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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
Conflict of Interest Disclosure Having an interest in an organization does not prevent a speaker from making a presentation, but the audience must be informed of this relationship prior to the start of the activity and any potential conflict must be resolved. In order to ensure balance, independence, objectivity, and scientific rigor at all programs, the planners and faculty must take full disclosure indicating whether the planner, faculty, or content specialist and/or his/her immediate family members have any relationships with sources of commercial support, e.g. pharmaceutical companies, biomedical device manufacturers and/or corporations whose products or services are related to pertinent therapeutic areas. All planners, faculty and content specialists participating in CE activities must disclose to the audience: A. Any relationship with companies that manufacture products used in the treatment of the subjects under discussion B. Any relationship between the planner, faculty, or content specialist and commercial supporter(s) of the activity C. Any intent to discuss the unlabeled or investigational use of a commercial product, or the use of a product not yet approved for the purpose under discussion.
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