybe, because
there are a lack in standardization and diagnosis difficulties as well as the expensive cost
behind histological study. This makes the diagnosis more practical only in NAFLD4,17.
There were studies did not report regarding common etiopathogenesis between NASH
and MS. They only limited to prevalence analysis9,14 . Others researches showed common
predictors to visceral adiposity, the IR and oxidative stress, however, they did not describe
the pathophysiological mechanisms10,14,16,18. Rodríguez et al (2014)16, for example,
showed that MS, visceral adiposity and IR are related to abnormal liver histology in
morbid obesity but they did not explain the pathophysiological mechanism that connects
them. Some authors list oxidative stress to hepatic fat accumulation2,3. A minor response
to insulin in adipocytes stimulates the tissue lipolysis and it contributes to progressive
accumulation of lipids in hepatocytes. The lipid stocks can reach toxic levels and to
exacerbate the production of reactive oxygen species in liver. Moreover, this can
stimulate macrophages multiplication and TNF production which interferes in insulin
sensitivity. Thus, the abnormal lipid peroxidation would yield in direct hepatic damage,
inflammation and even fibrosis as well.
When it looks at NAFLD and NASH with MS cofactors, namely: WC, HDL-c, TG, FBG
and Blood Pressure (Table 2), some results draw attention, such as lipemic factors, HDL-
c, TG and WC. They had enough evidence through the articles and it found 5 statistically
significant results for HDL-c2,3,9,13,16 and TG2,9,13,16,18 and regarding WC, it found six
results3,9,10,13,16,18.
It considered WC more sensitive to metabolic changes and it seems to be firmly related
to liver content of triglycerides, liver inflammation and fibrosis9. The studies explained
that, particularly, the central obesity must be strongly related to NAFLD and IR3,10,13,16,18,
despite two articles did not find significant correlation2,19. This correlation might occur
because the location of body fat in the abdominal region, regardless total fat, is predictor
factor for fat accumulation in the hepatocyte and, therefore, it is determinant in the
NAFLD pathogenesis. Thus, the central fat accumulation suggests the NAFLD as a MS
component related to IR2,4,16.
The intra-abdominal adipose tissue, in eutrophic individuals, constitutes about 10% body
deposits. It has fat around the internal viscera, where portal system gives the venous
drainage. Thus, the liver has direct exposure to cytokines and free fatty acids (FFA)
(visceral adipose tissue releases them), while the same diluted metabolites (adipose tissue
from other regions releases them) arrive in liver through systemic circulation. In “NAFLD
Portal Theory” there is exacerbated release of FFA, endotoxins and proinflammatory
cytokines from visceral fat via portal system. This promotes the IR hepatic development,
steatosis and NASH in obese individuals2. In addition, this abnormality predisposes SAH
development, dyslipidemia and inflammation and MS factors13. The association between
clinical evidence and excess adipose tissue involves both metabolic mechanisms and
inflammatory mechanisms, which increase cardiovascular risk13.
Three articles showed significant relation between SAH and NAFLD/NASH3,10,13.
However, they did not discuss this relation. The literature refers male individuals who are
not obese with fat in liver had a greater relation concerning hypertension as well as higher
coronary risk, regardless smoking or drinking habit24. The NAFLD effects are not limited
to liver in liver. In other words, they can affect several body systems and they can increase
the cardiovascular disease risks25. According to Gittoand & Villa (2016)26, the main risk
factors in NAFLD/NASH development are SAH and DM226.
Five authors verified the relation between NAFLD/NASH and FBG with significant
correlation in just two of them13,18. However, they did not clarify the causal relation
between factors. It suggested cause and effect bilateral relation between NAFLD and
DM227. It has described that patients with NAFLD and DM2 have mortality risk three
times greater compared to non-diabetic patients with NAFLD. In addition, patients with
DM2 have about 80% more fat in liver than non-diabetic patients28. Nevertheless, Leite
et al (2009)29 explained that this relation seems to be independent of glycemic control.
There is not significant difference in FBG in diabetic patients either with NAFLD or
without NAFLD29. Therefore, it seems the relation between DM2 and NAFLD is better
related to IR than glycemic changes29,30. Currently, it has been the accepted theory which
IR promotes oxidative stress, lipid peroxidation and hepatic injury as well27. The
probability to develop NASH increases with tolerance to abnormal glucose24.
It has proved increased liver fat in individuals with IR can be related to excess fat intake
and carbohydrates and decreased adipocyte lipolysis as well. This generates new
lipogenesis – it is a converting process of carbohydrates into fat for storage. The liver fat
is the most important predictor in hepatic insulin resistance31,32. The mechanism follows
the idea: the increase in visceral adiposity leads to IR peripheral, which stimulates
lipolysis because of lower insulin action. This leads to increased FFA in plasma. The FFA
metabolites, such as diacylglycerol and ceramides accumulate in liver and skeletal muscle
and they promote the phosphorylation of the insulin receptor substrate-1 (IRS-1), through
activation of the protein kinase C. This phosphorylation inhibits the activation of
phosphatidylinositol 3-kinase which inhibits insulin signaling. In addition, this leads to
IR in liver and increased gluconeogenesis. In this context, the glucose flow changed to
new lipogenesis2,4.
The correlation between lipemic abnormalities and NAFLD/NASH seems to be well
established. Some studies showed patients with NAFLD had a significant relation with
higher values of TG and lower values of HDL-c3,13. El Koofy et al (2012)9 showed that
hypertriglyceridemia in children with NAFLD was 81%. According to authors some
patients had clinical history concerning clinical hepatomegaly or high ALT. This idea has
a different approach in others studies. They explained this relation, first, as lipolytic
nature of visceral fat, thus, there is less sensitivity lower insulin sensitivity and higher
concentration of β-receptors in this region. Second, because it is next to portal system,
which drains visceral fat directly. This exposes liver to large amounts of FFAs and it
increases hepatic synthesis of triglycerides as well as it can decrease its ability to secret
them that causes non-hepatocyte accumulation. In addition, low levels in HDL-c are
results of lipid fractions disorders10,33. Researches evidenced a significant relation
between NAFLD and lower HDL-c values in patients with NAFLD34,21. Another study
verified that low serum concentration of HDL-c and high concentrations of TG were
different between patients with NAFLD and who without NAFLD, after age
standardization and glycated hemoglobin in diabetic patients. The low concentration in
HDL-c was a predictor in NAFLD regarding multiple logistic analysis35.
An important aspect is some articles compared NASH with steatosis but they did not
clarify which one represents greater risk in MS development10,16. These findings are
according to recent meta-analysis which conclude it12. In this meta-analysis, the authors
claimed there is not how to prove if the dose-response exists, that is, higher liver fat imply
higher metabolic disorder risks12. It did not clarify if the simple hepatic steatosis and
NASH have the same potential to MS development or if a greater degree hepatic
commitment results in a greater risk like in NASH case.

5. Conclusion
This study demonstrated that there is a possible relation between NAFLD and MS, but it
is necessary to standardize diagnosis in both changes, according to studied population, its
ethnicity, genre, age group, metabolic profile and specific pathophysiological
characteristics. It considered all articles regarding NASH and MS, since the search results
presented few articles in this field of research.
It noticed that, in majority, the articles suggest IR as main etiopathogenic factor for both
disorders due to increased WC, oxidative stress and vice versa. However, there are few
articles approach the relation between steatohepatitis and syndrome, since they are
focused on NAFLD understanding. Some studies only approached the prevalence
analysis, while ones reported correlation between MS and NASH: high WC, TG increase,
HDL-c decrease, SBP increase and blood glucose increase as well. However, there was
an interesting highlight concerning WC, HDL-c and TG cofactors. In other words, it
found higher statistic correlation with NASH and/or NAFLD but without to explain these
correlations.
This study contributes to make a point of lack in article publication which elucidate the
relation between NASH and MS. These metabolic disorders have high prevalence and,
apparently, they have related etiopathogens. Nevertheless, this study has a restriction in
its conclusions, since there is a gap in article publications. Therefore, it is necessary
studies in this field of research in order to clarify the theme through original and
randomized articles, case control as well. It is a great way to make clear points have not
clarified in field of prevention and best treatments as well as to promote faster diagnosis
and to provide less invasive methods as well as safe and low cost procedures.

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