Professional Documents
Culture Documents
NonalcoholicFattyLiverDisease2012 PDF
NonalcoholicFattyLiverDisease2012 PDF
NonalcoholicFattyLiverDisease2012 PDF
Preamble
These recommendations are based on the following: (1) a
formal review and analysis of the recently published
world literature on the topic [Medline search up to June
2011]; (2) the American College of Physicians Manual
for Assessing Health Practices and Designing Practice Guidelines;1 (3) guideline policies of the three societies approving this document; and (4) the experience of the authors
and independent reviewers with regards to NAFLD.
Intended for use by physicians and allied health professionals, these recommendations suggest preferred
approaches to the diagnostic, therapeutic and preventive
aspects of care. They are intended to be exible and adjustable for individual patients. Specic recommendations
are evidence-based wherever possible, and when such evidence is not available or inconsistent, recommendations
are made based on the consensus opinion of the authors.
To best characterize the evidence cited in support of the
recommendations, the AASLD Practice Guidelines Committee has adopted the classication used by the Grading
of Recommendation Assessment, Development, and
Evaluation (GRADE) workgroup with minor modications (Table 1).2 The strength of recommendations in the
GRADE system is classied as strong (1) or weak (2).
The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high
(A), moderate (B) or low-quality (C).2 This is a practice
Denitions
The denition of nonalcoholic fatty liver disease
(NAFLD) requires that (a) there is evidence of hepatic
steatosis, either by imaging or by histology and (b)
there are no causes for secondary hepatic fat accumulation such as signicant alcohol consumption, use of
steatogenic medication or hereditary disorders (Table 2).
In the majority of patients, NAFLD is associated with
metabolic risk factors such as obesity, diabetes mellitus,
and dyslipidemia. NAFLD is histologically further categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) (Table 3). NAFL is
dened as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning
of the hepatocytes. NASH is dened as the presence of
hepatic steatosis and inammation with hepatocyte
injury (ballooning) with or without brosis.
Incidence and Prevalence in the General
Population
The incidence of NAFLD has been investigated in a
limited number of studies. Two Japanese studies9,10
Submitted for Governing Board approval by AASLD, ACG, and AGA on February 22, 2012
Abbreviations: NAFLD, Nonalcoholic Fatty Liver Disease; NAFL,Nonalcoholic Fatty Liver; NASH, Nonalcoholic Steatohepatitis; T2DM, Type 2 Diabetes
Mellitus; AST, Aspartate Aminotransferase; ALT, Alanine Aminotransferase; HOMA,Homeostatic Model Assessment; RCT; Randomized Controlled Trial; PIVENS:
Pioglitazone versus Vitamin E versus Placebo for the Treatment of Non-diabetic patients with Nonalcoholic steatohepatitis; TONIC; Treatment of Nonalcoholic
Fatty Liver Disease in Children; NAS, NAFLD Activity Score; CK18; Cytokeratin 18 Fragments; ELF, Enhanced Liver Fibrosis Panel; TZD; Thiazolidinediones;
UDCA: Ursodeoxycholic Acid; ANA; Anti Nuclear Antibody; ASMA: Anti Smooth Muscle Antibody; US; Ultrasound; CT: Computerized Tomography; MR;
Magnetic Resonance.
From the 1Indiana University School of Medicine, Indianapolis, IN; 2Center for Liver Disease and Department of Medicine, Inova Fairfax Hospital, Falls Church;
3
Columbia University, New York, NY; 4Duke University, Durham, NC; 5Washington University, St. Louis, MO; 6University of Florida, Gainesville, FL; 7Mayo Clinic,
Rochester, MN; 8Virginia Commonwealth University, Richmond, VA
Received April 3, 2012; accepted April 3, 2012.
2005
2006
CHALASANI ET AL.
Strength of Recommendation
Strong [1]
Weak [2]
Quality of Evidence
High [A]
Moderate [B]
Low [C]
Factors inuencing the strength of the recommendation included the quality of the evidence,
presumed patient-important outcomes, and cost
Variability in preferences and values, or more uncertainty. Recommendation is made with less certainty,
higher cost or resource consumption
Further research is unlikely to change condence in the estimate of the clinical effect
Further research may change condence in the estimate of the clinical effect
Further research is very likely to impact condence on the estimate of clinical effect
reported an incidence rate of 31 and 86 cases of suspected NAFLD per 1,000 person-years respectively,
whereas another study from England showed a much
lower incidence rate of 29 cases per 100,000 personyears.11 More studies are needed to better understand
the incidence of NAFLD across different age, ethnic,
and geographic groups.
The reported prevalence of NAFLD varies widely
depending on the population studied and the denition used. The prevalence of histologically-dened
NAFLD was 20% and 51% in two different studies
comprised of potential living liver donors.12,13 The
reported prevalence of NAFLD when dened by liver
ultrasound ranged between 17% and 46% depending
on the population studied.4 In a study consisting of
nearly 400 middle aged individuals, the prevalence of
NAFLD dened by ultrasonography was 46% and the
prevalence of histologically conrmed NASH was
12.2%.14 In the Dallas Heart Study, when assessed by
MR spectroscopy the prevalence of NAFLD in the
general population was 31%.15 The prevalence of suspected NAFLD when estimated using aminotransferases alone without imaging or histology ranged
between 7% and 11%, but aminotransferases can be
normal in individuals with NAFLD.4 In summary,
estimates of the worldwide prevalence of NAFLD
ranges from 6.3% to 33% with a median of 20% in
the general population, based on a variety of assessment methods.4 On the other hand, the estimated
prevalence of NASH is lower, ranging from 3 to 5%.4
The prevalence of NASH cirrhosis in the general population is not known.
Prevalence of NAFLD in High Risk Groups
(Table 4)
Obesity is a common and well documented risk factor
for NAFLD. Both excessive BMI and visceral obesity are
recognized risk factors for NAFLD. In patients with
severe obesity undergoing bariatric surgery, the prevalence of NAFLD can exceed 90% and up to 5% of
patients may have unsuspected cirrhosis.4,16-20 There is
a very high prevalence of NAFLD in individuals with
type 2 diabetes mellitus (T2DM).4 An ultrasonographic
study of patients with T2DM showed a 69% prevalence
of NAFLD.21 In another study, 127 of 204 diabetic
patients displayed fatty inltration on ultrasound, and
87% of the patients with fatty inltration who consented to biopsy had histologic conrmation of
NAFLD.22 High serum triglyceride levels and low serum
HDL levels are very common in patients with NAFLD.
The prevalence of NAFLD in individuals with dyslipidemia attending lipid clinics was estimated to be 50%.23
Age, gender and ethnicity are also associated with a
differential prevalence for NAFLD.4 A number of
Address reprint requests to: Naga Chalasani, MD, FACG, Professor of Medicine and Cellular & Integrative Physiology, Director, Division of Gastroenterology
and Hepatology, Indiana University School of Medicine, RG 4100, 1050 Wishard Boulevard, Indianapolis, IN 46202. E-mail: nchalasa@iupui.edu; fax:
317-278-1949.
C 2012 by the American Association for the Study of Liver Diseases.
Copyright V
Published online in Wiley Online Library (wileyonlinelibrary.com).
DOI 10.1002/hep.25762
Potential conict of interest: Naga Chalasani, MD, FACG has received compensation for providing consulting related to NAFLD and NASH from Amylin,
Gilead, Genentech, and Mochida and he has received research support from Amylin, Eli Lilly, Intercept, and Cumberland Pharmaceuticals in the last 3 years.
Over the last 3 years, he has received compensation for providing consultation related to drug hepatotoxicity from J & J, Merck, GlaxoSmithKline, Karo Bio, Salix,
Advanced Life Sciences, BMS, Teva Pharmaceuticals, Abbott, Biolex, Sano-Aventis, and Vertex. Zobair Younossi, MD has received consulting fees from Salix,
Tibotec, and Vertex. Anna Mae Diehl, MD has received compensation for providing consulting related to NAFLD from Vertex, Norgine, and Celgene. Elizabeth
Brunt, MD has received compensation from Amylin, Pzer, and Geneva Foundation for NASH consulting. Kenneth Cusi, MD has received compensation from
Merck, Daichi-Sankyo, and Roche for providing consulting. Michael Charlton, MD has received compensation from Gilead and Genentech for providing consulting
related to NAFLD and NASH. Joel Lavine, MD, PhD has received compensation for providing consultations related to NAFLD from Quark Pharmaceuticals and
Synageva BioPharma, and received research support from Raptor Pharmaceuticals, all in the last 3 years. Arun Sanyal, MD has served as an ad hoc advisor to
Roche, Takeda, Merck, Astella, Sano, Exhalenz, and Immuron. He serves as the global PI for trials for Exhalenz and Immuron.
CHALASANI ET AL.
Macrovesicular steatosis
Excessive alcohol consumption
Hepatitis C (genotype 3)
Wilsons disease
Lipodystrophy
Starvation
Parenteral nutrition
Abetalipoproteinemia
Medications (e.g., amiodarone, methotrexate, tamoxifen, corticosteroids)
Microvesicular steatosis
Reyes syndrome
Medications (valproate, anti-retroviral medicines)
Acute fatty liver of pregnancy
HELLP syndrome
Inborn errors of metabolism (e.g., LCAT deciency, cholesterol ester storage
disease, Wolman disease)
2007
Encompasses the entire spectrum of fatty liver disease in individuals without signicant alcohol consumption,
ranging from fatty liver to steatohepatitis and cirrhosis.
Presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the
hepatocytes or no evidence of brosis. The risk of progression to cirrhosis and liver failure is minimal.
Presence of hepatic steatosis and inammation with hepatocyte injury (ballooning) with or without brosis.
This can progress to cirrhosis, liver failure and rarely liver cancer.
Presence of cirrhosis with current or previous histological evidence of steatosis or steatohepatitis
Presence of cirrhosis with no obvious etiology. Patients with cryptogenic cirrhosis are heavily enriched with
metabolic risk factors such as obesity and metabolic syndrome.
An unweighted composite of steatosis, inammation, and ballooning scores. It is a useful tool to measure
changes in liver histology in patients with NAFLD in clinical trials.
2008
CHALASANI ET AL.
Obesity
Type 2 diabetes mellitus
Dyslipidemia
Metabolic syndrome**
*Few studies suggested that individuals with type1 diabetes have increased
prevalence of hepatic steatosis based on liver imaging, but there is limited histological evidence.
**The Adult Treatment Panel III clinical denition of the metabolic syndrome
requires the presence of three or more of the following features: (1) waist circumference greater than 102 cm in men or greater than 88 cm in women; (2)
triglyceride level 150 mg/dL or greater; (3) high-density lipoprotein (HDL) cholesterol level less than 40 mg/dL in men and less than 50 mg/dL in women;
(4) systolic blood pressure 130 mm Hg or greater or diastolic pressure 85 mm
Hg or greater; and (5) fasting plasma glucose level 110 mg/dL or greater.199
CHALASANI ET AL.
2009
2010
CHALASANI ET AL.
Recommendations
10. As the metabolic syndrome predicts the presence of steatohepatitis in patients with NAFLD, its
presence can be used to target patients for a liver biopsy. (Strength 1, Evidence - B)
11. NAFLD Fibrosis Score is a clinically useful
tool for identifying NAFLD patients with higher
likelihood of having bridging brosis and/or cirrhosis. (Strength 1, Evidence - B)
12. Although serum/plasma CK18 is a promising
biomarker for identifying steatohepatitis, it is premature to recommend in routine clinical practice.
(Strength 1, Evidence - B)
When to obtain a liver biopsy in patients with
NAFLD?
Liver biopsy remains the gold standard for characterizing liver histology in patients with NAFLD. However, it is expensive and carries some morbidity and
very rare mortality risk. Thus, it should be performed
in those who would benet the most from diagnostic,
therapeutic guidance, and prognostic perspectives.
Recommendations
13. Liver biopsy should be considered in patients
with NAFLD who are at increased risk to have steatohepatitis and advanced brosis. (Strength 1, Evidence - B)
14. The presence of metabolic syndrome and the
NAFLD Fibrosis Score may be used for identifying
patients who are at risk for steatohepatitis and
advanced brosis. (Strength 1, Evidence - B)
15. Liver biopsy should be considered in patients
with suspected NAFLD in whom competing etiologies
for hepatic steatosis and co-existing chronic liver diseases cannot be excluded without a liver biopsy.
(Strength 1, Evidence - B)
CHALASANI ET AL.
2011
2012
CHALASANI ET AL.
compared with lifestyle intervention alone, independently of metformin dose or the presence of diabetes.
Recommendation
19. Metformin has no signicant effect on liver
histology and is not recommended as a specic treatment for liver disease in adults with NASH.
(Strength 1, Evidence - A)
Thiazolidinediones
Several studies investigated the effect of pioglitazone
and rosiglitazone on aminotransferases and liver histology in adults with NASH. In an early uncontrolled
open-label study117 in 22 subjects with biopsy-proven
NASH, rosiglitazone improved aminotransferases and
hepatic steatosis, ballooning and inammation scores,
but not brosis. But in a subsequent RCT, Ratziu et
al.118 observed that rosiglitazone improved aminotransferases and hepatic steatosis, but not necroinammation or brosis and its two-year open-label extension
phase also showed similar results.119 Belfort et al.120
conducted a RCT of pioglitazone (45 mg/day) in
patients with NASH who had impaired glucose tolerance or T2DM. Although there was a signicant
weight gain (2.5 6 0.5 kg) with pioglitazone, it significantly improved aminotransferases, steatosis, ballooning, and inammation. The NAS improved with pioglitazone in 73% compared to 24% of placebo-treated
patients (P<0.001) and there was a trend towards
improvement in brosis among patients randomized to
pioglitazone (P0.08). Aithal et al.121 performed a
RCT of lifestyle intervention with either pioglitazone
30 mg/day or placebo for 12 months in a total of 74
patients with NASH. While steatosis did not improve
signicantly compared to placebo, hepatocellular injury
and brosis improved signicantly.1210 The PIVENS122 study is a large multicenter RCT that randomized 247 non-diabetic patients with NASH to pioglitazone (30 mg/day), vitamin E (800 IU/day), or placebo
for 24 months. The primary endpoint was an
improvement in NAS 2 points with at least 1 point
improvement in hepatocellular ballooning and 1-point
improvement in either the lobular inammation or steatosis score, and no increase in the brosis score.122 It
was achieved in 19% in the placebo group compared
to 34% in the pioglitazone group (P0.04 vs. placebo)
and 43% in the vitamin E group (P0.001 vs. placebo).122 Because this study consisted of two primary
comparisons (pioglitazone vs. placebo and vitamin E
vs. placebo), a P-value of 0.025 was considered to be
signicant a priori. Therefore, although there were histological benets associated with pioglitazone, this
study concluded that pioglitazone did not meet the
vitamin E is associated with a decrease in aminotransferases in subjects with NASH, (2) studies where histologic endpoints were evaluated indicate that vitamin E
causes improvement in steatosis, inammation, and
ballooning and resolution of steatohepatitis in adults
with NASH, and (3) vitamin E has no effect on hepatic brosis. Although two meta-analyses8,129 failed
to observe signicant histological benets with vitamin
E in patients with NASH, these analyses were conducted before PIVENS122 and TONIC130 trials were
published. In the largest clinical trial (PIVENS)122
reported to date, the pure form of rrr a-tocopherol
was orally administered at a dose of 800 IU/day for
96 weeks. The primary endpoint as stated previously
was achieved in a signicantly greater number of participants receiving vitamin E compared to placebo
(42% vs. 19%, P< 0.001, number needed to treat
4.4).
One concern with vitamin E is the controversial
issue of whether it increases all-cause mortality. Some
meta-analyses have reported an increase in all-cause
mortality with high dose vitamin E,131,132 but others
failed to conrm such an association.133-135 A recently
published RCT showed that vitamin E administered at
a dose of 400 IU/day increased the risk of prostate
cancer in relatively healthy men (absolute increase of
1.6 per 1000 person years of vitamin E use).136
Recommendation
21. Vitamin E (a-tocopherol) administered at
daily dose of 800 IU/day improves liver histology in
non-diabetic adults with biopsy-proven NASH and
therefore it should be considered as a rst-line pharmacotherapy for this patient population. (Strength 1, Quality - B)
22. Until further data supporting its effectiveness
become available, vitamin E is not recommended to
treat NASH in diabetic patients, NAFLD without
liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis
(Strength - 1, Quality - C)
Ursodeoxycholic acid (UDCA), Omega-3 fatty
acids, and Miscellaneous Agents
Several studies126,137-140 investigated UDCA (conventional and high doses) to improve aminotransferases and steatosis in patients with NAFLD and liver
histology in patients with NASH. All but one study139
have been proof-of-concept studies with small numbers
of participants and/or surrogate endpoints. Notably, a
single large multicenter RCT convincingly showed that
UDCA offers no histological benet over placebo in
patients with NASH.139 Omega-3 fatty acids, currently
approved in the United States to treat hypertriglyceri-
CHALASANI ET AL.
2013
2014
CHALASANI ET AL.
CHALASANI ET AL.
2015
35. Patients with NASH cirrhosis should be considered for HCC screening according to the AASLD/ACG
practice guidelines.182(Strength 1, Quality B)
36. Current evidence does not support routinely
repeating a liver biopsy in patients with NAFL or
NASH. (Strength 2, Quality C)
Aspects of NAFLD Specic to Children and
Adolescents
Recognition of NAFLD in children is essential to
understanding the origin of disease in those likely to be
most genetically or environmentally susceptible. Adults
with onset of NAFLD in childhood may be most at risk
for early or severe complications. Denition of NAFLD
in childhood is the same as in adults. Children are
reported with NAFLD as early as 2 years and with
NASH-related cirrhosis as early as age 8.183,184
Prevalence and Risk Factors
Estimation of population prevalence in children
presents difculties for the same reasons detailed above
in adults. Estimates vary based upon the type of test
or imaging, the cut-points for detection, and the age,
sex, race and ethnicity of the geographic region
sampled. A school-based study of obese children in
Minnesota, California, Texas and Louisiana, using
abnormal serum ALT as a surrogate marker (>40U/L),
found that 23% of 17-18 year olds had elevated unexplained ALT.183 An autopsy study using the gold
standard of liver histology examined 742 children
between the ages of 2-19 y who died from unnatural
causes. The estimated NAFLD prevalence was 9.6%
when adjusted for age, gender, race and ethnicity.184
Multivariate analyses showed that obesity, older age (in
adolescence), male gender, and Hispanic ethnicity are
independent predictors of fatty liver prevalence.
2016
CHALASANI ET AL.
dation defects, lysosomal storage diseases and peroxisomal disorders, in addition to those causes considered for adults. (Strength 2, Quality C)
38. Low serum titers of autoantibodies are often
present in children with NAFLD, but higher titers,
particularly in association with higher serum aminotransferases and high globulin should prompt a liver
biopsy to evaluate for possible autoimmune hepatitis. (Strength 2, Quality B)
39. Due to a paucity of evidence, a formal recommendation cannot be made with regards to screening
for NAFLD in overweight and obese children despite
a recent expert committee recommendation for biannual screening for liver disease with liver enzyme
measurements in this population. (Strength 1,
Quality B).
When to obtain a liver biopsy for suspected
pediatric NAFLD?
The decision to perform a liver biopsy in a child to
conrm the diagnosis of NAFLD must be weighed
against the risks associated with biopsy and the likelihood that the result will impact management. In children with an uncertain diagnosis, biopsy may rule out
potential drug hepatotoxicity or lack of clarity due to
presence of serum autoantibodies. When there is an
interest in grading or staging NAFLD, instead of submitting all children with NAFLD to a liver biopsy it
would be optimal to identify those children who are
more likely to have NASH. The paucity of natural history data confounds the decision to biopsy since alteration of long-term outcomes with treatment based on
severity of histology at baseline is unknown.
As in adults, development of noninvasive biomarkers or imaging to identify those at risk for more
rapid progression or severe disease onset is desirable.
Particularly, accurate markers of cellular injury and brosis are needed. Two studies suggested that ELF
score can be used to accurately predict brosis in children with NAFLD, but both studies consisted of relatively small numbers of children and fewer with
advanced brosis.190,191 There is reported benet in
predicting brosis stage in pediatric patients, with a
AUROC of 0.92, although only 9 of the 76 subjects
studied had brosis stage 3 or more.190 Validation of
the serum CK18 levels to evaluate NASH needs to be
undertaken in children with NAFLD.
Recommendations
40. Liver biopsy in children with suspected
NAFLD should be performed in those where the diagnosis is unclear, where there is possibility of multiple diagnoses, or before starting therapy with
CHALASANI ET AL.
2017
2018
CHALASANI ET AL.
recommended in
1,Quality B)
clinical
practice
(Strength
Acknowledgment: This practice guideline was developed in collaboration with the AASLD Practice Guidelines Committee, and was approved by the ACG
Practice Parameters Committee, and the AGA Institute
Clinical Practice and Quality Management Committee. Raphael B. Merriman, MD, MRCPI and Benjamin L. Shneider, MD served as primary reviewers for
the AASLD Practice Guidelines Committee. Dr. Merriman declared no relevant conicts of interest. Dr.
Shneider serves as a scientic consultant with BristolMyers Squibb and the advisory board for Ikaria. External review was provided by Jean P. Molleston, MD
and Stephen A. Harrison, MD. Dr. Molleston received
research support from Schering-Plough and Roche.
Dr. Harrison serves as a consultant to Amylin Pharmaceuticals and has received research support from Rottapharm and Mochida.
References
1. Eddy DM. A manual for assessing health practices and designing practice
guidelines. Philadelphia. American College of Physicians. 1996;1-126.
2. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, AlonsoCoello P, Schunemann HJ. GRADE: an emerging consensus on rating
quality of evidence and strength of recommendations. BMJ 2008;336:
924-926.
3. Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and
non-alcoholic steatohepatitis: selected practical issues in their management. Hepatology 2009;49:306-317.
4. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and nonalcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34:
274-285.
5. Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of
nonalcoholic steatohepatitis: the central role of nontriglyceride fatty
acid metabolites. HEPATOLOGY 2010;52:774-788.
6. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in
patients with nonalcoholic fatty liver disease. N Engl J Med 2010;
363:1341-1350.
7. G, Gambino R, Cassader M, Pagano G. Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Annals of Medicine
2011;43(8):617-49.
8. Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of
randomized trials for the treatment of nonalcoholic fatty liver disease.
HEPATOLOGY 2010;52:79-104.
9. Suzuki A, Angulo P, Lymp J, St Sauver J, Muto A, Okada T, Lindor
K.. Chronological development of elevated aminotransferases in a
nonalcoholic population. HEPATOLOGY. 2005;41(1):64-71.
10. Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome
as a predictor of non-alcoholic fatty liver disease. Ann Intern Med
2005;143(10):722-8.
11. Whalley S, Puvanachandra P, Desai A, Kennedy H. HEPATOLOGY outpatient service provision in secondary care: a study of liver disease
incidence and resource costs. Clin Med. 2007;7(2):119-24.
12. Lee JY, Kim KM, Lee SG, Yu E, Lim YS, Lee HC, Chung YH, Lee
YS, Suh DJ. Prevalence and risk factors of non-alcoholic fatty liver
disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center. J Hepatol. 2007;47(2):
239-44.
13. Marcos A, Fischer RA, Ham JM, Olzinski AT, Shiffman ML, Sanyal
AJ, Luketic VA, Sterling RK, Olbrisch ME, Posner MP. Transplantation 2000;69:2410-2415.
14. Williams CD, Stenger J, Asike MI, Torres DM, Shaw J, Contreras M,
Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease
and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011;140:124-131.
15. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD,
Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in
an urban population in the United States: impact of ethnicity. HEPATOLOGY. 2004;40:1387-95.
16. Boza C, Riquelme A, Iba~
nez L, Duarte I, Norero E, Viviani P, Soza
A,Fernandez JI, Raddatz A, Guzman S, Arrese M. Predictors of nonalcoholic steatohepatitis (NASH) in obese patients undergoing gastric
bypass. Obes Surg. 2005;15:1148-53.
17. Haentjens P, Massaad D, Reynaert H, Peeters E, Van Meerhaeghe A,
Vinken S, Poppe K, Velkeniers B. Identifying non-alcoholic fatty liver
disease among asymptomatic overweight and obese individuals by clinical and biochemical characteristics. Acta Clin Belg. 2009;64:483-93.
18. Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in
obese patients undergoing bariatric surgery. J Hepatol. 2006;45:600-6.
19. Colicchio P, Tarantino G, del Genio F, Sorrentino P, Saldalamacchia
G,Finelli C, Conca P, Contaldo F, Pasanisi F. Non-alcoholic fatty liver
disease in young adult severely obese non-diabetic patients in South
Italy. Ann Nutr Metab. 2005;49:289-95.
20. Beymer C, Kowdley KV, Larson A, Edmonson P, Dellinger EP, Flum
DR. Prevalence and predictors of asymptomatic liver disease in
patients undergoing gastric bypass surgery. Arch Surg. 2003;138:
1240-4.
21. Leite NC, Salles GF, Araujo AL, Villela-Nogueira CA, Cardoso CR.
Prevalence and associated factors of non-alcoholic fatty liver disease in
patients with type-2 diabetes mellitus. Liver Int. 2009;29:113-9.
22. Prashanth M, Ganesh HK, Vima MV, John M, Bandgar T, Joshi SR,
Shah SR, Rathi PM, Joshi AS, Thakkar H, Menon PS, Shah NS.
Prevalence of nonalcoholic fatty liver disease in patients with type 2
diabetes mellitus. J Assoc Physicians India. 2009;57:205-10.
23. Assy N, Kaita K, Mymin D, Levy C, Rosser B, Minuk G. Fatty inltration of liver in hyperlipidemic patients. Dig Dis Sci 2000;45:
1929-1934.
24. Li H, Wang YJ, Tan K, Zeng L, Liu L, Liu FJ, Zhou TY, Chen EQ,
Tang H. Prevalence and risk factors of fatty liver disease in Chengdu,
Southwest China. Hepatobiliary Pancreat Dis Int. 2009;8(4):377-82.
25. Amarapurkar D, Kamani P, Patel N, Gupte P, Kumar P, Agal S, Baijal
R, Lala S, Chaudhary D, Deshpande A. Prevalence of non-alcoholic
fatty liver disease: population based study. Ann Hepatol. 2007;6(3):16126. Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, Sung IK,
Sohn CI, Keum DK, Kim BI. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol.
2006;21(1 Pt 1):138-43.
27. Frith J, Day CP, Henderson E, Burt AD, Newton JL. Non-alcoholic
fatty liver disease in older people. Gerontology. 2009;55(6):607-13.
28. Chen CH, Huang MH, Yang JC, Nien CK, Yang CC, Yeh YH, Yueh
SK. Prevalence and etiology of elevated serum alanine aminotransferase level in an adult population in Taiwan. J Gastroenterol Hepatol.
2007;22:1482-9.
29. Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liverrelated mortality in non-alcoholic fatty liver disease. J Hepatol. 2008;
49:608-12.
30. Hashimoto E, Yatsuji S, Kaneda H, Yoshioka Y, Taniai M, Tokushige
K, Shiratori K. The characteristics and natural history of Japanese
patients with nonalcoholic fatty liver disease. Hepatol Res. 2005;
33(2):72-6.
31. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005 l;129:
113-21.
32. Chen ZW, Chen LY, Dai HL, Chen JH, Fang LZ. Relationship
between alanine aminotransferase levels and metabolic syndrome in
nonalcoholic fatty liver disease. J Zhejiang Univ Sci B. 2008 Aug;
9(8):616-22.
33. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of
elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003;98:960-7.
34. Kallwitz ER, Kumar M, Aggarwal R, Berger R, Layden-Almer J,
Gupta N, Cotler SJ. Ethnicity and nonalcoholic fatty liver disease in
an obesity clinic: the impact of triglycerides. Dig Dis Sci. 2008;53:
1358-63.
35. Wagenknecht LE, Scherzinger AL, Stamm ER, Hanley AJ, Norris JM,
Chen YD,Bryer-Ash M, Haffner SM, Rotter JI. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity
2009;17:1240-6.
36. Fischer GE, Bialek SP, Homan CE, Livingston SE, McMahon BJ.
Chronic liver disease among Alaska-Native people, 20032004. Am J
Gastroenterol. 2009;104:363-70.
37. Bialek SR, Redd JT, Lynch A, Vogt T, Lewis S, Wilson C, Bell BP.
Chronic liver disease among two American Indian patient populations
in the southwestern United States, 2000-2003. J Clin Gastroenterol.
2008;42:949-54.
38. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC,
McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999 Jun;116(6):
1413-9.
39. Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB,
Srensen TI, Becker U, Bendtsen F. Long term prognosis of fatty liver:
risk of chronic liver disease and death. Gut. 2004 May;53(5):750-5.
40. Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M,
Bodemar G, Kechagias S. Long-term follow-up of patients with
NAFLD and elevated liver enzymes. HEPATOLOGY. 2006;44:865-73.
41. W Dunn, R Xu, D Wingard, C Rogers, P Angulo, ZM Younossi, JB
Schwimmer. Suspected Nonalcoholic Fatty Liver Disease and Mortality Risk in a Population-based Cohort Study. Am J of Gastroenterology 2008;103:2263-71.
42. N Raq, CH Bai, Y Fang, M Srishord, A McCullough, T Gramlich,
ZM Younossi. Long-Term Follow-Up of Patients with Non-Alcoholic
Fatty Liver. Clinical Gastro and HEPATOLOGY 2009;7:234-8.
43. Dam-Larsen S, Becker U, Franzmann MB, Larsen K, Christoffersen P,
Bendtsen F. Final results of a long-term, clinical follow-up in fatty
liver patients. Scand J Gastroenterol. 2009;44(10):1236-43.
44. M Stepanova, N Raq, ZM. Younossi. Components of metabolic syndrome as independent predictors of mortality in chronic liver disease:
A population-based study. Gut. 2010;59 (10):1410-5.
45. Soderberg C, Stal P, Askling J, Glaumann H, Lindberg G, Marmur J,
Hultcrantz R.Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. HEPATOLOGY. 2010;51:595-602.
46. Caldwell SH, Crespo DM. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease.
J Hepatol. 2004;40:578-84.
47. Browning JD, Kumar KS, Saboorian MH, Thiele DL. Ethnic differences in the prevalence of cryptogenic cirrhosis. Am J Gastroenterol.
2004;99:292-8.
48. Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P,
Musso A, De Paolis P, Capussotti L, Salizzoni M, Rizzetto M.
Expanding the natural history of nonalcoholic steatohepatitis: from
cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology.
2002;123:134-40.
49. Hashimoto E, Yatsuji S, Tobari M, Taniai M, Torii N, Tokushige K,
Shiratori K. hepatocellular carcinoma in patients with nonalcoholic
steatohepatitis. J Gastroenterol. 2009;44 Suppl 19:89-95.
50. Smedile A, Bugianesi E. Steatosis and hepatocellular carcinoma risk.
Eur Rev Med Pharmacol Sci. 2005;9:291-3.
51. Takuma Y, Nouso K. Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review. World J Gastroenterol. 2010;16:1436-41.
CHALASANI ET AL.
2019
52. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein
NN. The incidence and risk factor of hepatocellular carcinoma in
patients with nonalcoholic steatohepatitis. HEPATOLOGY 2010;51:
1972-1978.
53. Yasui K, Hashimoto E, Komorizono Y, Koike S, Arli S, Imai Y, et al.
Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011;9:
428-433.
54. Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, et al.
Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. HEPATOLOGY 2003;38:420-427.
55. Sanyal AJ, Banas C, Sargeant C, Luketic VA, Sterling RK, Stravitz RT,
et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. HEPATOLOGY 2006;42:132-138.
56. Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori
K. Clinical features and outcomes of cirrhosis due to non-alcoholic
steatohepatitis compared with cirrhosis caused by chronic hepatitis C.
J Gastroenterol Hepatol 2009;24:248-254.
57. Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G,
Adams LA, et al. The natural history of nonalcoholic fatty liver disease with advanced brosis or cirrhosis. An international collaborative
study. HEPATOLOGY 2011;54(4):1208-16.
58. Sanyal AJ, Brunt EM, Kleiner DE, Kowdley DE, Chalasani N, Lavine
JE, Ratziu V, McCullough A. End points and clinical trial design for
nonalcoholic steatohepatitis. HEPATOLOGY 2011;54:344-353.
59. Liagnpunsakul S, Chalasani N. What do we recommend our patients
with NAFLD about alcohol consumption? Am J Gastroenterol 2012
(In press)
60. Struben VM, Hespenheide EE, Caldwell SH. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med 2000;
108:9-13.
61. Willner IR, Walters B, Patil SR, Reuben A, Morelli J, Riely CA.
Ninety patients with nonalcoholic steatohepatitis: insulin resistance,
familial tendency, and severity of disease. Am J Gastroenterol 2001;
96:2957-2961.
62. Abdelmalek MF, Liu C, Shuster J, Nelson DR, Asal NR. Familial
aggregation of insulin resistance in rst-degree delatives of patients
with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol
2006;4:1162-1169.
63. Schwimmer JB, Celedon MA, Lavine JE, Salem R, Campbell N,
Schork NJ, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 2009;136:1585-1592.
64. Kowdley KV. The role of iron in nonalcoholic fatty liver disease: the
story continues. Gastroenterology 2010;138:817-819.
65. Bacon BR, Adams PC, Kowdley KV, Powell PW, Tavill AS. Diagnosis
and management of hemochromatosis: 2011 Practice Guideline by the
American Association for the Study of Liver Diseases. HEPATOLOGY
2011;54:328 - 343.
66. Vuppalanchi R, Gould RJ, Wilson LA, Unalp-Arida A, Cummings
OW, Chalasani N, Kowdley KV. Clinical signicance of serum autoantibodies in patients with NAFLD: results from the nonalcoholic
steatohepatitis clinical research network. Hepatol Int 2011; ePub
ahead of print.
67. Marchesini G, Bugianesi E, Forlani G et al. Nonalcoholic fatty liver,
steatohepatitis, and the metabolic syndrome. HEPATOLOGY 2003;37:
917-923.
68. Kang H, Greenson JK, Omo JT et al. Metabolic syndrome is associated with greater histologic severity, higher carbohydrate, and lower
fat diet in patients with NAFLD. Am J Gastroenterol 2006;101:
2247-2253.
69. Ryan MC, Wilson AM, Slavin J et al. Associations between liver histology and severity of the metabolic syndrome in subjects with nonalcoholic fatty liver disease. Diabetes Care 2005;28:1222-1224.
70. Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ,
Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. HEPATOLOGY 2006;44:27-33.
2020
CHALASANI ET AL.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108. Nair S, Diehl AM, Wiseman M, Farr GH, Jr., Perrillo RP. Metformin
in the treatment of non-alcoholic steatohepatitis: a pilot open label
trial. Aliment Pharmacol Ther. 2004;20:23-8.
109. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova
N, et al. A randomized controlled trial of metformin versus vitamin E
or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:1082-90.
110. Loomba, R., Lutchman, G., Kleiner, D.E., Ricks, M., Feld, J.J. et al.
Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2009;29:172-182.
111. Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. The
effect of metformin and standard therapy versus standard therapy
alone in nondiabetic patients with insulin resistance and nonalcoholic
steatohepatitis (NASH): a pilot study. Therap Adv Gastroenterol
2009;2:157-63.
112. Haukeland JW, Konopski Z, Eggesb HB, et al. Metformin in
patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009;44:853-60.
113. Idilman R, Mizrak D, Corapcioglu D, Bektas M, Doganay B, Sayki
M, et al. Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2008;28:200-208.
114. Duseja A, Das A, Dhiman RK, Chawla YK, Thumburu KT, Bhadada
S, et al. Metformin is effective in achieving biochemical response in
patients with nonalcoholic fatty liver disease (NAFLD) not responding
to lifestyle interventions. Ann Hepatol 2007;6:222-226.
115. Nar A, Gedik O. The effect of metformin on leptin in obese patients
with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta
Diabetol. 2009;46:113-8.
116. Omer Z, Cetinkalp S, Akyildiz M, Yilmaz F, Batur Y, Yimaz C,
Akarca U. Efcacy of insulin-sensitizing agents in nonalcoholic fatty
liver disease. European J Gastroenterol HEPATOLOGY. 2010;22:18-23.
117. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon
BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment
with the PPAR-gamma ligand rosiglitazone. HEPATOLOGY. 2003;38:
1008-17.
118. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A,
Serfaty L, et al. Rosiglitazone for nonalcoholic steatohepatitis: oneyear results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology
2008;135:100-110.
119. Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, LeNaour G,
Hartemann-Heurtier A, Bruckert E and Poynard T for the LIDO
Study Group. Long-term efcacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. HEPATOLOGY 2010;51:445-453.
120. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J,
et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297-307.
121. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I
et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology
2008;135:1176-1184.
122. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM,
Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic
steatohepatitis. N Engl J Med 2010;362:1675-1685.
123. Lincoff A, Wolski K, Nicholls S, Nissen S: Pioglitazone and risk of
cardiovascular events in patients with type 2 diabetes mellitus.
A meta-analysis of randomized trials. JAMA 2007;298:1180-1188.
124. Hasegawa T, et al. Plasma transforming growth factor-beta1 level and
efcacy of alpha-tocopherol in patients with nonalcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001;15:1667-1672.
125. Harrison SA, et al. Vitamin E and vitamin C treatment improves brosis is patients with nonalcoholic steatohepatitis. Am J Gastroenterol
2003;98:2485-2490.
126. Dufour JF, et al. Swiss Association for the Study of the Liver.
Randomized placebo-controlled trial of ursodeoxycholic acid with
CHALASANI ET AL.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
2021
2022
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
CHALASANI ET AL.
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
CHALASANI ET AL.
192.
193.
194.
195.
196.
197.
198.
2023