REVIEWS
Nonalcoholic Fatty Liver Disease and Nonalcoholic
Steatohepatitis: Selected Practical Issues in Their
Evaluation and Management
Raj Vuppalanchi and Naga Chalasani
Nonalcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver
disease in the western world. It is now recognized that these patients have myriad of important
co-morbidities (e.g., diabetes, hypothyroidism and metabolic syndrome). The workup of patients with suspected NAFLD should consist of excluding competing etiologies and systemic
evaluation of metabolic comorbidities. NAFLD is histologically categorized into steatosis and
steatohepatitis, two states with fairly dichotomous natural history. While significant progress has
been made in terms of noninvasively predicting advanced fibrosis, insufficient progress has been
made in predicting steatohepatitis. Currently, liver biopsy remains the gold standard for the
histological stratification of NAFLD. While sustained weight loss can be effective to treat NASH,
it is often difficult to achieve. Foregut bariatric surgery can be quite effective in improving hepatic
histology in selected patients without liver failure or significant portal hypertension. Thiazolidinediones have shown promise and the results from the ongoing, large multicenter study
should become available soon. Large multicenter studies of CB, receptor anatagonists are also
underway but their results will not be available for several years. Several recent studies have
highlighted that cardiovascular disease is the single most important cause of morbidity and
mortality in this patient population. Conclusion: Health care providers should not only focus on
liver disease but also concentrate on aggressively modifying and treating their cardiovascular risk
factors. (HEPATOLOGY 2009;49:306-317.)
N
onalcoholic fatty liver disease (NAFLD) is one
of the most common causes of elevated liver
enzymes and chronic liver disease in Western
1-3
countries. Its incidence in adults and children is rising
rapidly because of ongoing epidemics of obesity and type 2
diabetes.4,5 It is a multifaceted metabolic disorder and is en-
Abbreviations: BMI, body mass index; CI, confidence interval; CK-18, cytokeratin 18; HOMA-IR, Homeostatic Model Assessment—Insulin Resistance; NAFLD,
nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TZD, thiazolidinediones.
From the Division of Gastroenterology and Hepatology, Department of Medicine,
Indiana University School of Medicine, Indianapolis, IN. Affiliated with Clarian/IU Digestive Disease Center.
Received July 25, 2008; accepted July 13, 2008.
Supported in part by Public Health Service grant K24 DK072101 (to N.C.).
Address reprint requests to: Naga Chalasani, M.D., Professor of Medicine, Indiana University School of Medicine, RG 4100, 1050 Wishard Boulevard, Indianapolis, IN 46202. E-mail: nchalasa@iupui.edu; Fax: 317-278-1949.
Copyright © 2008 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.22603
Potential conflict of interest: Dr. Chalasani has served as a paid consultant to
Atherogenics, Pfizer, Takeda, Advanced Life Sciences, Karo-Bio, Metabasis and
Eli-Lilly over the past 12-months. He has agreements to conduct clinical trials
related to fatty liver disease with Debiovision, Sanofi-Aventis, Pfizer and Gilead.
Dr. Vuppalanchi received grants from Sanofi-Aventis.
306
countered in clinical practice by a variety of health care specialists ranging from primary care physicians and
gastroenterologists to cardiologists, radiologists, and gynecologists. It is comprised of a spectrum of liver disease ranging from simple steatosis to full-blown steatohepatitis that is
characterized by steatosis, lobular inflammation, ballooning,
and fibrosis.6 Over the last several years, much progress has
been made in terms of our understanding of its risk factors,
pathogenesis, natural history, noninvasive markers, and
treatment. This review is tailored toward clinicians caring for
patients with NAFLD and discusses practical issues related to
selected aspects of its evaluation and management.
Evaluation of Newly Suspected NAFLD
Suspected NAFLD represents one of the most common reasons why patients visit gastroenterologists and
hepatologists in an ambulatory setting.1-3 Although some
patients may have attributable abdominal symptoms and
tender hepatomegaly, most are asymptomatic, and their
liver disease is identified incidentally on routine blood
tests or abdominal imaging. Its initial assessment consists
of excluding competing and co-existing causes and identifying clinically important comorbidities.
HEPATOLOGY, Vol. 49, No. 1, 2009
Competing Causes
The diagnosis of NAFLD requires that there is no history of previous or ongoing significant alcohol consumption. There is no consistent agreement regarding the
definition of significant alcohol consumption; however, it
is generally believed that average alcohol consumption of
more than two drinks per day in women and more than
three drinks per day in men is necessary to develop alcoholic fatty liver.7,8 However, in individuals with metabolic risk factors such as obesity and diabetes, it is possible
that alcohol consumed at lower quantities may promote
hepatic steatosis. This notion is supported by a population-based study in which Ruhl and Everhart9 have shown
that one or more alcohol drinks per day cause elevated
alanine aminotransferase (ALT) in obese but not in normal weight individuals.9 This study is at odds with recent
epidemiological data suggesting that modest wine consumption may reduce the prevalence of NAFLD.10
When the alcohol consumption history is insufficient,
it becomes difficult to distinguish alcoholic and non-alcoholic forms of fatty liver, especially in those with obesity
and associated metabolic risk factors. Conventional markers such as gamma glutamyl transpeptidase, mean corpuscular volume, and aspartate aminotransferase (AST)/ALT
ratio are not useful, and specific serum markers for
chronic alcohol abuse are of limited utility.11 The carbohydrate-deficient transferrin is the most widely used and
perhaps the most specific serum marker for detecting
chronic alcohol abuse.12 This test evaluates the ratio of
desialylated transferrin to total transferrin, and it has 81%
sensitivity with 98% specificity in detecting chronic alcohol abuse. Unfortunately, this and other tests such as the
ratio of mitochondrial AST to total AST13 are not readily
available in clinical practice.
More recently, investigators from the Mayo clinic have
developed the “alcoholic liver disease/NAFLD index,”
which consisted of five easily available variables: mean
corpuscular volume, AST, and ALT values, height and
weight, and sex (http://www.mayoclinic.org/gi-rst/
mayomodel10.html).14 This weighted multivariate
model uses logistic regression analysis to generate the alcoholic liver disease/NAFLD index score, and a score
greater than 0 incrementally favors alcoholic liver disease,
whereas a value less than 0 favors NAFLD in decrement.
For example, an alcoholic liver disease/NAFLD index of
8.95 would correspond to greater than 99% probability of
alcoholic liver disease, whereas a value of ⫺5.04 would
correspond to greater than 99% probability of NAFLD.
Because most subjects with alcoholic liver disease in this
study had high model for end-stage liver disease scores,
this tool is more likely applicable to patients with decom-
VUPPALANCHI AND CHALASANI
307
pensated cirrhosis presenting for liver transplant evaluation rather than outpatients with fatty liver.
Elevated serum auto-antibodies are common in patients with NAFLD. Although low titer antinuclear antibody positivity can be seen in up to 33% of patients with
NAFLD, antinuclear antibody positivity in titers greater
than 1:320 is generally rare.15-17 Low titers of anti-smooth
muscle and antimitochondrial antibodies also may be
noted in patients with NAFLD.18 The presence of these
auto-antibodies is generally thought to be an epiphenomenon, although in one study their presence correlated
with more severe histological damage.19,20 In patients
with suspected NAFLD and antinuclear antibody positivity at titers greater than 1:160 or anti-smooth muscle
actin positivity at titers greater 1:40, a liver biopsy may be
considered to exclude the presence of autoimmune hepatitis.
Mildly increased serum ferritin is not uncommon in
patients with NAFLD, and it does not necessarily indicate
co-existing iron overload.21 Metabolic syndrome and hyperinsulinemia are known to be associated with increased
serum ferritin, and this association may be mediated by
the presence of NAFLD.22 Nonetheless, elevated serum
ferritin in a patient with suspect NAFLD should prompt
testing for hereditary hemochromatosis (HFE gene) mutations. The prevalence of HFE gene mutations in
NAFLD patients has been variable, depending on the
population studied, and their relevance remains largely
unknown.23,24 Although the prevalence of HFE gene mutations and their clinical relevance remain unclear,22-24
homozygote or heterozygote C282Y mutations along
with elevated serum ferritin may justify a liver biopsy in
patients with suspected NAFLD.
It is important to verify that chronic hepatitis B and
hepatitis C have been convincingly excluded, and, depending on the clinical scenario, rare disorders such as
alpha-1 antitrypsin deficiency and Wilson’s disease
should also be excluded. Thorough medication history is
important because several commonly prescribed medications (such as tamoxifen, methotrexate, and amiodarone)
are noted for their ability to cause hepatic steatosis.1
Evaluation for Co-morbidities
The patients with NAFLD frequently have many clinically significant co-morbidities (Table 1). Obesity, type 2
diabetes, and hyperlipidemia are well known to co-exist in
patients with NAFLD, and it is important to systematically characterize them. The body mass index (BMI) and
waist circumference should be measured to better characterize the degree (mild, moderate, and severe) and the
nature (central versus peripheral) of obesity. Type 2 diabetes and glucose intolerance are very frequent in patients
308
VUPPALANCHI AND CHALASANI
HEPATOLOGY, January 2009
Table 1. Comorbidities Commonly Associated with NAFLD
Established Conditions
Emerging Conditions
Obesity
Type 2 diabetes/glucose intolerance
Dyslipidemia
Metabolic syndrome
Obstructive sleep apnea
Hypothyroidism
Obstructive sleep apnea
Hypopituitarism
with NAFLD, and they have prognostic significance.25 In
patients without preexisting type 2 diabetes, the presence
of glucose intolerance and insulin resistance should be
evaluated by obtaining fasting blood glucose, insulin levels and hemoglobin A1c. In patients without diabetes,
insulin resistance should be assessed by calculating
HOMA-IR (homeostasis model assessment—insulin resistance) or QUICKI (quantitative insulin-sensitivity
check index).26,27 Both HOMA-IR and QUICKI are
mathematical transformations of fasting blood glucose
and insulin levels. In our practice, we calculate
HOMA-IR ([fasting insulin {U/mL} * fasting glucose
{mmol/L}]/22.5), and as a general guideline, we consider
an HOMA-IR value greater than 3 to be clinically significant.28 If not done recently, fasting lipid profile should be
obtained, because dyslipidemia is nearly universal. Typically, fasting serum triglyceride levels are high, along with
low high-density lipoprotein values. Recent data suggest
that high-sensitivity c-reactive protein is frequently elevated in patients with NAFLD and should be measured
along with fasting lipid profile to assess cardiovascular risk
(vide infra).29,30
In addition, patients should be systematically explored
for the presence of other comorbidities such as obstructive
sleep apnea,31,32 hypopituitarism,33 hypothyroidism,34
and polycystic ovary syndrome.35-37 Obstructive sleep apnea is commonly present in patients with NAFLD and
may contribute to the fatigue that these patients sometimes experience.38 Some studies have suggested a causal
relationship between obstructive sleep apnea and the
pathogenesis of NAFLD, but these are far from convincing.39,40 Previous studies have shown that patients with
hypothyroidism and hypopituitarism have increased
prevalence of NAFLD.33,34 Several studies have shown
high prevalence of NAFLD in premenopausal women
with polycystic ovary syndrome,35,37 and one study36 suggested that such individuals are at higher risk for disease
progression.
Identification of Nonalcoholic
Steatohepatitis in Patients with NAFLD
The NAFLD can be categorized into simple steatosis
and steatohepatitis (NASH). A well-defined case of
NASH histologically exhibits macrovesicular steatosis,
lobular inflammation, balloon degeneration of hepatocytes, and zone 3 pericellular fibrosis.41 Undoubtedly,
NASH is histologically progressive and can lead to cirrhosis and associated liver dysfunction. Simple steatosis has a
relatively benign course but is not totally without histological consequences.42 For example, investigators from
the Cleveland Clinic reported in their initial paper that
4% of patients with simple steatosis developed cirrhosis
and 2% had liver-related mortality over a median follow-up of approximately 8 years.6 The extended follow-up of the same cohort was reported in an abstract
form recently, and it confirmed that simple steatosis is not
entirely benign.43
Liver biopsy is the current gold standard to identify
steatohepatitis, but it is not without controversies and
practical difficulties. Several recent studies have highlighted its sampling variability and interobserver discordance.44-46 The precise histological definition of NASH is
not entirely known, and the experts believe that it should
be based on pattern recognition rather than a composite
score of individual components such as steatosis, ballooning, and fibrosis.47 It remains controversial whether ballooning or pericellular fibrosis should be considered as
critical for the histological diagnosis of NASH. The recently described NAFLD Activity Score is valuable for
quantifying histological changes, especially in clinical trials,47 but its generalizability and diagnostic utility are unknown.
Over the past several years, there has been significant
interest in noninvasively predicting liver histology in patients with NAFLD. However, it remains somewhat controversial which histological finding(s) should be targeted
for noninvasive assessment. Most studies have attempted
to predict advanced fibrosis (bridging fibrosis/cirrhosis),25,48,49 but it has been argued that one should attempt
to predict steatohepatitis rather than advanced fibrosis.50
It is our view that future studies should attempt to predict
three histological states (simple steatosis, NASH without
significant fibrosis, and NASH with advanced fibrosis),
rather than dichotomous descriptive states.
Aminotransferase values and common imaging tests
such as liver ultrasound, computed tomography, and
magnetic resonance are of limited value in predicting liver
histology. Numerous circulating biomarkers and prediction models have been investigated to noninvasively predict hepatic histology in patients with NAFLD (Table 2),
and their full discussion is beyond the scope of this review.
However, cytokeratin 18 (CK-18) fragments and serum
dehydroepiandrosterone, two hypothesis-driven circulating biomarkers, deserve further discussion. Based on experimental data that hepatocyte apoptosis may play an
important role in the pathogenesis of NAFLD, Wieck-
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VUPPALANCHI AND CHALASANI
309
Table 2. Noninvasive Biomarkers Previously Studied or Currently Under Evaluation
Serum Biomarkers
Fibrosis
Oxidative stress
Hepatocyte apoptosis
Inflammation
Imaging Studies
Breath Tests
58
BARD score
Fibrotest
NAFLD fibrosis score56
ELF/OELF57,59
Hyaluronic acid130
TBARS119
Oxidized-LDL119
Total antioxidant response137
Total lipid peroxide levels137
CK-18 fragments51,53
TNF-␣/adiponectin
ratio138,139
hsCRP29
IL-6140
CC-chemokine ligand-2141
owska et al.51 measured plasma CK-18 fragment levels in
44 consecutive individuals with suspected NAFLD undergoing liver biopsy.51 CK-18 is a major intermediate
filament protein in hepatocytes, and it is cleaved by the
effector caspases (mainly caspase 3) on activation of the
apoptosis cascade.52,53 Compared with individuals with
normal histology and those without NASH, patients with
definite NASH had significantly higher CK-18 fragment
levels.54 It was suggested that CK-18 fragment levels
greater than 380.2 U/L can predict definite NASH in a
very precise fashion.51 A puzzling and unexplained aspect
of this small cross-sectional study is that nearly 25% of
patients with suspected NAFLD supposedly had normal
hepatic histology on liver biopsy. More recently, Charlton
et al.55 have shown that serum dehydroepiandrosterone
levels had a consistent and stepwise inverse relationship
with the degree of hepatic fibrosis that persisted after adjusting for age.55 This observation, which was initially
made on a derivation cohort consisting of 122 patients,
was subsequently reproduced on a validation cohort consisting of 361 NAFLD patients recruited from two separate academic centers.55 These provocative preliminary
data deserve further study, but it may be too optimistic to
assume that a single biomarker can reliably predict histology in NAFLD, a condition with relatively complex phenotype and multiple comorbidities.
There are numerous papers published in the literature
describing noninvasive prediction models, but most of
them consisted of small sample size and lacked rigorous
external validation. Three recently described models with
relatively large sample size and some level of validation
have shown encouraging results.56-58 In a multicenter
study consisting of 480 patients in the derivation and 253
in the validation cohorts, Angulo et al.56 have shown that
a NAFLD fibrosis score consisting of six variables (age,
BMI, AST/ALT ratio, hyperglycemia, platelet count, and
61,131
Transient elastography
MR elastography132
MR spectroscopy133,134
[13C] methacetin135
[13C] ketoisocaproate135
Ethanol136
Acetone136
albumin) can reliably predict advanced fibrosis. The formula for the fibrosis score was “ ⫺1.675 ⫹ 0.037 ⫻ age
(years) ⫹ 0.094 ⫻ BMI (kg/m2) ⫹ 1.13 ⫻ impaired glucose
tolerance/diabetes (yes ⫽ 1, no ⫽ 0) ⫹ 0.99 ⫻ AST/ALT
ratio ⫺ 0.013 ⫻ platelets (⫻109/L) ⫺0.66 ⫻ albumin
(g/dL),” and a low cutoff point (score ⬍ ⫺1.455) signified
the absence of advanced fibrosis, whereas a high cutoff
point (score ⬎ 0.676) identified advanced fibrosis. It was
concluded that NAFLD fibrosis score can be used as a
triaging tool for optimizing liver biopsy yield in terms of
identifying or excluding advanced fibrosis. More recently,
Guha et al.57 have compared the performance of “enhanced liver fibrosis” (ELF) score with that of the
“NAFLD fibrosis score” in predicting advanced fibrosis.
The enhanced liver fibrosis is essentially the “original European liver fibrosis” test without “age” included in the
algorithm. The original European liver fibrosis test, a
model consisting of age and three serum markers of matrix turnover (tissue inhibitor of metalloproteinases, hyaluronic acid, and type III procollagen), predicted advanced
fibrosis in a variety of liver disorders.59 In this report, the
ELF score had excellent ability to predict different levels
of fibrosis (any fibrosis, moderate fibrosis, or advanced
fibrosis), and when it was combined with the “NAFLD
fibrosis score,” its ability to predict different levels of fibrosis improved further.57 Harrison et al.58 have recently
developed the BARD score to predict advanced fibrosis in
patients with NAFLD.57 The BARD score is a weighted
sum of three easily available variables (BMI ⬎ 28 kg/m2
[1 point], AST/ALT ⱖ 0.8 [2 points], and diabetes [1
point]), and the authors have shown that a score of 2 to 4
was associated with an odds ratio of 17 (95% confidence
interval [CI]: 9.2-31.9) for predicting advanced fibrosis.57
These promising models will need to be validated by external investigators before they are recommended for wide
clinical use.
310
VUPPALANCHI AND CHALASANI
One French study tested “Fibrotest” for predicting advanced fibrosis in NAFLD and found encouraging results.60 “Fibrotest” is a popular serum test for predicting
advanced fibrosis in individuals with chronic hepatitis C,
but more studies are needed to test its utility in NAFLD.
Similarly, liver stiffness measured by transient elastography (FibroScan) may have some role in predicting the
degree of fibrosis, but the data are sparse in terms of its
utility in NAFLD.61,62
In summary, there has been significant research in developing biomarkers of liver histology in patients with
NAFLD, and in fact one editorialist recently opined that
the future is around the corner for noninvasively diagnosing progressive NASH.63 Although this may be the case
for advanced fibrosis, insufficient attention has been paid
to developing markers for noninvasively identifying steatohepatitis in patients with NAFLD. Until more definite
data with external validation become available, we will
continue with our current practice of recommending liver
biopsy to selected patients with suspected NAFLD based
on the presence of certain risk factors such as older age,
diabetes, severe obesity, and metabolic syndrome.
Management of Patients with NAFLD
Advice Regarding Weight Loss, Exercise, and Specific Diets. The NAFLD is largely a manifestation of
obesity and metabolic syndrome and is characterized by
excess calorie intake and lack of optimal health-related
fitness or physical activity.64 It is generally believed that
weight loss is beneficial for patients with NAFLD, but
data are sparse in terms of specifics such as how, how much,
and how rapidly to lose weight. Furthermore, precise hepatic and extrahepatic benefits of weight loss are not well
defined. In a recent review, Bellentani et al.65 pointed out
that there are only four human studies consisting of fewer
than 40 total patients that evaluated the effect of calorie
restriction alone, and change in liver enzymes was the
primary end point in all but one study. There are 10
published studies consisting of 626 total patients that
evaluated the effect of calorie restriction combined with
exercise, but liver histology was the primary end point in
only four studies (123 patients).65 This paucity of data
makes it difficult to make evidence-based recommendations about dietary modification and exercise to treat
NAFLD and NASH.
It is generally recommended that overweight and obese
patients with NAFLD lose 7% to 10% of their body
weight by dietary modification and exercise over the
course of 6 to 12 months. This is based on short-term
studies showing that gradual weight loss of this magnitude improves insulin resistance and hepatic histology.3,66
HEPATOLOGY, January 2009
Table 3. Strategies to Enhance Patient Compliance in
Lifestyle Modification
●
●
●
●
●
●
●
●
Communicate with empathy
Be sensitive to general stigma against obesity
Discuss pros and cons of proposed changes to lifestyle
Explore reasons for perpetual poor dietary and exercise choices
Encourage self-efficacy
Offer specific choices of food and exercise
Design individualized program of eating and physical activity
Explain treatment and its benefits
Reproduced, with modification, from Bellentani et al., Hepatology 2008;47:
746-754.
Our recommendations to enhance patient compliance
with lifestyle modifications are shown in Table 3. Scientific evidence is lacking to make precise recommendations
specific to modifying macronutrient composition, but it
appears sensible to recommend low glycemic food with
decreased saturated and trans-fat intake but increased
mono and polyunsaturated fatty acid intake.67 Evolving
data suggest diets consisting of high fructose should be
avoided by these patients.68 Because of the lack of safety
and efficacy data, popular weight-loss diets such as Atkins,
Ornish, and South Beach diets should not be recommended.67 In our clinical practice, we recommend diminished portions of balanced diet (consisting of a lowglycemic and low-fat diet and increased portions of fruits
and vegetables) and five to seven sessions per week of
moderate aerobic exercise, with each session lasting for 30
to 45 minutes. However, such prescriptive recommendations made in a clinic setting are rarely effective both
short-term and long-term.65
Orlistat, a reversible inhibitor of gastric and pancreatic
lipase, may be effective in promoting limited weight loss
in selected patients, but side effects such as diarrhea and
bloating make it less desirable. In a randomized study,
Harrison et al.69 have shown that orlistat does not cause
weight loss or histological improvement above and beyond that accomplished with calorie restriction alone.69
Rimonabant (endocannabinoid receptor 1 antagonist) is
approved in Europe for promoting weight loss, and it may
have favorable anti-steatotic and anti-fibrotic properties.70-74 Large clinical trials are underway with this and
other similar compounds in NASH, but their results will
not become available for at least several years.
Advice Regarding Bariatric Surgery. Because many
patients with NAFLD have severe obesity, it often comes
up in clinical practice whether bariatric surgery is suitable
in this patient population. Jejunoileal bypass was widely
popular in mid-1950s to mid-1970s for the surgical treatment of obesity, but because of disastrous hepatic and
extrahepatic consequences it is now totally abandoned.75-77 Over the last decade, an increasing number of
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VUPPALANCHI AND CHALASANI
311
Table 4. Selected Studies of Metformin in Patients with NAFLD
N
Design
Comparator
Population
Duration
Liver
Enzymes
Histology
Marchesini et al.
14
Open label
Single arm
None
4 mo
Improved
Not evaluated
Nair et al.143
15
None
12 mo
Improved
Improved inflammation
Uygun et al.144
36
Open label
Single arm
Open label
Adults
Mostly
nondiabetic
Nondiabetics
Nondiabetics
6 mo
Improved
Improved inflammation
Bugianesi et al.145
55
Randomized
clinical trial
Non-diabetics
12 mo
Improved
Schwimmer et al.146
10
None
Nondiabetics
6 mo
Improved
Loomba et al.147
14
None
Nondiabetics
48 wks
Improved
Nobili et al.148
57
Open label
Single arm
Open label
Single arm
Open label
Antioxidant
Nondiabetics
24 months
No difference
Author (reference)
142
Calorie-restricted
diet
Calorie restricted
diet
foregut bariatric surgery procedures are being performed
to treat obesity and its complications, and its short-term
and long-term benefits are becoming well established.78-80
The commonly performed foregut bariatric surgery procedures include roux-en-Y gastric bypass (most common), adjustable gastric banding, gastroplasty, and sleeve
gastrectomy.81,82 There have been no studies that evaluated foregut bariatric surgery to specifically treat NAFLD,
but many published papers described its favorable effect
of hepatic histology when performed for other indications, thus introducing selection bias.78-80 In general, liver
histology improves significantly after foregut bariatric
surgery with very minimal risk of worsening.83,84 In a
recent meta-analysis consisting of 15 studies and 766
paired liver biopsies, Mummadi et al.84 have shown that
all components of NAFLD show significant improvement after foregut bariatric surgery. Pooled proportion of
patients with improvement or resolution in steatosis was
93% (95% CI: 84%-98%), and improvement or resolution of steatohepatitis was 82% (95% CI: 64%-95%);
improvement in fibrosis when assessed using needle biopsies was 73% (95% CI: 65%-81%). We speculate that
liver disease is unlikely to worsen in association with rapid
and profound weight loss unless there are additional risks
such as bacterial overgrowth (for example, jejunoileal bypass) or nutrient depletion (such as kwashiorkor). This
forms the basis for our view that very long roux limb (in
other words, ⬎150 cm) should be avoided in patients
with advanced fibrosis. Compensated cirrhosis is not a
contraindication for foregut bariatric surgery provided it
is performed by an experienced surgeon and clinically
evident portal hypertension is absent (no esophageal or
abdominal varices). There are reports that cirrhosis may
reverse after bariatric surgery.85,86
In our practice, we recommend foregut bariatric surgery as a therapeutic possibility for the severely obese
Improved steatosis,
inflammation and
fibrosis
Not evaluated
Improved steatosis and
inflammation
No difference
NAFLD patients with advanced fibrosis who failed to lose
weight despite repeated nutritional counseling. In those
with cirrhosis, we exclude clinical portal hypertension by
performing abdominal imaging and upper endoscopy.
Bariatric surgery may be particularly attractive for carefully selected patients with Child’s A cirrhosis not only
because it may stabilize or improve the liver disease but it
also may enhance their future suitability for liver transplantation.
Role of Insulin Sensitizers. Because insulin resistance is nearly universal in patients with NASH, it is not
surprising that many studies tested insulin sensitizers as its
treatment. However, a large number of them are proofof-concept studies with small numbers of patients without rigorous study design, making it difficult to make
definite recommendations. Biguanides (metformin) and
thiazolidinediones (pioglitazone and rosiglitazone) are the
two classes of insulin sensitizers studied in humans.
Metformin. Although its exact mechanism of action is
not entirely clear, metformin’s therapeutic benefit as an
antidiabetic agent and insulin sensitizer is well recognized. Its anti-diabetic action is likely related to decreased
hepatic gluconeogenesis, decreased glucose absorption,
and increased insulin sensitivity by facilitating glucose
uptake and utilization.86,87 In addition, its stimulatory
effect on adenosine monophosphate–activated protein kinase or modulation of hepatic tumor necrosis factor alpha
(TNF-␣) expression may result in benefits.88,89 A summary of studies evaluating metformin to treat NASH is
shown in Table 4. A recent meta-analysis published in
Cochrane database showed that metformin leads to normalization of serum aminotransferases in a significantly
greater proportion of patients compared with dietary
modification (odds ratio: 2.83; 95% CI: 1.27-6.31) and
improved steatosis by imaging (odds ratio: 5.25, 95% CI:
1.09-25.21).90 The total number of patients treated with
312
VUPPALANCHI AND CHALASANI
HEPATOLOGY, January 2009
Table 5. Randomized Controlled Trials of TZDs Consisting of at Least 50 Randomized Patients
Histological Improvement, Pre- and Post-
First Author
(Reference)
N
Study Design
Duration
102
Belfort
55
6 months
Ratziu103
63
Hypocaloric diet ⫹
Pioglitazone versus
Hypocaloric diet ⫹
placebo
*Patients with diabetes ⫹
patients without diabetes
Rosiglitazone versus placebo
* Patients with diabetes ⫹
patients without diabetes
Guruprasad104
74
Diet ⫹ exercise ⫹
Pioglitazone versus Diet
⫹ exercise ⫹
Pioglitazone
*Only patients without
diabetes
12 months
12 months
TZD
Versus
Placebo
Mean
Weight
Gain
No
Yes
No
No
No
No
No
No
No
No
Yes
Yes
Yes
Borderline
Yes
Yes
No
No
No
No
2.5 kg
TZD group had significant increase in
serum adiponectin levels, and this
inversely correlated with improved
hepatic steatosis
1.5 kg
Yes
No
Worse
No
N/A
No
No
Yes
No
N/A
- Primary end point was ⬎30%
reduction in hepatic steatosis and
predictors of response included
rosiglitazone treatment, lack of
diabetes at entry, and greater
steatosis at baseline
- No active lifestyle modification in
either groups
- Ranked assessment of
pretreatment and posttreatment
biopsies showed improved
steatosis, ballooning, and fibrosis
in the rosiglitazone group
- Relatively lower NAS at entry may
at least in part explain why no
change in NAS was seen in this
study
NAS score reported.
Placebo group had mean weight
loss of 3.5 kg but TZD group had
mean weight gain of 2.6 kg
Histological
Variable
TZD
Placebo
Steatosis
Inflammation
Ballooning
Fibrosis
NAS
Steatosis
Inflammation
Ballooning
Fibrosis
NAS
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
Steatosis
Inflammation
Ballooning
Fibrosis
NAS
Yes
Yes
Yes
Yes
N/A
metformin in controlled studies is admittedly small, and
its favorable effect on hepatic histology may not be robust,
but we favor its use in patients without diabetes with
NASH because of its safety profile. Because most patients
without diabetes with NASH have glucose intolerance, it
has the added benefit of lowering the risk of developing
frank diabetes.91 Because metformin has not been studied
to treat NASH in individuals with diabetes, its role in the
diabetic population is not known. An ongoing, multicenter study comparing metformin with vitamin E or
placebo in pediatric patients with NASH (TONIC;
NCT00063635) should provide more insight into metformin’s role in treating NASH.
Thiazolidinediones. Thiazolidinediones (TZDs) are
a novel class of oral antidiabetic medications that improve
insulin resistance by acting as selective peroxisome proliferator-activated receptor gamma agonists.92,93 Troglitazone, the first generation TZD, has been withdrawn from
the market because of its hepatotoxicity,94 whereas rosiglitazone and pioglitazone are the second-generation TZDs
that are currently available for clinical use.93,95 They redistribute fat from muscle and liver to adipose tissue and
thereby improving peripheral (skeletal muscle) and he-
2.6 kg
Comments
patic insulin sensitivity.93 In addition, they increase circulating levels of adiponectin, which is produced
exclusively by the adipose tissue and has insulin-sensitizing properties.96
There has been significant interest in evaluating
TZDs to treat NASH, and to our knowledge, eight
studies have been published either as full-length papers
or solely as an abstract.97-104 Troglitazone was tested in
one study,97 rosiglitazone in two,98,103 and pioglitazone
in five studies.99-102,104 Four were randomized controlled studies with 213 total enrolled patients with
histologically proven NASH.101-104 Selected characteristics and outcomes of three studies that randomized at
least 50 patients are shown in Table 5. In general,
TZDs improve hepatic histology in patients with
NASH, although their favorable effect on steatosis is
more striking than on other histological variables such
as inflammation, ballooning, or fibrosis. Their favorable effect on liver histology and liver biochemistries
disappears on their discontinuation, suggesting that
long-term treatment is needed to maintain their therapeutic benefits.105 This is potentially a significant issue; recent studies have questioned the long-term
HEPATOLOGY, Vol. 49, No. 1, 2009
VUPPALANCHI AND CHALASANI
Table 6. Various Agents in Evaluation to Treat NASH in
Humans (www. Clinicaltrials.gov)
Agent
Nature of the Study
Metformin versus vitamin E versus
placebo (TONIC)
Pioglitazone versus metformin versus
placebo (PIVENS)
Omega-3 fatty acids
Polyunsaturated fatty acids
Orlistat
Phase III, multicenter, RCT
Silophus
Silymarin
Rimonabant
Recombinant leptin
Pentoxifylline
Pentoxifylline vs. Pioglitazone
Exenatide
Rosi versus Rosi ⫹ metformin versus
rosi ⫹ losartan
SAMe
Iron depletion
CP 945598
TRO 19622*
ASP9831†
L-Alanine
313
Based on promising animal data107 and its ability to promote weight loss,108 we have initiated an open-label study
of exenatide in 2006, but its recruitment has been hampered because of its injectable route of administration and
potential gastrointestinal system side effects.
Phase III, multicenter, RCT
Phase II, pilot study
Phase II, pilot study
Phase III, multicenter
study
Phase II, pilot study
Phase II, multicenter RCT
Phase IIb, multicenter RCT
Phase II, pilot study
Phase II, pilot study
Phase II, pilot study
Phase II, pilot study
Phase III, single center
Phase II, pilot study
Phase II, pilot study
Phase IIb, multicenter RCT
Phase II, pilot study
Phase II, pilot study
Phase II, pilot study
*Cholesterol-like small molecule, a potent neuroprotective agent in vitro. May
have mitochondrial protective effects.
†Novel PDE4 inhibitor, which may improve hepatic inflammation and fibrosis.
safety of TZDs (especially rosiglitazone).106 Because
most of the participants in these studies did not have
diabetes, it is not clear whether TZDs are equally effective in patients with diabetes with NASH. In fact,
the presence of diabetes was a negative predictor of
response to rosiglitazone in one study.103 Furthermore,
Ratziu et al.103 recently raised the possibility that TZDs
alone without lifestyle modification may not be as effective.103 Overall, there are more questions than answers about
the role of TZDs in patients with NASH, and the ongoing
large U.S. multicenter study (PIVENS; NCT00063622)
may provide some additional insight.
Promising Agents
There is intense research into developing suitable treatment for NASH, and a list of compounds that are being
tested to treat NASH in humans is shown in Table 6. Oral
endocannabinoid receptor antagonists are of potential
benefit because of multiple potential favorable effects (on
body weight, fibrogenesis, and de novo lipogenesis), and
large multicenter studies are underway. Neuropsychiatric
side effects are of concern, but if proven effective, they
may have a role at least in a select group of patients without underlying neuropsychiatric co-morbidities. The
CB-1 receptor antagonist studies in humans have just
begun and their results will not be available for few years.
Cardiovascular Disease in NAFLD
The cardiovascular morbidity and mortality is perhaps
one of the most important aspects of NAFLD and NASH,
and our knowledge of their association is evolving rapidly.109-112 The patients with NAFLD have very high prevalence of cardiovascular risk factors and atherosclerosis
and high incidence of cardiovascular morbidity and mortality.43,113,114 Over the last decade, numerous studies
have demonstrated that patients with NAFLD are enriched with classic cardiovascular risk factors such as obesity, insulin resistance, type 2 diabetes, dyslipidemia, and
the metabolic syndrome.115-117 Cross-sectional studies
consisting of control groups have shown increased prevalence of endothelial dysfunction,118 elevated levels of oxidized low-density lipoprotein,119 and Framingham
coronary risk scores109,119 in NAFLD patients. Cross-sectional studies have also shown increased prevalence of
premature atheroma formation,120 carotid artery intima
media thickness (surrogate for atherosclerosis),121,122 vulnerable coronary plaques,123 increased mediastinal fat,
and abnormal left ventricular energy metabolism.124 Recently it has been suggested that NAFLD poses cardiovascular risk above and beyond that conferred by the
presence of the metabolic syndrome.43,113,114,125 In a
nested case-control, prospective study, Targher et al. have
shown that NAFLD in individuals with diabetes is associated with moderately increased risk of incident cardiovascular disease even after adjusting for classic risk factors,
glycemic control and the metabolic syndrome.125 Most
importantly, several longitudinal studies have shown that
cardiovascular disease is much more common than liver
disease as a cause of death in patients with
NAFLD.43,113,114 In a longitudinal study consisting of
420 Olmsted county residents with NAFLD, Adams et
al.113 have shown that ischemic heart disease accounts for
25% of deaths, compared with liver disease accounting
for 13% of deaths. By linking the Third National Health
and Nutrition Examination Survey to linked mortality
files, Ong et al.114 have shown that cardiovascular disease
is the most common cause of death, exceeding liver disease among 817 individuals with suspected NAFLD in
comparison with 10,468 persons without liver disease.
More recently, Rafiq et al.43 have reported extended follow-up of an expanded NAFLD cohort that has been
described previously. The mortality rate over an 11.1-year
median follow-up (longest follow-up, 28.5 years) was
314
VUPPALANCHI AND CHALASANI
45%, and the most common cause of death was coronary
artery disease. All these data provide unequivocal evidence
that coronary artery disease is a serious threat to patients
with NAFLD. Therefore, it has become our practice to
emphasize the significance of cardiovascular disease to patients with NAFLD and their primary care providers.
Statins remain a cornerstone for managing dyslipidemia
and coronary artery disease. Despite initial concerns, several
recent studies have shown that statins can be safely used in
patients with underlying liver disease.126-129 Studies have not
been conducted to specifically show that statins diminish
cardiovascular morbidity and mortality in patients with
NAFLD; however, there are no suspected reasons why they
would be any less effective. Minor fluctuations in aminotransferases on initiating statin therapy are not uncommon,
but serious hepatotoxicity is quite rare,126 and even when
happens, it is almost universally reversible on prompt recognition and withdrawal of the offending agent.127
In summary, when a patient with suspected NAFLD is
seen in the clinic, it is important to carefully evaluate for
competing causes and clinically important comorbidities.
Many advances have been made in terms of noninvasive
biomarkers for predicting advanced fibrosis, but insufficient
attention has been paid to predicting steatohepatitis. Sustained weight loss can be effective to treat NASH but it is
difficult to achieve. Foregut bariatric surgery can be quite
effective in improving hepatic histology in selected patients
without liver failure or significant portal hypertension.
TZDs have shown promise; however, recent studies raised
doubts about their long-term safety. Large multicenter studies of endocannabinoid receptor antagonists are underway,
but their results will not be available for several years. Several
recommendations made in this review are not entirely evidence-based and thus should be cautiously accepted while
we await more data and practice guidelines by the consensus
of the experts. There is an ongoing effort to develop a multisociety (American Association for the Study of Liver Diseases, American College of Gastroenterology, American
College of Physicians, and American Gastroenterological Association) consensus practice guideline for managing patients with NAFLD, and this would clearly identify the level
of evidence available for different recommendations.
Note Added in Proofs
In the fall 2008, Sanofi-Aventis has terminated its multinational clinical trials of rimonabant (CB1 receptor antagonist)
to treat NASH due to safety concerns. Similarly, Pfizer also
stopped its CB1 receptor antagonist development program.
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