NAFLD & NASH - American College of Gastroenterologygi.org/.../uploads/2012/08/12ACG_Midwest_Chalasani_NAFLD_and_NASH.pdfTreatment of liver disease in NAFLD Potential Options ... Alcohol

ACG Regional Course- IndianapolisCopyright ACG 2012

August 2012 1

NAFLD & NASH

Naga Chalasani, MD, FACGProfessor of Medicine and Cellular & Integrative Physiology

Director, Division of GI and HepatologyIndiana University School of MedicineIndiana University School of Medicine

ACG Midwest Regional Course, Indianapolis

Potential ConflictsPotential Conflicts

Conflicts related to NAFLDConflicts related to NAFLD

AmylinAmylin

Conflicts related to DILIConflicts related to DILI

Salix, Vertex, Merck, Salix, Vertex, Merck, SanofiSanofi, GSK, Lilly, Mochida, GSK, Lilly, Mochida

Research SupportResearch Supportpppp

Amylin, Intercept, Lilly, Amylin, Intercept, Lilly, GenFitGenFit, Takeda, Takeda


August 2012 2

Outline

Background and Definitions

Risk Factors

Natural History

Diagnosis

Treatment

Will not discuss pathogenesis, animal models, or newer GWAS data

NAFLDNAFLD

NAFLD is present in 30% US adults and 10NAFLD is present in 30% US adults and 10--15% hild15% hild15% children15% children

Most common cause of elevated liver enzymes Most common cause of elevated liver enzymes in both adults and childrenin both adults and children

Up to 5% US adults may have NASHUp to 5% US adults may have NASH

It t f t 80% f t iIt t f t 80% f t i It may account for up to 80% of cryptogenic It may account for up to 80% of cryptogenic cirrhosiscirrhosis


August 2012 3

Spectrum of Spectrum of NAFLD: NAFL vs. NASHNAFLD: NAFL vs. NASH

Simple fatty liver is histologically characterized by macrovesicular steatosis withcharacterized by macrovesicular steatosis with no additional pathology. Fatty liver is generally considered benign from a hepatic standpoint.

NASH is histologically advanced fatty liver. It i h i d b i i fl iis characterized by steatosis, inflammation, ballooning, and fibrosis. It can lead to cirrhosis and liver failure.

Spectrum of NAFLD

Steatosis (NAFL)

Normal Fibrosis/cirrhosis

Steatohepatitis(NASH)


August 2012 4

Risk Factors for NAFLDRisk Factors for NAFLD

Major CoMajor Co--morbiditiesmorbidities Emerging AssociationsEmerging AssociationsMajor CoMajor Co morbiditiesmorbidities

Type2 Type2 DiabetesDiabetes

DyslipidemiaDyslipidemia

ObesityObesity

Metabolic SyndromeMetabolic Syndrome

Emerging AssociationsEmerging Associations

HypothyroidismHypothyroidism

Sleep ApneaSleep Apnea

HypopituitarismHypopituitarism

HypogonadismHypogonadism

Polycystic Ovary SyndromePolycystic Ovary Syndrome

Lonardo A, et al. J Hepatol 2006; 44: 1196-1207McCullough A et al. J Clin Gastroenterol 2002;34:255-262

Hepatic Outcomes of NAFLDHepatic Outcomes of NAFLD

Simple steatosis is largely benign with minimal Simple steatosis is largely benign with minimal risk of cirrhosisrisk of cirrhosisrisk of cirrhosisrisk of cirrhosis

NASH is progressive with 20% risk of cirrhosis NASH is progressive with 20% risk of cirrhosis over a 10over a 10--yr time horizonyr time horizon

NASH cirrhosis is at moderate risk for HCC (2NASH cirrhosis is at moderate risk for HCC (2--4% per year)4% per year)p y )p y )

Cryptogenic cirrhosis is likely a burntCryptogenic cirrhosis is likely a burnt--out form out form of NASH in up to 80% of patientsof NASH in up to 80% of patients

PostPost--transplant recurrence may occurtransplant recurrence may occur


August 2012 5

Outcomes in NAFLDOutcomes in NAFLDSurrogates # Studies OR [95% CI]

Overall •NAFLD vs. General 8 studies 1.57 [1.18-2.10]OverallMortality

NAFLD vs. General Population

8 studies 1.57 [1.18 2.10]

IncidentCVD

•ALT as a surrogate•GGT as a surrogate•Imaging as a surrogate

6 studies10 studies7 studies

1.10 [0.85-1.41]1.57 [1.42-1.74]2.05 [1.81-2.31]

Incident •ALT as a surrogate 17 studies 1.97 [1.77-2.20]Incident type2 DM

ALT as a surrogate•GGT as a surrogate•Imaging as a surrogate

17 studies12 studies3 studies

1.97 [1.77 2.20]2.74 [2.39 – 3.14]3.51 [2.28-5.41]

Musso G et al. Annals of Medicine 2011

NASH Vs. SteatosisNASH Vs. Steatosis

O # di OR [95% CI]Outcomes # studies OR [95% CI]Overall Mortality 5 studies 1.81 [1.24-2.66]

Liver-related Mortality 5 studies 5.71 [2.31-14.31]

CVD related Mortality 5 Studies 0.01 [0.42-1.98]



August 2012 6

Work up of patients with NAFLD

Imaging to establish the presence of steatosisImaging to establish the presence of steatosis

Meticulous alcohol and medication historyMeticulous alcohol and medication history

Exclusion of coExclusion of co--existing or competing etiologiesexisting or competing etiologies

AutoAuto--antibodies and antibodies and hyperferritinemiahyperferritinemia are are commoncommon

Fasting Fasting lipid profile and measures of insulin lipid profile and measures of insulin resistanceresistance

Liver biopsy to establish the presence of NASHLiver biopsy to establish the presence of NASH

When to biopsy? When to biopsy?

Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease. AASLD, AGA, ACG Practice Guideline. Gastroenterology, Hepatology, AJG 2012


August 2012 7

Surrogate Markers/Predictive ModelsSurrogate Markers/Predictive Models

Predict NASHPredict NASH•• Metabolic SyndromeMetabolic Syndrome

Predict advanced fibrosisPredict advanced fibrosis FibrotestFibrotest•• Metabolic SyndromeMetabolic Syndrome

•• CKCK--18 fragments18 fragments

•• CKCK--18 + 18 + sFassFas

•• Oxidized Fatty acidsOxidized Fatty acids

•• NASH testNASH test

•• NASH Predictive IndexNASH Predictive Index

•• Obesity NAFLD scoreObesity NAFLD score

FibrotestFibrotest

NAFLD Fibrosis ScoreNAFLD Fibrosis Score

BARD scoreBARD score

ELFELF

FibrometerFibrometer

OWL GenomicsOWL Genomics

IU panelIU panelyy

•• NASH Clinical ScoreNASH Clinical Score

•• NAFIC (ferritin, insulin, collagen)NAFIC (ferritin, insulin, collagen)

pp

Transient elastographyTransient elastography

MR elastographyMR elastography


CKCK--18 fragments18 fragments

Circulating CKCirculating CK--18 fragment levels are elevated 18 fragment levels are elevated i NASH ii NASH iin NASH patientsin NASH patients

10 studies (adult and pediatric studies)10 studies (adult and pediatric studies)

Various cutVarious cut--off values, range 121.6 off values, range 121.6 –– 479 U/L479 U/L

Summary estimates:Summary estimates:AUC [95% CI]AUC [95% CI] 0 82 [0 780 82 [0 78 0 88]0 88]AUC [95% CI]:AUC [95% CI]: 0.82 [0.780.82 [0.78--0.88]0.88]

Median Sensitivity: 78%Median Sensitivity: 78%

Median Specificity: 87%Median Specificity: 87%



August 2012 8

Selected Fibrosis ModelsSelected Fibrosis Models# studies AUC [95% CI] Sens Spec

Fibrotest 2 studies ≥ F2 0.78 [0.72-0.85] 76% 74%

NAFLDFibrosis

13 studies ≥F3 0.85 [0.81-0.90] Cut-off-1.455

90% 60%

Score +0.676 64% 97%

BARDScore

6 studies ≥F3 0.78 [0.72-0.84] Cut-off2

72% 64%

ELF 1 study Any fibrosis

0.76 [0.69-0.83] 61% 80%

≥ F2 0.82 [0.75-0.88] 70% 80%

≥F3 0.90 [0.84-0.96] 80% 90%

Fibrotest: α2 macroglobulin, ApoA, haptoglobin, GGT, Total BilirubinNAFLD Fibrosis Score: Age, BMI, Diabetes, AST/ALT ratio, albumin, PlateletsBARD score: BMI > 28, AST/ALT ratio > 0.8, DiabetesELF: Hyaluronic acid, PIIINP, TIMP

NAFLD Fibrosis Scorehttp://nafldscore.comhttp://nafldscore.com

733 patients, 480 estimation group, 253 validation [US UK d A li ]group [US, UK, and Australia]

Independent predictors of advanced (bridging or cirrhosis) fibrosis: Age

BMI

A /A AST/ALT ratio

Hyperglycaemia (FBG >6.1mmol/l or diabetes)

Platelet count

AlbuminAngulo et al Hepatology 2007


August 2012 9

The “ELF” score

A HA PIIIP TIMP Age, HA, PIIIP, TIMP

Derived in400 test cases, validated in 521 Rosenberg, Burt Gastroenterology 2004

http://www.iqur.com/ELFTest.html

How to treat a patient with NAFLD?How to treat a patient with NAFLD?

If a patient has NASH, then attention should If a patient has NASH, then attention should be paid to both metabolic cobe paid to both metabolic co--morbidities as morbidities as well as liver diseasewell as liver disease

However, if a patient has steatosis alone, then However, if a patient has steatosis alone, then attention should be paid to metabolic and attention should be paid to metabolic and cardiovascular morbiditiescardiovascular morbiditiescardiovascular morbidities.cardiovascular morbidities.


August 2012 10

Treatment of liver disease in NAFLDTreatment of liver disease in NAFLD

Potential OptionsPotential Options Life style modificationLife style modification Insulin sensitizersInsulin sensitizers Vitamin EVitamin E Bariatric surgeryBariatric surgery

Tested but do not work:Tested but do not work: UDCA MetforminUDCA MetforminTested but do not work:Tested but do not work: UDCA, MetforminUDCA, Metformin

Under investigation:Under investigation: Pentoxifylline, Obeticholic Pentoxifylline, Obeticholic acid, Eicosapentanoic acid, and many others acid, Eicosapentanoic acid, and many others

Ongoing Phase 3 programsOngoing Phase 3 programs

Intercept 747 (Intercept 747 (ObeticholicObeticholic acid) acid) –– FXR agonistFXR agonistp (p ( )) gg

Phase 3 study through NASH CRNPhase 3 study through NASH CRN

EDAEDA--E (Ethyl Icosapentate) E (Ethyl Icosapentate) –– Phase 3, Phase 3, multicenter study (multicenter study (MedpaceMedpace/Fulcrum/Mochida)/Fulcrum/Mochida)

Combined PPARCombined PPARαα//δδ agonist (agonist (GenFitGenFit))g (g ( ))

Combined pioglitazone/Combined pioglitazone/roflumilastroflumilast (Takeda)(Takeda)


August 2012 11

Lifestyle ModificationLifestyle Modification

Weight loss, either by hypocaloric diet alone or Weight loss, either by hypocaloric diet alone or i j i i h i d h ii j i i h i d h iin conjunction with exercise, reduces hepatic in conjunction with exercise, reduces hepatic steatosissteatosis

Weight loss ~ 5% of body weight is necessary Weight loss ~ 5% of body weight is necessary for improving in steatosisfor improving in steatosis

Weight loss ~ 7Weight loss ~ 7--10% of body weight is10% of body weight is Weight loss 7Weight loss 7--10% of body weight is 10% of body weight is necessary for improving in necroinflammationnecessary for improving in necroinflammation

No data available on specific dietsNo data available on specific diets

Weight loss: Bariatric surgeryWeight loss: Bariatric surgery

Bariatric surgery improves steatosis and may Bariatric surgery improves steatosis and may i i fl i ( d ibli i fl i ( d iblimprove necroinflammation (and possibly improve necroinflammation (and possibly fibrosis) in carefully selected patientsfibrosis) in carefully selected patients

MetaMeta--analysis by Mummadi et al. showed that analysis by Mummadi et al. showed that steatosis, steatohepatitis, and fibrosis appear to steatosis, steatohepatitis, and fibrosis appear to improve following bariatric surgeryimprove following bariatric surgeryp g g yp g g y

However, Cochrane review highlights lack of However, Cochrane review highlights lack of well designed studieswell designed studies

Mummadi RR et al. Clinical Gastro Hepatol 2008Chavez-Tapia NC, et al. Cochrane Database of Systematic Reviews 2010


August 2012 12

Significant Improvement in histology following bariatric surgery

1st biopsy 2nd biopsy at 13 months

Mattar SG et al. Annals of Surgery 2005; 242: 610-620

Significant Improvement in histology following bariatric surgery

1st biopsy 2nd biopsy at 8.5 months

Mattar SG et al. Annals of Surgery 2005; 242: 610-620


August 2012 13

Significant Improvement in Fibrosis

Bariatric Surgery for NASHBariatric Surgery for NASH

Bariatric surgery specifically to treat NASH is Bariatric surgery specifically to treat NASH is hi ihi ipremature at this timepremature at this time

NASH would greatly respond to foregut NASH would greatly respond to foregut bariatric surgerybariatric surgery

It can be performed even in compensated It can be performed even in compensated cirrhotics as long as portal hypertension iscirrhotics as long as portal hypertension iscirrhotics as long as portal hypertension is cirrhotics as long as portal hypertension is absent (no varices and no intraabsent (no varices and no intra--abdominal abdominal collaterals by imaging)collaterals by imaging)


August 2012 14

Insulin SensitizersInsulin Sensitizers

Metformin Metformin –– No role in either adults or childrenNo role in either adults or children

TZDs TZDs –– improve liver histology but weight gain improve liver histology but weight gain is a problem. is a problem.

Rosiglitazone is essentially unavailableRosiglitazone is essentially unavailable

Role of pioglitazone is unclear Role of pioglitazone is unclear –– improves improves hi t l ihi t l i di b ti ith NASH b t it idi b ti ith NASH b t it ihistology in nonhistology in non--diabetics with NASH, but it is diabetics with NASH, but it is not approved in nonnot approved in non--diabetics. Accumulating diabetics. Accumulating evidence for unfavorable safety profile. evidence for unfavorable safety profile.

TZDs for NASHn Agent

Dose

Duration Enzymes Histology

Tetri 3030 Rosi

8 mg

48 weeks Improved Improved steatosis, Inflammation, and

fibrosisfibrosis

Sanyal 2121 Pio

30 mg

6 months N/A Improved steatosis, Inflammation

Belfort 5555 Pio

45 mg

6 months Improved Improved steatosis, Inflammation

Ratziu 6363 Rosi (8 mg) 12 months Improved Improved steatosis

Aithal 7474 Pio 30 mg 12 months Improved Improved Steatos, inflammation and

fibrosis

PIVENS 247247 Pio 30 mg 24 months Improved Improved steatosis, inflammation and

ballooning


August 2012 15

AASLD/AGA/ACG Practice GuidelineAASLD/AGA/ACG Practice Guideline

Vitamin E: PIVENS trialVitamin E: PIVENS trial Multicenter Multicenter RCT, 247 patients, Placebo RCT, 247 patients, Placebo vs. vit E vs. vit E

(800 (800 iuiu/d) vs. pioglitazone (30 mg/d/d) vs. pioglitazone (30 mg/d), 96 ), 96 weeksweeks

Histology primary end Histology primary end pointpoint

Compared to placebo (19%), significantly Compared to placebo (19%), significantly greater proportion of patients in vitamin E greater proportion of patients in vitamin E group (43%) met the primary end point (p<0.01, group (43%) met the primary end point (p<0.01, NNT:4 4NNT:4 4))NNT:4.4NNT:4.4))

TONIC trial in children also showed histological TONIC trial in children also showed histological improvement with vitamin Eimprovement with vitamin E

Sanyal AJ, et al. N Engl J Med 2010; 362:1675-1685Lavine JE, et al. JAMA 2011


August 2012 16

AASLD/AGA/ACG Practice AASLD/AGA/ACG Practice GuidelineGuideline

Alcohol use in patients with NAFLD and Alcohol use in patients with NAFLD and NASHNASH

While heavy drinking is certainly deleterious, While heavy drinking is certainly deleterious, h l i dh l i d hhthere are evolving data to suggest nonthere are evolving data to suggest non--heavy heavy

drinking may have hepatic and metabolic drinking may have hepatic and metabolic benefits.benefits.


August 2012 17

Cardiovascular disease in Cardiovascular disease in NAFLDNAFLD

Heavily enriched with cardiovascular risk factorsHeavily enriched with cardiovascular risk factors Heavily enriched with cardiovascular risk factorsHeavily enriched with cardiovascular risk factors

Increased prevalence of surrogate markers of Increased prevalence of surrogate markers of coronary artery diseasecoronary artery disease

Many studies have shown cardiovascular disease Many studies have shown cardiovascular disease as the single most common cause of death in as the single most common cause of death in ggpatients with NAFLDpatients with NAFLD

General guidelines for managing General guidelines for managing cardiovascular risk in NAFLDcardiovascular risk in NAFLD

A diet low in sodium and simple sugars, with b tit ti f t t d f t f t t d dsubstitution of unsaturated fat for saturated and

trans-fats, and increased consumption of fruits and vegetables. Consumption of food products enriched omega3 fatty acids

Caloric restriction to achieve and maintain ideal body weight. Moderate to vigorous exercise for 30 min to 60 minutes per day most days of the week

Smoking cessation & avoidance of alcohol


August 2012 18

Statins can be used safely in patients with fatty liver

Patients with NAFLD are important targets for Patients with NAFLD are important targets for statins statins

Risk of serious hepatotoxicity from statins is very Risk of serious hepatotoxicity from statins is very rarerare

Patients Patients with underlying liver disease are not at with underlying liver disease are not at higher risk for statin hepatotoxicityhigher risk for statin hepatotoxicity

Case series have shown histological improvement Case series have shown histological improvement g pg pin in NASHNASH

Fish oil is probably the first choice to treat Fish oil is probably the first choice to treat hypertriglyceridemiahypertriglyceridemia

Chalasani N. Hepatology 2005; 41:690-695; Hepatology. 2007;46:1453-63

All patients with NAFLD

Patients with NASH

COMMENTS

Weight Loss Yes Yes 5% Weight loss for improving steatosis & 7-10% weight loss is needed for

improving necro-inflammation.

Management of Yes, as appropriate Yes, as Fish oil is the first line medication for gDyslipidemia

, pp p ,appropriate hypertriglyceridemia & Statins are the

treatment of choice for improving LDL-Cholesterol

Insulin resistance and diabetes

Yes, as appropriate Yes, as appropriate

Metformin improves insulin resistance but has no effect on liver histology.

Bariatric Surgery Will help steatosis and necroinflammation if performed for other indications. Should not be performed to specifically treat NASH Should not beShould not be performed to specifically treat NASH. Should not be

performed in those varices.

Vitamin E No Yes Recent SELECT study showed increased risk of prostate cancer.

Pioglitazone No Yes Weight gain, CHF, bone loss, and bladder cancer (very rarely)


August 2012 19

Take Home MessagesTake Home Messages

Exclude competing etiologies and look for co-existing liver diseases

St t i i h ti ll b i b t NASH i Steatosis is hepatically benign but NASH is progressive and can lead to cirrhosis

Patients with NAFLD are at higher risk for incident type2 diabetes and cardiovascular disease

Liver biopsy can establish the diagnosis of NASH

Management of NAFLD include managing underlying metabolic and cardiovascular risks as well as managing liver disease

Referrals for Clinical TrialsReferrals for Clinical Trials

Naga ChalasaniNaga Chalasani317317--278278--0414 (Office)0414 (Office)

317317--413413--9635 (Cell)9635 (Cell)

h l @i i dh l @i i [email protected]@iupui.edu

Documents

NAFLD & NASH - American College of Gastroenterologygi.org/.../uploads/2012/08/12ACG_Midwest_Chalasani_NAFLD_and_NASH.pdfTreatment of liver disease in NAFLD Potential Options ... Alcohol