Evaluating Obese Persons With Abnormal Liver Chemistries

Transcription

1 Mary E. Rinella, MD, FAASLD Evaluating Obese Persons With Abnormal Liver Chemistries Postgraduate Course: Challenges in Management of Common Liver Diseases 275 1

2 25 year old obese Hispanic man with obesity, type 2 diabetes and elevated ALT o Referred by PCP due mild persistent elevation in ALT/AST (70/63), other liver chemistries normal over past year o PMHx: Dyslipidemia (untreated) and DM o Family Hx: DM and hypothyroid (mother), etoh cirrhosis (father) o Meds: None o Physical Exam: BP 130/85, BMI 32, + acanthosis nigricans, no stigmata of cirrhosis, cardiopulmonary exam normal, + central obesity, liver 3 cm below costal margin, no splenomegaly, skin and nails normal o Ultrasound: Increased echogenicity, suggestive of fatty infiltration AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES 2

3 Clinical Questions o Is this NAFLD or something else? What is common and needs to be ruled out? o How to differentiate NAFLD from NASH? o Is a liver biopsy necessary? o How reliable is non invasive assessment of liver fibrosis in NAFLD? 2016 AMERICAN ASSOCIATION 277 FOR THE STUDY OF LIVER DISEASES 3

4 Is this NAFLD or something else? 2016 AMERICAN ASSOCIATION 278 FOR THE STUDY OF LIVER DISEASES 4

5 How reliable is ultrasound in diagnosis of NAFLD? Findings: Bright liver Echotexture increased compared to kidney Vascular blurring Considerations: Changes consistent with NAFLD may not be detected if <30% of liver has fat * US findings for fatty liver cannot be distinguished from those of early cirrhosis 2016 AMERICAN ASSOCIATION 279 FOR THE STUDY OF LIVER DISEASES 5

6 What diseases need to be excluded in this patient? EtOH Autoimmune liver disease Wilson s Disease Common, father w/ alcoholism Mother with hypothyroidism Age, devastating if not treated Viral hepatitis Risk factors, can t miss this 2016 AMERICAN ASSOCIATION 280 FOR THE STUDY OF LIVER DISEASES 6

7 Other causes of hepatic steatosis o o o Toxins/Drugs Etoh Meds: Valproic Acid*,Anti-retrovirals, Amiodarone*, Methotrexate, Tamoxifen* Reye s syndrome* Jamaican Vomiting sickness Industrial toxins (paint thinners); petrochemicals; rapeseed cooking oil Viral Hepatitis C (genotype 3 = viral steatosis; Gt 1,4 exacerbates IR = metabolic steatosis) Acute HDV * Nutritional Starvation, rapid weight loss, pancreatic insufficiency (protein calorie malnutrition) Parenteral nutrition Hypo- and abetalipoproteinemia L-Carnitine deficiency o o o Metabolic Wilson disease Lipodystrophy Genetic Inborn errors of metabolism (e.g., LCAT deficiency, cholesterol ester storage disease, lysosomal acid lipase deficiency)* Tyrosinemia Galactosemia Hereditary fructose intolerance Cystinuria Other Cystic Fibrosis (in up to 60%) Acute fatty liver of pregnancy * Heat Stroke* Cocaine Ischemia and reperfusion injury Hepatic regeneration Aging Hypothyroidism 2016 AMERICAN ASSOCIATION 281 FOR THE STUDY OF LIVER DISEASES 7 Adapted from Brunt, E. M. et al. (2015) Nonalcoholic fatty liver disease Nat. Rev. Dis. Primers doi: /nrdp

8 A Adapted from Rinella ME, JAMA 2015 NAFLD ~70-75% ~20-25% Isolated steatosis Steatosis with mild inflammation Possible sampling variability with poorly defined risk of progression <4% 20% C 2016 AMERICAN ASSOCIATION 282 FOR THE STUDY OF LIVER DISEASES 8 D B NASH Risk Factors in our patient Central obesity Diabetes HTN Persistent elevation in ALT Family history of T2DM Mexican ethnicity (?PNPLA3)

9 Global Prevalence of NAFLD: Variable and Correlates with Obesity 24.1% 23.7% 31.8% 27.4% 13.5% 30.5% <1,600 1,800 2,000 2,200 2,400 2,600 2,800 3,000 3,200 3,400 3,600 >3,600 kcal/day Rinella, ME & Charlton, M. The Globalization of Nonalcoholic Fatty Liver Disease: Prevalence and Impact on World Health Hepatology. 2016, epub; Younossi et al. Hepatology AMERICAN ASSOCIATION 283 FOR THE STUDY OF LIVER DISEASES 9

10 A large percentage of the U.S. population is affected by NAFLD NAFLD: 19-45% NASH: 5 % NASH cirrhosis: 1.25 % US population 320,000,000 NAFLD 96,000,000 NASH 16,000,000 NASH cirrhosis 3,200, AMERICAN ASSOCIATION 284 FOR THE STUDY OF LIVER DISEASES 10

11 Association between NAFLD/NASH and DM is bidirectional Diabetics have o Increased risk of dying from cirrhosis o 3x risk of chronic liver disease, mostly NAFLD o Increased risk of advanced liver disease o Increased risk of NASH with family history of DM Those with NAFLD/NASH have o Approximately 4-fold increased risk of DM o More than additive risk when added to other risks: o Obesity, NAFLD, IR each: 2x risk of DM o All 3: 14x de Marco R, et al. The Verona Diabetes Study. Diabetes Care 1999; Campbell PT et al. Diabetes Care 2012; Zoppini et al. AJG 2014; Balkau et al BMC Gastro 2010; Angulo, Hepatology 1999; Ratziu, Gastroenterology 2000; Loomba et al. Hepatology 2012 Kasturiratne et al. JGK 2013; Shibata et al. Diabetes Care 2007; Sung KC,et al. J Clin Endocrinol Metab 2013; Ekstedt et al Hepatology AMERICAN ASSOCIATION 285 FOR THE STUDY OF LIVER DISEASES 11

12 Clinical predictors of NASH Age Gender Race HTN * Central obesity * Dyslipidemia ( TG, HDL) * Insulin resistance/ Diabetes * AST/ALT ratio >1 Low platelets Greater duration of disease Post-menopausal women accelerated disease Hispanic, Asian > Caucasian >> AA Risk increases with additional features of the Metabolic Syndrome * 66% prevalence of bridging fibrosis if age > 50 years and patient obese or diabetic 1-2 Suspicion for NASH cirrhosis Persistently elevated ALT * Based on ATP III criteria 1 Angulo, Hepatology 1999; 2 Ratziu, Gastroenterology 2000 Can be associated with more disease progression 2016 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES

13 ALT elevation in NAFLD: not reliable for diagnosis/prognosis Persistently elevated ALT can be associated with disease progression Patients with a normal ALT level can also develop progressive disease 60% with advanced disease can have normal ALT Diabetics with normal ALT have a high prevalence of NAFLD (76%) and NASH (56%) Mofrad et al. Hepatology 2003; Amarapurkar et al. Trop Gastroenterol ; Maximos et al. Hepatology 2015; Portillo Sanchez et al. J Clin Endocrinol Metab 2014

14 Diagnosis of NAFLD LIVER ENZYMES ALT GGT IMAGING Ultrasound Overall 1 >33% 2 <20-30% 2 Sensitivity Specificity Comments 45% 53% 85% 93% 20-30% 85% 65% 94% CT w/o contrast >30% 3 79% 97% 60% with advanced disease can have normal ALT None can distinguish NASH from IHS Cheap, accessible Fibrosis and steatosis have similar features None of these imaging modalities can distinguish NASH from non-nash NAFLD Better in morbid obesity Affected by iron, fibrosis Less accurate with less steatosis MRI Overall PDFF (>6.4%, >gr 1) 4 (17.4%, > gr 2) Spectroscopy HISTOLOGY Liver Biopsy 86% 64% Near 100% 83% 96% Near 100% 98%-100% 100% GOLD standard Sampling Error, Invasive Can detect mild steatosis and quantify hepatic fat most accurately 1 Hernaez et al Hepatology 2011; 2 Dasarathy S et al. J Hepatol. 2009; 3 Rogier et al. Liver Trans 2015; 4 Tang et al. Radiology

15 Non-invasive assessment of inflammation and injury (NASH) not ready for prime time Briohny Smith and Leon Adams, AMERICAN ASSOCIATION 289 FOR THE STUDY OF LIVER DISEASES 15

16 How reliable is non invasive assessment of liver fibrosis in NAFLD? o Laboratory tests Calculated from clinical and lab parameters Serum tests reflecting activation of the fibrogenic process o Imaging techniques 2016 AMERICAN ASSOCIATION 290 FOR THE STUDY OF LIVER DISEASES 16

17 Fibrosis staging in NASH Stage 1: Perisinusoidal Stage 2: Perisinusoidal + portal Stage 3: Bridging fibrosis Stage 4: Cirrhosis 2016 AMERICAN ASSOCIATION 291 FOR THE STUDY OF LIVER DISEASES 17

18 Non invasive assessment of liver fibrosis in NAFLD * * Brunt, E. M. et al. (2015) Nonalcoholic fatty liver disease Nat. Rev. Dis. Primers McPherson et al. Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis Am J Gastro 2016, epub 2016 AMERICAN ASSOCIATION 292 FOR THE STUDY OF LIVER DISEASES 18

19 NAFLD (Angulo) Fibrosis Score Impaired Fasting Glucose/Diabetes? Yes Age: 25 AST: 63 ALT: 70 Platelet Count: 200 BMI: 32 Albumin: 4 FIB4 Age: 25 AST: 63 ALT: 70 Platelet Count: 200 Gihep.com NFS Formula : age (years) BMI (kg/m 2 ) IFG/diabetes (yes = 1, no = 0) AST/ALT ratio platelet ( 10 9 /L) 0.66 albumin (g/dl) Fib 4 Formula : ( Age x AST ) / ( Platelets x ( sqr ( ALT ) ) 2016 AMERICAN ASSOCIATION 293 FOR THE STUDY OF LIVER DISEASES 19 Angulo P et al. Hepatology. 2007, Martínez SM1, Crespo G, avasa M, Forns X. Noninvasive assessment of liver fibrosis. Hepatology Jan;53(1):325-35

20 NAFLD (Angulo) Fibrosis Score FIB4 Impaired Fasting Glucose/Diabetes? Yes Age: 25 AST: 63 ALT: 70 Platelet Count: 200 BMI: 32 Albumin: 4 Calculate: < : F0-F : Indeterminate > 0.675: F3-F4 Note: Performance characteristics may not be accurate at extremes of age Age: 25 AST: 63 ALT: 70 Platelet Count: 200 Calculate: Interpretation: < 1.30 = F0-F1 > 2.67 = F3-F4 Gihep.com 0.94 NFS Formula : age (years) BMI (kg/m 2 ) IFG/diabetes (yes = 1, no = 0) AST/ALT ratio platelet ( 10 9 /L) 0.66 albumin (g/dl) Fib 4 Formula : ( Age x AST ) / ( Platelets x ( sqr ( ALT ) ) 2016 AMERICAN ASSOCIATION 294 FOR THE STUDY OF LIVER DISEASES 20 Angulo P et al. Hepatology. 2007, Martínez SM1, Crespo G, avasa M, Forns X. Noninvasive assessment of liver fibrosis. Hepatology Jan;53(1): McPherson et al. Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis Am J Gastro 2016, epub

21 Comparison of NASH Stage 0-2 vs. 3-4 Negative Predictive Value: NAFLD Fib Score: 92% FIB-4: 95% BARD: 95% AST/ALT: 93% APRI: 84% Strength of non-invasive fibrosis predictive tests is in their ability to exclude advanced disease Least accurate in identifying middle ranges of fibrosis May be less accurate age <35 and >65 McPherson, Gut 2010; McPherson et al. Am J Gastro 2016, epub 2016 AMERICAN ASSOCIATION 295 FOR THE STUDY OF LIVER DISEASES 21

22 Elastography for NASH Fibrosis Vibration controlled transient elastography (VCTE) (Fibroscan ) Predicts presence of advanced fibrosis Predicts risk of decompensation and complications Correlates with portal pressure Can quantify steatosis (CAP) Most widely used Shear wave elastography (SWE) Uses acoustic radiation force impulse (ARFI) technology pswe: ARFI 2-D SWE: Supersonic shear imaging (SSI) MR Elastography 2016 AMERICAN ASSOCIATION 296 FOR THE STUDY OF LIVER DISEASES 22

23 Diagnostic performance of SSI, Fibroscan and ARFI *M probe only Cassinotto et al., Hepatology AMERICAN ASSOCIATION 297 FOR THE STUDY OF LIVER DISEASES 23

24 Magnetic Resonance Elastography Low Stiffness High Simple Steatosis Inflammation, but no Fibrosis Most accurate of radiologic stiffness measures Fibrosis Can accurately predict or exclude advanced fibrosis Less accessible and more costly than US based options *Can detect even minimal steatosis 2016 AMERICAN ASSOCIATION 298 FOR THE STUDY OF LIVER DISEASES 24 Imajo et al. Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Than Transient Elastography. Gastroenterology 2016 Mar;150(3):

25 3D MRE is better than 2D MRE AUROC = P< AUROC = P< AUROC = P< AMERICAN ASSOCIATION 299 FOR THE STUDY OF LIVER DISEASES Loomba et al. AJG 2016

26 Non invasive assessment of liver fibrosis: Confounders Tapper et al. CGH AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES 26

27 Non invasive assessment of liver fibrosis in guiding treatment and monitoring progression o We are able to assess changes in steatosis o Reduction in ALT correlates with histological improvement o Limited data on non-invasive markers (FIB4) o No data using elastography to assess response to intervention published 2016 AMERICAN ASSOCIATION 301 FOR THE STUDY OF LIVER DISEASES 27

28 Dynamic assessment of fibrosis using kinetic biomarkers in guiding treatment and monitoring progression Decaris et al. in press Hepatology AMERICAN ASSOCIATION 302 FOR THE STUDY OF LIVER DISEASES 28

29 Is a liver biopsy necessary in our patient? 2016 AMERICAN ASSOCIATION 303 FOR THE STUDY OF LIVER DISEASES 29

30 The role of liver biopsy Isolated steatosis Steatohepatitis/NASH o Making diagnosis of NASH (surrogates insufficient) Initiate drug therapy Assess prognosis: Liver, cardiovascular etc. o Stage fibrosis If MRE, Fibroscan or serum markers indeterminate o Rule out concomitant liver disease Autoimmune, Wilsons, DILI Iron overload 2016 AMERICAN ASSOCIATION 304 FOR THE STUDY OF LIVER DISEASES 30

31 Back to our case NAFLD confirmed, but risk factors for AIH Diabetes, HTN, dyslipidemia Persistent elevation in ALT Mexican ethnicity FIB 4: 0.94 (low risk) NFS: (indeterminate) Fibroscan : 10 kpa, 10%IQR Rinella and Sanyal, Nature Reviews Gastroenterology and Hepatology AMERICAN ASSOCIATION 305 FOR THE STUDY OF LIVER DISEASES 31

32 Back to our case NAFLD confirmed, but risk factors for AIH Diabetes, HTN, dyslipidemia Persistent elevation in ALT Mexican ethnicity FIB 4: NFS: Fibroscan: 10 kpa, 10%IQR Rinella and Sanyal, Nature Reviews Gastroenterology and Hepatology AMERICAN ASSOCIATION 306 FOR THE STUDY OF LIVER DISEASES 32

33 Clinical take home points Is this NAFLD or something else? Its NAFLD, likely NASH (exclude other diseases) How to differentiate NAFLD from NASH? How reliable is non invasive assessment of liver fibrosis in NAFLD? Is a liver biopsy necessary? Use clinical predictors and noninvasive tests to guide decisions Reliable to exclude advanced fibrosis, very good to identify advanced fibrosis (caveats) Yes: Risk factors for NASH and progression Persistently elevated ALT 2016 AMERICAN ASSOCIATION 307 FOR THE STUDY OF LIVER DISEASES 33