Fatty Liver in HIV. Richard K. Sterling, MD, MSc, FACP, FACG

Transcription

1 Fatty Liver in HIV Richard K. Sterling, MD, MSc, FACP, FACG Professor of Medicine Chief, Section of Hepatology Director, HIV-Liver Disease Virginia Commonwealth University

2 Liver-Related Deaths in HIV 1246 deaths in 23,441 HIV+ pts followed for 3.5 yrs 22% HCV, 8% HBV % HIV/AIDS Liver Cardiovascular Non-AIDS Ca Other D:A:D Study Arch Int Med 2006

3 Liver Disease in HIV Viral hepatitis B and C Alcohol Steatohepatitis HIV Medications Opportunistic Infections TB, MAI, PCP, CMV

4 Objectives Scope of the problem Pathophysiology of steatohepatitis Clinical consequences

5 How Common Is Liver Disease in HIV? % HCV + HCV - % > ULN AST ALT JID 2005;192:

6 Prevalence of Abnormal Liver Enzymes*: VCU HIV Clinic N = HCV - HCV AST ALT ALP Sterling et al. DDS 2008 * Defined as > 1.25 ULN

7 Steatosis in HIV-HCV and HCV Author Year HIV-HCV HCV % Steatosis % Steatosis p N N HIV-HCV HCV Sulkowski Monto Marks McGovern Bani-Sadr Gaslightwala <.001 Castera <.001 Neau Rodriguez- Torres Borghi Verma Sterling Machado MV et al. Hepatology 2010;52:71-78

8 Factors with a significant association with the prevalence of hepatic steatosis in HIV/HCV-coinfected patients are mostly related to the Metabolic Syndrome. Machado MV et al. Hepatology 2010;52:71-78

9 The metabolic syndrome (syndrome-x) ATP III criteria: 3 or more of the following Abdominal obesity (waist > 102 cm for men, > 88 cm for women) Triglycerides > 150mg/dl HDL < 40 mg/dl for men, < 50 mg/dl for women BP > or = 130/85 Fasting blood glucose > or = 110 mg/dl

10 Metabolic Syndrome Dyslipidemia Obesity NAFLD Diabetes Hypertension

11 Prevalence of the metabolic syndrome in the US Adapted from Ford et al, JAMA, 287: , Based on 2000 census N= 47 million in US males females >70 Age range (yrs)

12 Persons Living with HIV/AIDS in USA CDC Surveillance Program 33.3% 25.4% 17.1% 19.7% By 2015, 50% of the HIV population will be 50 and older Centers for Disease Control and Prevention. HIV Surveillance Report, 2010; vol. 22.

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

14 Non-alcoholic Fatty Liver (NAFLD) 101 Spectrum of conditions Simple steatosis (NAFL) NASH Most common cause of elevated liver enzymes 14-34% (NAFLD) 3% (NASH) Associated with insulin resistance (IR) Decreased adiponectin (and adiponectin resistance) Increased FFA, leptin and TNF-α and IL6 Fat may not be present once cirrhosis develops Cryptogenic cirrhosis US may only detect >30% steatosis Remember Non-alcohol = < 21 alcohol drinks/week in men (<3/d) and <14 drinks/week (<2/d) in women

15 Associations with NAFLD Author Obesity Diabetes Lipid HTN Ludwig 90% 25% 67% 15% Powell 95% 36% 62% ND Bacon 39% 21% 21% 18% Angulo 60% 28% 27% ND Harrison 75% 45% ND 68% Chitturi 57% 29% ND ND Adapted from Stengel and Harrison Gastroenterology and Hepatology 2006;2:

16 Simple steatosis NAFLD vs. NASH NASH Pericellular Fibrosis

17 Causes of NAFLD The metabolic syndrome Drugs (steroids, diltiazem, amiodarone, ddi/d4t, PI) Lipodystrophy (HIV vs others) Congenital lipid disorders (abetalipoproteinemia) TPN Short bowel Chronic inflammatory disorders Wilson Disease HCV (genotype 3) Hypothyroid Unrecognized alcohol use

18 Natural History of NAFLD >80% Isolated fatty liver No increased morbidity or mortality NAFLD <20% NASH Increased morbidity and mortality CVD Liver-related Malignancy Adapted from Torres et al. CGH 2012;10: Cirrhosis 1-3%/yr HCC 2-3%/yr Decompensation 3-5%/yr

19 Prevalence of NAFLD Ethnic Variation % San Antonio (1) Dallas (2) 0 Overall Hispanic White AA NASH NASH among NAFLD 1. Gastroenterology 2011;140: Hepatology 2004;40: Adapted from Torres et al. CGH 2012;10:

20 Can you predict NASH in those with steatosis? No NASH NASH p N % Male T2DM MS AST (U/L) <.0001 ALT (U/L) <.0001 AST/ALT gggt (U/L) <.0001 HOMA-IR <.0001 Model including labs, demographics AUROC = 0.79 Adapted from: Hepatology 2010;52:

21 NASH and normal ALT Adapted from Mofrad et al, Hepatology, 2003 ALT (I.U./L) upper limit of normal 0 none portal bridging cirrhosis stage of fibrosis

22 Non-Invasive Assessment of NAFLD (never assessed in those with HIV) Model Components Cutoffs AUROC PPV NPV APRI AST, PLT <0.5 & > FIB-4 AST, ALT, Age, PLT <1.3 & > BAAT ALT, BMI, age, TG < BARD AST/ALT>.8, BMI>28, DM NAFLDscore* AST, ALT, Age, PLT, BMI, Albumin European Liver Fibrosis Fibrosure <-1.45 & > Age, TIMP1, PIIINP, HA Α2macroglobulin, apolipoprotein A1, haptoblobi9n, bilirubin, GGT * >50% will have intermediate range

23 Insulin resistance FFA -> lipotoxicity Leptin Adiponectin Oxidative stress Cytokines TNF-α IL-6 Pathophysiology of NASH The Players

24 NAFLD Pathophysiology fibrosis IL-6 Insulin Resistance inflammation ROS lipid peroxidation Increased lipolysis and lipogenesis FFA Adipokines: TNF α leptin adiponectin Adipocyte

25 The two hit hypothesis Insulin Resistance Reduced ability of insulin to suppress endogenous glucose production and increase glucose uptake by fat and muscle. Blunted insulin-mediated suppression of FFA release from adipocytes and reduced FA oxidation 1 st hit Lipid accumulation Mostly TG from excess FFA influx from higher rates of lipolysis with increased leptin and decreased adiponectin with decreased in FA oxidation Increased Mitochondrial Oxidative stress Reactive oxygen species production 2 nd hit Lipid peroxidation Cytokine induction FAS ligand induction Fibrosis NASH

26 Clinical Conditions Associated with NAFLD Cardiovascular Disease Pancreatic Steatosis Diabetes PCOS Increased Ferritin Hyperuricemia Hepatocellular Carcinoma Cirrhosis NAFLD Hypothyroidism Vitamin D Deficiency Adenomatous Colon Polyps Obstructive Sleep Apnea Adapted from Torres et al. CGH 2012;10:

27 Treatments for NASH Dietary Effect Comments Weight loss (7-10%) Reduce daily calories by kcal Reduce high fructose from diet Omega 3 FA Improves histology Increases lipogenesis Improves TG, may reduce steatosis <50% able to comply No data on improvement in fibrosis No prospective data High Fructose risk for NAFLD Need about 1g/d Reduced CVD Coffee (2-3 cups/d) Decrease risk of fibrosis I like coffee Exercise Effect Comments min 4-5 x week Improves LFTs and steatosis Need to combine with diet Pharmacology Effect Comments Vitamin E ( IU/d) Pioglitazone (30-45mg/d) Improves fat and inflammation Long term risks, not in DM Improves fat and inflammation Wt gain, long term risks Pentoxifylline (400 mg tid) Improves NASH and fibrosis Small studies Surgery Effect Comments RYGB, Sleeve, other Improves NASH and fibrosis Caution in cirrhosis

28 Pioglitazone (30 mg/d), Vitamin E (800 IU/d) or Placebo for NASH Sanyal et al. NEJM * * * * % Improvement Placebo Vit E Pioglit * = p<.05 N=84 N=83 N=80 0 Steatosis Lob Inflam Ballooning Fibrosis Resolution of NASH Although the study was not designed or powered to compare vit E to Pioglitazone, vit E did as well (or better) with less side effects

29 What do we know about fatty liver in HIV in the absence of viral hepatitis?

30 Steatosis/Steatohepatitis Is an Emerging Cause of Liver Disease in HIV 37% (83/225) of HIV patients with NAFLD based on CT-scans Mean age 48 years 72% male Mean duration of HIV 13 years Factors associated with steatosis Elevated ALT/AST Male sex Increased waist circumference Cumulative NRTI exposure Guaraldi G. et al. Clin Infect Dis 2008.

31 Steatosis in those without HCV or HBV Crum-Cianflone et al. JAIDS 2009;50: HIV subjects without HCV or HBV 60 Steatosis assessed by ultrasound % % had steatosis Independent associations with steatosis Increased waist (OR 2.1 per 10 cm) Increased TG (OR 1.2 per 100 mg/dl) Low HDL (OR 0.7 per 10 mg/dl) AA vs Whites (OR 0.4; p=.08) No associations with CD4, HIV RNA, Duration of infection, ART 0 None Mild Moderate Severe

32 Histology in those w/o HCV Ingiliz et al. Hepatology 2009;49: HIV pts with unexplained increased ALT (mean 80 U/L) No HCV, HBV, alcohol, other liver diseases 22/30 had abnormal bx 18/30 had steatosis Severe in 9 NASH in 16 Fibrosis in 18/30 Significant in 6 F0 Fibrosis 11 37% F1 Fibrosis 13 43% F2 Fibrosis 2 7% F3 Fibrosis 1 3% F4 Fibrosis 3 10% A0 Activity 14 47% A1-3 Activity 16 53% 5% steatosis 12 40% 6-30% steatosis 9 30% >30% steatosis 9 30% Macrovesicular 12 67% Mixed 6 33% NASH 16 53%

33 Histology in those without HCV, HBV, alcohol or diabetes 14 HIV + pts (mean age 45, 71% male, 57% Caucasian), all on HAART (CD4 614, all HIV RNA -) with elevated liver enzymes > 6 months All negative for HCV, HBV, other liver diseases, alcohol (>20g/d), and DM On day of biopsy, 2 hr OGTT, fasting insulin and glucose for HOMA-IR, DEXA for body fat Histology assessed for HAI, steatosis grade, and NAS by pathologist blinded to clinical data Sterling et al. J Clin Gastro 2012 In press

34 Histology HAI inflammation 3.43 ± 1.39 HAI fibrosis 1.71 ± 1.26 Steatosis grade 0: 36% 1: 21% 2: 28% 3: 14% Cyotologic ballooning 40% Steatohepatitis: 57% Advanced fibrosis: 14%

35 What are the unique factors in HIV that might predispose to NAFLD Protease inhibitors NRTIs (D drugs associated lipodystrophy) Metabolic syndrome Diabetes Hypertension Dyslipidemia Gut bacterial translocation Alcohol use

36 Alcohol and HIV PIs Alcohol HIV PI CYP 2E1 ROS Cyto Ca Sarco/ER Ca-ATPase ER Stress ER Ca Modified from Kao et al Hepatology 2012;56: Steatosis Cell Death Fibrosis

37 Why is liver disease more progressive? Bacterial Translocation Balagopal et al. Gastroenterology 2008;135:

38 Take home points Steatosis is common in those with HIV and will be associated with increased morbidity and mortality (both liver and cardiovascular) Mechanisms are poorly understood Drugs (NRTI and PI) Bacterial translocation Metabolic syndrome Chronic immune activation

39 Future Work HAART Dyslipidemia Insulin Resistance Oxidative Stress Steatosis Activation of lipo-oxygenase TNF, IL-6, proinflammatory cytokines Endothelial Dysfunction Increased atherosclerosis Cardiovascular Risks

40 Conclusions Liver disease is common in those with HIV. Although most of it is from HCV and HBV co-infection, we are seeing an increase in steatosis/nash. NASH is associated with increased cardiovascular disease. NASH related cirrhosis is predicted outpace HCV as number 1 indication for liver transplantation. More research into the prevalence and spectrum of NAFLD and its relationship to cardiovascular disease and non-invasive models to assess disease severity in HIV is needed.