Fatty Liver Disease

Donald Gardenier, DNP, FNP-BC, FAANP, FAAN Assistant Professor and Clinical Program Director

Icahn School of Medicine at Mount Sinai New York, NY

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I have no conflict disclosures � I will discuss therapies under investigation

Outline

• Epidemiology • Definitions • Diagnosis

liver biopsy noninvasive serum markers noninvasive imaging

• Prognosis- noninvasive estimation of fibrosis • Treatment

Rising Prevalence of NAFLD in the US (NHANES data)

0

5

10

15

20

25

30

35

40

1988-1994 1994-2004 2005-2008

NAFLD obesity type 2 DM HTNYounossi Clin Gastro Hepatol 2011

Indications for liver transplantation in the United States (2001-2009)

Charlton Gastro 2011

Spectrum of NAFLD

Steatosis Steatosis with: inflammation ballooning +/-fibrosis +/-Mallory’s hyaline +/-megamitochondria

Cirrhosis cryptogenic HCC

NASH NAFL

Kleiner Hepatology 2005

NAFLD Activity Score (NAS)

• Unweighted sum of: Steatosis (0-3) Lobular inflammation (0-3) Ballooning (0-2)

Perisinusoidal or portal

Perisinusoidal and portal

bridging

cirrhosis

Definitions

• Nonalcoholic fatty liver disease (NAFLD) includes simple steatosis

• Nonalcoholic steatohepatitis (NASH) • “Nonalcoholic” =

< 21 drinks/week (men) < 14 drinks/week (women) (AASLD/AGA Guidelines 2012, Level 2c)

Musso Annals of Medicine 2011, Chalasani Hepatology 2012

Prevalence of NAFLD/NASH

NAFLD NASH General adult population, US 17-50% 3-5% Metabolic syndrome 59% Dyslipidemia 50% Diabetes 50-70% 25-30% Obese 70% 25-30% Morbidly obese 90% 35%

Ekstedt Hepatology 2006

p = 0.01

Survival is decreased in NASH, but not in simple steatosis

p = ns

Mortality is increased in NASH compared to simple steatosis

Musso Ann Med 2011

Liver-related mortality is increased in NASH compared to simple steatosis

Musso Ann Medicine 2011

Take home point #1

• Not all patients with fatty liver are the same- important to distinguish patients with “simple steatosis” from those with NASH

Diagnosis

Challenges in the Diagnosis of NASH

• Routine imaging does not distinguish between simple steatosis and NASH

• Aminotransferases not reliable for diagnosis or staging

• Liver biopsy subject to sampling variability

Clinical Presentation

Asymptomatic Symptomatic

liver enzyme elevation fatty liver on imaging

Decompensated cirrhosis Hepatocellular carcinoma

hepatomegaly fatigue

Approach to Diagnosis of NASH:

Abnormal LFTs 1. Rule out other causes (viral, ETOH, autoimmune)

2. Imaging: ultrasound

Fatty liver on imaging

Assess for insulin resistance (HOMA*) and metabolic syndrome

rule out secondary causes of fatty liver

Consider liver biopsy versus noninvasive testing for diagnosis and staging

*fasting insulin x fasting glucose ___________________

22.5

Ultrasound Sensitivity 83-89% Specificity 93-100%

CT Sensitivity 86% Specificity 87%

Noninvasive diagnosis of steatosis

Noninvasive diagnosis of steatosis

Magnetic Resonance Spectroscopy

Transient Elastography- CAP

Sensitivity>90%

Controlled Attenuation Parameter

Karlas PLOS One 2014

Magnetic Resonance Elastography

Chen Radiology 2011

Simple steatosis inflammation without fibrosis fibrosis

MR Elastography for distinguishing NASH vs simple steatosis

Chen Radiology 2011

Threshold (kPa)

Sensitivity (%)

Specificity (%)

PPV (%) NPV (%)

2.74 94 73 85 89

2.90 83 82 88 75

Prognosis

Ekstedt Hepatology 2006

Natural History of NASH

5.4% cirrhosis-related complications

41% fibrosis progression

43% stable

16% improvement

N = 68 mean follow-up 13.7 years

NASH

Natural History of Non-alcoholic Fatty Liver Disease in Adults: A Paired Biopsy Study from the NASH CRN

• n=359 patients mean age 47 mean time between biopsies: 4.4 years (range: 1 – 17.3) Factors associated with fibrosis

progression: Ballooning Mallory-Denk bodies Caucasian race

progression, 128, 35%

regression, 103, 29%

no change, 128, 36%

FIBROSIS CHANGE

AASLD 2013 Abstract #577 (Kleiner, et al)

Progression to bridging fibrosis in NAFLD over 4 years

• Aim: Identify predictors of progression to advanced stage NASH

• Methods: adults enrolled in NASH CRN with paired biopsies first biopsy fibrosis stage < 3 endpoint- progression to bridging fibrosis or cirrhosis

• Compare baseline factors between progressors vs non-progressors

AASLD 2013 Abstract #602: (Brunt, et al)

Progression to bridging fibrosis in NAFLD over 4 years

• Results: 270 patients mean 4.4 years between biopsies 16% with progression to bridging fibrosis/cirrhosis

• Statistically significant baseline predictors of progressors as compared to non-progressors: older age higher ALT, AST, glucose DM metabolic syndrome

2013 Brunt, et al

Progression to bridging fibrosis in NAFLD over 4 years

Predictors of progression (multivariate model): OR 95% CI p

Portal inflammation 2.14 1.01-4.53 0.047

Acidophil bodies 2.3 1.03-5.16 0.04

Mallory Denk bodies 4.91 1.68-14.37 0.004

Metabolic syndrome 6.46 0.98-42.53 0.05

ALT 5.24 1.78-15.40 0.003

2013: (Brunt, et al)

Take home point #2: fibrosis matters

• Patients with NASH have a variable prognosis • Older age, metabolic syndrome/DM, and

elevated ALT correlate with progression to advanced fibrosis

• Baseline histologic features aid in prediction of fibrosis progressors

• Consider liver biopsy in patients with these high risk clinical features for fibrosis staging and prognosis estimation

Noninvasive scoring systems

1. NAFLD Fibrosis score (http://nafldscore.com) age, BMI hyperglycemia platelet count, albumin AST/ALT ratio

2. APRI AST/platelet ratio index

3. FIB-4 score age, AST, platelets, ALT

4. BARD score BMI, AST, ALT, DM

Angulo et al, Gastroenterology 2013

• Multicenter, international study • N=320, biopsy proven NAFLD • Median follow-up 104.8 months (range 3-317) • 50% fibrosis stage 3-4 • Liver related outcomes: ascites, variceal bleeding, SBP, HCC,

HPS, HRS • Overall rates for liver-related adverse events or death/OLT:

14% and 13%

Angulo et al, Gastroenterology 2013

Angulo et al, Gastroenterology 2013

Kim et al, Hepatology 2013

• 11,154 NHANES III participants (1988-1994) • 4,083 individuals (34%) with NAFLD based on ultrasound/clinical parameters • Followed for mortality until 2006 using National Death Index • Median f/u 14.5 years • Baseline NAFLD-FS, APRI, FIB-4 scores as a predictor of death

Transient elastography (Fibroscan)

Wong Hepatology 2010

Wong Hepatology 2010

Summary: diagnosis/staging

• Liver biopsy remains gold standard for diagnosis and staging of NASH

• Noninvasive diagnosis of steatosis: conventional imaging Transient elastography/CAP MR Spectroscopy

• Noninvasive estimation of fibrosis: NAFLD Fibrosis score MR Elastography Transient Elastography

NASH (F3-4)

NASH (F0-2)

Simple steatosis

Treatment

Randomized controlled treatment trials for NASH

• Insulin sensitizers Pioglitazone Belfort NEJM 2006

Sanyal NEJM 2010 (PIVENS)

Rosiglitazone Ratziu Gastro 2008 (FLIRT)

Ratziu Hepatol 2010 (FLIRT-2)

Rosiglitazone + Metformin Torres Hepatol 2011

• Vitamin E Sanyal NEJM 2010 (PIVENS)

• Pentoxifylline Zein Hepatol 2011

Meta Analysis: Insulin sensitizing agents for NASH

Musso Hepatology 2010

Sanyal NEJM 2010

Non-diabetic adults with NASH

Pioglitazone 30 mg/day

Vitamin E 800 IU/day Placebo

n = 247

n = 80 n = 84 n = 83

96 weeks

Liver biopsy performed before and at end of treatment Primary endpoint: decrease in NAS score by 2 points, no worsening of fibrosis

PIVENS trial

Pioglitazone Vitamin E Placebo

Met primary endpoint

34% (NNT 6.6, p=0.04)

43% (NNT 4.4, p=0.001)

19%

Improved steatosis

+ p<0.001

+ p=0.005

Improved inflammation

+ p=0.004

+ p=0.02

Improved Ballooning

+ p=0.08

+ p=0.01

Improved Fibrosis

- -

Improved ALT + p<0.001

+ p=0.001

Sanyal NEJM 2010

Challenges in identifying pharmacologic treatment for NASH

• Rebound effect after discontinuation of treatment • Long term safety concerns:

Rosiglitazone Rosen NEJM 2010 Vitamin E Miller Ann Int Med 2005 Klein JAMA 2011

• Identification of appropriate therapeutic targets insulin resistance inflammation altered lipid metabolism fibrosis

• Validation of noninvasive markers to assess therapeutic response

Current management approach

• Lifestyle modification weight loss (3-5% improves steatosis >9% improves necroinflammation) exercise diet

• Diagnose and manage any comorbid features of metabolic syndrome

• Identify patients with advanced fibrosis/cirrhosis

Case

1/23/12 4/23/12 8/6/12 2/25/12

AST 217 38 25 20

ALT 320 68 24 20

Weight 244 220 209 204

BMI 37 33 32 31

28yoF elevated LFTs in the setting of 30# wt gain AST 178/ALT 255 Stage 3 NASH on biopsy 2011 h/o comorbid hypothroidism, HOMA 2.2 Treatment regimen: Vitamin E, diet, exercise

Steatosis Cirrhosis Steatohepatitis

Overt Metabolic Syndrome (MS)

Yes No

Treat MS Rx DM Anti-HTN Lower lipids

Treat NAFLD Fibrosis estimation: Physical exams (portal HTN) Blood tests (platelets, AST/ALT) Fibrosis assessment (Fibroscan, MRE, liver biopsy)

Reduced kcals Exercise

Enroll in trial Rx portal HTN Screen for HCC OLT

NAFLD: Treatment Approach

Summary

• Prevalence of NASH is rising • Important to distinguish between individuals with NASH vs.

simple steatosis • Of those with NASH, identify and target ones with advanced

fibrosis • Noninvasive alternatives to liver biopsy are available and have

reasonable sensitivity for detection of steatosis and advanced fibrosis. These have not yet been validated as markers of treatment response

• Liver biopsy remains the gold standard for diagnosis and treatment trial endpoints

• Ongoing treatment trials targeting insulin resistance, lipid metabolism, and fibrosis

Acknowledgement

Charissa Chang, MD

Thank You