Fatty Liver Disease. Donald Gardenier, DNP, FNP-BC, FAANP, FAAN Assistant Professor and Clinical Program Director

Transcription

1 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

2 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

3 Outline Epidemiology Definitions Diagnosis liver biopsy noninvasive serum markers noninvasive imaging Prognosis- noninvasive estimation of fibrosis Treatment

4 Rising Prevalence of NAFLD in the US (NHANES data) NAFLD obesity type 2 DM HTN Younossi Clin Gastro Hepatol 2011

5 Indications for liver transplantation in the United States ( ) Charlton Gastro 2011

6 Spectrum of NAFLD Steatosis NAFL Steatosis with: inflammation ballooning +/-fibrosis +/-Mallory s hyaline +/-megamitochondria Cirrhosis cryptogenic HCC NASH

7 NAFLD Activity Score (NAS) Unweighted sum of: Steatosis (0-3) Lobular inflammation (0-3) Ballooning (0-2) Kleiner Hepatology 2005

8 Perisinusoidal or portal Perisinusoidal and portal bridging cirrhosis

9 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)

10 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% Musso Annals of Medicine 2011, Chalasani Hepatology 2012

11 Survival is decreased in NASH, but not in simple steatosis p = 0.01 p = ns Ekstedt Hepatology 2006

12 Mortality is increased in NASH compared to simple steatosis Musso Ann Med 2011

13 Liver-related mortality is increased in NASH compared to simple steatosis Musso Ann Medicine 2011

14 Take home point #1 Not all patients with fatty liver are the sameimportant to distinguish patients with simple steatosis from those with NASH

15 Diagnosis

16 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

17 Clinical Presentation Asymptomatic Symptomatic liver enzyme elevation fatty liver on imaging Decompensated cirrhosis Hepatocellular carcinoma hepatomegaly fatigue

18 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 * fasting insulin x fasting glucose 22.5 Consider liver biopsy versus noninvasive testing for diagnosis and staging

19 Noninvasive diagnosis of steatosis Ultrasound Sensitivity 83-89% Specificity % CT Sensitivity 86% Specificity 87%

20 Noninvasive diagnosis of steatosis Magnetic Resonance Spectroscopy Transient Elastography- CAP Sensitivity>90%

21 Controlled Attenuation Parameter Karlas PLOS One 2014

22 Magnetic Resonance Elastography Simple steatosis inflammation without fibrosis fibrosis Chen Radiology 2011

23 MR Elastography for distinguishing NASH vs simple steatosis Threshold (kpa) Sensitivity (%) Specificity (%) PPV (%) NPV (%) Chen Radiology 2011

24 Prognosis

25 Natural History of NASH 16% improvement NASH 43% stable N = 68 mean follow-up 13.7 years 41% fibrosis progression 5.4% cirrhosis-related complications Ekstedt Hepatology 2006

26 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: ) FIBROSIS CHANGE Factors associated with fibrosis progression: no change, 128, 36% progression, 128, 35% Ballooning Mallory-Denk bodies Caucasian race regression, 103, 29% AASLD 2013 Abstract #577 (Kleiner, et al)

27 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)

28 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

29 Progression to bridging fibrosis in NAFLD over 4 years Predictors of progression (multivariate model): OR 95% CI p Portal inflammation Acidophil bodies Mallory Denk bodies Metabolic syndrome ALT : (Brunt, et al)

30 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

31 Noninvasive scoring systems 1. NAFLD Fibrosis score ( 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

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33 Multicenter, international study N=320, biopsy proven NAFLD Median follow-up 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

34 Angulo et al, Gastroenterology 2013

35 Angulo et al, Gastroenterology 2013

36 11,154 NHANES III participants ( ) 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 Kim et al, Hepatology 2013

37 Transient elastography (Fibroscan) Wong Hepatology 2010

38 Wong Hepatology 2010

39 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

40 NASH (F3-4) NASH (F0-2) Simple steatosis

41 Treatment

42 Randomized controlled treatment trials for NASH Insulin sensitizers Pioglitazone Belfort NEJM 2006 Rosiglitazone Sanyal NEJM 2010 (PIVENS) Ratziu Gastro 2008 (FLIRT) Ratziu Hepatol 2010 (FLIRT-2) Rosiglitazone + Metformin Torres Hepatol 2011 Vitamin E Pentoxifylline Zein Hepatol 2011 Sanyal NEJM 2010 (PIVENS)

43 Meta Analysis: Insulin sensitizing agents for NASH Musso Hepatology 2010

44 PIVENS trial Non-diabetic adults with NASH n = 247 n = 80 n = 84 n = 83 Pioglitazone 30 mg/day Vitamin E 800 IU/day Placebo 96 weeks Liver biopsy performed before and at end of treatment Primary endpoint: decrease in NAS score by 2 points, no worsening of fibrosis Sanyal NEJM 2010

45 Pioglitazone Vitamin E Placebo Met primary endpoint Improved steatosis Improved inflammation Improved Ballooning Improved Fibrosis 34% (NNT 6.6, p=0.04) + p< p= p=0.08 Improved ALT + p< % (NNT 4.4, p=0.001) + p= p= p= p= % Sanyal NEJM 2010

46 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

47 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

48 Case 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 1/23/12 4/23/12 8/6/12 2/25/12 AST ALT Weight BMI

49 NAFLD: Treatment Approach Overt Metabolic Syndrome (MS) Treat MS Rx DM Anti-HTN Lower lipids Yes Steatosis Treat NAFLD Fibrosis estimation: Physical exams (portal HTN) Blood tests (platelets, AST/ALT) Fibrosis assessment (Fibroscan, MRE, liver biopsy) Steatohepatitis No Cirrhosis Reduced kcals Exercise Enroll in trial Rx portal HTN Screen for HCC OLT

50 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

51 Acknowledgement Charissa Chang, MD

52 Thank You