Evaluation and Management of Obesity-Related Nonalcoholic Fatty Liver Disease

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www.nature.com/clinicalpractice/gasthep
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Evaluation and management of obesity-related
nonalcoholic fatty liver disease
Clare Nugent and Zobair M Younossi*
Continuing Medical Education online
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Learning objectives
Upon completion of this activity, participants should be
able to:
1 Describe the epidemiology of nonalcoholic fatty liver
disease (NAFLD).
2 Identify risk factors for developing NAFLD.
3 Specify useful imaging modalities in diagnosing
NAFLD.
4 Describe treatment of NAFLD.
INTRODUCTION
Metabolic syndrome and its componentstype 2
diabetes mellitus and central obesitylead to the
development of nonalcoholic fatty liver disease
(NAFLD), in part due to insulin resistance, apop-
tosis and altered adipokine and cytokine pathways.
Indeed, NAFLD is now considered the hepatic
manifestation of metabolic syndrome. Globally,
NAFLD is a common cause of chronic liver disease
and, as the obesity epidemic continues, the preva-
lence of NAFLD is anticipated to increase. The
clinicopathologic spectrum of NAFLD ranges
from simple steatosis to nonalcoholic steato-
hepatitis (NASH). Whereas simple steatosis seems
to have a relatively benign clinical course, patients
with NASH can develop fibrosis, cirrhosis, and
complications such as hepatocellular carcinoma
(HCC). Once cirrhosis is present, the distinctive
histological features of NASH, such as steatosis,
might no longer be evident. At present, many
cases of cryptogenic cirrhosis are thought to be
the result of burned out NASH.
Currently, the diagnosis of NASH requires
histologic confirmation and the exclusion of
The clinicopathologic spectrum of nonalcoholic fatty liver disease
(NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis
(NASH). Simple steatosis has a relatively benign clinical course, but NASH
can progress to cirrhosis and hepatocellular carcinoma. NAFLD occurs in
the absence of significant alcohol use and is considered to be the hepatic
manifestation of metabolic syndrome. NAFLD affects approximately
30% of the US population and the incidence seems to be rising as the
obesity epidemic continues. At present, the most accurate modality for
the diagnosis of NASH is liver biopsy; however, many patients do not have
a liver biopsy, and in the absence of more-accurate imaging technologies
and serum markers, the diagnosis is frequently one of exclusion. As yet
there is no convincingly effective treatment for NAFLDa multimodal
treatment plan that targets obesity, insulin resistance, hyperlipidemia and
hypertension might be the best option for these patients.
KEYWORDS fatty liver, NAFLD, NASH, nonalcoholic fatty liver disease,
nonalcoholic steatohepatitis
C Nugent is a Research Project Associate at Inova Fairfax Hospital
Annandale, VA, USA. ZM Younossi is Executive Director of Research for
Inova Health System, Executive Director of the Center for Liver Diseases
at Inova Fairfax Hospital, Professor of Medicine, Virginia Commonwealth
University, Inova Campus, and Affiliate Professor of Biomedical Sciences at
George Mason University.
Correspondence
*Center for Liver Diseases, Inova Fairfax Hospital, Suite 375, 3289 Woodburn Road, Annandale,
VA 22042, USA
zobair.younossi@inova.org
Received 21 February 2007 Accepted 17 May 2007
www.nature.com/clinicalpractice
doi:10.1038/ncpgasthep0879
REVIEW CRITERIA
Medline was searched in December 2006 and again in April 2007 for papers
published between 1970 and 2007 in English-language journals by using the
following keywords alone and in combination: fatty liver, NAFLD and NASH.
In addition, the authors own collections of pertinent articles were used. The
criteria for inclusion required original articles, review articles and book chapters.
Case reports were not included. Only fully published articles were included.
SUMMARY
CME
432 NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY AUGUST 2007 VOL 4 NO 8
2007 Nature Publishing Group

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AUGUST 2007 VOL 4 NO 8 NUGENT AND YOUNOSSI NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY 433
other causes of chronic liver disease including
excessive alcohol consumption. Although
controversial, the minimum histologic criteria
for the diagnosis of NASH are hepatic stea-
tosis, ballooning degeneration of hepatocytes
and lobular inflammation. Despite their wide-
spread use in clinical practice, imaging modali-
ties are unable to distinguish simple steatosis
from NASH. In 2007, therefore, liver biopsy
remains the gold standard for diagnosis of
NAFLD subtypes. Although the NAFLD activity
score was developed to standardize the patho-
logic diagnosis of NAFLD, use of liver biopsy
to diagnose NAFLD has limitations associated
with sampling error and potential risks to the
patients. Although numerous NAFLD treat-
ment regimens have been tried, none has been
convincingly shown to be effective. This Review
summarizes current understanding of NAFLD,
the evaluation of patients at risk of developing
NAFLD and potential treatment approaches for
these patients.
EPIDEMIOLOGY OF NAFLD
Incidence
Data on the incidence of NAFLD are quite
limited. In one Japanese study, the annual inci-
dence of NAFLD was estimated to be about 10%.
1

Another Japanese study reported an incidence
of 31 per 1,000 person years, by using elevated
aminotransferase levels as a marker for NAFLD in
individuals who did not drink alcohol.
2
Despite
these initial findings, larger studies in more ethni-
cally diverse populations are needed to determine
the true incidence of NAFLD.
Prevalence
The prevalence of NAFLD in the general popu-
lation is estimated to be as high as 36.9%.
311

This prevalence varies according to ethnicity
it is higher in whites and Hispanics and lower
in African Americans.
1215
The prevalence
of NAFLD in the US is about 30%,
15
with the
prevalence of NASH estimated at 5.7%.
16
Certain patient populations have a very
high prevalence of NAFLD. In patients with
diabetes the prevalence of NAFLD is 62%
17

and in patients undergoing bariatric surgery
it is 91%.
18
In the latter group of patients, the
prevalence of NASH is as high as 37%.
18
NAFLD
seems to affect both sexes equally, but it occurs
earlier in men than in women; the prevalence
peaks in the fourth decade for men and in the
sixth

decade for women.
19
Natural history
The clinical course of NAFLD is dependent on
the initial histology. The benign course of simple
steatosis contrasts with the progressive course
of NASH. Some individuals with hepatic stea-
tosis are predisposed to develop NASH, and in
a subgroup of these patients disease progression
will lead to fibrosis.
20
One study demonstrated
that patients with established NASH also have a
variable course, with progression of fibrosis in
one third of patients, and rapid progression noted
in a third of these.
20

Advanced forms of NAFLD are more common
in obese patients who also exhibit other features
of metabolic syndrome, such as insulin resist-
ance and central obesity.
21
The prognosis for
patients with NASH-related cirrhosis is not very
favorable as they develop cirrhotic complications
such as HCC.
22

Patients with confirmed NASH-related cirrhosis
are at risk of developing HCC.
22
Cases of HCC
also occur in patients with so-called cryptogenic
cirrhosis, which is now thought to result from
burned out NASH in many cases; histologic
features of NASH disappear in these patients by
the time cirrhosis is established.
23
Cryptogenic
cirrhosis is considered part of the spectrum of
NAFLD because there is a higher prevalence
of obesity and diabetes among patients with crypto-
genic cirrhosis than among patients with other
chronic liver diseases (supporting the hypo-
thesis that cryptogenic cirrhosis is burned out
NASH).
24,25
Cryptogenic cirrhosis is estimated
to be the reason for 10% of orthotopic liver trans-
plantations in the US. The fact that NASH seems
to recur after liver transplantation in patients with
cryptogenic cirrhosis provides further support
for the hypothesis that cryptogenic cirrhosis is
burned out NASH.
26,27
Recurrence of NAFLD
post-transplantation might be a consequence
of the high prevalence of diabetes and central
obesity in this patient group.
26
NASH seems to progress relatively slowly to
HCC. Hui et al.
28
followed 23 patients with NASH
and matched controls who had HCV-related
cirrhosis for a mean duration of 84 months. HCC
developed in 17% of the HCV-related cirrhosis
group, whereas no cases developed in the
NASH group. By contrast, in a study that followed
21 patients with NASH-related cirrhosis for a
mean duration of 7.6 years, HCC occurred in
10% of patients.
22

By the time HCC is diagnosed in NASH
patients they have a poor life expectancy because

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their relatively advanced age and associated
metabolic syndrome comorbidities often limit
therapeutic choices (including orthotopic liver
transplantation).
29
NASH patients with cirrhosis
should, therefore, be enrolled in HCC screening
programs to ensure diagnosis of HCC at the
earliest stage, when a wider array of treatment
options are available.
30,31
As the prevalence of
metabolic syndrome and NAFLD increase, the
proportion of HCC cases attributable to NASH
might also increase.
NAFLD and NASH in children
NASH in children was first described in 1983,
32

and the entire spectrum of NAFLD has since
been identified in the pediatric population.
33,34

The youngest case of NASH reported so far was
in a child of 27 months.
35
A review of 742 pedi-
atric autopsies found fatty liver disease in 13% of
cases,
36
and a study of Japanese children showed
a prevalence of fatty liver of 2.6%.
37

In children, NAFLD can present in the context
of a clinical syndrome, such as PraderWilli
38
or
Wilsons disease
39
, but most cases occur in the
obese pediatric population. This is especially
true for the preadolescent and adolescent age
groups, with male children being more commonly
affected.
40
Some studies have demonstrated
that NAFLD is present in two or more genera-
tions of the same family, suggesting that it has a
genetic component.
41
The course of NAFLD in children is yet to be
determined, but it seems that as the childs BMI
increases so does the severity of the liver disease.
As discussed later in this article, evidence-based
data that support any treatment options for
NAFLD are currently lacking, and this is especially
true for pediatric NAFLD.
PATHOGENESIS OF NAFLD
The pathogenesis of NAFLD is not well understood,
but several mechanisms are thought to be impor-
tant. Factors implicated in the development of
NAFLD include insulin resistance, oxidative stress,
stellate cell activation, apoptosis, and cytokine and
adipokine pathways. Mechanisms that underlie
the variable progression of different subtypes of
NAFLD (relatively benign simple steatosis versus
potentially progressive NASH) remain the focus
of investigation. As a full review of the pathogen-
esis of NAFLD and NASH is beyond the scope of
this article, the reader is referred to several recent
review articles for a more complete discussion of
the pathogenic mechanisms involved.
4245
METABOLIC SYNDROME AS A RISK
FACTOR FOR NAFLD
NAFLD is now recognized as the hepatic manifes-
tation of metabolic syndrome.
46
Although there is
not a complete consensus on the criteria required
to define metabolic syndrome, the most popular
definition includes the presence of central obesity,
hypertension, hyperlipidemia and insulin resist-
ance.
47
Importantly, however, metabolic syndrome
can occur in nonobese individuals and can still be
associated with NAFLD in these individuals. The
separate components of metabolic syndrome have
also been independently linked to NAFLD.
Central obesity
Almost 75% of obese patients have NAFLD, and
central obesity poses a particular risk of developing
NAFLD.
48
Although BMI is a measure of total
body fat, athletes with significant muscle mass can
have a high BMI but not be obese. Indeed, athletes
with a high BMI but no evidence of central obesity
or other components of metabolic syndrome
might not be at risk of developing NAFLD. On the
other hand, lean individuals with a low BMI and
evidence of central obesity might be at greater risk
of developing NAFLD than those with a high BMI
but no evidence of central obesity.
Type 2 diabetes mellitus
Patients with type 2 diabetes mellitus are at a high
risk of developing NAFLD.
3
In one study, NAFLD
was detected by ultrasound in 62% of patients with
newly diagnosed type 2 diabetes mellitus.
17
Type
2 diabetes mellitus is also a risk factor for severe
fibrosis in patients with NAFLD. In one study
cohort, patients with NAFLD and type 2 diabetes
mellitus had higher overall mortality and liver-
related mortality than NAFLD patients without
type 2 diabetes mellitus.
49
Hypertension, hypertriglyceridemia
and mixed hyperlipidemia
NAFLD has been shown to be associated with
hypertension in two Japanese studies
50,51
and one
Italian study.
52
Hypertriglyceridemia and mixed
hyperlipidemia have also been independently
linked to NAFLD.
53

NAFLD, metabolic syndrome and
cardiovascular disease
NAFLD is an independent risk factor for another
manifestation of metabolic syndromecardio-
vascular disease.
54
Several studies of patients with
NAFLD have shown that they have abnormal

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vascular physiology.
5557
The clinical relevance
of these findings was demonstrated in a large
Italian cohort of patients with diabetes, in
whom NAFLD was an independent predictor of
cardiovascular mortality.
58
PRESENTATION AND INVESTIGATION
OF NAFLD
NAFLD is frequently asymptomatic; however, a
few patients report right upper quadrant discom-
fort and fatigue. On physical examination, hepato-
megaly might be noted and, if advanced liver
disease is present, signs of hepatic decompen-
sation (e.g. ascites, encephalopathy and jaundice)
can also be observed.
The most frequent presentation of patients with
NAFLD is elevation of serum aminotransferase
levels. In fact, NAFLD is the most frequent cause
of elevated aminotransferase levels and of a bright
liver echo pattern, as observed by ultrasound.
59,60

By contrast, some patients with NASH or NASH-
related cirrhosis have normal aminotransferase
levels.
61
Indeed, some patients with cryptogenic
cirrhosis seem to develop cirrhosis without
having significant clinical symptoms or elevated
levels of liver enzymes.
When a patient presents with suspected
NAFLD the case should be investigated in a step-
wise manner by considering the identification of
risk factors, the interpretation of laboratory test
results, the usefulness of imaging modalities,
liver biopsy and histological assessment, and
noninvasive approaches.
Identifying risk factors
A thorough history and physical examination are
important steps in establishing the diagnosis of
NAFLD as the information generated can provide
valuable clues about the risk factors present. As
noted previously, metabolic syndrome and its
components are the most common risk factors
for NAFLD; however, other causes of chronic liver
disease must be excluded. Other causes include
excessive alcohol consumption (>10 g per day
for females and >20 g per day for males), hepa-
titis C, drug-induced hepatotoxicity and Wilsons
disease. It is especially important to exclude
Wilsons disease in young patients, as the disease
can masquerade as NAFLD.
Interpreting laboratory test results
Serum aminotransferase levels are not always
helpful in establishing the diagnosis of NAFLD.
Although most patients with NAFLD may
have elevated liver enzyme levels, these levels
can be normal, even in the presence of severe
disease.
15,61
When abnormalities are noted,
serum aminotransferase levels are typically
only mildly elevated, while alkaline phosphatase
are rarely elevated. Patients with NAFLD and
elevated liver enzyme levels are at an increased
risk of developing progressive liver disease
compared with NAFLD patients with normal liver
enzyme levels.
62
In addition, an aspartate amino-
transferase/alanine aminotransferase (AST/ALT)
ratio greater than 1 is suggestive of advanced
fibrosis.
63
In the setting of hypoalbuminemia,
thrombocytopenia and elevated bilirubin levels,
advanced liver disease should be suspected.
In addition to the measurement of liver enzyme
levels, laboratory testing is required to exclude
other causes of chronic liver disease. Laboratory
assessment for dyslipidemia and insulin resist-
ance must also be undertaken, because although
serum lipid measurement is widely available, a
measure of insulin resistance is more difficult to
obtain in clinical practice. One simple labora-
tory test to consider performing is homeostasis
model assessment (HOMA), which is defined
as the fasting insulin level (U/ml) multiplied
by the fasting glucose level (mmol/l) divided by
22.5. Although homeostasis model assessment
is not a perfect measure of insulin resistance, it is
an easy way to estimate insulin resistance.
64
Imaging modalities
Despite their widespread use, radiologic modali-
ties have not been shown to provide a definitive
diagnosis of the subtypes of NAFLD or the stage
of liver disease. Ultrasound is noninvasive and
useful for the qualitative assessment of hepatic
steatosis, but is not sensitive enough to detect
mild steatosis (i.e. steatosis affecting <33% of
hepatocytes) and is unable to distinguish between
the subtypes of NAFLD. The radiologic appear-
ance of hepatic steatosis is a hyperechogenic liver
with fine echoes seen as the bright liver echo
pattern by ultrasound. Relative to this bright
liver the kidney appears comparatively hypo-
echoic. Hepatomegaly and reduced visualization
of the portal and hepatic veins are also observed
by ultrasound examination of patients with
fatty liver. Sometimes it is difficult to distinguish
between steatosis and fibrosis. Nevertheless, the
pattern of the echoes and Doppler assessment of
hepatic veins can be helpful.
65

CT, MRI and magnetic resonance spectroscopy
(MRS) have also been used to assess patients with

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NAFLD. Although they can all provide an accu-
rate measure of hepatic fat content, their ability
to distinguish different subtypes of NAFLD
is limited.
6668

CT examination is useful for the detection of
steatosis. Unenhanced images are preferred to
enhanced images for the diagnosis of NAFLD.
The density of liver, as visualized by CT,
decreases as the severity of steatosis increases.
CT can also visualize splenomegaly in the pres-
ence of portal hypertension, which is suggestive
of advanced fibrosis in patients with NAFLD.
CT allows steatosis to be graded when splenic
attenuation is also measured. In this case, the
calculated liver attenuation index seems to
correlate with the degree of steatosis.
6668
Conventional pulse sequence MRI is not
useful for the diagnosis of steatosis, but the
gradient-echo chemical-shift technique is a
sensitive method for the detection of hepatic fat
deposition. There is evidence to suggest that fast
gradient-echo sequence MRI provides an accu-
rate and rapid assessment of hepatic steatosis.
69,70

MRS provides another quantitative measure of
hepatic triglyceride content. In the future, MRS
might provide us with an accurate and low-risk
modality that may be suitable for the long-term
monitoring of patients with NAFLD.
7173
When a biopsy is not available, radiographic
evidence of hepatic steatosis supports the diag-
nosis of NAFLD; however, the currently available
radiologic modalities are not yet capable of accu-
rately diagnosing the progressive type of NAFLD
(i.e. NASH) or the stage of hepatic fibrosis.
6673

In the future, modern technologies such as
contrast ultrasound with Levovist (Schering
AG, Berlin, Germany) and transient elasto-
graphy (FibroScan; Echosens, Paris, France)
could provide more accurate diagnostic modal-
ities.
74,75
Of these newer modalities, transient
elastography measures liver stiffness in a painless
and reproducible manner and has been shown to
predict fibrosis in patients infected with HCV.
In the NAFLD population, however, associated
obesity could make this diagnostic modality
more difficult to use and less accurate.
76
Liver biopsy and histologic assessment
As clinical, laboratory and radiologic modalities
are not able to diagnose NASH accurately, histo-
logic assessment of liver biopsy samples from
patients with NAFLD remains important. Indeed,
assessment of liver biopsy samples remains
the only way to establish a definitive diagnosis
of NASH and determine the stage of hepatic
fibrosis, thereby also providing prognostic
information. There are, however, several prob-
lems associated with liver biopsy in patients with
NAFLD and the role of liver biopsy in clinical
practice remains controversial.
One problem with using liver biopsy samples
to diagnose NASH is that experts have not
agreed on the minimal criteria for the histo-
logic diagnosis of NAFLD. In early descrip-
tions of NAFLD, four subtypes were described:
fatty liver, fatty hepatitis, fatty fibrosis and fatty
cirrhosis.
77
In 1980, the histologic diagnosis of
NASH was described as steatosis, mixed lobular
inflammation and hepatocellular ballooning;
in some patients, perisinusoidal fibrosis, glyco-
genated nuclei and Mallory hyaline were also
identified.
78
In 1997, a pathologic scheme catego-
rized NAFLD into four types: type 1 repre-
sented simple steatosis whereas types 3 and 4
fulfilled the criteria for NASH.
79
More recently,
however, the National Institute of Diabetes and
Digestive and Kidney Disease (NIDDK) NASH
Clinical Research Network developed a stand-
ardized approach for the histologic assessment
of NASH.
80
This scoring systemthe NAFLD
activity score (NAS)is based on three patho-
logic features: steatosis, lobular inflammation,
and ballooning degeneration. Scores range from
08; a score of 5 or more is equivalent to NASH,
a score of 3 or 4 is borderline NASH, and a score
of 2 or below equates to non-NASH NAFLD.
Although the NAFLD activity score has not been
fully validated, it might provide a standardized
approach to categorization that is useful in the
clinical trials of patients with NASH.
Potential sampling error is another limitation
of using liver biopsy for the diagnosis of NASH.
Only a small fraction of the liver parenchyma
is sampled, which means that a sampling error
could exist and be compounded by variation
in pathologists interpretations of liver biop-
sies.
80,81
Finally, obtaining liver biopsy samples
is expensive and invasive, with mortality occur-
ring in 0.01% of patients and complications in
0.3% of patients.
82

Importantly, many NAFLD patients are
asymptomatic and are reluctant to undergo a
biopsy. This is especially pertinent when there
is no definitive treatment for NASH. The deci-
sion to perform a liver biopsy should, there-
fore, be made on an individual basis after other
diseases have been excluded. Until noninvasive
biomarkers for the diagnosis of NASH become

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available, it is prudent to reserve liver biopsy
for those patients for whom there is evidence
of metabolic syndrome and chronic elevation
of liver enzymes, despite medical interventions
to treat type 2 diabetes mellitus, hyperlipidemia
and obesity.
Noninvasive approaches
In response to the disadvantages of liver biopsy
discussed above, several groups are trying to
develop noninvasive ways of establishing a
diagnosis of NASH.
8384
One approach is to develop algorithms (using
clinical variables such as age, insulin resistance,
hypertension, triglyceride levels) to predict
NASH in certain cohorts of patients with
NAFLD, such as those undergoing bariatric
surgery. In addition, different serum markers
of fibrogenesis have been combined with clin-
ical parameters to develop predictive models
of fibrosis in NASH (FibroTest). These tests
are inconclusive in many patients, however,
and have not been fully validated in patients
with NAFLD.
85

Pathogenic markers of liver fibrosis (including
thioredoxin, tumor necrosis factor, leptin and
adiponectin) have also been studied, but clear
associations with the stage of fibrosis have yet to
be demonstrated.
8688
In the future, diagnostic
biomarkers could be part of a serum-based
assay and used in combination with one of the
newer imaging modalities: such biomarkers
hold great promise for the development of
noninvasive tests for patients with NASH.
TREATMENT OF NASH
Although many treatment modalities have
been used in patients with NASH, none have been
convincingly shown to be effective
89109
. Most of
the current regimens have been tested in open-
label, uncontrolled trials that have been carried
out over a relatively short period of time. In
addition, most of these studies did not adhere
to a strict histologic end point. Notwithstanding,
the following paragraphs summarize some of the
regimens used to treat NASH.
Weight loss through lifestyle changes
Lifestyle changes, including weight loss and
exercise, have been shown to improve alanine
aminotransferase levels
89,90
and, less frequently,
liver histology.
91
To achieve sustained weight
loss, comprehensive programs including diet,
exercise and behavior modification might be
needed. Rapid weight loss has been associated
with worsening liver histology,
89
and most
experts, therefore, recommend that weight
loss in obese patients with NAFLD should be
gradual (<1.6 kg per week). The validity of this
recommendation in the era of bariatric surgery,
however, might no longer be substantiated.
Weight loss with antiobesity medication
In one study, orlistat (an enteric lipase inhibitor)
has been shown to promote weight loss and to
reduce aminotransferase levels, with improved
liver histology in 9 out of 10 NAFLD patients.
92

Sibutramine (a selective serotonin reuptake
inhibitor) has been compared with orlistat;
93
both
treatment groups lost weight and improvements
were demonstrated in both liver enzyme levels
and in the extent of steatosis visible on ultra-
sound. Despite these encouraging findings, ques-
tions remain as to whether these medications can
be tolerated long term by patients and whether
sustained weight loss can be achieved.
94

Weight loss through antiobesity surgery
For morbidly obese patients (BMI >35), lifestyle
modification might not be enough to achieve
sustained weight loss. In these patients, bari-
atric surgery is now a viable option for achieving
sustained weight loss. The risks of bariatric
surgery vary depending on the procedure under-
taken. At the moment, there is a trend towards
performing less invasive procedures with lower
morbidity and mortality (e.g. laparoscopic adjust-
able gastric band). In patients who undergo bari-
atric surgery, an improvement can be expected in
the severity of their metabolic syndrome, in both
their mental and physical health, and potentially
in their life expectancy.
95
The hepatic effects of
bariatric surgery in NAFLD patients seem to be
favorable. Both Roux-en-Y gastric bypass and
gastroplasty have been shown to reduce hepatic
steatosis and even fibrosis.
96,97
In obese NASH
patients who underwent a laparoscopic adjust-
able gastric band procedure, regression of NASH
was shown in paired liver biopsies.
95

As already noted, there is evidence to suggest
that rapid weight loss (>1.6 kg per week)
achieved by following a rigid diet can lead to
the development of inflammation and fibrosis.
Although it is not entirely clear how rapid weight
loss and worsening liver histology are linked,
this phenomenon could result from the massive
liberation of free fatty acids into the blood-
stream during these drastic diets.
98
This issue

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has become an important concern in relation
to some types of bariatric procedures, such as
biliopancreatic diversion and Roux-en-Y gastric
bypass. Nevertheless, the available data suggest
that in the setting of appropriate surgical skill,
these procedures can be safe and may reverse
NASH and fibrosis.
Drugs targeting insulin resistance
As previously noted, most NASH patients
have insulin resistance. In fact, in patients with
NAFLD who have type 2 diabetes mellitus, the
level of insulin resistance has been correlated
with the grade of steatosis and even fibrosis.
79

Treatment strategies focused on improving
insulin resistance by using thiazolidinediones
and metformin have therefore been explored.
Thiazolidinediones
Among the thiazolidinediones, troglitazone was
the first to be studied in NASH patients, who
showed some biochemical improvement;
99

however, troglitazone was subsequently with-
drawn due to hepatotoxicity. The potential of
two newer types of thiazolidinedionerosiglita-
zone and pioglitazoneto treat patients with
NASH has since been assessed. Both rosiglitazone
and pioglitazone have been shown to improve
liver enzyme levels and liver histology.
100102

Although histologic improvement occurred
with pioglitazone treatment, however, a signifi-
cant reduction in fibrosis was not seen.
102
It
also seems that the improvement generated by
rosiglitazone and pioglitazone is short lasting,
and liver enzyme levels become abnormal again
once these medications have been discontinued.
There remains concern associated with thiazo-
lidinedione treatment as these drugs do have
the potential for toxicity
103
and patients tend to
gain weight on treatment. Furthermore, because
these studies were conducted with relatively
small numbers of individuals and over short
time periods, well-controlled clinical trials are
needed to establish their efficacy.
Metformin
Another antidiabetic medication, metformin,
has been used to treat NAFLD. The lack of weight
gain associated with metformin treatment might
provide an advantage in the typically obese
NAFLD population. Although metformin has
been shown to improve liver enzyme levels,
104

extensive data on histologic improvement are
currently lacking.
Vitamins E and C
The theory that NASH develops as a result of
oxidative stress on the fatty liver has prompted
interest in the therapeutic role of antioxidants in
NAFLD. Therapy with Vitamin E has been studied
alone and in combination with Vitamin C
105108
,
but the findings have been inconsistent and future
studies are needed to assess the efficacy of anti-
oxidants in combination with other medications
or regimens.
Other regimens
Cytoprotective agents such as betaine, urso-
deoxycholic acid and agents that lower lipid levels
have been used to treat patients with NAFLD.
So far, none of these medications has shown
convincing therapeutic potential; however, several
other agents are currently under investigation as
treatments for NAFLD.
109
Until pharmaceutical agents are available to
treat NAFLD, patients require support to main-
tain the recommended lifestyle modifications.
Those NAFLD patients who have cirrhosis should
be enrolled in a screening program for esophageal
varices and HCC, to enable diagnosis and treat-
ment of these complications of cirrhosis at the
earliest possible stage.
109
CONCLUSIONS
In 2007, NAFLD is considered the hepatic mani-
festation of metabolic syndrome and clinicians
should consider it as part of the management
of the other components of this syndrome. The
clinical spectrum of NAFLD warrants continued
research to determine its pathogenesis and to
improve diagnostic modalities. It is hoped that
improved imaging techniques and the discovery of
serum biomarkers, as well as the development
of clinical algorithms, will enable a more accu-
rate diagnosis of NASH without the need for a
liver biopsy.
Since no proven, effective treatment is currently
available for NASH, well-designed clinical trials
are needed to provide evidence-based recom-
mendations for the treatment of these patients. So
far, preliminary data suggest that weight loss can
be beneficial and should be encouraged in over-
weight patients with NAFLD. As insulin resist-
ance has a key role in the development of NAFLD,
treating insulin resistance in the NAFLD popu-
lation is a promising strategy. Although there is
no current treatment for NASH, patients with
NASH who have cirrhosis should be screened
for esophageal varices and HCC.

REVI EW REVI EW
KEY POINTS
Nonalcoholic fatty liver disease (NAFLD) is
considered to be the hepatic manifestation of
metabolic syndrome
Approximately 30% of the US population have
NAFLD and its incidence seems to be rising as
the obesity epidemic continues
The NAFLD spectrum ranges from relatively
benign simple steatosis to nonalcoholic
steatohepatitis, which can progress to
cirrhosis
At present, the most accurate modality for
the diagnosis of nonalcoholic steatohepatitis
is liver biopsy; however, liver biopsy is not
performed in a significant number of cases
and in the absence of more-accurate imaging
technologies and serum markers, the
diagnosis is frequently one of exclusion
There is currently no proven effective treatment
for NAFLD; however, a multimodal treatment
plan that targets obesity, insulin resistance,
hyperlipidemia and hypertension might be the
best option
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Acknowledgments
Charles P Vega, University
of California, Irvine, CA,
is the author of and is
solely responsible for the
content of the learning
objectives, questions and
answers of the Medscape-
accredited continuing
medical education activity
associated with this article.
Competing interests
ZM Younossi has declared
associations with the
following companies:
Axcan, Idenix, Roche and
Vertex. See the article
online for full details of
the relationship. C Nugent
declared no competing
interests.

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