Dr Masrul Lubis SpPD-KGEH

Divisi Gastroenterologi dan Hepatologi

Departemen Ilmu Penyakit Dalam FK USU/RSUP Adam
Malik /RSU USU Medan
Epidemiology
NAFLD is one of the most common liver disorders 
in industrialized countries, with type 2 diabetes,
obesity, hyperlipidemia, and cardiovascular
disease being the most frequently evaluated and
cited risk factors for the presence of NAFLD and
accelerated disease.
Terminology
Alcoholic Liver Disease ALD: 
Significant alcohol consumption*
> 21 drinks/week for males
> 14 drinks/weeks for females
Non-Alcoholic Fatty Liver Disease NAFLD: 
steatosis without hepatocyte
injury
Non-Alcoholic Steatohepatitis NASH: 
steatosis with inflammation,
hepatocyte injury
with or without fibrosis
*Sanyal, et al Hepatology 2011
Natural History of FLD

fatty liver

steatohepatitis

steatohepatitis + fibrosis

steatohepatitis + cirrhosis

cryptogenic cirrhosis
Fatty liver Normal liver
Currently, it is widely accepted that lipopolysaccharide 
(LPS), a gut bacteria-derived endotoxin, is important
for the development and progression of ASH and
NASH through TLR-4 activation and induction of
Kupffer cell activity.
 Oxidative stress may directly activate an immune 
response and, subsequently, drive further
inflammation, or may be the result of inflammation.
Hepatic oxidative stress, lipid peroxidation and ER 
stress can directly activate the inhibitor of NF-κB
kinase or JNK to activate transcription of
proinflammatory cytokines.
Predisposing factors for progression of
NAFLD
Obesity – Pt undergoing Bariatric surgery (90% steatosis, 30% NASH, 10% (1
advanced fibrosis / cirrhosis)

Metabolic conditions (2
Type 2 DM – 66% will have US evidence of NAFLD 
Polycystic ovarian syndrome – 50% 

Age (may reflect longer standing undiagnosed NAFLD) (3

Gender (4
M>F (?protective effect of oestrogen)

Ethnicity (5
Hispanics > Other white > African Americans 

Genetics 6)
PNPLA3 gene (Others include NCAN, GCKR, LYPLAL1) 

Other (HCV/HIV) 7)
Vernon G, Baranova A, Younossi ZM (2011). Systematic review: the epidemiology and natural history of NAFLD and NASH in
adults. Alimentary Pharmacology and Therapeutics 34:274-285
Signs and symptoms
Asymptomatic in majority of cases •
Fatigue (not correlated with liver injury severity) •
RUQ pain or discomfort •

Hepatomegaly (50%) •
Cirrhosis and portal hypertension •

Obesity •
Hypertension •
Cardiovascular or cerebrovascular diseases •
OSA •
Lipodystrophy (in non obese) •
Diagnosis NAFLD is a diagnosis of exclusion 
-Alcoholic Hepatitis
-Drug induced Hepatitis (tamoxifen, amiodarone)
-Viral Hepatitis
-Autoimmune Hepatitis
-Metabolic (Wilson and Hemochromatosis)
Laboratory Investigations
~ 80% in normal range •

None of the currently used tests are specific for the •

diagnosis of NAFLD

Aminotransferase elevation (< 4 times ULN) •

It does not correlate with the severity of steatosis or •

fibrosis
 AST/ALT ratio (AAR) > 1 suggesting cirrhosis 

Higher AST , ALT levels and AAR are associated with 

NASH

The pattern of aminotrasferase elevation do not 

provide a distinction between simple fatty liver and
NASH.
Imaging studies Ultrasonography

Safe, easy to perform, and acceptable -

First line imaging -
Hyperechogenic liver parenchyma in contrast to kidney or spleen -
Sensitivity is dependent on the degree of steatosis (decreased in •
morbid obesity)

Specificity is high (~ 90%) •

Can not differentiate steatosis from fibrosis •

Contrast enhanced ultrasonography •

 Diagnosis at US
The echogenicity of the normal liver equals or minimally exceeds
that of the renal cortex or spleen.

Intrahepatic vessels are sharply demarcated, and posterior

aspect
of the liver are well depicted .

Fatty liver may be diagnosed if liver echogenicity exceeds that of

renal cortex and spleen and there is attenuation of the ultrasound
wave, loss of definition of the diaphragm, and poor delineation of
the intrahepatic architecture.

To avoid false-positive interpretations, fatty liver should not be

considered present if only one or two of these criteria are fulfilled.
 Normal appearance of the liver at US. The
echogenicity of the liver is equal to or slightly
Greater than that of the renal cortex (rc).
Imaging-based
Diagnosis of Fatty Liver
Liver biopsy and histologic analysis is considered
the diagnostic reference standard for the
Assessment of fatty liver.
However, fatty liver also can be diagnosed with
the use of cross sectional imaging
Who to refer?
Calculate NAFLD fibrosis score or fatty liver index!
(Age, BMI, hyperglycaemia, plts, albumin, AST/ALT ratio). –
AUROC 0.85 for advanced fibrosis. (There’s an app!!)

www.nafldscore.com
Dowman JK, Tomlinson JW, Newsome PN (2011). Systematic review: the diagnosis and staging of NAFLD and NASH. Alimentary
Pharmacology and Therapeutics 33: 525-540
 Management of NAFLD in Primary
Care
1) Lifestyle changes – WEIGHT LOSS 

Explain diagnosis and set realistic target weight 

Nutritional counselling – refer to dietician 
Exercise – 3-4 times per week, expend 400 kcal per session 
Promrat et al 2010: Intensive lifestyle intervention (diet, exercise, behaviour 
modification) vs structured education alone.
Weight loss 9.3% vs 0.2% (p = 0.003) 
Decrease in NAS 72% vs 30% (p=0.03) 

Younossi ZM (2008). Review article: current management of NAFLD and NASH. Alimentary Pharmacology and Therapeutics 28:
2-12
Dowman JK, Armstrong MJ, Tomlinsomn JW, Newsome PN (2011). Current therapeutic strategies in NAFLD. Diabetes, Obesity
and Metabolism 13: 692-702
 Medication for NAFLD
1) Metformin 

2) Lipid-lowering agents (statins) 

commonest cause of death is cardiovascular. 
Reduced rate of HCC and improvement in LFTs 
Statins are safe in liver disease!! (RCTs) 

3) Vitamin E 
PIVENS trial 2010 – Improvement in NASH: 43% vs 19%, p=0.001 
Considered 1st line for pharmacotherapy of NASH (not in diabetic patients!) 

4) Thiazolidinediones (pioglitazone) 
Improvement in liver histology whilst on drug but may relapse on stopping. 
Causes weight gain

5) ?role for Glucagon-like peptide 1 (GLP-1), DPP-4 inhibitors. 

6) Small proof of concept studies in Angiotensin receptor blockers / 
pentoxyfilline.

Sanyal AJ et al (2010). Pioglitazone, Vitamin E or placebo for NASH. New England Journal of Medicine 362: 1675-85
 Weight loss Interventions for NAFLD?
1) Orlistat
Zelber-Sagi et al 2006: Orlistat vs no orlistat 
6/12 treatment resulted in improved transaminases, steatosis on USS, 
and weight loss
Hussein et al 2007: Orlistat in NASH 
6/12 treatment improves histological steatosis, fibrosis and 
inflammation
2) Gastric Band/Bypass –
Mathurin et al.Gastroenterology 2009;137:532-540 – Prospective •
study – clinical, metabolic and liver histology at baseline, Yr 1 and
r 5 after bariatric surgery. (56% Gastric Band, 21% Gastric bypass,
Bilio-intestinal bypass 23%)
gnificant Improvement in steatosis and hepatocyte ballooning, but •
equivocal as to whether fibrosis improves.
Cost neutral at 18 months •
 When to refer abnormal LFTs
Refer? 
Any patient with clinical, biochemical or radiological signs of liver 
cirrhosis.

Any patient in whom there is any doubt about the diagnosis of 

NAFLD.

Any patient whose LFTs fail to normalise with weight loss. 

Any patient who despite above management options fails to lose 

weight, in whom a liver biopsy / Fibroscan is indicated
(NAFLD fibrosis score / F.L.I.)
NAFLD: risk factors Auto-immune disease 
Middle age  Malnutrition 
Female gender  Abetalipoproteinemia 
Over-weight or obese  Overgrowth of bacteria in small 
Viral hepatitis  intestines
Iron overload  TPN 
Medications  Acute fatty liver of pregnancy 
Rapid weight loss  HELLP syndrome 
Starvation/refeeding  Hispanic ethnicity 
syndrome Hereditary 
Reye’s syndrome 
Risk factors: Established association

Obesity 
Type 2 DM: insulin resistance (IR) 
Dyslipidemia 
Metabolic syndrome (MS) 
Risk factors: Emerging association
Polycystic ovary syndrome 
Hypothyroidism 
Obstructive sleep apnea 
Hypopituitarism 
Hypogonadism 
Pancreatic-duodenal resection 
Risk factor: Medications
Amiodarone 
Methotrexate 
Tamoxifen 
Corticosteroids 
Diltiazem 
Valproic acid 
Highly active antiretroviral therapy 
Risk factor: Bacteria overgrowth
Grieco, et al. Hepatology 2009 
35 pts with NAFLD bx confirmed 
27 pts with celiac disease 
24 healthy individuals 
Those with FLD had increased intestinal permeability and increased 
small bowel bacterial overgrowth
Compare, et al Nutrition Metabolism & Cardiovascular 
Disease Feb 2012
Liver is 1st line of defense against gut-derived antigens 
Levels of bacterial lipopolysaccharide (component of GN bacteria) 
are increased in the circulation in several types of chronic liver
disease
Can modulation of gut microbia represent a new way to 
treat/prevent NAFLD????
Screening Considerations
AASLD rec’s
Liver biochemistries can be normal 
Ultrasounds are expensive 
General population screening not recommended 
Undergoing surgical procedure? 
Planned pregnancy with obese mother? 
Systematic screening of family members: not 
recommended at this time
Assessment
Symptoms 
Malaise, fatigue, RUQ discomfort 
Snores, disturbed sleep, wakes up tired 
Chronic pain disorders, achy muscles 
Physical exam 
Abdominal obesity 
Enlarged liver 
RUQ tenderness on palpation 
Labs 
Consistent with metabolic syndrome 
Elevated bilirubin, AST, ALT, AP, GGT 
Liver biopsy
AASLD rec’s
Incidental finding on imagery with normal enzymes: 
no biopsy indicated, monitor.
Presence of metabolic syndrome and persistently 
elevated biochemistries may benefit from liver biopsy
Patients with biopsy proven NASH cirrhosis should be 
screened routinely for esophageal varices and HCC
Lifestyle Interventions
Weight loss by lower caloric intake and increased
physical exercise * led to improvement in biopsy.
9.3% weight loss: improvement in steatosis,
necrosis, and inflammation; not fibrosis
3-5% weight loss improves steatosis but more is needed 
to improve inflammation
Alcohol consumption: 
heavy intake should be avoided 
light intake (<1/day) may have benefits**, may not*** 

* Promrat, et al. Hepatology 2010

** Dunn, et al. Hepatology 2008
** Gunji. et al. Am J Gastro 2009
** Moriya, et al. Alim Pharm Ther 2011
***Ruhl , et al. Clin Gastro Hepatol 2005
Insulin sensitizing agentsMetformin * 
reduction in IR and enzymes, 
no improvement in histology 
Thiazolidinediones 
Rosiglitazone**: improved enzymes and steatosis, but not 
inflammation
Pioglitazone:***+weight gain, but improvement in 
hepatocellular injury
*Uygun, et al Aliment Pharm Ther 2004
*Nair, et al Aliment Pharm Ther 2004
**Ratziu, et al Gastroenterology 2008
***Sanyal, et al NE J Med 2010
PIVENS StudyPioglitazone , Vitamin E, placebo 
96 weeks 
Adults 
with NASH 
without DM, cirrhosis, Hep C, heart failure 
limited alcohol intake over previous 5 years 
Randomized trial 
Pio group: 80 
Vit E group: 84 
Placebo: 83 
Sanyal et al, New England J of Medicine 2010
Primary outcome
Vitamin E vs placebo Pio vs placebo
43% improvement vs 34% improvement vs 19%:
19%: significant not significant
(Steatosis, lobular
inflammation,
hepatocellular
ballooning and fibrosis)

Sanyal et al, New England J of Medicine 2010

PIVEN Conclusions
Vitamin E was superior to placebo in adults with 
NASH and without DM
Pioglitazone may have a role in treating patients with 
biopsy-proven NASH, however long term safety and
efficacy has not been established

Sanyal et al, New EnglJ of Med 2010

AASLD recommendations:
Pio can be used to treat certain patients with biopsy- 
proven NASH who do not have DM but long term
safety and efficacy has not been established
Vitamin E 800 IU/day improves liver histology in 
NASH pts
Not recommended to treat NASH in those with other 
chronic liver diseases, diabetics, those with NASH
cirrhosis or cryptogenic cirrhosis, NAFLD without
biopsy
Other meds for NASH
Ursodeoxycholic acid* 
no histologic benefit 
Omega-3 fatty acids** 
Effective in treating hypertriglyceridemia in pts with 
NAFLD
Evidence for treatment of NASH inconclusive to date 
Large multi-center trial on-going now 
*Lindor, et al. Hepatology 2004
**Capanni, et al. Alimen Pharm Ther 2006
Statins
CVD common cause of death for NAFLD and NASH 
Stratify risks and treat accordingly 
Several studies show NAFLD and NASH pts are not at 
increased risk of liver injury over general population*
No RCTs with histological end points using statins to 
treat NASH
*Chalasani, et al. Am J Gastro 2012
GREACE study*

Concluded statins significantly improve

liver biochemistries and CV outcomes
in pts with elevated enzymes likely due
to NASH

Athyros et al Lancet 2010 

AASLD Recommendation on Statins
“Given lack of evidence that patients with NAFLD and
NASH are at increased risk for serious drug-induced
liver injury from statins, they can be used to treat
dyslipidemia in patients with NAFLD and NASH.”
Bariatric surgery No RCTs 
Cochrane review 2010: lack of RCTs prevents 
definitive assessment of risks/benefits
Prospective study* 
381 adults with severe obesity, fibrosis score<3 
Clinical, metabolic, liver biopsy comparisons at 1 year 
and 5 years
Significant improvement in steatosis, ballooning, 
resolution of probable/definite NASH at 1 and 5 years
Small but significant increase of fibrosis score at 5 years 
(96% had improvement)

*Mathurin et al Gastroenterology 2009

AASLD Recommendation on Bariatric
Surgery
Premature to consider foregut surgery as an option to 
specifically treat NASH
Foregut surgery is not contra-indicated in otherwise 
eligible pts with NASH or NAFLD WITHOUT cirrhosis
For those with cirrhosis: type, safety and efficacy of 
foregut surgery is not established
NASH and Hepatocellular Carcinoma
Retrospective study* 6,508 pts with NAFLD by US 
F/up 5.6 years 
Primary end point: onset of HCC 
16 new cases of HCC (0.25%) 
Cumulative rates of NAFLD-related HCC: 
0.02% at year 4 
0.19% at year 8 
0.51% at year 12 
*Kawamura et al, Am J Gastroenterology 2011
Acute Fatty Liver & Pregnancy
Presents at 35-36 weeks 
Mitochondrial dysfunction preventing oxidation of FFA 
which accumulate in liver
Presents with malaise, N/V in 3rd trimester, RUQ pain, 
UGI bleed, ARF, FHF, confusion, HTN, jaundice,
hypoglycemia
Mortality: maternal 12.5-18%, infant 7-66% 
Postpartum: may resolve or proceed to needing a 
transplant
PRACTICAL STRATEGIES FOR ACHIEVING LIFESTYLE
MODIFICATIONS
IN PATIENTS WITH NASH

When discussing physical activity with patients, the discussion •

should focus on impediments to increasing physical activity and
finding ways for patients to incorporate exercise into their lives
on a regular basis indefinitely.
It is often helpful to separate the benefits of exercise from •
weight loss. Because exercise has its own benefits in terms of a
sense of well-being and improved insulin responsiveness, being
discouraged about lack of weight loss should not be a reason to
quit.
To most, the idea of dieting to achieve weight loss has many •
negative connotations because of prior failures and typically
invokes the strongly counterproductive psychology of denial.
Instead of discussing diets and dieting, the focus needs to be on
healthy eating habits, or the positive side of changes in eating
habits
HCC, diet and metabolic factors
A diet rich that is in polyunsaturated fatty acids and, 
possibly, B-carotene could reduce the risk of HCC, and
high dietary GL is associated with an increased risk
independently of cirrhosis or diabetes.
Diet only interventions
Six using low-to-moderate fat/moderate-to-high •
carbohydrate energy restricted diets, one of which also
specifically restricted iron intake
Three groups were given low carbohydrate ketogenic diets •
Two high protein diets •
Two studies employed biopsy ,but only one at follow-up •
The other used ALT and AST at follow-up •
Three used 1H-MRS ,two used CT ,three •
studies relied on ALT and AST .Only two studies had a •
Control group ,in one the control group were those with •
low adherence to the protocol
Diet only interventions
Interventions lasted 1–6 months and achieved mean body •
weight reductions of 4–14%.
All studies using biopsy or imaging techniques to estimate IHTAG reported reductions.
The three studies using 1H-MRS reported absolute reductions of 4–10% •
and relative reductions of 42–81%.
The only study to do a post intervention biopsy (n = 5) reported reduced inflammation •
and
trend towards reduced fibrosis (p = 0.07), as well as the reduction
in steatosis, following a ketogenic diet and a mean weight reduction
of 14%
Five out of seven studies reporting liver enzymes showed reductions and one showed no •
change.
The study that found an increase in ALT and AST, but only in women, suggested •
this might have been due to the analysis being done before •
weight had stabilised . •
Five out of six studies reporting glucose control/insulin sensitivity noted improvements. •
Exercise only interventions
Two studies published contained exercise only groups •
The interventions involved moderate intensity aerobic activity. •
Four weeks of stationary cycling three times per week resulted in
a reduction in 1H-MRS measured IHTAG of 1.8%, relative
reduction of 21%, but no statistically significant change in
HOMA relative to either baseline or control .
Three months of aerobic exercise including brisk •
walking/jogging or rhythmic aerobic exercise resulted in a 47%
and 48% reduction in ALT and AST,
Exercise only intervention groups in both studies maintained •
their baseline weight suggesting that weight reduction is not a
prerequisite for liver fat or biomarker reduction.
Exercise combined with diet
Seven studies employed a selection of behaviour •
change methods to decrease energy intake and
increase physical activity/exercise over 3–12 months
,these studies provided general physical activity
guidelines, but did not prescribe specific exercise
protocols.
The focus was predominantly on body weight reduction
and
Discussion
Weight reductions of 4–14% resulted in statistically significant •
relative reductions in IHTAG of 35–81%. The magnitude of
change strongly correlated to degree of weight reduction,
There is also limited evidence that physical activity/exercise can •
lead to modest reductions in IHTAG without weight change.
Low (800–1800 kCal/day) and very low-calorie diets •
(<800 kCal/day), and/or carbohydrate restriction (20–50 g/d) •
resulted in the most rapid reductions in body weight and
IHTAG.
The combination of caloric and carbohydrate restriction resulted •
in a 30% reduction in IHTAG and equally substantial
improvements in glucose control and insulin sensitivity within
48 h; a time when weight reduction can only be small and largely
accounted for by glycogen depletion and water loss
INDICATIONS FOR TREATMENT

Indications for Pharmacotherapy not been established. •

The spectrum of NAFLD covers bland steatosis and •

steatohepatitis.

Currently it is believed that only steatohepatitis carries a •

significant risk of liver disease progression, while the risk
associated with bland steatosis is largely extrahepatic.

Therefore first-line diet and lifestyle changes should be enforced •

in any patient with NAFLD

Pharmacologic therapy specifically aimed at improving the •

liver condition is most certainly necessary only in patients with
steatohepatitis
PHARMACOLOGIC TREATMENTS

The need for treatment in NAFLD is based on the 

concern for progressive liver disease
and cirrhosis.
Natural history studies indicate this occurs in a 
minority of patients,
the high prevalence of the disease means an 
effective treatment could have major
economic and health benefits.
Insulin sensitizers

• Glitazones 
• Weight loss agents 
• Metformin 
• CB1R blockers 
TZD therapy, especially with pioglitazone, seems to 
be an effective treatment for NASH
but needs to be given indefinitely and, given its 
propensity for weight gain, it needs further study.
It can be considered one of the preferred agents in 
diabetic patients with NASH
Weight loss agents

Orlistat is a pancreatic and gastric lipase inhibitor •

which inhibits the absorption of up to 30% of
dietary triglycerides .
Side effects such as diarrhoea and bloating •
loss of ≥5% BW correlated with improvements in •
insulin sensitivity and steatosis, whereas a loss of
≥9% BW was required for an improvement in overall
NAS
Larger studies with longer treatment durations are •
required
 Sibutramine is a serotonin and noradrenaline 
reuptake inhibitor
Rimonabant, a cannabinoid receptor antagonist 
Were taken off the market. 
 Glucagon-Like Peptide-1 (GLP-1) analogues •
Exenatide and Liraglutide •
Weight loss of 4.8 and 7.2 kg in those taking 1.8 and 3.0 •
mg liraglutide for (20-week trial)
Liraglutide also reduced blood pressure and the •
prevalence of prediabetes
Genetic and pharmacological elevated levels of GLP-1 in •
rodent models have been shown to reduce insulin
resistance, liver enzymes and hepatic steatosis [88,89].
Although human clinical trials examining the specific
role of GLP-1 analogues in NAFLD patients are yet to be
published,
Metformin

Metformin, a biguanide, is traditionally considered 

first-line treatment for non–insulin dependent
diabetes.
Because there is a high prevalence of diabetes in 
patients with NAFLD, targeting insulin resistance
with metformin seems like an appropriate
pharmacologic option
 Recent trials continue to provide mixed results. •
Omer and colleagues21 •
compared metformin with rosiglitazone in a 1-year •
randomized trial of diabetic NASH patients.
Metformin significantly reduced the waist •
circumference and BMI of patients, but no effect on
transaminase levels or NAS. On the other hand, the
combination of
metformin with rosiglitazone significantly improved •
transaminase levels and NAS,
suggesting that metformin may have a role in •
potentiating TZD effects in NAFLD.
 Metformin may improve insulin sensitivity in 
NAFLD, but its effects on transaminases,
steatosis, inflammation, and fibrosis remain
unclear.
Further trials of longer duration and larger sample
sizes that look at histologic outcomes are necessary
before metformin can be recommended for use in
NAFLD
Vitamin E

Vitamin E (-tocopherol) is a naturally occurring 

antioxidant. Its effects in NASH may be secondary
to its function as a
free radical scavenger or its ability to 
inhibit cytokines such as transforming growth 
factor (TGF-), which plays a role in hepatic stellate
cell activity and fibrogenesis as shown in rat models
 Vitamin E treatment seems to be beneficial in NASH, •
but there is a note of caution.
High-dose vitamin E therapy has been associated with •
increased mortality in other studies,31 and most NAFLD
trials have used doses of vitamin E above the current
recommended dose..
It would be prudent until more data emerges to use •
vitamin E selectively in NASH patients with more severe
changes on histology.
Combination regimens including vitamin E cannot •
currently be recommended.
Probucol

Probucol is a lipid-lowering agent with potent 

antioxidant properties, allowing it to
function as a free radical scavenger
Merat and colleagues40 have conducted 3 trials of •
probucol in NAFLD.
In their original pilot study, •
500 mg of probucol for 6 months •
significantly reduced transaminase •
as well as reduced total cholesterol. •
However, most of the reduction in cholesterol was •
due to a drop in high-density lipoprotein cholesterol
(HDL);
LDL and TG levels did not change significantly •
 Probucol can lower HDL levels and cardiac 
arrhythmias have also been seen.
Therefore, until randomized,controlled trials show 
consistent histologic benefits and no adverse effects,
probucol cannot be recommended for use in 
NAFLD.
Pentoxifylline

Pentoxifylline is a phosphodiesterase inhibitor, 

resulting in decreased activity of TNF,TGF. 
Therefore,
pentoxifylline could theoretically function as an 
antioxidant, antifibrotic,and insulin-sensitizing
agent in NAFLD
Pentoxifylline at 1200 mg/d is a safe and promising •
potential agent in NAFLD.
However, until a larger placebo-controlled study •
evaluates histologic end points,
pentoxifylline cannot be recommended.
UDCA

UDCA is a secondary bile acid that plays a role in 

lipid metabolism by
regulating intestinal cholesterol uptake. 
preventing the formation of cholesterol 
gallstones,
UDCA has also been hypothesized to have anti- 
apoptotic and anti-oxidant effects.50,51
 UDCA has not consistently shown any•
superiority over placebo in multiple large trials
until convincing histologic evidence is presented

UDCA cannot be recommended as a first-line

agent for NAFLD.
Endoscopic Treatment

In comparison with surgery, such as laparoscopic •

sleeve gastrectomy,
Intragastric balloon placement is equally effective •
in inducing weight loss and
has less morbidity, •
but lacks the ability to maintain weight loss when •
the balloon is removed
Spanish study in 714 consecutive patients •
demonstrating a decrease in mean BMI of 6.5 kg/m2
(from 37.6 to 31.1 kg/m2).
SURGICAL OPTIONS
Bariatric Surgery
In 1991 that the National Institutes of Health issued 
a consensus statement that
bariatric surgery was an appropriate indication for 
patients with a BMI over 40 kg/m2
or 35 kg/m2 with comorbidities 
 laparoscopic bariatric surgery such that it is 
among the most common operative procedures 
performed in the United States with more than
200,000 procedures in 2009.6
The most popular is the Roux-en-Y gastric bypass 
RYGB, which typically
leads to the greatest and most durable decrease in 
BMI.
A recent review and meta-analysis of 15 studies of 
bariatric surgery in
NAFLD with paired liver biopsy data determined 
that the
vast majority of patients had improvement in 
steatosis and NASH, with
resolution seen in 70% and 
fibrosis regression in 66%. 
LIVER TRANSPLANTATION
Decompensated liver disease in the setting of 
NASH cirrhosis is a relatively uncommon
finding compared with other common causes of liver 
disease such as HCV, but
the sheer scale of the obesity epidemic in the United 
States has lead to predictions
that NASH cirrhosis will become the leading 
indication for OLT in the next decade
According to the United Network of Organ Sharing, 
the first adult OLT for
a definitive diagnosis of NASH cirrhosis took place 
in 1996 and was only a tiny fraction of the total adult
OLT performed in that year (0.11%).
Since then, the number of OLTs 
performed for NASH cirrhosis has increased by more 
than 40-fold in 10 years
87
Potential Pharmacologic Treatment Options
for NALFD
Insulin Sensitizing Agents
Membrane-Stabilizing
Troglitazone/Rosiglitazone 
Metformin  Ursodeoxycholic Acid
Betaine ( SAMe)
Lipid-Lowering Agents
Clofibrate 
Gemfibrizole  Anti-Oxidants
Vitamin E 
Lecithin 
Future Potential Treatments Vitamin C 
Antifibrotics  B-Carotene 
Probiotics  Selenium 
Vitamin B Complex 
Silymarin, SAMe 

88
NAFLD and T2DM
NAFLD is closely associated with features of the metabolic 
syndrome and is regarded as the hepatic manifestation 
of the syndrome .The amount of intrahepatic 
fat closely correlates with serum liver enzyme levels and 
the number of metabolic syndrome features Patients 
with T2DM have approximately 80% more intrahepatic 
fat content than age-, sex-, and body weight-matched 
nondiabetic

Controls, and their serum liver enzymes are less

representative of the severity of intrahepatic fat 
accumulation
NAFLD AND T2DM
patients with NAFLD and T2DM are 
also more likely to develop the more advanced forms 
of
NAFLD, such as NASH, advanced fibrosis, cirrhosis, 
and
in some cases hepatocellular carcinoma 
Poor glycemic control
Because NAFLD is strongly associated with IR, 
patients
With T2DM and NAFLD often have poor glycemic 
control
compared to their counterparts without NAFLD 
The presence of NAFLD in people with T2DM often 
makes it difficult to obtain good glycemic control 
in insulin treated T2DM with stable glycemic control
patient it has
been demonstrated that the intrahepatic triglyceride 
content
was more closely correlated with the daily insulin dose 
and the ability of insulin to suppress hepatic glucose 
production
and better explained the interindividual variation 
in insulin requirements 
In addition, when the relationship between NAFLD 
and peripheral glucose metabolism was explored in 
the healthy individuals, the association between 
intrahepatic
triglyceride content and systemic IR was stronger 
than the association with intramyocellular lipid 
content,
visceral fat content, or sc fat content 
 NAFLD and risk of chronic diabetic
complications
and mortality among T2DM patients
The presence of NAFLD among patients with T2DM 
appears to be an important risk factor for all-cause mortality. 
A community-based study of T2DM individuals 
reported that those with NAFLD had a 2.2-fold increased 
risk of all-cause mortality compared with those 
without NAFLD; the most common causes of death 
were malignancy, CVD, and liver-related complications 
Evidence is mounting that NAFLD is associated 
with the presence of vascular disease, ie, the most common 
cause of death in people with T2DM 
Evidence Linking NAFLD With Risk of
Developing T2DM
modestly increased serum GGT and ALT levels 
were independent,
long-term predictors of incident T2DM in 
both sexes 
Treatment Options for NAFLD
Presently, there is no licensed treatment for human 
NAFLD
Most interventions evaluated for the treatment 
of NAFLD are those commonly used for the treatment of 
T2DMand exert a rather indirect effect through 
improvement
in IR and glycemia 
Statins
statins can be used in dyslipidemic individuals with 
increased
baseline liver enzymes and may even produce 
Some histological benefit in NASH 
Lifestyle modifications
gradual weight reduction, 
achieved either by hypocaloric diet alone or in combination 
with increased physical exercise, can be effective in 
decreasing hepatic steatosis and necroinflammation (the 
reduction of hepatic steatosis and necroinflammation is 
proportional to the intensity of the lifestyle intervention 
and generally requires a weight loss between 5 and 10%) 
Insulin-sensitizing agents
Metformin, the first-line choice in oral therapy for 
T2DM, has beneficial effects on serum 
aminotransferases
and IR but has no significant effect on liver 
histology and
is not recommended as a specific treatment for 
liver disease
in patients with NAFLD/NASH
Insulin-sensitizing agents
Pioglitazone can 
be used to treat steatohepatitis in patients with 
biopsyproven NASH;
there are no randomized clinical trials with 
histological endpoints that investigated pioglitazone 
to
specifically t reat patients with NAFLD. A recent 
metaanalysis
reported that pioglitazone improved steatosis and 
necroinflammation, but not fibrosis 
Omega-3 polyunsaturated fatty acid (PUFA)
supplementation
supplementation 
High doses of omega-3 PUFAs are effective in treating 
hypertriglyceridemia that is often a feature of NAFLD 
and
T2DM. 
Glucagon-like peptide agonist
(GLP-1 analog)
GLP-1 agonists have proved to be effective therapies 
to
improve glycemic control in people with T2DM; and 
interesting
additional effects of treatment are weight loss, 
decreased appetite, and improved IR, which can 
prove
helpful in people with NAFLD 
Vitamin E
It is known that increased oxidative stress occurs in 
Both NAFLD and T2DM .Consequently, besides targeting 
IR or lipid synthesis mechanisms per se, another 
therapeutic
option for NAFLD treatment may be to decrease 
oxidative stress by administration of an antioxidant such 
as vitamin E. Vitamin E therapy, as compared with placebo, 
was associated with significant improvements in liver 
enzymes
and some histological features of NASH such as 
steatosis and necroinflammation 
Vitamin D
Preliminary experimental evidence 
suggests that via effects in both adipose tissue and liver, 
low serum vitaminD levels may predispose to intrahepatic 
lipid accumulation and hepatic inflammation, 
contributing
to the development and progression of NAFLD 
. However, whether vitamin D supplementation 
ameliorates
NAFLD is uncertain, and randomized clinical 
trials are needed in man. 
Vitamin D