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Non-alcoholic Fatty Liver Disease: A Clinical Update


Abstract and Figures

Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease in developed countries because of the obesity epidemic. The disease increases liver-related morbidity and mortality, and often increases the risk for other comorbidities, such as type 2 diabetes and cardiovascular disease. Insulin resistance related to metabolic syndrome is the main pathogenic trigger that, in association with adverse genetic, humoral, hormonal and lifestyle factors, precipitates development of NAFLD. Biochemical markers and radiological imaging, along with liver biopsy in selected cases, help in diagnosis and prognostication. Intense lifestyle changes aiming at weight loss are the main therapeutic intervention to manage cases. Insulin sensitizers, antioxidants, lipid lowering agents, incretin-based drugs, weight loss medications, bariatric surgery and liver transplantation may be necessary for management in some cases along with lifestyle measures. This review summarizes the latest evidence on the epidemiology, natural history, pathogenesis, diagnosis and management of NAFLD.
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Review Article
Non-alcoholic Fatty Liver Disease: A Clinical Update
Joseph M Pappachan*
, Shithu Babu
, Babu Krishnan
and Nishal C Ravindran
Department of Endocrinology, Diabetes & Metabolism, Royal Lancaster Infirmary, University Hospitals of Morecambe Bay NHS
Trust, Lancaster, UK;
Department of Medicine, Dorset County Hospital, Dorchester, UK;
Department of Gastroenterology &
Hepatology, Royal Bournemouth Hospital, Bournemouth, UK;
Department of Gastroenterology & Hepatology, Hinchingbrooke
Hospital, Hinchingbrooke, Huntingdon, UK
Non-alcoholic fatty liver disease (NAFLD) is currently the
most common chronic liver disease in developed countries
because of the obesity epidemic. The disease increases liver-
related morbidity and mortality, and often increases the risk
for other comorbidities, such as type 2 diabetes and cardio-
vascular disease. Insulin resistance related to metabolic
syndrome is the main pathogenic trigger that, in association
with adverse genetic, humoral, hormonal and lifestyle factors,
precipitates development of NAFLD. Biochemical markers
and radiological imaging, along with liver biopsy in selected
cases, help in diagnosis and prognostication. Intense lifestyle
changes aiming at weight loss are the main therapeutic
intervention to manage cases. Insulin sensitizers, antioxi-
dants, lipid lowering agents, incretin-based drugs, weight loss
medications, bariatric surgery and liver transplantation may
be necessary for management in some cases along with
lifestyle measures. This review summarizes the latest evi-
dence on the epidemiology, natural history, pathogenesis,
diagnosis and management of NAFLD.
Citation of this article: Pappachan JM, Babu S, Krishnan B,
Ravindran NC. Non-alcoholic fatty liver disease: A clinical up-
date. J Clin Transl Hepatol 2017;5(4):110. doi: 10.14218/
Non-alcoholic fatty liver disease (NAFLD) has emerged as the
most prevalent chronic liver disease in developed nations in
recent years. It is defined as the presence of $5% steatosis
in the absence of secondary causes of fat accumulation in the
liver (described below). Prevalence of NAFLD is growing, even
in the developing world, because of the global obesity
epidemic. Moreover, very close association between the
disease and metabolic syndrome has been identified.
Epidemiological data shows the global prevalence of
NAFLD in different populations as follows: United States
30%, Middle East 32%, South America 30%, Asia 27%,
Europe 24% and Africa 13%.
Wide variations in the prev-
alence have also been identified among different ethnic
groups of these populations. Another interesting trend
noted is the increasing prevalence of NAFLD among paediatric
age groups. Autopsy-based data showed that NAFLD preva-
lence among children aged 219 years to be 9.6% after
adjustment for age, sex, race and ethnicity, and up to 38%
in obese children.
The disease starts with fatty liver or hepatic steatosis and
may progress to steatohepatitis with hepatic inflammation.
Five to twenty percent of patients with fatty liver develop
nonalcoholic steatohepatitis (NASH) in their clinical course, of
which 1020% develop into higher-grade fibrosis and <5%
progress to full-blown cirrhosis.
The prevalence of NASH
may be underestimated, as the diagnosis requires histological
confirmation. It is considered that at least 5% of the popula-
tion may have NASH.
Prevalence of NAFLD among the at-risk
group is even higher.
Eighteen to thirty-three percent of cases with NAFLD
were found to have type 2 diabetes mellitus (T2DM), and up
to 6683% of NAFLD cases were identified with markers of
insulin resistance (IR).
Even without a significant degree of
dyslipidaemia, increasing levels of low-density lipoprotein
cholesterol (LDL) levels (ranging from < 2.0 mmol/L to
2.7 mmol/L) increased the prevalence of NAFLD from 19%
to 42% in patients in a recent study.
Prevalence of NAFLD
also increases with age (up to 46%), with the older age
groups having higher mortality rates.
Natural history
The natural history of NAFLD is not well established, with
significant knowledge gaps about the marked inter-individual
variations in disease onset, progression, and complications.
NAFLD represents a wide spectrum of clinical entities from
asymptomatic hepatic steatosis to more advanced liver
disease with hepatic failure or hepatocellular carcinoma
The rate of disease progression in most cases
is slow, although rapid development of advanced liver disease
may be occasionally found. About one-third of people even-
tually develop NASH;
however, regression of fibrosis is
also noticed in about 20% of these cases.
Journal of Clinical and Translational Hepatology 2017 vol. XX | 110
Copyright: © 2017 Authors. This article has been published under the terms of Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0), which
permits noncommercial unrestricted use, distribution, and reproduction in any medium, provided that the following statement is provided. This article has been published
in Journal of Clinical and Translational Hepatology at DOI: 10.14218/JCTH.2017.00013 and can also be viewed on the Journals website at
Keywords: Nonalcoholic fatty liver disease (NAFLD); Nonalcoholic steatohepatitis;
NASH; Insulin resistance; Metabolic syndrome; Lifestyle interventions; Bariatric
Abbreviations: ALT, alanine aminotransferase; AST, aspartate transaminase; CT,
computed tomography; DPP-4, dipeptidyl peptidase-4; FXR, farnesoid X receptor;
GLP-1, glucagon-like insulinotropic peptide-1; HDL, high density lipoprotein; HCC,
hepatocellular carcinoma; IR, insulin resistance; LDL, low density lipoprotein; MRI,
magnetic resonance imaging; MS, metabolic syndrome; NAFLD, nonalcoholic fatty
liver disease; NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis; NFS,
NAFLD fibrosis score; OCA, obeticholic acid; PCSK9, proprotein convertase subtili-
sin/kexin type 9; PPAR, peroxisome proliferator activated receptor; RCT, random-
ized control trial; SAF score, steatosis, inflammatory activity and fibrosis score;
T2DM, type 2 diabetes mellitus; TE, Transient elastography; VLDL, very low
density lipoprotein.
Received: 24 February 2017; Revised: 31 May 2017; Accepted: 24 June 2017
*Correspondence to: Dr. Joseph M Pappachan, Department of Endocrinology,
Diabetes & Metabolism, Royal Lancaster Infirmary, University Hospitals of More-
cambe Bay NHS Trust, Lancaster, LA1 4RP, UK. E-mail:
Although increased cardiovascular mortality rate has been
demonstrated in patients with NAFLD compared to general
it is difficult to predict the risk for all-cause
mortality in the absence of large population-based epidemio-
logical study data. However, NASH was associated with a
three-fold increase in liver-related mortality compared to
the general population.
Although NAFLD-associated cirrho-
sis was previously considered to have a higher risk for the
development of HCC, recent evidence showed that up to
50% of patients with NAFLD-associated HCC did not have
Co-existent T2DM and obesity further increase
risk of developing HCC in patients with NAFLD.
NAFLD is considered as a metabolic disorder that results from
complex interaction between genetic, hormonal and nutri-
tional factors.
Recent evidence suggests that several genetic
risk factors predispose to the development and progression of
For example, polymorphisms of PNPLA3, TM6SF2,
FTO,LIPA,IFNl4 HFE, and HMOX-1 genes have been found to
be associated with development/progression of the disease.
Obesity and metabolic syndrome (MS) are the most
important risk factors identified in the development of
NAFLD, and diabetes mellitus and hypertension are also
linked to greater progression of the disease.
Because of
the similarity in pathogenesis IR leading to hyperinsulinemia
and gross alterations in carbohydrate and fat metabolism
NAFLD and T2DM often co-exist in many individuals with met-
abolic syndrome. Moreover, both the disorders modify the risk
for each other in a vicious circle.
Full-blown T2DM also con-
tributes to further worsening of hepatic steatosis and pro-
gression of established NASH, fibrosis and cirrhosis, with a
higher risk of development of HCC.
Hyperinsulinemia and IR lead to increased adipocyte lip-
olysis and circulating free fatty acids (FFAs) that are taken
up by hepatocytes, initiating various complex metabolic
pathways that lead to NAFLD (Fig. 1).
Because of the very
strong association with MS, NAFLD is considered as the
hepatic component of MS.
Systemic IR reduces plasma
adiponectin (an adipokine that increases insulin sensitivity
and reduces inflammation) levels and increases the concen-
tration of leptin (a cytokine secreted by adipocytes that plays
a role in reducing body weight and fat mass). Reduced adipo-
nectin levels
and increased leptin levels (possibly from
leptin resistance)
are observed in patients with NAFLD.
Adipose tissue lipolysis continues, even with hyperinsuli-
nemia, because of the IR that results in increased plasma FFA
concentration. Liver takes up the FFA in circulation, that if not
oxidised gets stored in the liver in various forms or exported
as very low density lipoproteins (VLDLs), as shown in the
figure. High hepatic VLDL output also results in high circulat-
ing triglycerides and LDL and low circulating high density
lipoprotein (HDL) levels that increase atherosclerosis risk.
Increased glucagon levels with altered insulin/glucagon
ratio is seen in patients with NAFLD.
This promotes hepatic
de novo lipogenesis (DNL), glycogenolysis and gluconeogen-
esis with higher hepatic glucose production and IR. Several
gastrointestinal hormones and adipokines that regulate
glucose and lipid metabolism, along with hormones control-
ling appetite and satiety, are also thought to contribute to the
pathogenesis of NAFLD.
Glucagon-like insulinotropic
peptide-1 (GLP-1), ghrelin, selenoprotein P, leptin, adiponec-
tin and the myokine irisin are some of these chemicals.
As in the case of T2DM, the predominant risk factor for
development of NAFLD is IR because of overweight/obesity
that result from adverse lifestyle factors, such as over-
nutrition and physical inactivity. Although the majority of
cases with NAFLD are obese/overweight individuals, a small
but significant proportion of patients with the disease are
lean. This phenomenon is especially common in the non-
Caucasian populations, accounting for about 20% of cases.
Predominant visceral obesity rather than generalized
obesity, high dietary intake of fructose and cholesterol, and
genetic risk factors may predispose to non-obese NAFLD.
Higher rates of the mutant PNPLA3 gene variants and
reduced serum adiponectin concentrations were reported in
Caucasians with lean NAFLD compared to controls in a recent
Potential roles of various lysophosphatidylcholines,
phosphatidylcholines, lysine, tyrosine and valine were
revealed in these cases using metabolomics studies.
Physical activity stimulates production of various soluble
chemicals from muscle fibres, collectively termed as myo-
kines, that show auto, para and endocrine functions.
These myokines function as messengers between skeletal
muscle and other tissues, such as liver, adipose tissue,
heart, brain and blood vessels, signalling cascades of neuro-
hormonal changes that modulate energy balance, metabo-
lism and homeostasis. Although several myokines are
described that may alter human metabolism, irisin is the
most studied one among them. Physical activity increases
irisin levels, leading to thermogenesis with a possible protec-
tive effect on metabolic disorders.
However, there are
studies showing increased levels of irisin in patients with met-
abolic syndrome and NAFLD.
Acute response to exercise is shown to involve an increase
in plasma irisin levels, whereas chronic exercise leads to
reduction of the levels.
Therefore, these conflicting reports
on the plasma levels and metabolic effects of irisin may be
related to development of resistance to the hormone or its
effectors at tissue level that should be elucidated in future
research. With the available evidence, we can conclude that
by modulation of multiple metabolic parameters and the
effects on body energy homeostasis, irisin may alter the risks
for obesity, T2DM, NAFLD and cardiovascular disease.
Alterations in the functions and composition of gut micro-
biome, otherwise known as intestinal dysbiosis, have been
found to associated with obesity and its consequent metabolic
disorders, including NAFLD, in animal models.
Several sub-
sequent studies in animal models and humans revealed clear
association between gut dysbiosis and NAFLD.
Even the
degree of intestinal dysbiosis has been found to be correlated
to the severity of NAFLD and the fibrosis.
Several local
and systemic factors, such as disruption of gastrointestinal
mechanical barrier function,
metabolites released by intestinal microbial metabolism/
and ethanol production by the microbiota
were proposed as the potential pathogenic mechanisms.
Fig. 2 summarizes the pathogenesis of NAFLD and the
potential therapeutic targets.
NAFLD remains asymptomatic in a significant proportion of
patients, and the diagnosis is often suspected when liver
functions are found abnormal on biochemical testing or
hepatic imaging (ultrasonography, computed tomography
[CT] or magnetic resonance imaging [MRI] of liver) suggest
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Pappachan J.M. et al: Non-alcoholic fatty liver disease
fatty liver, when performed for some other reasons. The
diagnosis of NAFLD is established when $5% of the hep-
atocytes show steatosis in the absence of causes for secon-
dary steatosis, such as excessive alcohol consumption (> 20
grams/day in females and 30 grams/day in males) or chronic
liver conditions associated with steatosis (viral, autoimmune,
metabolic and toxic disorders).
Biochemical markers
Liver enzymes can often be normal in a number of patients
with NAFLD. For example, alanine aminotransferase (ALT) can
be normal in up to 60% of patients with NASH, and 53% of
patients with high ALT had no evidence of NASH and advanced
Although several biochemical markers, such as
TNF-a, IL-6, CRP, Pantraxin, Ferritin, serum prolidase enzyme
activity, soluble receptor for advanced glycation end product
and cytokeratin-18, have been proposed as useful in predict-
ing the severity of NAFLD/NASH in the past, none of these
markers have shown sufficient sensitivity or specificity for
routine clinical application for diagnosis.
NAFLD fibrosis score (NFS) using clinical and biochemical
parameters to predict the severity of liver involvement is the
most validated non-invasive tool to assess the disease. NFS is
based on age, body mass index, aspartate transaminase
(AST), ALT, platelets, albumin, and presence or absence of
impaired fasting glucose.
A low cut-off score < 1.455
excludes advanced fibrosis with a negative predictive value
of 93%, while a high cut-off value exceeding 0.676 suggests
advanced fibrosis with a positive predictive value of 90%.
Although the specificity of NFS is good, the sensitivity was
recently reported as being low.
Fig. 1. Pathophysiological mechanisms involved in the development and complications of nonalcoholic fatty liver disease (NAFLD). BAT, brown adipose
tissue; DNL, de novo lipogenesis; FC, free cholesterol; FFA, free fatty acid; GLP-1, glucagon-like insulinotropic peptide; GNG, gluconeogenesis; IR, insulin resistance; LDL,
low density lipoprotein; SeP, selenoprotein P; VLDL, very low density lipoprotein; WAT, white adipose tissue. Figure reproduced with permission from Petta et al.
Journal of Clinical and Translational Hepatology 2017 vol. XX | 110 3
Pappachan J.M. et al: Non-alcoholic fatty liver disease
Radiological diagnosis
Ultrasonography, CT and MRI of the liver are the standard
imaging modalities used in clinical practice for diagnosis of
NAFLD. In general, about 30% of liver steatosis should be
present for these techniques to detect NAFLD.
nography is cheap, available easily and easy to perform, even
from the bedside. The reported sensitivity of the test is > 90%
in experienced hands when hepatic steatosis is >30%,
although the sensitivity is much lower at lower degrees of
However, ultrasonography is highly operator-
dependent and, therefore, results can vary widely depending
on the performer.
Transient elastography (TE) is an ultrasound-based
imaging technique to detect the degree of fibrosis in patients
with NAFLD and NASH. Sensitivity and specificity of TE to
diagnose various stages of fibrosis have been reported to be
7992% and 7592% respectively.
Recent evidence also
suggests that ultrasound-based controlled attenuation
parameter value used in the TE technique can predict the
degree of steatosis in patients with NAFLD.
CT scan is reported to be highly sensitive in quantifying the
hepatic and visceral fat to measure the degree of adiposity in
patients with metabolic syndrome and NAFLD.
However, the
test is expensive and associated with risk of radiation, and,
therefore, not usually recommended in clinical settings. MRI
is highly sensitive and specific for both quantitative and qual-
itative assessment of NAFLD. Newer MRI techniques, such as
MR elastography, proton density fat fraction and the FerriScan
method, can stage the degree of fibrosis non-invasively to
diagnose and assess the prognosis of patients with
However, these techniques are expensive and avail-
able only in specialized centres.
Liver biopsy and histology
Liver biopsy remains the gold standard for diagnostic evalua-
tion of NAFLD. Biopsy not only confirms the diagnosis but
provides information on extent of fibrosis and steatosis,
necro-inflammation, and architectural distortion. In the
past, the NASH Clinical Research Network histological
scoring system was the widely used histological scoring
system, representing a validated scoring system that gen-
erates a NAFLD activity score (NAS). A NAS score of 5 or > 5 is
considered NASH and < 3 is not NASH.
However, recent evidence suggests that NAS score cannot
be used as a surrogate for discrimination between NASH and
NAFLD, although it is useful for the histological diagnosis.
Therefore, the European Association for the Study of liver
recommends NAS for evaluation of the disease activity, and
not for the diagnosis. The steatosis, inflammatory activity and
fibrosis (SAF) score introduced in 2012, provides a reliable
and reproducible measure for the diagnosis, grading and
staging of NAFLD without much inter-observer variability.
SAF score assesses both and separately the grade of steatosis
(S), the grade of activity (A), and the stage of fibrosis (F), the
latter according to the NASH Clinical Research Network.
Cost, procedure-related complications and intra- and
inter-observer variations in reporting the histology are the
major draw backs of liver biopsy, and, therefore, it is usually
not recommended in clinical practice, except in circumstances
where other differential diagnoses are to be excluded.
Treatment of NAFLD
There is no single intervention that is proven to be fully
effective in the treatment and cure of NAFLD. The main goals
of treatment are to improve steatosis and to prevent pro-
gression of the disease. Intense lifestyle modification and
treatment of the risk factors are the cornerstones of disease
management. Medical and surgical interventions serve as
second-line treatments, or as adjuvants.
Lifestyle interventions
Sustained and effective weight loss through calorie restriction
and increased physical activity have been shown to improve
liver function and histology in multiple studies.
exercise and dietary interventions in isolation or in combina-
tion have been shown to improve biochemical and histological
parameters of NAFLD. Low-carbohydrate high-fat diet has
been shown to be effective in improving all the abnormal clin-
ical and biochemical parameters of metabolic syndrome and
NAFLD in multiple studies.
These dietary interventions are
also associated with weight loss in patients. Even without sig-
nificant weight loss, however, lifestyle interventions were
found to improve NAFLD, especially if patients are adherent
to the changes.
Yet, patient compliance issues always rep-
resent a challenge to these interventions.
Insulin sensitizing agents
Being a disease associated with IR and metabolic syndrome,
insulin sensitizing agents are expected to alter the pathophy-
siological mechanisms of NAFLD. Metformin and the thiazo-
lidinedione group of antidiabetic agents are the most studied
medications in this group.
Although metformin use was associated with significant
improvements in IR and liver transaminases (AST and ALT),
the drug failed to show improvement in the histological
parameters, such as steatosis, inflammation, hepatocellular
ballooning and fibrosis.
However, because of the
Fig. 2. Pathogenesis of nonalcoholic fatty liver disease and effects of
various therapeutic interventions. indicates positive effect and indicates
negative effect.
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Pappachan J.M. et al: Non-alcoholic fatty liver disease
antidiabetic efficacy, metformin should be considered for
patients with T2DM or even prediabetic states and NAFLD.
Metformin is found to be safe, even in patients with cirrhosis,
and may protect against development of HCC in cases with
T2DM and chronic liver diseases.
These drugs modulate tissue insulin sensitivity through the
peroxisome proliferator activated receptor (PPAR)-gsignal-
ling, and improve blood glucose control. Rosiglitazone and
pioglitazone are the agents widely studied in this class of
drugs for management of T2DM. Following the controversy
about increased cardiovascular events, rosiglitazone use has
been much lower in recent years, with pioglitazone being the
agent widely used currently. Pioglitazone has been shown to
improve the hepatic insulin sensitivity and fatty acid oxida-
tion, and to inhibit hepatic lipogenesis.
There is moderate
quality evidence to suggest the benefits of pioglitazone in
improvement of biochemical and histological parameters of
NAFLD, although the drug use may be associated with
weight gain.
In combination with intense lifestyle modi-
fication, this drug should be considered in patients with NASH.
Oxidative stress plays a major role in the pathogenesis of
NAFLD and several investigators studied the effects of anti-
oxidants extensively.
Vitamin E is the most studied anti-
oxidant in this group. Supplementation of this was associated
with significant improvement in all histological parameters,
such as steatosis, hepatocyte ballooning, lobular inflamma-
tion and fibrosis, as compared to placebo.
Vitamin E is used
in the dose of 800 International Units daily for patients with
NASH, especially in non-diabetic cases.
Although multiple
agents such as N-acetylcysteine, betaine, probucol, viusid,
and silibinin (milk thistle) have been used in different trials,
the use of these agents are not recommended in current clin-
ical practice because of conflicting/insufficient evidence on
the benefits.
Incretin-based therapy
There are two main groups of incretin-related drugs exten-
sively studied for use in NAFLD, viz., GLP-1 analogues
(e.g., exenatide, liraglutide, lixisenatide, dulaglutide and sem-
aglutide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g.,
sitagliptin, saxagliptin, vildagliptin, alogliptin and linagliptin).
Both classes of drugs augment the meal-related insulin
secretion from the pancreas, along with extra-pancreatic
effects on multiple organs that make them very useful for the
management of T2DM.
Use of GLP-1 analogues are associ-
ated with weight loss, and DPP-4 inhibitors are weight neutral.
Incretin-based therapy is very commonly used in overweight/
obese T2DM patients, many of whom suffer from NAFLD as
well. Remarkable benefits of both the conditions make this
class of agents unique in managing the cases.
Recent evidence suggests that patients with NASH, partic-
ularly those with T2DM, get significant benefits from GLP-1
analogue therapy, with improvement in liver histology and
reduction in liver transaminase levels from baseline.
patients with NAFLD/NASH with or without T2DM, the benefits
of GLP-1 analogue therapy may outweigh the risk of use, and,
therefore, it should be considered. Although less effective,
DPP-4 inhibitors are also reported as effective in patients
with NAFLD and T2DM.
Lipid lowering agents
Lipid lowering agents are useful for treatment, especially
in patients with concurrent dyslipidaemia and NAFLD.
A Cochrane review in 2013 reported possible improvements
in serum aminotransferase levels and ultrasonological abnor-
malities in cases treated with statins, although the studies
included in the review were small with high risk of bias.
review concluded that statins can improve the adverse out-
comes related to NASH in patients with concurrent diseases,
such as hyperlipidaemia, diabetes mellitus, and metabolic
syndrome. A more recent small randomized control trial
(RCT) found that rosuvastatin monotherapy could ameliorate
biopsy-proven NASH with resolution of metabolic syndrome
within 12 months of treatment.
Unfortunately, the potential
for complications associated with liver biopsy makes it diffi-
cult to perform large RCTs in patients with NASH.
In experimental models of NAFLD, fenofibrate use was also
found to reduce liver steatosis associated with high-fat diet,
T2DM and metabolic syndrome.
Some small clinical studies
also showed beneficial effects. However, small sample sizes
and lack of histological data limit the validity of these
Multiple RCTs and meta-analyses showed beneficial
effects of omega-3 fatty acids both in adults and children with
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a
molecule secreted by hepatocytes that inhibits uptake of LDL
by targeting the receptor for degradation, and which aug-
ments lipogenesis.
Circulating PCSK9 levels have been
found to be elevated in patients with NAFLD. PCSK9 inhibitors
have been recently shown to be highly effective in reducing
hypercholesterolemia in patients with remarkable improve-
ment of the associated cardiovascular risk.
Because the treatment is expensive, these drugs are often
reserved for patients with statin intolerance and familial
forms of lipid disorders inadequately managed by full doses
of other lipid lowering agents.
Drugs for weight loss
Medications that help weight loss may potentially alter the
pathogenic mechanisms of NAFLD and may be useful in
selected patients. Most of these medications are associated
with only modest weight loss benefit and several of them have
been withdrawn from the market owing to undesirable side
This medication inhibits pancreatic lipase, resulting in fat
malabsorption and weight loss as a consequence. Although
two previous RCTs showed some beneficial effects of orlistat
in patients with NASH, it is not clear if the benefit was related
to weight loss conferred by the drug or direct effect.
Therefore, the drug use should be selected for individual
patients as per the clinicians discretion and situation.
This is an appetite suppressant associated with about 4%
weight loss in 12 months when combined with lifestyle
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Pooled data from three lorcaserin RCTs showed
that there was modest reduction in ALT levels and improve-
ment of cardiovascular outcomes in treated patients with
NAFLD compared to placebo.
Naltrexone/bupropion combination
This drug combination is associated with a weight loss of
approximately 5%. Modest reductions in hepatic aminotrans-
ferase levels were observed in patients who lost > 10%
weight in 12 months with higher dose of the combination.
This combination is also associated with significant weight
loss benefit and may be associated with improvement of
High-dose liraglutide treatment (3 mg daily) has been
approved by the United StatesFood and Drug Administration
and the European Medicine Agency recently for primary
management of obesity in patients without diabetes. About
8.5% weight loss has been observed in the treated patients
compared to placebo in a major clinical trial, although the
data on NAFLD was not available in this study.
another recent phase 2 clinical trial reported significant
improvement of liver histology when 1.8 mg liraglutide was
administered to patients.
Therefore, high-dose liraglutide
treatment also may be associated with the same benefit.
Other novel agents
Pentoxyphylline is a competitive nonselective phosphodiester-
ase inhibitor which raises cyclic adenosine monophosphate
and inhibits tumour necrosis factor-a. Both animal studies and
clinical trials in humans showed beneficial effects of this novel
Although prebiotics and probiotics have been
claimed to be useful in the treatment and prevention of
patients with obesity and NAFLD, inadequate supporting data
from high-quality clinical studies is against recommendation
of the use of these medications in normal clinical practice.
Obeticholic acid (OCA) is a synthetic bile acid and agonist
of farnesoid X receptor (FXR) that has been recently devel-
oped for treatment of primary biliary cirrhosis and has shown
promise in the management of NAFLD.
FXR is an important
nuclear receptor involved in the regulation of bile acid,
glucose and cholesterol homeostasis in the human body.
Both animal and human studies showed beneficial effects of
OCA in the management of NAFLD.
Another novel agent
elafibranor, a PPAR-a/dagonist, was shown to improve
NASH without fibrosis worsening in patients with moderate
or severe NASH compared to placebo in a recent clinical
The drug is well tolerated and yields improved cardi-
ometabolic risk profile in patients.
Bariatric surgery
Obese patients undergoing bariatric surgery showed signifi-
cant improvements in both histological and biochemical
parameters of NAFLD in a recent meta-analysis.
ical features of the disease, such as steatosis, fibrosis,
hepatocyte ballooning and lobular inflammation, as well as
reduction in the liver enzyme levels including ALT, AST, alka-
line phosphatase and g-glutamyl transferase were observed
in patients who underwent surgery. In 2015, based on level B
evidence, the Japanese Society of Gastroenterology in coop-
eration with the Japan Society of Hepatology recommended
weight loss surgery as an effective treatment option for
patients with NAFLD/NASH complicated by severe obesity
for improving fatty changes in the liver and inflammation
associated with NASH.
Although there is no clear global consensus from different
professional bodies on the indications for recommending
metabolic surgery in patients with NAFLD, rapidly emerging
evidence may lead us towards such a consensus in near
future. The most recently published data from the STAMPDE
clinical trial that revealed remarkable improvements in the
parameters of metabolic syndrome following bariatric surgery
is a good example of such high-quality evidence.
Liver transplantation
Recent data suggests that NASH-related end-stage liver
disease is the third leading cause for hepatic transplants in
the United States and is expected to become the most
common cause for liver transplant in 12 decades because
of the obesity epidemic.
The upward global trend in the
prevalence of obesity is expected to cause the same health
burden in most other regions of the world in the near future.
Therefore, liver transplants would become a standard treat-
ment option in a significant proportion of patients with
advanced stages of NAFLD.
Based on level B and strength 2 evidence, the Japanese
Society of Gastroenterology in association with the Japan
Society of Hepatology recommend liver transplant for patients
with advanced NASH hepatic failure.
The overall survival
rates after hepatic transplantation in these patients are
almost identical to those receiving transplants for liver failure
from other hepatic disorders. However, almost one-third of
patients who receive liver transplant for NASH will have recur-
rence of the disease in the transplanted liver in the absence of
intense post-transplant lifestyle modifications.
Table 1. NASH Clinical Research Network histological scoring system
NAFLD activity score NASH fibrosis stage
533%: 1
3466%: 2
> 66%: 3
None: 0
24: 3
Ballooning of
None: 0
Few ballooned: 1
Many ballooned: 2
NAS score (08)
< 3: not NASH
$5: NASH
Stage 0
No fibrosis
Stage 1
Zone 3 perisinusoidal fibrosis
Mild 1a
Moderate 1b
Portal/periportal 1c
Stage 2
Perisinusoidal and portal/
periportal fibrosis
Stage 3
Bridging fibrosis
Stage 4
6 Journal of Clinical and Translational Hepatology 2017 vol. XX | 110
Pappachan J.M. et al: Non-alcoholic fatty liver disease
Table 2 summarizes some of the therapeutic agents avail-
able for management of patients with NAFLD/NASH and the
level of evidence for the use of these medications.
There has been an exponential increase in the global inci-
dence and prevalence of NAFLD because of the obesity
pandemic. In the absence of therapeutic interventions, sig-
nificant proportion of cases progress to NASH, with increased
morbidity and mortality. Diagnosis of NAFLD often depends on
biochemical and radiological investigations, as early stages of
the disease are often clinically silent. Management of the
disease primarily depends on intense lifestyle changes to lose
weight. Insulin sensitizers, antioxidants, incretin-based
drugs, lipid lowering agents, weight loss medications, bari-
atric surgery and liver transplantation are therapeutic options
that can be added to lifestyle interventions when necessary
for management of cases. Continued research for optimizing
management strategies of this common disorder is important
for reducing the global burden of NAFLD.
Conflict of interest
The authors have no conflicts of interests related to this
Author contributions
Prepared the initial draft (SB, BK), conceived the manuscript
plan, and grossly modified the initial draft which had been
prepared by (JMP), helped in draft modification and revision
of the paper (NCR). All authors contributed to the literature
search and writing of the final manuscript.
Table 2. Drug classes, main mode of actions and side effects, and level of evidence for use in clinical practice
Category of drug
drug Main mode of action
side effects
Evidence for benefit
Biguanide Metformin Improved insulin sensitivity Gastrointestinal
Recommended in
patients with T2DM and
NAFLD (1/444)
Thiazolidinediones Pioglitazone Modulate tissue insulin
sensitivity through PPAR
Worsening heart
Recommended in
patients with NASH and
T2DM (1/444)
GLP 1 analogues Exenatide/liraglutide Suppress appetite, helps
weight loss and enhances
endogenous insulin production
Recommended in
obese/overweight T2DM
and NAFLD (1/444)
DPP 4 inhibitors Sitagliptin/linagliptin Enhances endogenous insulin
Suggested in obese/
overweight T2DM with
NAFLD (2/44○○)
Antioxidants Vitamin E Reduces oxidative stress Haemorrhagic
Recommended in
patients with NASH and
without diabetes
Pentoxyphylline Raises c-AMP and reduces
Suggested in NASH
Statin Atorvastatin Lowers plasma lipids Muscle pains
and myopathy
Suggested in patients
with dyslipidaemia &
NAFLD (2/44○○)
Lipase inhibitor Orlistat Decreases fat absorption from
intestine and reduces body
Diarrhoea Suggested in obese
patients (2/4○○○)
Farnesoid XR
Obeticholic acid Alters hepatic lipogenesis and
reduces steatosis and
Pruritus Suggested in patients
with NASH (2/44○○)
PPAR-a/dagonist Elafibranor Reduces steatosis,
inflammation and fibrosis
increase in
Suggested in patients
with NASH (2/44○○)
The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system is used to describe the strength of recommendations and the quality of
evidence. Strong recommendations are denoted by Recommendand the number 1, and weak recommendations by the phrase Suggestedand the number 2. Cross-filled
circles indicate the quality of the evidence, such that 4○○○ denotes very low quality evidence, 44○○ denotes low quality, 444denotes moderate quality, and 4444
denotes high quality.
Journal of Clinical and Translational Hepatology 2017 vol. XX | 110 7
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... In many other studies, raised BMI (93%) in our study was also found to be associated with disease of fatty liver and no significant difference in male and females BMI. Benedict M, et al. found raised BMI in 80% of the patients 18 .Some studies labelled obesity as a biggest risk factor of fatty liver like many other studies 19 . ...
... Our raised AST/ALT were found to be more in males. Male and old age are significantly associated with higher risk of developing NAFLD 19,22 . ...
Background: Non-alcoholic Fatty liver disease, also known as NAFLD is said to result from a number of disorders such as insulin resistance, Obesity & diabetes mellitus possibly as a result of an unhealthy and sedentary life style. The prevalence of NAFLD is stated to be 25.23%, but it ranges between 115 to 45% in Asian countries globally. Plasma aminotransferases (aspartate1aminotransferase [AST] & alanine aminotransferase [ALT]) are increased in patients with non-alcoholic fatty liver disease (NAFLD). Aim:To find the relationship between alanine and aspartate transaminases (ALT and AST) and fatty liver on ultrasound. Study design & duration: Retrospective Study, September 2017-2018. Settings: Radiology Department of Avicenna Medical College and Hospital, Lahore. Methods: 274 patients present with age of 18 years and above with demographic features as body mass index, grade of fatty liver and also noted ALT, AST and size of fatty liver were included from the study. Grade I was labeled if there was increased hepatic echogenicity but visible periportal & diaphragmatic echogenicity. Grade II was considered if increased hepatic echogenicity causes imperceptible periportal echogenicity, without obscuration of diaphragm. Grade III was considered as marked increase in liver echogenicity with imperceptible periportal echogenicity and diaphragm. The patients were then followed for the Alanine transaminase (ALT) and Aspartate transaminase (AST) Results: In this study The mean age of patients 53.8±11.94. There were 116(42.3%) male and 158(57.6%) females. Majority of patients were of grade II fatty liver 126(45.9%). Grade III fatty liver was found in 110(40.1%) and grade I fatty liver was found in 38(13.8%). hepatomegaly was seen in 153(55.8%) patients. None of the grade I fatty liver patients were found to have raised ALT or AST. Raised ALT was found in 21 patient of grade II and 15 of grade III fatty liver patients. Raised AST was found in 20 of grade II and 7 had grade III fatty liver patients. Conclusion: The conclusion of this study that mean of ALT increased as compare to AST. None of the grade I fatty liver patients were found to have raised ALT or AST. Raised ALT was found in 21 patient of grade II and 15 of grade III fatty liver patients. Keywords: Fatty liver disease, Grade I, II, III, AST, ALT
... There is no single treatment for NAFLD that has been demonstrated to be completely successful, The mainstays of NAFLD management are changing dietary habits and increasing physical activity to lose weight, and reducing hepatic lipid contents as weight reduction is favorable and the degree of improvement in liver histology is proportional to the quantity of decreased weight, moreover, even without considerable weight reduction, lifestyle modifications are beneficial for NAFLD patients, particularly when patients continue the lifestyle modifications program. The majority of researches also showed that changing of lifestyle leads to reductions in risk factors for cardiovascular diseases such as serum lipid values and insulin resistance (11)(12)(13) . ...
... As a result, the mean worldwide body mass index and occurrence of obesity, which are the main causes of NAFLD, have increased markedly during the previous three decades. NAFLD is now the most widespread chronic liver disease in developed countries (11,13,19) . ...
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non-alcoholic fatty liver disease (NAFLD) is one of the widespread chronic liver diseases; it is ranging from simple fat buildup in the liver (steatosis) to non-alcoholic steatohepatitis (NASH) presence of inflammation and hepatocyte injury. This study aims to assess the effect of vitamin E on the degree of fatty infiltration in the liver, liver enzymes, and lipid profile. A prospective open-labeled clinical trial involved (39) Participants diagnosed with NAFLD depending on ultrasonography findings, they were administered vitamin E 800IU\day for 12wks and advised to take low fat, low carbohydrate diet and to do regular sport. Steatosis score, liver enzymes, fasting blood sugar and lipid profile were measured at baseline and repeated at 4wks and 12wks of the study period. Results of this study found that vitamin E reduces steatosis score significantly at 12wks (p=0.0001), while liver enzymes ALT and ALP did not show significant difference throughout the study period at 12wks (p=0.081 for ALT, P=0.117 for ALP) only AST showed significant difference ( p=0.008 at 12wks ), total cholesterol and triglyceride were reduced significantly (p=0.0001 for both) at 4wks and 12wks where HDL and fasting blood glucose were not altered significantly through the study period. In conclusion, vitamin E and lifestyle modifications have a positive impact on patients with NAFLD by reducing steatosis score, lipid profile, and BMI
... Fat accumulation in the liver promotes insulin resistance, which increases the sensitivity of the liver to subsequent damage. Other factors such as oxidative stress, lipid peroxidation, mitochondrial dysfunction, intestinal flora, adipose tissue dysfunction, and adipokines may also be involved [4]. ...
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This study investigates whether serum prolactin (PRL) is a key factor for nonalcoholic fatty liver disease (NAFLD) in children. A total of 691 obese childred participated in this study and were divided into a NAFLD group (n=366) and simple obesity (SOB) group (n=325) according to the hepatic ultrasound results. The two groups were matched for gender, age, pubertal development, and body mass index (BMI). All patients underwent an OGTT test, and fasting blood samples were collected to measure prolactin. Stepwise logistic regression was performed to identify significant predictors of NAFLD. Serum prolactin levels were significantly lower in NAFLD subjects than in the SOB subjects [82.4 (56.36, 118.70) vs. 99.78 (63.89, 153.82), p<0.001] (mIU/l). NAFLD was strongly associated with insulin resistance (HOMA-IR) and prolactin, with lower levels of prolactin increasing the risk of NAFLD (adjusted ORs = 1.741; 95% CI: 1.059–2.860) across the prolactin concentration tertiles after adjustment for confounders. Low serum prolactin levels are associated with the presence of NAFLD; thus, increased circulating prolactin might be a compensatory response for obesity in children.
... Liver biopsy remains the gold standard for making a definitive diagnosis of NASH, which is a clinicopathological presence 4 . However, its routine use is controversial due to its invasive procedure, high costs, and related complications 11,12 . Therefore, researchers have begun to search for new non-invasive methods that could predict the severity of NASH. ...
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Objective: Non-alcoholic steatohepatitis (NASH) is a type of hepatic disease characterized by excessive fat accumulation in the liver, fibrosis and hepatic inflammation. Pentraxin-2 (PTX-2) is a serum protein that inhibits inflammation and fibrosis. In this study, we aimed to investigate the role of PTX-2 as a biomarker in detecting NASH while obtaining information about the possible relationship between biopsy results and PTX-2 in NASH. Materials-Methods: A total of 65 patients followed up with the diagnosis of NASH and 15 healthy volunteers were included in the study. Demographic data such as age, gender, weight, height, body mass index (BMI) and waist circumference of the patients were recorded. After PTX-2 levels were measured by enzyme-linked immunosorbent assay, Biochemical, hematological parameters, and liver biopsy results were compared with PTX-2 levels. The severity of liver fibrosis was interpreted according to National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network Scoring System by the same pathologist. Liver biopsies were also performed by the same radiologist. Results: The PTX-2 levels were statistically lower in the patient group compared with healthy subjects (p<0.001). No statistically significant correlation was found between PTX-2 level and liver biopsy results of patients. PTX-2 level was negatively correlated with alkaline phosphatase in the patient group (r=-0.294, p=0.017). There was no statistically significant correlation between PTX-2 level and the other biochemical and hematological parameters. Conclusion: In conclusion, we could mention that serum PTX-2 levels may be used as a non-invasive biomarker in the prediction of NASH. However, serum PTX-2 levels are insufficient to obtain information about the severity of the disease and the degree of steatosis. Key Words: Non-alcoholic steatohepatitis, NASH, Pentraxin-2, fibrosis, liver biopsy.
... 9 Defined as non-alcoholic fatty liver if ≥5% steatosis is present in the absence of a secondary cause of fat accumulation in the liver. 10 According to various studies, the exact prevalence of non-alcoholic fatty liver is unknown, but it ranges from 3% to 24%. Nonalcoholic fatty liver is a prevalent liver disease in the United States, affecting about 20% of adults. ...
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Indonesia is facing increased consumption of calorie-dense foods, such as fast food, among its society. Changes in diet and physical activities towards unhealthy ones can result in an imbalanced lifestyle, leading to various consequences, including hyperlipidemia. Pregnant women experience significant increases in plasma concentrations of lipids, lipoproteins, and apolipoproteins. Excessive cholesterol levels in pregnant women will result in the formation of fat in the liver. The purpose of this study was to determine the effect of a high-fat diet to pregnant Wistar rats (Rattus norvegicus) on the histopathological features of the liver. A true experimental with post test only control group design was applied in this study, which was conducted from August 2020 to November 2021. Fourteen (14) pregnant female rats were divided into two groups. The first group of rats was fed with a high-fat diet, while the second group, which was the control group, was given a standard diet. The high-fat diet used was 3 mL/rat/day beef brain. After the rats delivered their litters, the rats’ livers were retrieved, then examined histopathologically under a microscope. This research was conducted from No fatty liver was identified in the control group or the treatment group. Hence, a high-fat diet does not affect the liver histopathological features in pregnant Wistar rats.
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Nonalcoholic fatty liver disease (NAFLD) is one of the most important causes of liver disease. NAFLD is commonly associated with obesity, insulin resistance and other metabolic abnormalities such as hypertriglyceridemia and hyperuricemia. Patients with NAFLD can be properly rationalized and with early exploration and management of fatty liver the progression and complications of NAFLD in relation to liver fibrosis can be reduced on priority basis because the APRI is noninvasive and a simple calculation of two laboratorial variables. Objective: To determine the frequency of liver fibrosis by non-invasive marker in patients with non-alcohol fatty liver disease. Methods: This cross-sectional descriptive study was conducted upon 164 patients with NAFLD, presented at Department of Medicine, Liaquat University Hospital, Hyderabad. All the patients with NAFLD were evaluated and explored for liver fibrosis through APRI by taking 2cc venous blood sample in a sterilized syringe by principal investigator and send to laboratory for analysis to get the AST and platelet count. An APRI score greater than 0.7 was set cut off for significant hepatic fibrosis. The data were collected on pre-designed proforma. The study lasted 6 months from 26th February 2020 to 31st August 2020. Results: The mean age of the patients was 48.15±11.13 years. Frequency of liver fibrosis by non-invasive marker in patients with non-alcohol fatty liver disease was 10.98% (18/164). The mean APRI score was found to be 1.8±0.6. Conclusions: It was concluded that APRI is noninvasive and a simple calculation of two laboratory variables and can easily be used at the bedside or in an outpatient setting to assess the liver fibrosis. In this way, the management of NAFLD can be improved.
Fibrosis is mainly triggered by inflammation in various tissues, such as heart and liver tissues, and eventually leads to their subsequent dysfunction. Fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) proteins (e.g., collagens) produced by myofibroblasts. The well-developed actin cytoskeleton of myofibroblasts, one of the main features differentiating them from resident fibroblasts in tissues under inflammatory conditions, contributes to maintaining their ability to produce excessive ECM proteins. However, the molecular mechanisms via which the actin cytoskeleton promotes the production of fibrosis-related genes in myofibroblasts remain unclear. In this study, we found, via single-cell analysis, that developmentally regulated brain protein (drebrin), an actin-binding protein, was specifically expressed in cardiac myofibroblasts with a well-developed actin cytoskeleton in fibrotic hearts. Moreover, our immunocytochemistry analysis revealed that drebrin promoted actin cytoskeleton formation and myocardin-related transcription factor (MRTF)- serum response factor (SRF) signaling. Comprehensive single-cell analysis and RNA-Seq revealed that the expression of collagen triple helix repeat containing 1 (Cthrc1), a fibrosis-promoting secreted protein, was regulated by drebrin in cardiac myofibroblasts via MRTF-SRF signaling. Furthermore, we observed the pro-fibrotic effects of drebrin exerted via actin cytoskeleton formation and the Cthrc1 expression regulation by drebrin in liver myofibroblasts (hepatic stellate cells). Importantly, RNA-Seq demonstrated that drebrin expression levels increased in human fibrotic heart and liver tissues. In summary, our results indicated that the well-developed actin cytoskeleton and Cthrc1 expression due to drebrin in myofibroblasts promoted cardiac and hepatic fibrosis, suggesting that drebrin is a therapeutic target molecule for fibrosis.
Amaç: Bu çalışma toplumda non-alkolik yağlı karaciğer hastalığı (NAYKH) taramasında antropometrik ve biyokimyasal indekslerin tanımlayıcı performansını değerlendirmek amacıyla yapılmıştır. Bireyler ve Yöntem: Bu araştırma Mart-Temmuz 2021 tarihleri arasında bir devlet hastanesinin diyet polikliniğine başvuran 19-64 yaş arası 52 NAYKH hastası ve 52 kontrol olmak üzere toplam 104 katılımcı ile yürütülmüştür. Katılımcılara uygulanan anket formuna antropometrik ölçümleri ve son bir ay önceki bazı biyokimyasal bulguları kaydedilmiştir. Bireylerin antropometrik ölçümleri ve biyokimyasal bulguları kullanılarak çalışmada kullanılan indeksler (Viseral Adipozite İndeksi-VAİ, Framingham Steatoz İndeksi-FSİ, Lipid Birikim Ürünü-LAP) hesaplanmıştır. Bulgular: Her iki cinsiyet için de vaka grubunda kontrol grubuna kıyasla çalışmada kullanılan tüm indeksler anlamlı şekilde yüksek bulunmuştur (p<0.05). Lojistik regresyon analizine göre erkeklerde VAİ, Framingham steatoz indeksi ve lipid birikim ürünü ile NAYKH görülme riski arasında anlamlı bir ilişki gözlenmemiştir (p>0.05). ROC analizine göre erkeklerde hepatik steatoz indeksi, kadınlarda ise lipid birikim ürününün ultrasonografik NAYKH tanısı için en yüksek doğruluk oranına sahip olduğu bulunmuştur. Sonuç: NAYKH’den şüphelenilen, ileri tetkik ve tedaviye ihtiyaç duyan hastaların basit ve hızlı bir şekilde tespiti için lipid birikim ürünü ve hepatik steatoz indeksinin kullanımı faydalı olabilir.
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Lipids are a class of complex hydrophobic molecules derived from fatty acids that not only form the structural basis of biological membranes but also regulate metabolism and maintain energy balance. The role of lipids in obesity and other metabolic diseases has recently received much attention, making lipid metabolism one of the attractive research areas. Several metabolic diseases are linked to lipid metabolism, including diabetes, obesity, and atherosclerosis. Additionally, lipid metabolism contributes to the rapid growth of cancer cells as abnormal lipid synthesis or uptake enhances the growth of cancer cells. This review introduces the potential drug targets in lipid metabolism and summarizes the important potential drug targets with recent research progress on the corresponding small molecule inhibitor drugs. The significance of this review is to provide a reference for the clinical treatment of metabolic diseases related to lipid metabolism and the treatment of tumors, hoping to deepen the understanding of lipid metabolism and health.
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The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation.
Background Long-term results from randomized, controlled trials that compare medical therapy with surgical therapy in patients with type 2 diabetes are limited. Methods We assessed outcomes 5 years after 150 patients who had type 2 diabetes and a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 27 to 43 were randomly assigned to receive intensive medical therapy alone or intensive medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy. The primary outcome was a glycated hemoglobin level of 6.0% or less with or without the use of diabetes medications. Results Of the 150 patients who underwent randomization, 1 patient died during the 5-year follow-up period; 134 of the remaining 149 patients (90%) completed 5 years of follow-up. At baseline, the mean (±SD) age of the 134 patients was 49±8 years, 66% were women, the mean glycated hemoglobin level was 9.2±1.5%, and the mean BMI was 37±3.5. At 5 years, the criterion for the primary end point was met by 2 of 38 patients (5%) who received medical therapy alone, as compared with 14 of 49 patients (29%) who underwent gastric bypass (unadjusted P=0.01, adjusted P=0.03, P=0.08 in the intention-to-treat analysis) and 11 of 47 patients (23%) who underwent sleeve gastrectomy (unadjusted P=0.03, adjusted P=0.07, P=0.17 in the intention-to-treat analysis). Patients who underwent surgical procedures had a greater mean percentage reduction from baseline in glycated hemoglobin level than did patients who received medical therapy alone (2.1% vs. 0.3%, P=0.003). At 5 years, changes from baseline observed in the gastric-bypass and sleeve-gastrectomy groups were superior to the changes seen in the medical-therapy group with respect to body weight (−23%, −19%, and −5% in the gastric-bypass, sleeve-gastrectomy, and medical-therapy groups, respectively), triglyceride level (−40%, −29%, and −8%), high-density lipoprotein cholesterol level (32%, 30%, and 7%), use of insulin (−35%, −34%, and −13%), and quality-of-life measures (general health score increases of 17, 16, and 0.3; scores on the RAND 36-Item Health Survey ranged from 0 to 100, with higher scores indicating better health) (P<0.05 for all comparisons). No major late surgical complications were reported except for one reoperation. Conclusions Five-year outcome data showed that, among patients with type 2 diabetes and a BMI of 27 to 43, bariatric surgery plus intensive medical therapy was more effective than intensive medical therapy alone in decreasing, or in some cases resolving, hyperglycemia. (Funded by Ethicon Endo-Surgery and others; STAMPEDE number, NCT00432809.)
Objectives: Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of manifestations ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), fibrosis and eventually cirrhosis. The prevalence of NAFLD has been shown to be increasing over time; however, the prevalence of NASH cirrhosis and advanced fibrosis over time has not been well studied. Estimate the changes in prevalence of NASH cirrhosis and NAFLD-associated advanced fibrosis among adults in the United States. Methods: National Health and Nutrition Examination Survey (NHANES) data obtained during the periods from 1999-2002 and 2009-2012 were analyzed to estimate the prevalence of NASH cirrhosis and NAFLD-associated advanced fibrosis in subjects aged ≥18 years at the time of enrollment. We excluded patients with viral hepatitis, excessive alcohol consumption, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >500 and patients who were pregnant. Cirrhosis was defined by AST to platelet ratio index (APRI) >2 and abnormal liver function tests. NASH cirrhosis was defined as cirrhosis that presented with at least one of the following: obesity, diabetes, insulin resistance (HOMA-IR≥3), and metabolic syndrome. Advanced fibrosis was defined by using well-established cutoff values for APRI, fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS). Population weighted prevalence was calculated separately for two groups to account for complex sampling method of NHANES. Results: A total of 7034 NHANES participants from 1999-2002 and 2009-2012 group were included with mean age of 46.2±0.59 and 47.3±0.51 years, respectively, at the time of screening. The prevalence of NASH cirrhosis was significantly higher in 2009-2012 group (0.178% with an estimated 417,524 American adults with NASH-associated cirrhosis) compared to 1999-2002 group (0.072%); P value<0.05. The prevalence of NAFLD with advanced fibrosis also increased from 0.84 to 1.75% during the same time period (P value<0.001) corresponding to 4,104,871 American adults. During these time periods, there were also significant increases in obesity (29.8 vs. 36.6%), diabetes (8.3 vs. 11.9%), and insulin resistance (34.7 vs. 42.1%); P value <0.005 for all of them. Conclusions: There has been a 2.5-fold and 2-fold increases in the prevalence of NASH cirrhosis and NAFLD-associated advanced fibrosis, respectively, in 2009-2012 compared to 1999-2002. Extrapolation of NHANES data suggests that in 2010, 417,524 in the US had NASH cirrhosis, and 4,104,871 had NAFLD-associated advanced fibrosis. This represents a major disease burden and suggests the need for widespread programs to identify and treat those affected, and public health efforts aimed at controlling the burden of NAFLD and its complications.
Objective: Numerous studies have assessed the association between Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). However, results have been conflicting due to variability in definitions of NAFLD and ascertainment of CVD, often combining clinical and surrogate endpoints. We therefore systematically reviewed published literature to assess the association between NAFLD and clinical cardiovascular events (CVE) and performed a meta-analysis. Methods: We searched PubMed, Medline, Cochrane, CINAHL, and Web of Science databases using terms "nonalcoholic fatty liver disease", "nonalcoholic steatohepatitis", "cardiovascular disease", and their combinations to identify prospective studies published from inception through March 2016. Data from selected studies was extracted and meta-analysis was then performed using random effects model. Results: A total of six studies with 25,837 patients (NAFLD: 5953; controls: 19,884) were included in the final analysis. Patients with NAFLD had a significantly higher risk of clinical CVE compared to controls (RR: 1.77; 95% CI: 1.26-2.48, p<0.001). Exclusion sensitivity analysis did not alter the above results. The association remained consistent for subgroups with clinical coronary artery disease (RR: 2.26; 95% CI: 1.04-4.92, p<0.001) and ischemic stroke (RR: 2.09; 95% CI: 1.46-2.98, p<0.001). The risk of cardiovascular mortality was also increased in the NAFLD group (RR 1.46, 95% CI 1.31-1.64, p<0.001). Conclusion: NAFLD patients have a significantly higher risk for clinical CVE compared to those without. These results need to be confirmed in large prospective studies.
Background and objective: New drugs are urgently needed for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The aim of this meta-analysis was to evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in NAFLD/NASH. Methods: We searched the MEDLINE, Embase, and Cochrane Library Central to identify randomized controlled trials (RCTs) and observational studies that compared GLP-1RAs with a control treatment or baseline values with respect to efficacy and safety in patients with NAFLD/NASH. Mean differences (MDs) with 95% confidence intervals (CIs) and odds ratios (ORs) were pooled using a random-effect model. Results: Six studies were eligible and included. Among the 329 NAFLD/NASH patients included in these studies, 277 patients had type 2 diabetes (T2D). GLP-1RA treatment produced significant reductions relative to baseline in liver histology scores for steatosis (MD, 0.80; 95% CI, 0.49 to 1.11), lobular inflammation (MD, 0.22; 95% CI, 0.00 to 0.45), hepatocellular ballooning (MD, 0.41; 95% CI, 0.15 to 0.67) and fibrosis (MD, 0.35; 95% CI, 0.00 to 0.70). Compared with placebo and positive agents, GLP-1RAs significantly reduced gamma-glutamyl transpeptidase (GGT) levels (MD, 13.8 U/L; 95% CI, 7.4 to 20.3; P<0.001). The reported major adverse events associated with GLP-1RA treatment included mild to moderate gastrointestinal discomfort that resolved within a few weeks. Conclusions: Our study suggests that in NASH patients, particularly patients with diabetes, GLP-1RAs may improve liver histology and reduce aminotransferase levels from baseline. Benefits of GLP-1RAs are considered to outweigh the risks in NAFLD/NASH patients with or without diabetes.
Low-carbohydrate high-fat (LCHF) diets are a highly contentious current topic in nutrition. This narrative review aims to provide clinicians with a broad overview of the effects of LCHF diets on body weight, glycaemic control and cardiovascular risk factors while addressing some common concerns and misconceptions. Blood total cholesterol and LDL-cholesterol concentrations show a variable, highly individual response to LCHF diets, and should be monitored in patients adhering to this diet. In contrast, available evidence from clinical and preclinical studies indicates that LCHF diets consistently improve all other markers of cardiovascular risk—lowering elevated blood glucose, insulin, triglyceride, ApoB and saturated fat (especially palmitoleic acid) concentrations, reducing small dense LDL particle numbers, glycated haemoglobin (HbA1c) levels, blood pressure and body weight while increasing low HDL-cholesterol concentrations and reversing non-alcoholic fatty liver disease (NAFLD). This particular combination of favourable modifications to all these risk factors is a benefit unique to LCHF diets. These effects are likely due in part to reduced hunger and decreased ad libitum calorie intake common to low-carbohydrate diets, allied to a reduction in hyperinsulinaemia, and reversal of NAFLD. Although LCHF diets may not be suitable for everyone, available evidence shows this eating plan to be a safe and efficacious dietary option to be considered. LCHF diets may also be particularly beneficial in patients with atherogenic dyslipidaemia, insulin resistance, and the frequently associated NAFLD.
Background/Objectives Although lifestyle modifications remain the cornerstone therapy for non-alcoholic fatty liver disease (NAFLD), the optimal lifestyle intervention is still controversial. The aim of this meta-analysis was to evaluate the effect of exercise and/or dietary interventions, type or intensity of exercise and type of diet, on liver function outcomes (liver enzymes, intrahepatic fat and liver histology), as well as on anthropometric and glucose metabolism parameters in NAFLD patients. Subjects/Methods Literature search was performed in Scopus and US National Library of Medicine databases to identify all randomized controlled clinical trials (RCTs) in adult patients with NAFLD, diagnosed through imaging techniques or liver biopsy, published in English between January 2005 and August 2016. Studies' quality was evaluated using the Cochrane Risk of Bias Tool. Heterogeneity was tested using the Cochran's Q test and measured inconsistency by I2. Effect size was calculated as the standardized mean difference (SMD). The meta-analysis was performed in accordance with PRISMA guidelines. Results Twenty RCTs with 1073 NAFLD patients were included. Compared to standard care, exercise improved serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (all P < 0.05). Ιntrahepatic fat also improved, irrespectively of weight change (SMD = − 0.98, 95% CI: − 1.30 to − 0.66). Regarding the type of exercise, aerobic compared to resistance exercise did not yield any superior improvements on liver parameters, whereas moderate-to-high volume moderate-intensity continuous training was more beneficial compared to continuous low-to-moderate-volume moderate-intensity training or high intensity interval training. Interventions combining exercise and diet showed decreases in ALT (P < 0.01) and improvement in NAFLD activity score (SMD = − 0.61, 95% CI: − 1.09 to − 0.13). Moderate-carbohydrate diets yielded similar changes in liver enzymes compared to low/moderate-fat diets. Conclusions Exercise alone or combined with dietary intervention improves serum levels of liver enzymes and liver fat or histology. Exercise exerts beneficial effects on intrahepatic triglycerides even in the absence of weight loss.
Background & aims: The prevalence of fatty liver underscores the need for non-invasive characterization of steatosis, such as the ultrasound based controlled attenuation parameter (CAP). Despite good diagnostic accuracy, clinical use of CAP is limited due to uncertainty regarding optimal cut-offs and the influence of covariates. We therefore conducted an individual patient data meta-analysis. Methods: A review of the literature identified studies containing histology verified CAP data (M probe, vibration controlled transient elastography with FibroScan®) for grading of steatosis (S0-S3). Receiver operating characteristic analysis after correcting for center effects was used as well as mixed models to test the impact of covariates on CAP. The primary outcome was establishing CAP cut-offs for distinguishing steatosis grades. Results: Data from 19/21 eligible papers were provided, comprising 3830/3968 (97%) of patients. Considering data overlap and exclusion criteria, 2735 patients were included in the final analysis (37% hepatitis B, 36% hepatitis C, 20% NAFLD/NASH, 7% other). Steatosis distribution was 51%/27%/16%/6% for S0/S1/S2/S3. CAP values in dB/m (95% CI) were influenced by several covariates with an estimated shift of 10 (4.5-17) for NAFLD/NASH patients, 10 (3.5-16) for diabetics and 4.4 (3.8-5.0) per BMI unit. Areas under the curves were 0.823 (0.809-0.837) and 0.865 (0.850-0.880) respectively. Optimal cut-offs were 248 (237-261) and 268 (257-284) for those above S0 and S1 respectively. Conclusions: CAP provides a standardized non-invasive measure of hepatic steatosis. Prevalence, etiology, diabetes, and BMI deserve consideration when interpreting CAP. Longitudinal data are needed to demonstrate how CAP relates to clinical outcomes. Lay summary: There is an increase in fatty liver for patients with chronic liver disease, linked to the epidemic of the obesity. Invasive liver biopsies are considered the best means of diagnosing fatty liver. The ultrasound based controlled attenuation parameter (CAP) can be used instead, but factors such as the underlying disease, BMI and diabetes must be taken into account. Registration: Prospero CRD42015027238.
Background: The most typical chronic liver disease in children and adolescents is non-alcoholic fatty liver disease (NAFLD). The dietary addition of ω-3 polyunsaturated fatty acids (PUFAs) provides a promising therapy for children with NAFLD due to its convenience and safety; however, several studies suggested contradictory results for PUFA supplementation in children. Hence, we performed a systematic review and meta-analysis to evaluate the effectiveness of PUFA supplementation in children with NAFLD. Methods: Published randomized controlled trials (RCTs) that evaluated the effectiveness of the dietary addition of PUFA in children with NAFLD were considered. The primary result was the alteration in hepatic steatosis grade on ultrasound after treatment. The secondary outcomes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), C-reactive protein (CRP) and components of metabolic syndrome. Predefined sensitivity analysis was also performed to explore possible explanations for heterogeneity in the evaluations. Results: In total, 4 studies with 263 subjects were identified. PUFA supplementation was associated with significantly improved hepatic steatosis grade on ultrasound (risk difference: 25%, 95% CI: 12-38%), without heterogeneity (P = 0.27, I(2) = 24%). Sensitivity analysis confirmed the robustness of our findings. PUFA supplementation could decrease AST levels after 6 months, but could only reduce ALT levels after 12 months. PUFA did not have a significant effect on most components of metabolic syndrome and the CRP level. Conclusion: ω-3 PUFA supplementation can improve liver steatosis and liver functions, and it is a potential food supplementation to treat NAFLD in children.
Background: The degree of liver fibrosis in non-alcoholic fatty liver disease (NAFLD) is a critical predictive factor for patient prognosis. This study was intended to perform external validation of the various fibrosis prediction models for assessing advanced fibrosis in Korean NAFLD patients. Methods: A retrospective study of 412 patients with NAFLD confirmed by liver biopsy in hospitals affiliated with the Koran NAFLD study group was conducted and the predictive ability of existing liver fibrosis prediction models including NAFLD fibrosis score (NFS), BARD, and FIB-4 were compared. Results: Among 412 samples, 328 liver slides were suitable for evaluation. Advanced fibrosis was present in 60 (18.3%) of the patient samples. Univariate analysis found that the group with advanced fibrosis showed low ALT values and high AST/ALT ratios as well as a high incidence of diabetes. However, multivariate analysis showed that only the presence of diabetes and triglycerides were independent risk factors. The receiver operating characteristic was 0.64 in NFS, 0.58 in FIB-4, and 0.594 in the BARD model. The NFS was found to be the best at predicting advanced fibrosis among the three prediction models. The negative predictive value (NPV) which predicts advanced fibrosis using the low cutoff (<-1.455) was high (86.6%). However, the positive predictive value (PPV) which predicts advanced fibrosis using the high cutoff (>0.676) was 50.0% when we applied the NFS. Conclusion: NPV using the low cutoff value was high, but PPV using the high cutoff value was low in a Korean NAFLD cohort using NFS.