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GASTROENTEROLOGY 2008;134:16821698ss index and improving insulin resistance viaarmacologic, surgical, dietary, or exercise regi-ns. Other potential therapeutic agents directed atoprotection or reduction of fibrosis are under in-stigation. This article focuses on diagnosis anderapy available and under development for thisronic liver disease.

ecause obesity has become commonplace in todaysmodern society, the face of chronic liver disease is

anging to reflect a significant increase in patients withtures of the metabolic syndrome, leading to an in-ased prevalence of nonalcoholic fatty liver diseaseAFLD). It is estimated that 30% of the adult popula-

cost. Subsequently, noninvasive tools to correctly identifyNAFLD patients who have histopathologic evidence ofNASH with or without advanced fibrosis are in develop-ment and include a variety of techniques that vary fromcomposite laboratory and biomarker data to tests that

Abbreviations used in this paper: ADP, adiponectin; BMI, body massindex; CRP, C-reactive protein; CT, computed tomography; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MR, magnetic reso-nance; NAFLD, nonalcoholic fatty liver disease; NAS, nonalcoholic fattyliver disease activity score; NASH, nonalcoholic steatohepatitis; NPV,negative predictive value; PPV, positive predictive value; PUFA, poly-unsaturated fatty acid; RCT, randomized controlled trial; ROC, receiveoperating curve; ROS, reactive oxygen species; SFA, saturated fattyacid; TZD, thiazolidinediones; US, ultrasound.iagnosis and Therapy of Nonalcoho

Dawn M. Torres Stephen A. Harrison

artment of Gastroenterology, Fort Sam Houston, Brooke Army Medical Center,

e increasing prevalence of obesity, insulin resis-ce, and the metabolic syndrome has significantplications for the future of chronic liver disease.e resultant increase in the number of patients withnalcoholic fatty liver disease (NAFLD) is expectedtranslate into increased numbers of patients withd-stage liver disease (cirrhosis), liver failure, andpatocellular carcinoma. It is particularly importantidentify the patients who are at greatest risk ofese aforementioned complications of chronic liverease, those nonalcoholic fatty liver disease patientsth nonalcoholic steatohepatitis. Currently liver bi-sy is the gold standard for diagnosis, but less in-sive, highly accurate, and affordable screening toolsrequired. These tools may include radiologic ororatory studies to identify patients noninvasivelyo may benefit from therapeutic interventions.inical scoring systems that may be used in generalactice as initial screening tools also may prove use-l. Most therapeutic modalities available or undervelopment target the major pathways thought es-n in the United States now has NAFLD, with anreasing prevalence to 90% in morbidly obese popula-Steatohepatitis

ntonio, Texas

ns presenting for bariatric surgery.13 This is worri-e because patients with NAFLD appear to have a

her all-cause mortality in addition to liver-relatedse of death and recent data points to an increased riskcardiovascular disease.4 8 However, in clinical and

topathologic studies, the course of isolated fatty liverpears more indolent and less likely to progress tovanced liver disease.9 Alternatively, a subset of NAFLDtients have a more aggressive form of fatty liver knownnonalcoholic steatohepatitis (NASH), in which pa-

nts are at greater risk for progression to cirrhosis,d-stage liver disease, and likely hepatocellular carci-ma. It is estimated that 3% 6% of the United Statespulation has NASH, with upwards of 30% of morbidlyese patients showing features of NASH.3,10

Because of the inordinately high prevalence of NAFLD,is important to identify those patients with NASH,rticularly those at risk for advanced disease. Liver bi-sy traditionally has been the gold standard used toke the diagnosis of NASH. However, without adequate 2008 by the AGA Institute0016-5085/08/$34.00

doi:10.1053/j.gastro.2008.02.077

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May 2008 DIAGNOSIS AND THERAPY OF NASH 1683asure hepatic tissue elasticity such as the Fibroscanhosens, Paris, France).

Establishing the diagnosis of NASH is helpful only ifappropriate care plan can be developed and this in-des providing an effective treatment for the disease.ese therapeutic modalities should be readily available,e, effective, and relatively inexpensive. Therapies thatget the underlying metabolic syndrome through life-le modification, dietary adjustments, exercise regi-ns, bariatric surgery, or medications are all potentialnues of treatment. Other potential therapeutic targetslude cytoprotective and antifibrotic agents. This arti-focuses on the diagnostic and therapeutic tools cur-tly available as well as those under investigation forure clinical use.

DiagnosisPatients with NAFLD often are asymptomatic and

me to attention secondary to mild to moderate in-ases in hepatic aminotransferase levels or abnormaler appearance on abdominal imaging. Liver enzymeel increases tend to show an alanine aminotransferaseLT) predominance and rarely are increased more thantimes the upper limits of normal.11,12 The alkalineosphatase level occasionally may be increased mildly,d rarely is the only liver enzyme abnormality identi-d.13

Conventional radiology studies used in the diagnosisfatty liver include ultrasound (US), computed tomog-hy (CT), and magnetic resonance (MR) imaging (Ta-1). US can identify hepatic steatosis with reasonable

uracy. Typical criteria used to assess for steatosis in-de hepatorenal echo contrast, liver brightness, deepsterior beam) attenuation, and vascular blurring. Aent Italian study of 235 patients showed an excellent

ecificity of 97%, but a lower sensitivity of 64%. Thisreased to 100% specificity and 89.7% sensitivity whenly including patients with at least 30% steatosis.14

maguchi et al15 used a 6-point scoring system based

ble 1. Radiology Studies in the Diagnosis of NAFLD

Modality Sensitivity Specificity

1418 49%89% 75%100%ovist US34 100% 100%

9,20 54%93% 95%with liver-spleenttenuation ratios21

82% 100%

imaging22 NA NAspectroscopy24 NA NAelastography38 98% 99%elastography36 87% 91%liver brightness, attenuation, and vascular blurring onto evaluate for NAFLD and showed 100% specificity

d 91.7% sensitivity when compared with liver biopsy.

recliptriwever, this study was performed in relatively thintients. When performed in morbidly obese patients,ers have shown the sensitivity and specificity to be

ly 49.1% and 75%, respectively, for identifying steato-.16 Other studies have emphasized the difficulty intinguishing steatosis from fibrosis on US and thebility of US to correlate with the other essential he-

tic histology required for the diagnosis of NASH.17,18

CT has shown a similar diagnostic yield similar to US.enhanced CT is accurate in predicting steatosis ofater than 30%, but has been shown to be much lessurate in predicting lower-grade steatosis.19 Diagnosticuracy has been improved with unenhanced CT scan

ing liver:spleen attenuation ratios with up to 100%ecificity and 82% sensitivity for hepatic steatosis greatern 30%.19 21

Hepatic steatosis may be quantified from MR imagingsed on the signal differences between fat and water andows good correlation with microscopic fat content.22

itations of this modality include expense, inability toe in patients with implantable devices or claustropho-, and altered values in patient with iron overload.23

gnetic reasonance spectroscopy is a specialized radio-ic study that can measure triglyceride content nonin-ively. This technique was used on 2349 patients from

Dallas Heart Study with highly reproducible andurate results, but widespread application of this tech-logy is limited by cost and availability.24

As a group, radiologic studies have been shown tontify hepatic steatosis accurately and often bring aup of asymptomatic patients to clinical attention.casionally, patients with NAFLD are symptomatic andscribe a fullness or discomfort in their right upperadrant that does not appear to be associated witherity of disease. Physical examination generally is nor-l with the exception of the common finding of hepa-egaly. A novel finding of increased dorsocervical li-

hypertrophy in patients with NAFLD was described

Comments

Identifies steatosis onlySmall preliminary study of 64 patientspotentially useful in

NASH patients30% steatosis, cannot differentiate NASHBetter than standard CT for hepatic steatosis 30%; no

NASH distinctionHighly accurate in determining steatosis 30%Highly accurate for steatosisGood for both steatosis and fibrosis; early studies onlyFor stage 4 fibrosis, cannot differentiate NASH (accuracy in

obese patients is unknown)accno

idegroOcdequsevmatompoently by Cheung et al.25 Interestingly, dorsocervicalohypertrophy was found to be the single greatest con-butor to the severity of histologic findings of steato-

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1684 TORRES AND HARRISON GASTROENTEROLOGY Vol. 134, No. 6patitis and may prove to be a useful tool in the diag-sis of NASH.NAFLD patients typically meet criteria for the met-olic syndrome as defined by the American Heartsociation and National Heart, Lung, and Blood In-tute, with prevalence rates reported from 47% to%.26 28 In addition, the presence of the metabolicdrome has been linked to NASH as well as severe

rosis in NAFLD patients on multivariate analysis.29

fining criteria for the metabolic syndrome (applyinge earlier-described society guidelines) include any 3the following 5 laboratory and physical examinationdings: increased waist circumference (men, 40 in;men, 35 in), increased triglyceride levels of 150 orher, reduced high-density lipoprotein (HDL) levels

less than 40 mg/dL in men or less than 50 mg/dL inmen, increased blood pressure of greater than 130

Hg systolic or greater than 85 mm Hg diastolic, orreased fasting glucose level of greater than 100/dL.30 Lipid and glucose measurements are consid-d positive if the patient is already on cholesterol- orcose-lowering medications.

Percutaneous liver biopsy remains the standard fortinguishing isolated fatty liver from NASH. Key his-athologic criteria seen with NASH include macrove-

ular steatosis, lobular inflammation, hepatocyte bal-ning, and often perisinusoidal/perivenular fibrosis as

ll as MalloryDenk bodies.31 However, agreementong pathologists is not universal. The NAFLD activityre (NAS) is a histologic scoring system that was de-oped by the National Institutes of HealthsponsoredSH Clinical Research Network, which focuses on ste-sis, lobular inflammation, and hepatocyte ballooning.

NAS of 5 or greater is consistent with NASH and are of 2 or less is not associated with NASH, withres of 3 or 4 falling somewhere in between. The NASs not intended to be used as a diagnostic tool, buther to provide a uniform tool for assessing diseaseerity, ideally in clinical trials.32

Recent data have shown that significant sampling vari-ility exists for fibrosis and inflammation, although thisy be attenuated with good core biopsy samples.33

fortunately, adequate biopsy samples remain an issued given the significant prevalence of NAFLD coupledth the previously described limitations of biopsy, fewerasive tests are being developed to identify NASH withwithout advanced fibrosis. These diagnostic modalities

be divided into tests using image analysis and testst combine biomarker and clinical data.

Imaging for NASHAn important limitation of all imaging modalities

luding CT scan, US, and MR imaging is the inability

these techniques to differentiate isolated hepatic ste-sis from steatohepatitis. The definitive study by Saa-

h et al18 of 90 consecutive patients with biopsy-proven

elainpliFLD who underwent CT, US, and MR imaging clearlyowed that these radiologic studies were unable to ac-rately discriminate between NASH and isolated fattyer. All 3 radiologic studies were best able to predict 33%greater steatosis, but were not accurate in assessing fory features of steatohepatitis.Novel techniques are under development that may

ve to be useful radiologic tools to diagnose NASHninvasively. One such idea involves contrast ultra-nd using Levovist (Shering, Berlin, Germany), with

layed images taken at 5- to 10-minute increments forminutes, and has shown great accuracy in diagnosingSH with a receiver operating curve (ROC) of 100%ong the 21 NASH, 33 NAFLD, and 10 healthy patient

ntrols.34 This minimally invasive novel application ofrequires further study but shows early promise as a

gnostic tool.

Imaging for NASH FibrosisAlthough efforts to use noninvasive imaging stud-

to accurately grade NAFLD in terms of NASH haveen unsuccessful, the investigations that use imaging toge fibrosis in patients, and thus identify those withvanced disease, have shown more promise. Transientstography is an ultrasound-based technology that ised to measure liver stiffness. In a recent study of 68tients with NAFLD, a stepwise increase in elasticity wasown with severity of hepatic fibrosis.35 This studyowed good correlation between liver biopsy fibrosisges 1 4 and liver stiffness using ROCs with positivedictive values (PPVs) between 64% and 93.5% for theying stages of fibrosis. A recent meta-analysis of 9dies using this technology showed pooled estimatessensitivity and specificity of 87% and 91%, respec-

ely, for patients with stage IV fibrosis and 70% sensi-ity and 84% specificity for stages IIIV fibrosis.36 Oneportant caveat that requires further investigation ist steatosis and high body mass index (BMI; 25) has

en shown to reduce the reproducibility of this newhnology.37

An MR equivalent to transient elastography also hasen investigated as a noninvasive means to evaluate forpatic fibrosis. A recent study by Yin et al38 showed

mising results yielding 98% and 99% sensitivity andecificity, respectively, for identifying the presence ofy fibrosis. Hepatic steatosis also was identified cor-tly and the degree of steatosis did not seem to con-nd fibrosis measurements. One limitation of this ini-

l study was that the liver biopsies were on average 6.5nths apart from the imaging study, but the signifi-ce of this separation is uncertain. Further study into

s novel imaging technique is warranted. Both of these

stography techniques require large multicenter trialsconjunction with liver biopsy before they can be ap-ed to regular clinical practice.

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May 2008 DIAGNOSIS AND THERAPY OF NASH 1685Differentiating Isolated Fatty LiverFrom NASHBiomarkersSerum biomarkers that could be used as nonin-

ive tests to distinguish NASH from isolated fatty livero have been investigated. One or several laboratoryts that could accurately identify, grade, and stageSH would allow for screening of the large population

patients with NAFLD and avoid invasive and expensiveer biopsies. Several classes of biomarkers are in thetial stages of study that are directed at the pathwayslieved to be involved in the pathogenesis of NASHable 2).Oxidative stress is presumed to be central to thethogenesis of NASH and therefore biomarkers thatasure oxidative stress through reactive oxygen spe-s (ROS) have been looked at as potential surrogaterkers of NASH.39 Chalasani et al40 compared serumels of oxidized low-density lipoprotein (LDL) and

iobarbituric acid-reacting substances in 21 NASHtients with 19 control patients without liver diseasesimilar age, BMI, and nutritional intake. Signifi-tly higher levels of lipid peroxidation products weren in NASH patients, but limitations included a lackliver biopsy in the control patients and small num-

rs overall. In contrast, no correlation between oxida-e stress and steatosis or fibrosis was seen in anotherdy of 64 patients with either NAFLD or viral hep-tis.41 These discordant results may reflect that he-tic oxidative stress is not reflected accurately byum measurements, but further study is required toder a final verdict on the utility of measuring serumS in NAFLD/NASH patients.

Another area of interest has been serum measurementsspecific adipocytokines (produced by adipose tissue)

ble 2. Noninvasive Biomarkers in NASH

Serum biomarker Marker of Findings

S40,41 Oxidative stress Conflicting results: somecorrelation betweenNASH and increasedlevel of ROS

tin4447 Insulinresistance

Conflicting results: higherlevels in some studies

ponectin4854 Insulinsensitivity

ADP lower in NASHpatients

h-sensitivity CRP5557 Systemicinflammation

Conflicting results: someincreased high-sensitivity CRP withNASH compared withNAFLD

okeratin 185961 Hepaticapoptosis

Significantly higher inNASHch as leptin and adiponectin (ADP).42 Obesity andess caloric intake enhance up-regulation of leptin re-

lting in increased free fatty acid delivery to the liver,

cytaptoontributing to hepatic steatosis.43 Initial investigationsowed an association between higher leptin levels and

presence of NASH as well as steatosis grade, althought inflammation or fibrosis.44,45 However, several subse-ent studies have failed to show any associations be-een leptin levels and the presence or absence of hepaticatosis, inflammation, or fibrosis.46,47

In contrast to leptin, ADP is thought to promoteulin sensitivity and increase glucose utilization ande fatty acid oxidation in the liver. Hui et al48 foundnificantly lower serum levels of ADP in patients withSH when compared with both normal controls andividuals with simple steatosis. Numerous other stud-have confirmed that ADP is generally lower in NAFLD

tients compared with healthy controls.49 53 Targher et4 recently showed that ADP levels were associatedsely with severity of liver histology to include hepaticatosis, necroinflammation, and fibrosis. Although all 3mponents of hepatic histology were associated with

ADP levels, only steatosis and necroinflammationre found to be independent predictors in multivariatealysis. Further study is required to fully delineate theationship between ADP and severity of liver disease inFLD patients.

Other markers of systemic inflammation such as C-re-ive protein (CRP) also have been studied with conflict-

results. An Australian study found no differencetween high-sensitivity CRP levels in patients with sim-

steatosis and NASH.55 This is in contrast to otherdies showing significant increases in high-sensitivityP levels in patients with NASH compared withFLD controls.56,57 Given these conflicting results, CRPa marker for hepatic inflammation requires furtherestigation, although its association with other diseasecesses may limit its clinical usefulness.

Hepatic apoptosis is a prominent feature of NASH,d, as such, biomarkers of hepatic apoptosis have beenlored as a potential diagnostic tool.58 Wieckowska et

9 showed a striking relationship between plasma levelscaspase-generated cytokeratin-18, a protein involved ine of the final steps of apoptosis, and the histologicsence of NASH on liver biopsy. Similarly, Yilmaz et

0 measured serum levels of extracellular cytokeratin 1830 antigen and M65 antigen) in patients with NAFLDd varying degrees of severity of NASH. Both of thesetigens were found to be significantly higher in NASHtients with a sensitivity of 60% 69% and a specificity of%97% in predicting NASH if the antigen levels wererkedly abnormal. The utility of cytokeratin 18 recentlys validated independently in a study of 21 pediatricFLD patients, which directly correlated the level of

okeratin-18 to severity of liver disease.61 This modalitypears to offer significant promise as a future diagnosticl to differentiate isolated fatty liver from NASH.

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1686 TORRES AND HARRISON GASTROENTEROLOGY Vol. 134, No. 6Scoring Systems for Identifying NASH FromNAFLDScoring systems using one or several clinical

d/or laboratory parameters to identify patients withSH from the larger pool of NAFLD patients also have

en assessed. Several studies have looked at a variety ofiables that might prove suitable (Table 3). Palekar et

2 developed a clinical model that sums 5 risks factorsNASH identified on multivariate logistic regression.

ese factors include age 50 or older, female sex, aspar-e aminotransferase (AST) level of 45 or greater, BMI ofor greater, AST/ALT ratio of 0.80 or greater, and

aluronic acid level of 55 or greater. Combining 3 orre of these factors yielded a sensitivity of 73.7% and a

ecificity of 65.7% for detecting NASH with an ROC of63. This study provided a relatively simple means ofntifying NASH patients but requires further valida-n in a larger study population.A larger European study assessed the utility of theSH Test (Biopredictive) to distinguish NASH fromlated fatty liver.63 This complex test including 13 clin-l and laboratory parameters was developed using 160tients in the training group, 97 patients in a multi-ter validation group, and 383 control patients. Overall

ecificity was shown to be 94%, with a much lowersitivity of 33% and an ROC of 0.79. Further scoringtems are under development that may better identifyFLD patients with NASH, but will require indepen-

nt, prospective validation before being applied broadlyclinical practice.

Distinguishing Advanced Fibrosis in NASHThe ability of one or several screening tests to

dict hepatic fibrosis in patients with NAFLD also has

ble 3. Macronutrients in NAFLD

Macronutrient Found In

urated fatty acids Lard, butter, coconut oil, palm oil Incrnounsaturated fattycids

Olive oil, nuts, avocados, peanutbutter, peanut oil

Highin

FAs (n-6) Sunflower, corn oil Deco

FAs (n-3) Fish oil, walnuts, salmon,shellfish

DecTN

ns fatty acids Fast foods, baked goods, deepfried foods

Dairy products (5%)Ruminants (cows/sheep)Margarine

Incra

(Natn

rose/fructose Sweetened drinks/sodas, candy Wortein Meat, fish, eggs, dairy Uncer Whole grains, fruits, and

vegetablesImp

, tumor necrosis factor; ?, conflicting data.en an area of intense interest. Study of potential sur-ate markers of fibrosis have shown success in identi-

ng those with advanced fibrosis but have been less

lowad88urate in predicting mild to moderate fibrosis (Table64 One of the early scoring systems developed called

body mass index; age at liver biopsy; alanine amino-nsferase; and serum triglycerides (BAAT) score used 4ily determined clinical variables to assess for hepaticrosis.65 This scoring system showed good PPV in de-mining advanced fibrosis but fell short of an idealeening test to identify mild to moderate disease. The

e group expanded their efforts with the developmentthe FibroTest-FibroSURE (Biopredictive) based on 2-croglobulin, apolipoprotein A1, haptoglobin, total bil-bin, and -glutamyltransferase levels.66 A 90% negativedictive value (NPV) for advanced fibrosis and a 70%

V for advanced fibrosis were noted in final analysis.e diagnosis of borderline NASH was harder to make

th a 72% NPV and 74% PPV. This is an importantitation of the FibroTest-FibroSURE, which translateso one third of total patients enrolled still requiring aer biopsy.The European Liver Fibrosis study evaluated 1021 pa-nts using 9 surrogate markers of fibrosis and devel-ed an algorithm using 4 of these markers that showed% sensitivity in detecting fibrosis as well as 92% NPV inling out fibrosis.67 This study was limited in the factt it combined patients with all types of chronic liverease and requires further study in NAFLD-specifictient populations.The NAFLD fibrosis scoring system, developed inllaboration between multiple liver centers, uses 6mmonly measured parameters including age, hyper-cemia, BMI, platelet count, albumin level, and AST/T ratio.68 This scoring system uses a 2-point cut-offtem similar to the FibroTest-FibroSURE. By using a

Action Findings in NASH

LDL Higher intake in NASH patientstake decreases LDL,es HDL

Uncertain

s HDL, ? increaseve stress

High n-6/n-3 ratio in NASH patients

s FFA, glucose, insulin, Higher intake decreases hepaticsteatosis (small studies)

inflammatory markersLderived trans FAs do

ve above actions)

Uncertain

insulin resistance Higher intake in NASH patientsUncertain

insulin resistance Lower intake in NASHlimintliv

tieop90ruthadispa

cocoglyALsyscut-off score (1.455), the NPV for excludingvanced fibrosis was 93% in the estimation group and% in the validation group. When a high cut-off score

(0.fibNAansiesepforforlowbioforme

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May 2008 DIAGNOSIS AND THERAPY OF NASH 1687676) was used, the PPV for predicting advancedrosis was 90% and 82%, respectively. Overall, theFLD fibrosis score predicted advanced fibrosis withROC of 0.82. The authors68 suggest that liver biop-s could therefore be avoided in 75% of patients. Aarate validation study of 79 patients found the NPVexcluding advanced fibrosis to be 93%, but the PPVpredicting advanced fibrosis was only 42%. This

er PPV translates into fewer patients avoiding liverpsy.69 Therefore, further validation is necessary be-e this or any other scoring system can be recom-nded broadly.

A recent review by Guha et al70 tabulated 29 studiesat looked at noninvasive markers of hepatic fibrosisNAFLD either as primary or secondary end points.is comprehensive review identified the key variablesnd in the majority of these studies, which included

e presence of diabetes, increasing age, increased ho-ostatic insulin resistance, increased AST/ALT ratio,

creased platelets, hyaluronic acid, and BMI. Al-ough these models are good in predicting advancedrosis at any one time point, they fall short in defin-

ure 1. Potential pathophysiologic effects of therapies that are undeatohepatitis is multifaceted. Several therapeuticmodalities under investie pleiotrophic effects in improving NAFLD. *Endocannabinoid receptonclude adipocytes, liver, and possibly skeletal muscle and the pancreaan excellent screening test to identify patients withSH noninvasively who are at risk of progressing toere fibrosis.

obcalheTreatment for NASHMuch like the biomarkers being studied to diag-

se NASH noninvasively, current therapies are focusedthe various pathways thought central in the patho-esis of this disease (Figure 1). Treatment regimens

geting insulin resistance, oxidative stress, diabetes, hy-rlipidemia, obesity, and hepatic fibrosis all warranttical appraisal. Multiple modalities to include diet,rcise, surgical interventions, and finally pharmaco-rapy require evaluation to determine the most effec-

e treatment algorithms. Although one panacea has noten found and is unlikely to exist, a multimodalityatment regimen may prove effective.

Weight LossCalorie Reduction

Patients with NAFLD typically are overweight orese, insulin resistant, and have a consistently higherergy intake when compared with individuals withoutpatic steatosis.71 Data have shown that in the setting of

stigation. The development of hepatic steatosis and subsequentsuch as the TZDs, diet, and exercise, and possibly rimonabant, maye been identified in multiple organs involved in energy homeostasisnoongentarpecriexethetivbetre

obenhe

r invegationrs havs.esity, moderate weight loss of approximately 6% viaoric restriction improves insulin resistance and intra-patic lipid content.72 Furthermore, caloric restriction

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1688 TORRES AND HARRISON GASTROENTEROLOGY Vol. 134, No. 6proves serum aminotransferase levels and hepatic his-ogy.7377

The degree of caloric restriction has been questioned. Aall study by Anderson et al74 showed that extremeight loss via starvation leads to worsening liver histol-y, including fibrosis. In addition, 2 bariatric surgerydies have shown mild worsening of lobular inflamma-n and fibrosis in a subset of patients with a meanight loss of 32 and 38 kg, respectively.78,79 In contrast,ers have shown significant histologic improvement

th weight loss through either caloric reduction or bari-ic surgery.80 84 Huang et al85 counseled patients tolow a 1400 kcal/day diet for 12 months in 15 biopsy-ven NASH patients with a subsequent mean weight

s of 2.9 kg (3% of body weight). Among the 9 of 15tients (60%) who had a histopathologic improvement

repeat liver biopsy, the average weight loss was 7%.patic fibrosis did not change significantly in this smalldy. No significant change in fibrosis also was seen ineta-analysis of 15 studies that evaluated weight re-

ction without bariatric surgery in the treatment ofnalcoholic fatty liver.86 Although it would seem that

preponderance of the evidence supports that moder-caloric restriction resulting in modest weight loss is

lpful in improving biochemical parameters, insulinsitivity, and hepatic steatosis, its role in hepatic fibro-is less clear. In keeping with the vast majority ofays clinical practices, the recommendations for mod-te caloric restriction as an initial therapy in NAFLD

tients is supported by data, but well-controlled, largerdies are needed to conclusively show a fibrosis benefit.

Altering Macronutrient ContentEvidence suggests that NASH patients have diets

her in simple carbohydrates and lower ratios of poly-saturated fatty acids (PUFAs) to saturated fatty acidsAs).87,88 Thus, the concept of altering the macronutri-

t content rather that the total calories of NASH pa-nts also has been investigated. Several areas of dietcronutrient manipulation have been studied to in-de overall fat vs carbohydrate vs protein intake as wellspecific regimens of fatty acids designed to reduce

patic steatosis and potentially steatohepatitis.The ideal diet composition for NASH patients has noten established, although the general consensus hasen that excessive intake of either fat or carbohydrate isrmful. A randomized controlled trial (RCT) of low-fatlow-carbohydrate diet showed greater weight loss andproved lipid panels in the low-carbohydrate group.89 Aall pilot trial of 5 NAFLD patients who followed a-carbohydrate (20 g/day) diet for 6 months showed

tologic improvements in 4 of the 5 patients who hadean weight loss of 12.8 kg.90Other studies have shown benefit with lower-fat diets.provements in hepatic steatosis via MR spectroscopys shown in 2 recent trials: 1 of 10 obese nondiabetic

spsodgenmen91 and 1 of 8 NAFLD patients.92 A recent compre-nsive review by Zivkovic et al93 examined the role ofious popular weight-loss diets to include Atkins, Or-h, Zone, and South Beach diet in the treatment ofFLD. This intriguing article suggested that diets that

prove insulin sensitivity, promote foods with low gly-ic indices, and yield sustainable weight loss offer the

st potential benefit, although well-designed clinicalals are lacking.Another concept in the arena of dietary compositiondification is the difference in the various types oftary fat (Table 4). Excess SFAs have been shown tomote endoplasmic reticulum stress, hepatic steatosis,

d inflammation in animal models, although it remainscertain if a minimum intake of SFAs are required fortimal metabolism.87,9395 On the other hand, monoun-urated fatty acids such as found in olive oil, peanuttter, nuts, and avocados are thought to be generallyneficial because they decrease total cholesterol, triglyc-des, serum LDL, and maintain HDL. A small study ofinsulin-resistant patients showed improvement in in-

lin resistance and increased adiponectin levels after 1nth of a monounsaturated fatty acid enriched diet.96

Altering the amount of PUFAs in diets also has beendied. When PUFAs have been used to replace SFAs in

diet, significant cardiovascular benefits have beented.97 Hepatic steatosis in obese mice also has beenproved with dietary PUFAs via negative regulation ofpatic lipogenesis.98 The ratio of n-6 to n-3 PUFAs alsoms to be important in predicting insulin resistance.excessive amount of n-6 PUFAs with a high n-6/n-3

io was shown in a recent study of 45 NASH patientsmpared with 856 age- and sex-matched controls.99 N-3FAs such as alpha-linoleic acid (fish oil) appeared to be

neficial in 2 small studies in patients with NAFLD withprovement in serum triacylglycerol concentrations,ting glucose, liver enzyme levels, and hepatic steato-.100,101 Walnuts are another source of alpha-linoleicd that has been shown to improve lipid profiles inbetes.102

On the other hand, trans fatty acids occurring in dairyds as well as hydrogenated margarine products have

en less well studied in patients with NAFLD. However,ormation in healthy subjects suggests that intake ofse hydrogenated oils increases inflammatory markers

d increases the LDL:HDL ratio.103,104 Based on thesedies, general recommendations to avoid or reduce theake of trans fatty acids seems reasonable.The increased intake of sucrose and fructose in West-

diets also may play a role in the development ofFLD. A recent population-based study showed thatFLD patients consumed almost twice the amount oft drinks than control counterparts.105 It has beeneculated that the high fructose content of nondietas is associated with increased hepatic de novo lipo-esis, hypertriglyceridemia, and hepatic insulin resis-

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May 2008 DIAGNOSIS AND THERAPY OF NASH 1689ce.106 This corresponds to a recent study in a mousedel showing that rapidly absorbed carbohydrates pro-tes hepatic steatosis when compared with consump-n of slowly absorbed carbohydrates with a lower gly-

ic index.107

This field of diet composition manipulation representsew and intriguing area of study in the treatment ofSH that requires further study. Large RCTs are needed

fore final recommendations can be made as to the idealt for NAFLD patients. The general concept that foods

th low glycemic index as well as diets containing morenounsaturated fatty acids and n-3 PUFAs, low SFAs,

d limited to no fructose seem to be acceptable generalidelines to offer patients who are agreeable to lifestyleanges in their treatment.

ExerciseExercise is another area of interest in the field of

style modification as therapy for NAFLD althoughre are only limited data available. Most of the evidencet does exist uses exercise in combination with diet to

ble 4. Pharmacologic Therapies in the Treatment of NASH

Treatment Mechanism Biochemical effe

istat Weight loss 2 LFTs and insulin re

onabant Weight loss, possibleperipheral effects

2 Insulin resistance,triglyceride levels, L1 HDL, adiponectin

retin analogsexendin-4)

Weight loss 2 LFTs, insulin resisthemoglobin A1C

s PPAR- agonists 2 LFTs, insulin resistand TNF-1 Adiponectin

tformin 1 AMP kinase 2 LFTs and insulin reNo effect on adiponec

min E 2 Oxidative stress 2 LFTs

aine 2 Oxidative stress 2 LFTs

CA Hepatoprotective No changetoxifylline Hepatoprotective 2 LFTs, TNF-G CoA-reductasenhibitors

Improve lipid panel ? LFTs

timibe Blocks cholesterolabsorption inintestine

? LFTs

iotensin-receptorlockers

? Inhibits stellatecells

2 LFTs

decreases; AMP, adenosine 5=-monophosphate; LFT, liver functioydroxy-3-methylglutaryl-coenzyme A; TNF, tumor necrosis factor.mote weight loss. The general consensus has beent exercise works synergistically with diet modificationproduce beneficial metabolic effects.108 Suzuki et al109

imtoNAnd that in a population of 348 male patients whoeived annual health physicals, regular exercise andight loss over a 1-year period was associated with anificant improvement in serum aminotransferase lev-. Another study that followed up 25 obese NAFLDtients prospectively for 3 months confirmed that reg-r exercise defined as walking or jogging daily along

th a reduced-calorie diet produced significant improve-nt in serum aminotransferase levels, fasting glucose,

d hepatic steatosis compared with a control popula-n.110

Hickman et al111 followed up 31 NASH patients for 3nths with combined dietary modifications and mod-te exercise of 150 minutes of aerobic exercise weekly

th a mean weight loss of 4% of total body weight.tients who lost weight experienced improvement inum aminotransferase levels that were maintained at 15nths of follow-up evaluation provided the weight loss

s sustained. Repeat liver biopsy in 14 patients 3 6nths after lifestyle modification showed significant

Histologic effects Comments

nce 2 Steatosis, inflammation,NAS score

Improvement ininflammation and NASseen if weight loss 9%

2 Steatosis Animal data, psychiatricside effects

2 Steatosis Animal and pilot studies inNAFLD; extensivelystudied in type 2diabetes mellitus

2 Steatosis, inflammationand fibrosis

Side effects: weight gain,peripheral edema,cardiac, fractures, needfor maintenance therapy

nce / improvement insteatosis, inflammation,and fibrosis

Data conflicting; no RCTs

Uncertain Large trials with histologicfollow-up evaluationrequired

2 Steatosis, inflammation,fibrosis

Pilot study only

No change Not beneficial in large RCT2 Steatosis, inflammation Pilot study onlyUncertain Conflicting studies

2 Steatosis and fibrosis Animal data

2 Fibrosis Animal and pilot studies

t; PPAR, peroxisome proliferatoractivated receptor; HMG CoA,fourecwesigelspaulawimeantio

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n tesprovement in steatosis and fibrosis. This correspondsa recent study that inversely correlates the presence ofFLD and a patients physical fitness level.112

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1690 TORRES AND HARRISON GASTROENTEROLOGY Vol. 134, No. 6Collectively these studies support the general conceptt slow gradual weight loss through diet and exercisey prove beneficial in the treatment of NASH. Clearly,wever, larger RCTs are needed to better define thetimal exercise regimen as well as the most beneficialtary composition and total calorie intake.

Medical Therapies That Augment Weight LossOrlistat. The reversible inhibitor of gastric and

ncreatic lipase, orlistat, appears to be the most studiedight loss medication used in the treatment of NASH.is medication is taken with meals and blocks approx-ately 30% of dietary triglycerides. Early pilot workggested this medication may be beneficial in the treat-nt of NASH.113,114 Two subsequent randomized con-lled trials were performed to further investigate thetentially beneficial effects of orlistat in the treatmentNASH.115,116 Six to 9 months of therapy with orlistatplacebo produced 8% vs 6% total body weight loss,pectively. ZelberSagi et al115 showed steatosis onlyproved in the orlistat group despite significant weights in each group. Harrison et al116 obtained repeat liverpsies at 9 months and showed that regardless ofimen, a 9% body weight reduction produced improve-nt in biochemical markers, serum aminotransferaseels, steatosis, and necroinflammation, but no improve-nt in fibrosis. The implications of these 2 RCTs weret weight loss is the common pathway through whichistat may exert a beneficial effect. Other weight lossdications are under investigation in search of a med-tion with minimal side effects and excellent efficacy.ese data, combined with diet and exercise studies,

ggest that relatively modest amounts of weight loss, onorder of 5%10%, will lead to improvement in both

chemical and histopathologic abnormalities seen inSH.

Rimonabant. Increasing evidence suggests the en-cannabinoid system is enhanced in the setting of over-ight or obesity. Activation of cannabinoid (CB-1) re-tors located both centrally and peripherally (tolude organs involved in energy homeostasis such as

liver, adipocytes, and possibly skeletal muscle andncreas), lead to enhanced weight gain and altered en-y metabolism. Inhibition of these receptors has beensubject of recent intense investigation.

Although not specifically studied in NASH patients tote, several large randomized placebo-controlled trialsth the cannabinoid-1 antagonist, rimonabant, in botherweight/obese nondiabetic and diabetic patients haveen performed.117 Rimonabant given at a dose of 20/day for 1 year is associated with a weight loss of 4.75.4 kg and improved waist circumference. Significantprovement in serum triglyceride levels, HDL levels,

ulin resistance, and adiponectin levels also has been

own and seem to be greater than what would be ex-cted with weight loss alone, suggesting an added pe-

sigtioly.heral effect. In addition, significant improvement inum ALT levels, -glutamyltransferase levels, alkalineosphatase levels, and hepatic steatosis has been shownan animal model of NAFLD.118 Multicentered RCTs ofonabant in human beings with NASH are underway.

e recent association of this medication with psychiat-issues to include depression may limit its future use,

d it is currently not available in the United Statestside of clinical research trials.

Glucagon-like protein-1receptor agonist (incre-analogs). Peptides that are derived from glucagon-

e protein-1receptor agonists such as exenatide alsoy prove to be potential therapeutic agents in the treat-nt of NASH. These incretin analogs have been studiedensively in patients with type 2 diabetes mellitus andve been found to promote insulin secretion, suppressppropriate glucagon secretion, slow gastric emptying,uce satiety, and are associated with modest weights. Nausea occurs in up to 57% of patients, typicallyly in the course of therapy, and can be mitigated withse titration.119 A recent study in obese mice showeduced markers of oxidative stress and insulin resistancewell as decreased hepatic steatosis.120 A recent caseort of a diabetic male patient with NAFLD treated forweeks with exenatide showed improvement in seruminotransferase levels and hepatic steatosis.121 Numer-s other studies have supported the glycemic benefits ofnatide (exendin-4) with further well-designed studies

ecific to NASH populations required.

Surgical Therapy for Weight LossUntil medical therapy is developed that effectively

motes and sustains weight loss, surgical therapy willntinue to remain a viable alternative in select patientpulations. Surgical therapy for obesity has becomeeedingly popular in the past decade and has evolvednificantly from the early malabsorptive surgeries.ese early surgeries such as the jejunoileal bypass pro-ced dramatic weight loss but were shown to causenificant worsening of liver disease postoperative-

122,123 Newer surgical techniques such as adjustablestric banding and Roux-en-Y gastric bypass are overalltter tolerated and have been shown to improve meta-lic syndrome, insulin resistance, and hepatic histology.Adjustable gastric banding in 22 obese NASH patients

duced an average 34-kg weight loss as well as signif-nt improvement in hepatic steatosis, inflammation,d fibrosis at repeat liver biopsy more than 2 years afterrgery.82 Roux-en-Y gastric bypass has been used to

duce even greater weight loss and its utility in im-ving NASH has been well studied. A recent study ofmorbidly obese NASH patients who lost a mean of 52of body weight after Roux-en-Y gastric bypass showed

nificant improvement in steatosis, lobular inflamma-n, and fibrosis on average 21.4 months postoperative-

83 Another study of 70 patients undergoing bariatric

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May 2008 DIAGNOSIS AND THERAPY OF NASH 1691rgery showed a mean weight loss of 59% at 15 monthser surgery and 82% improvement in steatohepatitisd 39% improvement in fibrosis.124 Others also haveown large metabolic and histologic improvementsst gastric bypass with no patients showing worseninghepatic fibrosis and 50%75% of patients showing

provement in hepatic fibrosis.125,126 These studies pro-e compelling evidence that bariatric surgery, usingher adjustable gastric banding or Roux-en-Y gastricpass, results in substantial weight loss, and is associ-d with a marked improvement in biochemical andtologic parameters of NASH patients. Subsequently,se invasive therapies should be considered in morbidly

ese patients with other medical conditions that cumu-ively would warrant the risks of surgical intervention.

Medical Therapies That ImproveMetabolic ProfilesIn a similar manner to the tests under develop-

nt using specific biomarkers to diagnose NASH baseda common pathway of insulin resistance and oxidative

ess, pharmacologic therapies have been evaluated thatve targeted these same pathways. As the steps involvedthe development of steatohepatitis and fibrosis arecidated further, pharmacologic therapies may be bet-directed to cause histologic and biochemical improve-nt.

Insulin-Sensitizing MedicationsThiazolidinediones. Thiazolidinediones (TZDs)

prove insulin resistance in skeletal muscle, adiposesue, and the liver through their action as peroxisomeliferatoractivated receptor agonists that increasesma adiponectin levels and fatty acid oxidation and

crease fatty acid synthesis.127 These agents have beenmost studied insulin sensitizers used in the treatment

NASH. Pioglitazone and rosiglitazone are the 2 cur-tly available TZDs and both have been evaluated inall prospective trials.

A preliminary study of 22 NASH patients (50% withpaired glucose tolerance or diabetes) treated for 48eks with rosiglitazone showed overall improvement inulin sensitivity and serum aminotransferase levels. Re-

at liver biopsy at 48 weeks showed significant improve-nt in necroinflammation, ballooning, and zone 3 peri-usoidal fibrosis with 45% (10 patients) no longereting criteria for NASH. However, this study lacked a

ntrol arm and within 6 months posttherapy seruminotransferase levels were almost back to pretreatmentels.128 A subsequent randomized, placebo-controlledal in 63 NASH patients (32% with diabetes) treated forear with rosiglitazone 8 mg/day showed significantly

ater improvement in steatosis compared with placebo,

d significantly less histologic progression in referenceballooning, inflammation, and fibrosis.129 However,

neadtivprovement in steatosis was not seen uniformly in alltients treated with rosiglitazone.Pioglitazone also was evaluated in several small pilotd proof-of-concept trials. An open-label trial in 18ndiabetic NASH patients treated with 30 mg/day forweeks showed overall histologic improvement in twords of patients with significant improvement in ste-sis, cellular injury, parenchymal inflammation, and

rosis.130 Another pilot study compared pioglitazone 30/day plus vitamin E 400 IU/day with vitamin E alone

d showed improvement in steatosis in both groups butprovement in hepatic inflammation and fibrosis in theglitazone plus vitamin E arm only.131 A more recentcebo-controlled study by Belfort et al132 in 55 NASH

tients with impaired glucose tolerance or type 2 diabe-mellitus provided evidence that therapy with 6

nths of a low-calorie diet plus pioglitazone improvedchemical and histologic parameters significantly moren patients prescribed a low-calorie diet and placebo.hough significant improvement was seen for steatosisd inflammation compared with placebo, fibrosis im-vement did not reach significance when compared

th the placebo group (P .08). These preliminarydings are supported by another randomized placebo-ntrolled trial that followed up 74 nondiabetic patients

12 months and showed significant improvement intabolic and histologic parameters, including fibrosis,the pioglitazone group when compared with place-

.133 Interestingly, lobular inflammation and steatosisre not improved between groups and further investi-tion is necessary to understand these findings.Although these studies provided some evidence that

TZDs may be beneficial in the short term, the long-m benefits remain to be seen. Lutchman et al134

owed that continued therapy may be required to main-n histologic benefit. In this study of 21 patients treated

48 weeks with pioglitazone, liver biopsies were per-med at baseline, at end of therapy, and, in 9 patients,weeks after stopping therapy. In the patients who

derwent the 3 serial liver biopsies, initial improvementbiochemical and histologic parameters were not main-ned at the 48-week posttherapy evaluation, with 7 of 9tients developing histopathologic evidence of NASHce again, despite no change in average body weight.The side-effect profile of the TZD class of medicationo must be addressed. Modest weight gain of approxi-tely 23 kg has been shown routinely and appears tocaused by increased peripheral fat deposition. Somerospective studies also suggest that TZDs promotene loss and may contribute to osteoporosis and in-ased fractures, particularly in postmenopausal wom-.135 If limited durations of therapy were adequate, thisuld be less of an issue, but if long-term therapy is

cessary to maintain hepatic benefit, this must be betterdressed. Further investigation is required to defini-ely address this issue.

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1692 TORRES AND HARRISON GASTROENTEROLOGY Vol. 134, No. 6Moreover, a recent meta-analysis of diabetic male pa-nts taking rosiglitazone has suggested an increasedk of cardiovascular events.136 Although this study tab-ted an increased risk of myocardial infarction of 43%

d cardiovascular death of 64%, it has been widely crit-zed for its inclusion criteria, methods of statisticalalysis, and overall low event rate.137 Other analysesing broader inclusion criteria and different statisticalalysis failed to show a significant increase in myocar-l infarction in this same patient population. Further-re, a similar meta-analysis with pioglitazone showed a

% reduction in cardiovascular events.138 Additional in-tigation is required to address the issue definitively.

The risk of congestive heart failure exacerbation withuse of TZDs also has been reported and has been

ributed to TZD-related fluid retention and diastolicsfunction in susceptible individuals. Subsequentlyse agents are contraindicated in patients with New

rk Heart Classification stage 3 4 heart failure. Lago et39 recently showed an increased risk of congestive heartlure, but did not show increased cardiovascular deathong patients taking TZDs. Large prospective trials aregoing and their results will determine the future ofDs in the treatment of NASH.

Metformin. Metformin is a biguanide that im-ves insulin sensitivity by decreasing hepatic glucone-

enesis and limiting triacylglycerol production. Animaldel data has been promising, with early studies of

ese mice given metformin showing improved serumnsaminase levels, hepatomegaly, and steatosis.140 Datam human studies are limited. Marchensini et al141 first

owed improvement in insulin sensitivity and seruminotransferase levels in an open-label trial of 20 pa-

nts treated with metformin 1500 mg/day for 4nths. This was followed by a 6-month randomized

en-label trial of metformin 850 mg twice daily plust vs dietary restriction of 1600 to 1800 kcal/day.142

nificant improvement was seen in the metforminup compared with the diet-alone group. However, no

nificant improvement in necroinflammation or fibro-was found. A similar open-label trial of metformin

en for 1 year in 15 patients showed improvement inum aminotransferase levels and insulin sensitivity at 3nths, but return of serum aminotransferase levels totreatment levels were seen by the completion of thedy.143

A subsequent open-label RCT in 110 NAFLD patientss performed in Italy that compared metformin treat-nt with 2 control groups of vitamin E 800 IU/day orrescriptive, weight-reducing diet.144 Metformin showedher rates of aminotransferase normalization. Repeat liverpsy in 31% of the metformin group showed improve-nt in steatosis, necroinflammation, and fibrosis, al-

ugh there was no histologic follow-up evaluation in thetrol groups. Interestingly, metformin compared with

iglitazone in a study of 20 patients with type 2 diabetessuthewed improvement in insulin resistance and transami-se levels in both groups but decreased hepatic fat asasured by proton spectroscopy in the rosiglitazoneup.145

Overall, the insulin-sensitizing medications show thest promise to date in improving histopathology in

tients with NASH. Current data suggest that met-min may be less efficacious than the TZD class ofdications; however, randomized, placebo-controlleddies with metformin using histopathologic end points

ve yet to be performed. Interestingly, one differencetween the 2 classes of insulin sensitizers is the ability of

TZD class to up-regulate adiponectin expression.ven the multiple effects of adiponectin including up-ulation of adenosine 5=-monophosphate (AMP) ki-

se and peroxisome proliferatoractivated receptor- in-ition, the inability of metformin to positively impact

iponectin expression may have important conse-ences on the overall effectiveness of this medication in

treatment of NASH, at least when used as mono-rapy. Combination therapy with metformin and theD class of medications deserves consideration in clin-l trials because the untoward weight gain with TZDnotherapy may be mitigated.

Antioxidant therapy. The depletion of antioxi-nts within hepatocytes resulting in impaired ROS in-ivation is the basis for antioxidant supplementation aspotential treatment for NASH.146 The lipid-solubletioxidant, tocopherol (vitamin E), has been shown toibit lipid peroxidation and suppress inflammatoryokines such as tumor necrosis factor-, and its use in

treatment of NASH has been studied. One studymparing 6 months of 1000 IU vitamin E and 1000 mgamin C daily vs placebo showed significant improve-nt in hepatic fibrosis within the vitamin group but not

tween groups and no change in serum aminotransfer-levels or hepatic inflammation.147 Alternatively, oth-have shown improvement in serum aminotransferase

els and insulin resistance although follow-up histopa-logy was not assessed.148,149

Betaine, another antioxidant studied in the treatmentNASH, increases S-adenosylmethionine levels and isught to reduce fat deposition in the liver.143 Marked

provement in serum aminotransferase levels, hepaticatosis, inflammatory activity, and fibrosis was seen inilot trial of 10 NASH patients treated with betaine

hydrous in a 20-mg divided dose daily for 12nths.150 Rigorous follow-up studies are required with

rticular attention paid to the formulation of betaineed because betaine anhydrous is a medication regu-ed by the Food and Drug Administration whereas there readily available betaine hydrochloride is a dietary

pplement found in nutrition stores.151Phlebotomy targeting hepatic iron overload with re-ltant increased oxidative stress is another potentialrapeutic modality that has been investigated in the

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May 2008 DIAGNOSIS AND THERAPY OF NASH 1693atment of NASH. In a study of 64 NAFLD patientsdergoing therapeutic phlebotomy to a goal of a ferritinel of less than 80 ng/mL for 8 months in addition tostyle modification vs lifestyle modification alone, thelebotomy group showed significantly improved insulinistance.152 Serum aminotransferase levels were not sig-cantly different between the 2 groups and hepatictology was not assessed in this preliminary study.rger studies with histologic follow-up evaluation arecessary to determine the utility of this treatmentdality.

Overall, antioxidants represent a novel class of medi-ions that have shown some promising initial results in

treatment of NASH but further well-designed largeTs are required and it is likely that these therapies willused in combination regimens with other agents thatect insulin sensitivity.

OthersCytoprotective agents. Cytoprotective agents are

ught to work by preventing apoptosis and down-ulating the inflammatory cascade that has been shownoccur in NAFLD patients. Ursodeoxycholic acid

DCA) is the most studied and initial pilot trials provedmising as a NASH-specific therapy. However, a well-

nducted, multicenter, double-blind, placebo-controlledal of UDCA for 2 years failed to show significantange in biochemical or histologic parameters.153 Inter-ingly, Dufour et al154 showed biochemical benefit asll as reduced steatosis with the combination of UDCAth vitamin E compared with UDCA plus placebo oruble-placebo groups after 2 years of therapy.154 It re-ins to be seen whether UDCA in combination wither medications may prove clinically efficacious.

Pentoxifylline, another cytoprotective agent, exerts itsect through inhibition of tumor necrosis factor-.elve months of pentoxifylline 400 mg 3 times dailyen in 2 recent pilot trials improved serum aminotrans-ase levels as well as steatosis and lobular inflamma-n.155,156 Although no dangerous side effects have beented, the high rates of nausea with this medicationulting in a 50% drop-out rate may limit the clinicallity of this medication.

3-hydroxy-3-methylglutaryl-coenzyme A reduc-e therapy. Medications that exert beneficial effects onid profiles offer another potential therapeutic class ofdications. The most studied of this family of lipid-ering medicines are the statins, which work throughibition of 3-hydroxy-3-methylglutaryl-coenzyme A re-

ctase, which catalyses an essential step in cholesterolsynthesis. Initially statins were noted to cause in-ases in hepatic transaminase levels in patients when

ed to treat hyperlipidemia, and therefore were thought

be harmful to liver function. However, recent studiesve shown statins to be safe when given to patients withFLD.157,158 An early pilot trial with atorvastatin raised

to

TZerest in using statins to treat NASH,159 but a moreent study with simvastatin showed no affect on adi-nectin or improvement in insulin sensitivity in a grouppatients with metabolic syndrome.160 Questions re-in in reference to the specific mechanisms of action ofse drugs and it may be that they have positive effects

yond altering insulin sensitivity or adipocytokine lev-, but these studies have yet to be performed.

Ezetimibe. Ezetimibe (Zetia, Kenilworth, NJ) isother lipid-lowering medication that may have hepaticnefits in the treatment of NASH. This medicationectively inhibits intestinal cholesterol absorption andcontrolled studies with statins appears to lower serumL cholesterol by 24% as well as triglycerides by 16%.161

ecent study by Deushi et al162 showed improved insu-resistance and decreased lipid deposition and fibrosisobese rats treated with ezetimibe. No clinical trials

th this therapy have been published.Angiotensin-receptor blockers. A novel class of

dications that have been evaluated in the treatment ofSH are the angiotensin-receptor blockers. These med-

tions, which have been used to treat hypertension andngestive heart failure, have been shown to have liver-ecific beneficial effects. Obese mice given angiotensin-eptor blockers showed improved serum aminotrans-ase levels and reduced expression of inflammatoryokines and hepatic fibrosis through inhibition of he-tic stellate cell activity.163 Two human pilot studieso have been completed and suggest that angiotensin-eptor blockers may improve serum aminotransferaseels and provide histologic benefit in NASH pa-nts.164,165 Similar to most of the research conducted inards to NASH therapy, large placebo-controlled RCTsrequired to ascertain if any substantial benefit can beieved with long-term angiotensin-receptor blockerrapy in NASH patients.

ConclusionsThe myriad of public health issues related to the

esity epidemic continues to grow as more medicalnditions are linked to obesity, insulin resistance, and

metabolic syndrome. The growing incidence ofFLD, and subsequently NASH, almost certainly willreflected in subsequent increases in cirrhosis and hep-cellular carcinoma in the future. Noninvasive andurate screening tests to correctly identify patients at

k for disease progression as well as effective treatmentimens must be developed for these high-risk patients.rrently, there is no ideal treatment regimen but thoseerventions that produce sustained substantial weights such as bariatric surgery seem to provide the singlest benefit. Modest but sustained weight loss, regularrcise, and diet composition modification also appear

ameliorate biochemical and histologic abnormalities.Thus far, medical therapies with the exception of theDs have not been subjected to randomized, placebo-

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1694 TORRES AND HARRISON GASTROENTEROLOGY Vol. 134, No. 6ntrolled trials and have shown only modest prelimi-ry benefits. The TZDs, although appearing to be effec-e in reducing steatosis, inflammation, and fibrosis areited by small proof-of-concept trials and potentially

toward effect profiles as well as an apparent need forintenance therapy. Other therapies directed at insulinistance, oxidative stress, cytoprotection, and fibrosiso may offer benefit, but further study is required. Altifaceted approach that relies on lifestyle changes,ited weight loss, and pharmacotherapy requires fur-r investigation because no one treatment approach

s proved universally applicable to the large generalpulation with NASH.

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