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89]. Megamitochondria appear in all zones and hepatocytes with microvesicular fat
[6]. Acidophilic bodies are hepatocytes that have undergone apoptosis and are typi-
cally found in NAFLD, usually in the sinusoids [90]. Glycogenated bodies are
found in the liver in type 2 diabetes and are often found in NAFLD, which can dif-
ferentiate NAFLD from alcoholic liver disease [91].
The NAFLD activity score (NAS), based on a revision from a prior score [92],
was developed by the NAFLD research network and is comprised of the sum of
semiquantitative scores, from 0 to 8. It consist of the following variables: 1) steato-
sis where 0 is <5% of fat in the sample, 1, 5–33%, 2, 34 to 66%, and 3>66%, 2)
ballooning of hepatocytes where 0 is none, 1, mild and few, and 2 many, moderate,
and marked, and 3) lobular inammation, where 0 is none, 1<2 foci per 20× eld,
2 is 2–4/20× eld, 3>4/20× eld [93, 94]. The stage of brosis is graded as: 0 for
no signicant brosis; 1a for delicate, perisinusoidal brosis in zone 3 where col-
lagen stain is required for identication, 1b for dense perisinusoidal brosis in zone
3, and 1c for portal brosis only; 2 for zone 3 perisinusoidal brosis with periportal
brosis; 3 for bridging brosis; and 4 for cirrhosis [93, 94]. A score of less than 3
and greater than 5 separates not NASH from NASH; however, when the score is
greater than 5, the sensitivity and specicity of the NAS for the diagnosis of NASH
is 57% and 95%, respectively, [95].
Histological information is of prognostic value; bad outcomes in patients with
NAFLD occur more frequently in association with ballooning degeneration, Mallory
bodies, and brosis than when these ndings are absent [96]. Characteristically,
NAFLD is devoid or associated with mild portal chronic inammation, which, when
more than mild, is related to increased age, female gender, high body mass index,
high homeostasis model assessment of insulin resistance score (HOMA-IR), high
insulin levels, diabetes, hypertension, and the use of medications to treat
ab
Fig. 9.2 (a) Liver histology in a patient with nonalcoholic fatty liver disease exhibiting marked
steatosis. Fat droplet (arrow) in a hepatocyte pushes the nucleus to the periphery of the cell. (b)
Liver histology in a patient with nonalcoholic steatohepatitis and ballooning degeneration (arrow)
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NAFLD.Thus, it was concluded that more than mild portal chronic inammation in
NAFLD might be a marker of advanced disease [97]. The progression from NAFLD
to NASH and brosis is variable; it was reported from a study that included 22
patients with NAFLD who had more than one liver biopsy over 5years that a third
increased in brosis score, the minority had a decrease, and the percentage of
patients with brosis stages 3 and 4 doubled in follow up. In the minority, the dis-
ease progressed from brosis scores from 1 to 3in less than 2years, and from 2 to
4in less than 3. The only test that correlated with histological progression was a
high AST [78]; however, from a group of 106 patients with NASH, 22 underwent a
repeat liver biopsy at least 3years after the rst one, in which brosis progression
was documented in 32% of the patients, an outcome that correlated only with obe-
sity and body mass index [79]. These series of observations helped to identify bro-
sis as a prognostic factor for progression, for which evidence has been provided
from a study that included 229 well-characterized patients with NAFLD who under-
went follow up for an average of 26years, and who exhibited increased mortality as
compared to the reference population, with a hazard ratio (HR) of 1.29, CI:
1.04–1.59, p=0.020, and increased risk for cardiovascular disease, hepatocellular
carcinoma, and cirrhosis, all statistically signicant. There was also an increase in
mortality in patients with brosis stage 3 and 4, with HR 3.3, CI 2.27–4.76,
p<0.001, regardless of the NAS [98].
As reported above, liver histology is the gold standard to determine the state of
disease, i.e., inammation and brosis; however, the invasive nature of liver biopsy
deters clinicians from the procedure in many cases; accordingly, efforts continue to
establish the use of non-invasive tests for the diagnosis of NAFLD.In this regard,
tests that include the NAFLD brosis score, the FIB-4, and FibroTest/Fibrosure
have been adopted for clinical use and are available commercially. For example, the
NAFLD brosis score is a measure that includes age, hyperglycemia, body mass
index, platelet count, albumin, and AST/ALT ratio; a score of −1.455 excluded
advanced brosis, and a score of 0.676 identied advanced brosis accurately [99].
These ndings were conrmed in excluding advanced brosis in a study of patients
from China [100]. The procedure of transient elastography concerns the measure-
ment of a low frequency shear wave velocity transmitted via an ultrasound
probethrough the intercostal spaces overthe liverareaas an estimate of liver stiff-
ness, measured in kilopaskals, which has been documented to correlate with brosis
and cirrhosis [101–103]. Magnetic resonance elastography(MRE) in nonalcoholic
fatty liver disease to assess liver brosis was reported to identify accurately the
degree of brosis in patients with histologically proven NAFLD, independent from
inammation and obesity [103, 104]. In a study that included 58 patients with
NAFLD, documented by liver histology, magnetic resonance elastography (MRE)
was performed to assess liver stiffness, relative fat fraction, inammatory activity,
and brosis stage. Steatosis and inammation without brosis had the signicantly
different scores of 2.5 and 3.24kPa, respectively. Inammation without brosis
yielded a score lower than that of brosis, the latter being 4.16kPa. A threshold of
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2.74kPa as a liver stiffness measures accurately differentiated patients with NASH
from those with steatosis. These data supported the value of MRE to identify
patients’ inammation before progression to brosis in NAFLD.This methodology
is being explored widely as an alternative tool to assess liver disease from
NAFLD [105].
Inammation: ItsPotential Role inthePathogenesis
ofNAFLD
Macrophage activation has been proposed as an initiator and perpetuator of NAFLD
[106]. In the context of hepatic steatosis, from animal models, it is reported that
hepatocytes release damage-associated molecular patterns (DAMPs) [107] and
extracellular vesicles (EVs); in addition, diet components have an impact on the gut
microbial environment [108, 109] and intestinal permeability, which, when
increased [110], facilitates the vascular delivery of pathogen-associated molecular
patterns (PAMPs) to the liver. This supportive hepatic microenvironment is associ-
ated with the release of inammatory cytokines and chemokines, which can induce
lipogenesis and recruit monocytes originating in the bone marrow, all of which can
stimulate stellate cells and, thus, liver brosis [106]. Cluster of Differentiaion163
(CD163) is a macrophage specic protein with a soluble form, which, when acti-
vated, changes prole towards a participant in the inammatory response [111]. The
concentration of CD163 was reported to be signicantly and independently associ-
ated with the degree of brosis in patients with NAFLD, ndings that suggested a
role of macrophages in brosis in association withthis condition [112].
CD44 proteins are adhesion molecules [111] that may contribute to the patho-
genesis of NAFLD.In obese patients, the soluble form of CD44 was increased in
steatosis and NASH.CD44 liver expression was increased and correlated with fea-
tures of NASH in obese patients. After bariatric surgery, “correction” of NASH was
documented in association with decrease in the liver expression of CD-44. These
ndings suggested a role of CD44in NASH and a therapeutic pathway [113].
NAFLD Associated Diseases
Robust data to prove cause and effect between NAFLD and systemic complications
appear to be lacking [114]; however, there is literature to support associations with
several chronic conditions that render the individuals vulnerable to experience
extrahepatic complications from the liver disease.
Cardiovascular disease is the most common association of NAFLD, which is an
independent predictor of the former and informs the comorbidities that patients may
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experience. Data from a meta-analysis to quantify the association between NAFLD
and events associated with cardiovascular disease documented from the 34,043 sub-
jects included in the analysis, and of whom 36.3% had NAFLD that 2600 experi-
enced a cardiovascular event, and over 70% of the group, death from cardiovascular
disease over a period close to 7years, with random effect odds ratio [OR] calculated
as 1.64 (95% CI: 1.26–2.13). NAFLD was associated with a greater risk of experi-
encing a cardiovascular event, of a more severe impact if advanced liver disease was
present (OR 2.58; 1.78–3.75) [115].
There is an association between type II DM and NAFLD; however, a genetic
predisposition to support this association has not been unequivocally documented
and, robust prospective studies in its support are lacking. In this context, the use of
non-invasive indices to predict fatty liver, the fatty liver index, and the NAFLD fatty
liver score (NAFLD-FLS) predicted the incidence of DM after 9years of follow up,
independently from glucose, family history, insulin, life style, smoking, and alcohol
consumption, suggesting a screening measure to identify the development of DM in
patients with NAFLD [116]. Also, in a prospective study from Europe that followed
patients with histologically documented NAFLD for a mean of 13years, 78% had
diabetes or impaired glucose tolerance at follow up [81]. These studies support the
idea that NAFLD is a predictor of insulin resistance and DM.
It was reported that NAFLD increases the risk of incident chronic kidney disease
(CKD). The combination of nine observational studies that included 96,595 sub-
jects, mostly Asian, 34% of whom had NAFLD, none histologically proven, docu-
mented that 4653 had incident CKD stage ≥3 over 5.2years. In association with
NAFLD, a signicantly higher risk of incident CKD, especially in subjects with
advanced liver disease, than in those without NAFLD was reported, with a random-
effects HR of 1.37 (95% CI 1.20–1.53; I
2
=33.5%). This analysis suggested that
there is an approximately 40% increase in long-term incident CKD, although cause
and effect could not be proven by the nature of the study [117].
The outcomes of eighteen cross-sectional studies that included 2183 subjects
documented that the pooled OR for the presence of obstructive sleep apnea (OSA)
and NAFLD diagnosed by histology was 2.01(95% CI: 1.36–2.97), with similar
results for other indirect diagnostic means including radiographical and biochemi-
cal ndings; in addition, the pooled ORs of OSA for NASH, brosis of any stage,
or histologically documented advanced brosis were 2.37(1.59–3.51),
2.16(1.45–3.20), and 2.30(1.21–4.38), respectively, data that suggested that evalua-
tion for the presence of NAFLD in patients with OSA is prudent [118]; in this
regard, the importance of insulin resistance in association with OSA may be related
to the reported occurrence [119].
Associations between polycystic ovarian syndrome (PCOS) and NAFLD have
also been reported. A recent analysis of the world literature documented that the risk
of NAFLD in patients with PCOS was signicantly higher than that of controls
when associated with hyperandrogenism [120].
Other associations with NAFLD have included cholelithiasis, psoriasis, and
hypopituitarism [121].
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Lean Nonalcoholic Fatty Liver Disease
Some patients who are not obese and have insulin resistance are at risk for develop-
ing type 2 diabetes, hypertriglyceridemia, and early coronary artery disease [122].
This important and not small group of individuals also develop NAFLD in a lean
body, i.e., lean NAFLD, as it is now termed, with a body mass index (BMI) within
the ethnic-specic cutoff of 25kg/m
2
in Caucasian and 23kg/m
2
in Asian subjects.
The proportion of nonobese patients with NAFLD in epidemiological studies
from Taiwan, Korea, and the United States comprised of Asian and Caucasian indi-
viduals ranged from 3.8 to 17% [12, 123–125].
Genetic polymorphisms have been identied in the genes PNPLA3, CETP,
TMSF2, interferon lambda, and PENT as a predisposition for lean NAFLD.The
pathophysiology of lean NAFLD includes an increase in the circulation of FFA, a
decrease in adiponectin, insulin resistance, reduced mitochondrial function,
increased de novo lipogenesis, decreased capacity to store fat in subcutaneous adi-
pose tissue, decrease in muscle mass, and decreased Faecalibacterium and
Ruminococcus and deciency of lactobacillus. In this context, in mice, it was
reported that the infusion of intestinal microbiota from lean donors to male recipi-
ents with metabolic syndrome was associated with an increase in insulin sensitivity
in the latter and increased levels of intestinal microbiota that produce butyrate,
which improves insulin sensitivity and increases energy expenditure [126].
From a study that used the NHANES III from 1988 to 1994 that included radio-
graphic and laboratory data, and 11,613 subjects, of which 18.77% had NAFLD,
and 11.78 of these, NASH, independent predictors of lean NAFLD were identied
as relatively young age (i.e., median of 40years), female gender, low probability of
insulin resistance, and hypercholesterolemia, whereas Hispanic ethnicity, relatively
young age, and components of the metabolic syndrome were independently associ-
ated with NASH, dened as suggestive imaging studies in association with type 2
DM, and with increased serum activity of transaminases [125]. From a European
study, the relevance of lean NAFLD as a cause of cryptogenic liver disease was
documented as 2.8% of a group of 1777 subjects all of whom had liver histology
data, a contribution of 38% as a cause of cryptogenic liver disease [127]. Similar to
the ndings from the United States study [125], the patients were relatively young
but, in contrast, most were men; brosis and steatohepatitis were present in more
than 50% of the samples from patients with lean NAFLD [127].
There is limited information on the natural history of lean NAFLD.Published in
abstract form, a study documented a follow up of 3 to 332months of 1090 subjects,
11.5% of whom were reported as lean. The lean group was mostly comprised of
men, non-Caucasian, and had a lower prevalence of diabetes, hypertension, hyper-
triglyceridemia, low-HDL cholesterol, central obesity, metabolic syndrome, less
steatosis, lower levels of ALT, less advanced brosis, and less insulin resistance
(HOMA) than the non-lean NAFLD group [128]. There was a signicant difference
in survival not in favor of lean subjects, even after statistical adjustment with only
lean NAFLD and age, remaining signicant, with HRs of 11.8 (95% CI: 2.8 to 50.1,
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p=0.001), and 1.05 (CI: 1.008 to 1.1, p=0.02) [128]. In contrast, a study from
Hong Kong that recruited 307 patients with NAFLD of whom 72 were nonobese,
and who had less severe disease as suggested by lower NAS, and lower CAP score
than their overweight counterparts were followed for a median of 49months over
which time, six from the group of obese patients died, two developed hepatocellular
carcinoma, and one died of liver failure [129] suggesting that nonobese patients
with NAFLD have a better prognosis than obese patients with NAFLD; however, in
lean patients with NAFLD hypertriglyceridemia and a higher serum creatinine than
the obese patients were factors associated with advanced disease [129]. Thus, the
identication of these characteristics in lean patients with fatty liver may help in
their follow up.
Treatment
The treatment of NAFLD concerns the treatment of comorbidities and the search for
specic treatment for its hepatic components, e.g., steatohepatitis and brosis.
Behavior modication is fundamental as an intervention, and has been associ-
ated with some improvement [130]; pharmacological interventions are expected to
be identied for use in patients with advanced disease [131].
Lifestyle modication that included diet and exercise on NAFLD was associated
with decreased inammation and brosis. There was an improvement in glucose
control and insulin sensitivity reported from most of the studies. These reports have
supported the idea that behavior modication, i.e., diet and exercise associated with
weight loss, could affect the histological lesions of fatty liver leading to improve-
ment, in general [130]. The effects of an intensive lifestyle intervention program on
portal hypertension in patients with compensated cirrhosis and obesity were recently
reported from a prospective uncontrolled study. The study enrolled 60 patients,
most of whom were men. The intervention was a behavior modication 16week
program that included low calorie and normal protein diet in association with super-
vised physical activity of 60min/week. Fifty patients with a mean age of 56±8years
old completed the study. Nonalcoholic steatohepatitis was reported in 24%, associ-
ated with hepatic venous pressure gradient (HVPG) ≥10mm Hg in 72% of the
participants. The intervention was associated with a decrease in body weight by at
least 5% and 10% in 52% and 16% of the subjects, a signicant decrease in HVPG
from 13.9± 5.6 to 12.3 ±5.2mm Hg; p<0.0001) with a decrease of ≥10% and
≥20% in 42% and 24% of the participants, respectively. The decrease in HVPG was
most substantial and signicant in association with a weight loss of ≥10%, i.e.
−23.7± 19.9% vs. −8.2 ±16.6%. The intervention was safe, and the weight loss
documented at the end of the 16week study period was sustained for six months
[132]. This sophisticated study conducted by experts in the eld of cirrhosis and
portal hypertension remarkably revealed the importance of life style modication
with a well delineated structure, and supports behavior modication as a
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fundamental aspect in the management of cirrhosis in association with obesity. This
type of intervention should be considered in patients with NAFLD [84, 86].
Different medications according to the disease state and the mechanisms that can
potentially inuence the pathogenesis of NAFLD are being studied, including
obeticholic acid, a farnesoid receptor agonist, the stimulation of which regulates
lipogenesis and the conversion of cholesterol to bile acids in the steatosis phase,
elabranor, a PPAR alpha and beta agonist in steatosis and steatohepatitis phases,
vitamin E, an antioxidant, liraglutide, a GLP 1 agonist, pioglitazone, a PPAR gamma
agonist in steatohepatitis, selonsertib, an Ask-1 inhibitor, and ceniciviroc, a CCR2/
CCR2in the brosis stage [133].
In a prospective, randomized, placebo controlled, 96week duration study of
patients with NASH not associated with DM, vitamin E, an antioxidant [134], was
associated with histological improvement related to inammation but not in brosis
as compared to placebo [135]. The effect of placebo was no different from that of
pioglitazone, which was included in the study [135]. Pioglitazone is a nuclear recep-
tor PPARγ agonist that increases insulin sensitivity [136]. Vitamin E is recom-
mended forpatients without DM with NASH at a dose of 800IU perday.
In regard to vitamin E, and further to the study cited above [135], it was reported
from a systematic review that vitamin E signicantly decreased the degree of steato-
sis, hepatocyte ballooning, lobular inammation, and brosis in patients with
NASH, supporting its use in the treatment of this condition [137]. The guidelines
from the American AssociationfortheStudy of Liver Disease (AASLD) state that
vitamin E may be used in patients with NASH without DM and who do not exhibit
cirrhosis on histology [138]. However, a retrospective study revealedthat patients
with advanced brosis and cirrhosis who took vitamin E at the dose stated above
had a signicantly higher adjusted transplant-free survival and a decrease in the rate
of hepatic decompensation than those who did not take vitamin E, at a median fol-
low- up up 5.62 (interquartile range [IQR], 4.3–7.5) and 5.6 (IQR, 4–6.9) years for
those who took vitamin E versus those who did not. These ndings applied to
patients with and with DM [139]. Thus, considering the lack of adverse events in
association with vitamin E, the use of this drug in patients with brosis and cirrho-
sis, irrespective of the presence of DM, may be a therapeutic option althoughdata
from robustly designed prospective studies are desired.
In a randomized, double blind, placebo controlled trial that included 101 patients
with NASH and pre-diabetes, pioglitazone, at a dose of 45mg/day in conjunction
with a hypocaloric diet for a period of 18months, was associated with a reduction
of at least 2 points in the NAS in 58% of subjects, and resolution of NASH in 51%,
and individual reductions in the brosis score, in contrast to placebo. In addition,
hepatic triglyceride content decreased and adipose tissue, muscle, and hepatic insu-
lin sensitivity were reported to have improved. The effects in association with pio-
glitazone persisted over 36months of therapy, which was open label for an additional
18months, and side effects were no different between the drug and placebo [140].
Consistent with the benecial effects of pioglitazone, the AASLD indicates that this
drug may be used to treat patients with NASH with or without type 2 DM; it is
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implicit in this recommendation that a liver histology is required prior to ther-
apy [138].
Glucagon-like peptide 1 (GLP-1) is a peptide hormone produced in the intestinal
epithelial endocrine cells and its function is to stimulate insulin secretion and to
inhibit glucagon secretion thus contributing to modulated glucose excursions, to
decrease gastrointestinal motility and secretion, and to regulate, in part, appetite
[141]. In animal studies, GLP-1 analogues are associated with a reduction in liver
steatosis, thus, the GLP-1 analogue liraglutide at doses of 1 and 8mg subcutane-
ously once a week, was studied in a randomized, double blind, placebo controlled
trial of 1year duration in patients with steatohepatitis, from which it was reported
that in patients who had a post treatment liver biopsy, 39% had resolution of NASH,
versus those who were randomized to placebo. Fibrosis progressed in 9% of the
patients on liraglutide versus 36% of those on placebo; diarrhea, constipation, and
appetite loss were more common in the treatment group [142].
Obeticholic acid is a semi- synthetic bile acid analogue structured as 6α-ethyl-
chenodeoxycholic that activates the farnesoid X nuclear receptor(FXR), a receptor
that regulates genes involved in cholesterol catabolism and bile acids biosynthesis
[143]. The activation of FRX is associated with the induction of Small Heterodimer
Partner (SHP), a nuclear receptor that inhibits the production of bile acids, decreases
the expression of Na+ taurocholate cotransport peptide (NTCP), a transporter of
bile acids into the hepatocyte located in its sinusoidal side, and enhances the expres-
sion of the bile salt export pump (BSEP), the principal transporter of bile acids from
the hepatocyte to the canalicular space, thus, protecting the liver from cholestasis
induced liver injury. In animal models, obeticholic acid was reported to decrease
steatosis and brosis. In a multicenter, double blind, placebo controlled, parallel
group, randomized clinical trial of patients with NASH the administration of
obeticholic acid at a dose of 25mg per day was associated with improved liver his-
tology, i.e., a decrease of two or more points in the total NAFLD activity score and
no worsening in the brosis score, documented in 45% of the 110 subjects who had
liver histology at baseline and 72weeks, as planned, versus the improvement docu-
mented in the placebo group, which was in 21% of the 109 patients in whom liver
biopsy was planned from that group. The ndings on steatohepatitis, which were
encouraging, were accompanied by an increase in total serum concentrations of
cholesterol and LDL cholesterol, and a decrease in HDL cholesterol, posing con-
cerns regarding cardiovascular health, a matter that remains under investigation.
From A phase 3, double blind, randomized, placebo controlled multicenter study of
obeticholic acid in patients with NASH and brosis stages 2 or 3 it was reported that
the drug was associated with either improvement of brosis by equal or greater than
one stage without worsening of NASH, or with its resolution without an increase in
brosis, in 23.1% of 308 patients, randomized to a daily dose of 25mg, versus,
17.6% of 312 randomized to 10mg, both ndings signicantly different from pla-
cebo [144, 145]. Pruritus was a side effect documented in 23% of the patients [146],
as reported in other studies with this medication [147].
PPARα receptor is at the center of all pathways related to fat metabolism; it has
been characterized as the master regulator of hepatic lipid metabolism whereas its
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loss is associated with increased hepatic steatosis, and its activation with reduction
of steatosis [148]. The activation of PPAR-δ is associated with a reduction of glu-
cose use by skeletal muscle by switching the mitochondrial substrate preference
from carbohydrates to lipids, increasing their combustion and exerting an antidia-
betic effect in animals [149]. Elabranor is an agonist of thePPAR-α andPPAR-δ.
It was studied in doses of 80 and 120mg/day in a randomized, double blind, placebo
controlled study of 52weeks duration in patients with NASH, which resolved with-
out worsening of brosis in association with the highest dose of the drug in 19% of
the patients versus 12% in the placebo group, with an OR of 2.31, and 95% CI:
1.02–5.24, and a p = 0.045 analysis provided as post hoc; however, the primary
outcome, which was resolution of NASH without brosis worsening in an intention
to treat analysis was not met as there was no signicant difference between the treat-
ment groups. Other improvements reported in association with elabranor were lip-
ids and glucose proles. Of note, there was a signicant, although reversible increase
in serum creatinine in association with the drug [150]. A phase 3 study on the effect
of elabranor on steatohepatitis is being conducted [151].
Apoptosis contributes to the pathogenesis of NAFLD.In animal studies, inhibi-
tion of apoptosis through signal-regulating kinase 1, a serine/threonine kinase, has
been reported to be associated with a decrease in inammation and brosis [152].
In a human study, the safety and efcacy of selonsertib, a selective inhibitor of
apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, a
humanized monoclonal antibody that binds to LOX2, a molecule that interacts with
collagen bers, being studied for the treatment of brosis [153], wasevaluated in a
multicenter, phase 2 study of patients with NASH and stage 2 or 3 brosis. The
results of this study were reported to document a decrease in the brosis by at least
one stage in 43% and 30% of the 30 and 27 patients assigned to selonsertib 18 and
6 mg, respectively, ndings conrmed byMRE, which was reported to show a
decrease in liver stiffness, consistent with decreased brosis; in addition, liver col-
lagen content and lobular inammation decreased [154]. The lack of effect on bro-
sis of simtuzumab in this study [154] was also reported in a subsequent publication
[155]. A phase 3 trial on the effect of selonsertib for NASH has been com-
pleted [156].
Cenicriviroc is a dual antagonist of the chemokine receptors CCR5 and CCR2,
the latter being a coreceptor involved in metabolic and cardiovascular diseases
[157]. From a randomized, placebo controlled trial of cenicriviroc for treatment of
NASH in patients with brosis it was reported that 150mg of the drug was associ-
ated with a decrease in brosis by more than one stage in 20% of the 145 patients
randomized to the drug in contrast to the 10% of the 144 randomized to placebo
[158]. In follow up to this study, phase3studies are being conducted with cenicrivi-
roc for the treatment of NAFLD and brosis [159, 160].
n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) can prevent obesity,
dyslipidemia, and insulin resistance in association with high-fat diet in animal mod-
els [161]. According to a meta-analysis, the use of n-3 LC-PUFAs, predominantly
EPA and/or DHA supplementation, in patients with NAFLD was associated with a
signicant decrease in liver fat content, assessed by magnetic resonance imaging/
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spectroscopy, and liver sonogram; however, no histological changes were reported
in patients with NASH.These are encouraging ndings and support the early iden-
tication of patients with steatosis for treatment with n-3 LC-PUFAs supplementa-
tion, however, the identication of factors that lead to progression from steatosis to
steatohepatitis and to brosis remains a challenge in choosing patients who may
benet from that intervention. The investigators conclude that additional trials are
necessary to understand the effects of LC-PUFAs on NAFLD [162].
Recently, from a prospective study over 2006 to 2015 that included 361 patients
with NAFLD, daily use of aspirin was reported in association with a signicant
decrease in the risk for developing incident brosis versus nonaspirin users, effect
that appeared to be related to the duration of aspirin use, with the highest benet
reported to be intake of aspirin for at least 4years [163]. Surely, editorials and addi-
tional studies on this important observation will follow.
Bariatric Surgery
The AASLD guidelines for the management of patients with NAFLD state that bar-
iatric surgery can be considered in patients with obesity who meet criteria for the
procedure [138].
From a prospective study that examined the effects of bariatric surgery on
NAFLD in 381 patients without advanced disease, 56% of whom underwent gastric
banding, 23%, biliointestinal bypass, and 21%, gastric bypass, it was reported that
5years after the operation, the percentage of patients who had NASH decreased
from 27.4% to 14.2%. The majority of patients exhibited signicant increase in
brosis, although assessed as equal or less than F1 [164], a nding that differs from
that from a prospective study from which, at 1year post surgery, the degree of bro-
sis had decreased in 33.8% of the 109 patients [165]. The proportion of patients
with steatosis decreased from 37.4% at baseline to 16percent post surgery, with
ballooning degeneration decreasing from 0.2 to 0.1, as per the NAFLD score [164].
The best predictor of persistence of steatosis and ballooning at 5years post surgery
was the presence of insulin resistance, which was suggested to be a good target for
specic improvement post surgery in regard to liver disease [164]. From a system-
atic review and meta-analysis, it was reported that bariatric surgery was associated
with a decrease in short-term mortality, and might be associated with long-term
decrease in all-cause mortality, including cardiovascular disease and cancer [166].
However, from a review of the data in the Nationwide Inpatient Sample from
patients who underwent bariatric surgery in the United States from 1998 to 2007 it
was documented that patient without cirrhosis had a signicantly lower mortality
rate in association with the surgery, i.e. 0.3% than those with cirrhosis, compen-
sated, 0.9% versus decompensated, 16.3%. Analysis after adjustment for covariates,
the adjusted OR of mortality among patients with compensated cirrhosis was 2.17
(95% CI: 1.03–4.55) versus that of patients with decompensated cirrhosis, which
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