REVIEW ARTICLE

Pharmacological and Non-Pharmacological

Treatment in Non-Alcoholic Fatty Liver Disease
Perdana Aditya*, C Rinaldi A Lesmana**
* Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta
** Division of Hepatology, Department of Internal Medicine, Faculty of Medicine
University of Indonesia/Dr. Cipto Mangunkusumo General National Hospital, Jakarta

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease, from steatosis to liver cirrhosis
in individual who does not consume alcohol in significant amount. The prevalence of NAFLD in Indonesia
was estimated around 30%, this condition related to the increased incidence of metabolic disorders. Current
understanding of NAFLD pathogenesis is the third-hit theory, in which insulin resistance resulting in free
fatty acid accumulation that triggers inflammation causing fibrosis and hepatocyte death, and these
conditions are not followed by adequate hepatocyte proliferation.
Treatment of NAFLD requires both non-pharmacologic and pharmacologic interventions. Life style
intervention includes restricting calories, low saturated fat and low sugar diet, and also physical activity.
Bariatric surgery remains controversial since in several study participants had experienced deterioration of
disease. There are no definitive treatment for NAFLD currently. Treatment is aimed to improved insulin
sensitivity, decreased oxidative stress and inflammation. Several agents use for treatment of NAFLD are
insulin sensitizer (metformin and glitazones), statin, omega-3, vitamin E, ursodeoxycholic acid, orlistat,
pentoxyphylline, and losartan.

Keywords: NAFLD, treatment, pharmacologic, non-pharmacologic

ABSTRAK

Penyakit perlemakan hati non alkoholik (PPHNA) merupakan suatu spektrum penyakit hati dari steatosis
hingga sirosis hati pada individu yang tidak mengkonsumsi alkohol dalam jumlah yang signifikan. Prevalensi
PPHNA di Indonesia sekitar 30%, terkait dengan meningkatnya insiden penyakit metabolik. Patogenesis
PPHNA yang kini berkembang adalah third-hit theory, dimana akibat resistensi insulin didapatkan akumulasi
asam lemak bebas yang memicu inflamasi sehingga terjadi fibrosis dan kematian hepatosit yang tidak
diimbangi dengan regenerasi hepatosit.
Pengobatan PPHNA memerlukan intervensi non-farmakologis dan farmakologis. Mulai dari melakukan
perubahan gaya hidup dengan pembatasan kalori, diet rendah lemak jenuh dan rendah gula, serta aktivitas
fisik. Pembedahan bariatrik masih menjadi kontroversi dalam tatalaksana pasien PPHNA, karena pada
beberapa studi didapatkan beberapa subyek yang mengalami perburukan penyakit. Belum ada obat-obatan
yang menjadi terapi definitif PPHNA, selain dengan melalui perbaikan sensitivitas insulin, menurunkan
stres oksidatif dan inflamasi. Beberapa pengobatan farmakologis pada PPHNA dapat diberikan insulin
sensitizer yaitu metformin dan glitazon, statin, omega-3, vitamin E, asam ursodeoksikolat, orlistat,
pentoksifilin, dan losartan.

Kata kunci: PPHNA, pengobatan, farmakologis, non-farmakologis

174 The Indonesian Journal of Gastroenterology, Hepatology and Digestive Endoscopy

Perdana Aditya, C Rinaldi A Lesmana

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 Pharmacological and Non-Pharmacological Treatment in Non-Alcoholic Fatty Liver
Disease
INTRODUCTION Till date, theory which is still developing about
pathogenesis of NAFLD and NASH is two-hit
Non-alcoholic fatty liver disease (NAFLD) is
theory,
a spectrum of liver disease, from steatosis until
cirrhosis in individual who does not consume alcohol
in significant amount. NAFLD becomes a huge
health problem in Asia Pacific countries, including
Indonesia. A literature showed that there was quite
high incidence of NAFLD in Indonesia, particularly
about
30%.1 High prevelance in various places is associated
with the increase incidence of metabolic diseases,
such as diabetes melitus, dyslipidemia, obesity, or
metabolic syndrome.1 NAFLD is also a risk factor for
hepatocelullar carcinoma, therefore important to be
managed.2 For Asia Pacific countries, this burden is
added with the high incidence of chronic viral
hepatitis. The association between NAFLD and
metabolic syndrome is related to insulin resistance.3
In United States, it was obtained that 30.1 million
individuals with obesity suffered from steatosis and
8.6 million suffered from steatohepatitis. Obesity
becomes a separated risk factor for NAFLD, with 5
fold increased risk, diabetes melitus either type 1 or
2 becomes a dependant risk factor to the occurrence
of NAFLD, as well as dyslipidemia and viceral
adipocytosis, which all are part of metabolic
syndrome.4
Pathogenesis of NAFLD and non-alcoholic
steatohepatitis (NASH) alone cannot be explained
precisely, several current known theories were two-
hits model. The model was introduced by Day et al in
1998, where insulin resistance played important role
in causing accumulation of triacylglycerol and free
fatty acid, which then experienced oxidation and
produced reactive oxygen species (ROS) and
caused the occurrence of inflammatory response due
to oxidative stress.3 Till date, it still cannot be
explained how NASH can happen in a person and not
to the other person.3,4
Diagnosis of NAFLD is still a challenge for
practitioner. Till current, liver biopsy is a gold
standard for the establishment of diagnosis.
Therefore, considering that the procedure is quite
invasive, it is not performed often. In general,
suspicion of NAFLD is based on the presence of
abnormal liver function, in individual whose risk has
been described above, so that NAFLD become the
first possibility. However, in individual with normal
liver function results, the possibility of NAFLD
cannot be kept aside.5

PATHOGENESIS

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Perdana Aditya, C Rinaldi A Lesmana
however many factors are believed to play role in the
occurrence of NAFLD and its progression. Metabolic
syndrome and insulin resistance is a common
condition found in NAFLD patients, however not all
individual with insulin resistance develop NAFLD
and vice versa, therefore other factors are also
predicted to play role in the occurrence of NAFLD.
Genetic factors associated to endogen anti-oxidants
and fat distribution are suspected to play role in
disease progression, where some experienced
progression to NASH, but not in other individuals.
Fat accumulation in hepatocytes, particularly in the
form of triglycerides become the absolute
requirement to the occurrence of NAFLD, however
the primary metabolic disorder causing this is
which involve many factors. Understanding NAFLD
pathogenesis show that free fatty acid plays
important role, and triglyceride is suspected to have
protective role. Free fatty acid induces inflammation
through nuclear factor-κB (NF-κB) and also causes
mitochondria dysfunction. Other theory known as
third-hit theory, is a modification of two-hit theory
where post inflammation hepatocyte death happens,
not balanced with regeneration.5,6,7

Figure 1. Pathogenesis of NAFLD based on third-hit theory7

Molecularly, lipid peroxidation happens as a

result of oxidative stress through mitochondria
dysfunction, P450 cytochrome activation, and iron
overload. Oxidative stress causes cell impairment
through the impairment of organelles, DNA and
mtDNA through inflammation process mediated by
NF-KB activation and IKB degradation.
Inflammation that happens is also mediated by
endoplasmic reticulum stress which also causes
apoptosis, further exacerbated by necrosis, oxidative
stress, and activation of NF-KB and other mitogenic
pathway.8
Insulin play role in regulation of fatty acid
metabolism, where 25% fatty acid originated from
lipogenesis which is controlled by sterol regulatory
element binding protein (SREBP) whose work is

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Perdana Aditya, C Rinaldi A Lesmana

mediated by insulin. In NAFLD, there is decrease Table 1. Histopathological criteria in NAFLD6

level of double unsaturated fatty acid, particularly γ Grading for steatosis
Grade 1, < 33% of hepatocytes affected
linolenat acid and increase of fatty acid level Grade 2, 33-66% of hepatocytes affected
accompanied with decrease ability of fatty acid Grade 3, > 66% of hepatocytes affected
Grading for steatohepatitis
oxidation. Regulators contributing to this event, such Grade 1, mild
as SREBP, peroxisome proliferator-activated Steatosis: macrovesicular, involves up to 66% of lobules
receptor (PPAR), and farnesyl X receptor are Ballooning: occasionally found; zone 3 hepatocytes
Lobular inflammation: scattered and mild acute
mediated by insulin and adipositoxin effect.8 inflammation (polymorphonuclear cells) and occasional
chronic inflammation (mononuclear cells)
Portal inflammation: none or mild
DIAGNOSIS Grade 2, moderate
Steatosis: any degree; usually mixed macrovesicular
Liver biopsy becomes the gold standard in and microvesicular
establishment of NAFLD diagnosis, particularly Ballooning: obvious and present in zone 3
Lobular inflammation: polymorphonuclear cells may
in differentiating pure steatosis and steatohepatitis. be noted in association with ballooned hepatocytes;
NAFLD is generally suspected in individual with pericellular fibrosis; mild chronic inflammation may be
seen
transaminase elevation with no apparent reason and Portal inflammation: mild to moderate
no history of alcohol consumption. Ultrasonography Grade 3, severe
Steatosis: involves > 66% lobules (panacinar);
and other radiological modality may give typical commonly mixed steatosis
appearance in NAFLD, however it is often inaccurate Ballooning: predominantly zone 3; marked
Lobular inflammation: scattered acute and chronic
in determining degree of impairment, therefore inflammation; polymorphonuclear cells may be
biopsy still become gold standard.6,9 concentrated in zone 3 areas of ballooning and
perisinusoidal fibrosis
Several non-invasive techniques are developed for Portal inflammation: mild to moderate
NAFLD evaluation, however there is none which has Staging for fibrosis
been well validated, including transient elastography, Stage 1: zona 3 perivenular, perisinusoidal, or pericellular
fibrosis; focal or extensive
tissue inhibitor of metalloproteinase (TIMP)-1, Stage 2: as above, with focal or extensive periportal fibrosis
hyaluronate acid and procollagen III type III n- Stage 3: bridging fibrosis, focal or extensive
Stage 4: cirrhosis
peptide (PIIINP). Some of these modalities become
component in non-invasive evaluation in the degree
of NAFLD.9 TREATMENT

In principle, management of NAFLD also

involves treating the associated comorbidity,
such as obesity, diabetes, and dyslipidemia.
Non-pharmacological Treatment
• Life style intervention
Several interventions which are believed to be
beneficial for NAFLD patients, include aerobic
exercise with the intensity equal to walking 30
minutes per day or 5 km per day 3 times a week,
calorie restriction up to 30 kcal/kg/day with
lower composition of saturated and trans fatty
acid, also simple sugar, decrease of 10% body
weight in 6 months and not so fast because it may
aggrevate NAFLD. Life style modification is also
adjusted to the existing comorbidities,
particularly cardiovascular problem, the most
common cause of death in NAFLD patients was
coronary heart disease, where frequently
dyslipidemia, obesity, and diabetes condition
were found, and diabetes is a risk factor of
Figure 1. Histopathological appearance showing steatosis cardiovascular disease. NAFLD also increases
(A) and fibrosis (B)6 the risk of cardiovascular problem through
inflammation process.10

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Perdana Aditya, C Rinaldi A Lesmana

A study by Bhat et al, in which 60 NAFLD of improvement in liver impairment, improvement

patients were involved in India, showed that of diabetes, dyslipidemia decrease the degree of
routine physical activity for 30 minutes a day liver impairment, also showed NASH
with frequency of 5 times a week can decrease improvement in
transaminase level and also improve histological 82% patients who undergo laparascopic
appearance in 6 months evaluation. 11 Several adjustable gastric banding.14
population studies stated that in NAFLD patients,
Pharmacological Treatment
there was lower omega-3 consumption, higher
Several drug groups which can be used in
omega-6 consumption, and also higher amount
NAFLD treatment based on AASLD guidelines and
of cholesterol and saturated fatty acid, and less
several studies reported some drugs commonly used
consumption of some vitamins, such as: ascorbic
were insulin sensitizer, statin, omega-3, vitamin E,
acid, tocopherol, and fiber. Meanwhile a study
ursodeoxycolate acid, orlistat, pentoksifilin, losartan.9,15
• Metformin
using 1,000 mg/day and 2,700 mg/day omega-3
Metformin is a drug from the insulin sensitizer
in NAFLD patients revealed that omega-3
group, where this drug can be used because
decrease ALT, improve the degree of
insulin resistance is known to have role in the
perlemakan in ultrasound, and improve
pathogenesis of NAFLD. Several studies showed
histological appearance, however the number of
that metformin improve insulin resistance in
samples included were 42 and 23 patients.12
NAFLD patients and also improve transaminase.
Alcohol consumption is known as risk factor
Some studies which use metformin include
of liver impairment, however in small amount
treatment of NAFLD in children (TONIC) study,
several studies exhibited the opposite effect. The
this study compare metformin and vitamin E,
American Association for the Study of Liver
both decrease aminotransferase level, however
Disease (AASLD) recommend NAFLD patients
vitamin E is better in improving
to not consume alcohol in large amount, which is
histopathological appearance in NASH. Other
4 times per day or 14 times per week for male
and studies by Larine et al and Bugianessi et al, in
3 times per day or 7 times per week for female. 9 year
• Bariatric surgery 2005 revealed that metformin 2 g/day improve
Ninety percent patients who undergo bariatric aminotransferase
E. better compared to vitamin16,17
surgery will suffer from NAFLD, however Garinis et al conducted RCT in 50 NAFLD
this procedure is one of the choices in treating patients comparing metformin and hypocaloric
NAFLD. A study by Mathurin which was cited (decrease 500 kcal per day) and hypocaloric diet
only, obtained improvement in ultrasound results
in the group which
received metformin (p < 0.0001).18 Haukeland et al
in the guidelines by American Association for the
compared administration of metformin and
Study of Liver Disease (AASLD), showed the placebo
incidence of NAFLD decrease in obese in 48 patients and obtained insignificant result in
individuals who undergo bariatric surgery, and in histological appearance of those
individuals with NAFLD or NASH, there was patients.19
histological improvement in one or five years Other studies by Nadeau et al comparing
after surgery. AASLD does not contraindicate metformin and placebo in 55 NAFLD patients,
bariatric surgery in obesity individuals with there was no significant difference through
NAFLD or NASH as long as cirrhosis has not ultrasound.20 Study by Shields et al comparing 19
happened.9 NAFLD patients receiving metformin 500 mg
Chavez et al, in their publication in Cochrane uptitrated to 1,000 mg with diet and exercise or
Review concluding from several prospective and diet and exercise alone, showed improvement in
histological appearance.21
on the role bariatric surgery was still lacking.13
retrospective cohort, stated that bariatric surgery
Publication by Younossi showed that bariatric
revealed improvement of steatosis and
surgery improve output of cardiovascular risk
inflammatory degree, however some publications
factors, although not specifically stating parameter
reported the disease worsening in several
individuals, but randomized control trial (RCT)

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 Pharmacological and Non-Pharmacological Treatment in Non-Alcoholic Fatty Liver
Disease
• Glitazone
Glitazone, is an insulin sensitizer working in
skeletal muscle and liver, increasing glucose
uptake by improving peripheral insulin
resistance. First drug from this group is
troglitazone, however there is no study which use
this drug. Troglitazone has higher hepatotoxic
side effect compared to the following two drugs,
particularly rosiglitazone dan pioglitazone.22

182 The Indonesian Journal of Gastroenterology, Hepatology and Digestive Endoscopy

 Aithal et al performed an RCT in 74 non-DM analysis towards RCT, there was no
patients who have been proven to suffer from significant improvement in
NASH through histology and ultrasound, patients
received pioglitazone 30 mg and plasebo, results
showed pioglitazone improve hepatocelullar
impairment, but not for other parameter.23 Belfort
et al in 2006 compare pioglitazone 30 mg
uptitrated up to 45 mg with placebo, both groups
received low calorie diet, through histology there
was significant improvement in steatosis,
necroinflammation and fibrosis in group
receiving pioglitazone.24
Sanyal et al conducted two studies; initial study
in
2004 compared pioglitazone 30 mg and vitamin
E 400 IU, concluded that there was inflammation
improvement in both groups. The following
study in 2010, Sanyal performed RCT to 247
patients comparing vitamin E, pioglitazone and
placebo, observation was conducted for 96
weeks, resulted in histological improvement in
vitamin E and pioglitazone groups.25,26
Other group of glitazone, which is rosiglitazone
is said to improve degree of NAFLD better
compared to metformin, however both
combination has better effects compared to
single administration.27
In histological evaluation, rosiglitazone inhibit
hepatocytes ballooning, portal inflammation and
fibrosis overall compared to placebo.28
• Omega-3
Omega-3 improve lipid metabolism in liver,
as regulator of transcription factors such as
peroxisome-poliferator-activated receptor
(PPAR), sterol receptor element binding protein
(SREBP-1), and carbohydrate responsive
element building (ChERBP) which have role in
the progression of NAFLD to NASH.29
In their publication in 2012, Di Minno et al
reviewed 7 studies on the use of omega-3 in
NAFLD, from those 7 studies, several performed
randomization, however the number of subjects
included in the studies were not big and the
dose being used varied.30 Those studies showed
that omega-3 improved transaminase and liver
profiles, several studies measure homeostatic
model assessment insulin resistance (HOMA IR)
and showed improvement.29
Other meta-analysis and systematic review
revealed that supplementation of polyunsaturated
fatty acid (PUFA) gave effect to the biochemistry
parameter, such as accumulation of liver fat and
transaminase, however if performing meta-
 transaminase. In this review the dose of omega-3 level, however the incidence of severe liver
seemed to give significant difference, however dysfunction was very rare. Some publications and
the duration of administration was more also AASLD
influential. Minimal dose needed to gave effect
was > 0.83 mg/day. Beside improving
transaminase, omega-3 has cardio-metabolic
effect which often found in NAFLD patients,
such as: insulin resistance, diabetes,
dyslipidemia.31
• Ursodeoxycholic acid
Ursodeoxyc holic a cid (UDCA) has ant
i- inflammation, anti-oxidant, and antifibrosis
effect and can improve liver impairment.32
Studies on the administration of conventional
and high dose ursodeoxycholic acid, most
showed transaminase and histological
improvement. However, one RCT with large
sample size showed that UDCA did not improve
the histologic appearance of NAFLD.9 A study
by Ratziu et al involving 126 subjects with
NASH which had been proved through biopsy
and experienced elevation of transaminase, were
given high dose of UDCA 28-35 mg/kg/day, the
results were patient experienced improvement of
transaminase and also decreasing fibrosis marker
level in the serum.32
• Statin
NAFLD is closely associated with the presence
of dyslipidemia, where statin is the most
commonly used treatment in dyslipidemia
through its effect inhibiting cholesterol synthesis
through HMG-coA- reduktase inhibition.
However, statin is suspected to have other
effects in NAFLD treatment, particularly
anti-inflammatory and anti-fibrosis. Statin is
known may cause transaminase elevation,
therefore its use in NAFLD is controversial.33
Studies on statin administration in NAFLD are
still limited, statin type, dose, duration, number
of participating samples, there is no RCT with
quite big sample size. However, studies which
use statin, showed satisfying results.34 In 2010,
Hyogo et al performed a study to 43
dyslipidemia patients, who were given
atorvastatin 10 mg and in the evaluation of
biochemistry marker for NASH, improvement
was reported. This was in line with the previous
study. This effect is obtained because statin has
TNF-α inhibition effect.31,35 There is no RCT to
evaluate the effect of statin administration to
histopathological appearance, the use of statin
alone becomes controversial because in several
patients, there was elevation of transaminase
 in its guidelines in 2012 stated that statin was of NAFLD to NASH, resulted in the idea to use
safe to be used in patients with liver dysfunction anti- TNF. TNF-α as a pro-inflammatory
and in patients with chronic liver disease cytokine plays
(including NAFLD and NASH) the increase risk
of drug induced liver disease (DILI) was not
proven.9,36
• Vitamin E
AASLD guidelines stated that study on vitamin E
in NASH is still limited, both in the quantity and
strength of the results. Two large studies on the
use of vitamin E in NAFLD were pioglitazone,
vitamin E, or placebo for nonalcoholic
steatohepatitis (PIVENS) dan treatment of
NAFLD in children (TONIC). PIVENS compared
pioglitazone, vitamin E, and plasebo by
randomization of 247 adult patients with NASH
and did not suffer from diabetes mellitus (DM).
Eighty patients received pioglitazone 30 mg,
84 received vitamin E 800 IU, and the rest
received placebo. Both gace significant results if
compared with placebo in terms of decrease of
transaminase level, steatosis improvement,
however not in fibrosis score. While vitamin E is
more superior compared to pioglitazone in
NASH resolution. This study also reported that
cardiovascular incidence was insignificantly
different in three groups, where this became an
issue in the use of high dose vitamin E.9,37
TONIC study, compared vitamin E 400 IU
twice daily, metformin 500 mg twice daily, and
placebo in 175 children aged 8–17 year old.
These three groups equally experience
transaminase improvement, however in the group
which received metformin, decrease of
transaminase achieved earlier, which is in the
first 24 weeks. In terms of histologic
improvement, vitamin E is better in NASH
resolution, particularly improve ballooning
(44%), improve NASH score (41%), but does not
effect to steatosis, fibrosis and inflammation.
While metformin only improve ballooning
(21%). The results of this study is also in line
with smaller study by Bugianesi et al, as has been
discussed above where vitamin E improve
histologic appearance compared to metformin.17
Other study by Akcam et al in 2011, comparing
metformin and vitamin E, in this study metformin
was reported to be better in improving steatosis in
ultrasound, however this study only involved 67
patients.38
• Anti-TNF
The development of second-hit theory where
inflammation further had role in the progression
 role in stimulating hepatic stellate cells in matrix
remodelling, further there was suspect in bacteria
translocation which has role in causing further
inflammation also support the use of anti-TNF
in inhibiting progression of NAFLD. One of the
drugs which has been tried is pentoksifilin which
has anti-TNF effect, study showed improvement
of transaminase level in 12 months and histologic
improvement in 55% patients, however this study
only involved 18 patients.39,40
There has been no study which specifically use
anti-TNF, such as: entanercept, infliximab or
adalimumab in NAFLD patients, however a study
in psoriasis, metabolic syndrome, and NAFLD
patients using entanercept involving 89 patients,
showed improvement in transaminase, CRP,
fasting insulin level, HOMA index in 24 weeks,
however in this study, NAFLD diagnosis is only
established based on ultrasound.41

CONCLUSION

Until now, there is no single drug which can be

used as definitive therapy in NAFLD. Medications
which is used based on the pathophysiology include:
(1) insulin resistance, (2) oxidative stress, and (3)
inflammation. However, there is no clinical trial with
quite big sample size which can be used as guideline
in choosing therapy for NAFLD. Several existing
studies and with quite big sample size, vitamin E and
insulin sensitizer group can be used in the
management of NASH to improve histological
appearance. In the management of NAFLD or
NASH, it need to be noted the presence of risk
factors, comorbidity, and patients' adherence.
Managing and controling risk factors are important
in the management of NAFLD; presence of
comorbidity can be a consideration in choosing
treatment in NAFLD.

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Correspondence:
C Rinaldi A Lesmana
Division of Hepatology
Department of Internal Medicine
Dr. Cipto Mangunkusumo General National Hospital
Jl. Diponegoro No. 71 Jakarta 10430 Indonesia
Phone: +62-21-31900924 Facsimile: +62-21-3918842
E-mail: [email protected]