Investigating general liver disease/transaminitis

Transcription

1 BHIVA Autumn Conference London 14 October 2016 Investigating general liver disease/transaminitis Emmanuel A. Tsochatzis Senior Clinical Lecturer and Consultant Hepatologist Institute for Liver and Digestive Health UCL Institute of Liver and Digestive Health Royal Free Hospital

2 Talk outline Causes of transaminitis How to investigate NAFLD Who needs referral to the hepatologist Treatment

3 Liver disease in HIV infected patients Viral hepatitis Alcohol Drug toxicity NAFLD Infection Cancer/lymphoma

4 The dark ages Diagnosis No of patients Granulomatous hepatitis 191 (37%) (M.avium, other acid-fast bacilli) Other infections 501 biopsies 14 (3%) (CMV, P.carinii, Candida) Neoplasia 19 (4%) Main indications: 1) Abnormal LFTs 2) FUO (lymphoma, HCC) Viral hepatitis/cirrhosis 91 (18%) Alcoholic hepatitis Nonspecific findings 15 (3%) 179 (36%) 3) Hepatomegaly Poles JAIDS 1996

5 The developing world Diagnosis Number of patients Drug-induced liver injuries Granulomatous inflammation Viral hepatitis NAFLD/NASH Alcohol 127 (42%) 86 (29%) 66 (22%) 58 (19%) 16 (5%) 301 biopsies ( ) South Africa Mean CD4 count 127 Sonderup Hepatology 2015

6 The developed world 30 patients with chronic unexplained transaminases Diagnosis Steatosis Steatohepatitis Number of patients 18 (60%) 16 (53%) Any fibrosis 19 (63%) Advanced fibrosis (F3-F4) 4 (13%) Ingiliz Hepatology 2009

7 Royal Free Hospital experience Retrospective analysis Patients with viral hepatitis co-infection excluded Demographics, indication for biopsy, stage of HIV related disease documented. Steatosis, fibrosis and inflammation were recorded Definitive diagnoses were noted Lever EASL 2015

8 Results A total of 143 biopsies were performed on a cohort consisting of 4456 HIV positive individuals (2.8%) 75% males, mean age 49.6 years at biopsy Mean time between HIV diagnosis and biopsy was 8.1 years (range 0.1 years to 29 years) Abnormal LFTs main biopsy indication (70%)

9 Steatosis/inflammation Inflammation (n=143) Steatosis (n=143) Not commented 21% Not documented 9% None 31% Inadequate sample 3% Inadequate sample 4% Minimal 19% None 22% Severe 5% Moderate 14% Mild 26% 69% had some degree of steatosis Mild 33% Marked 3% Moderate 10% 43% at least minimal inflammation

10 Fibrosis and other diagnoses Not commented on Inadequate 8% sample 8% Other 0% Other Diagnoses on Liver Biopsy (n=37) Fibrosis (n=143) Tuberculosis 11% Cholestasis 11% Drug reaction 16% Cirrhosis 3% Severe 2% Granulomas 27% Moderate 6% Mild 8% None 65% AIH 8% Other neoplasm 5% Some fibrosis in 20%, no fibrosis in 65% Lymphoma 22%

11 Liver test abnormalities in patients with HIV mono-infection Cross-sectional audit of consecutive HIV mono-infected patients Patients with persistently elevated LFTs in at least two measurements six months apart 156/2398 (6.5%) persistently elevated transaminases Lombardi EASL 2016, manuscript submitted

12 Abnormal LFTs in HIV mono-infection 97% on cart treatment US in 42%, of which 71% had steatosis APRI <0.5 n=81 (51.9%), >1.5 n=5 (3.2%) FIB4>1.45 in 33%, >3.25 in 4% TE only in 19 patients Liver biopsy NASH 13/20 patients, 1 with cirrhosis Lombardi EASL 2016, manuscript submitted

13 A look for DDI hepatopathy Sampling frame (n=376) Refused bx (n=5) HBV/HCV co-infection (84) or known DDI related liver disease (n=2) excluded Normal Liver (n=4) Bhagani S 2016

14 How to investigate transaminitis Drug history Viral hepatitis markers Alcohol history Ferritin, transferrin saturation CD4 count ANA, SMA, LKM, immunoglobulins Caeruloplasmin, a1-antithrypsin Liver ultrasound Non-invasive (Fibroscan) fibrosis assessment

15 Drug toxicity Metabolic host-mediated (intrinsic and idiosyncratic) Hypersensitivity (early occurrence) Mitochondrial toxicity (prolonged exposure) Didanosine/stavudine more consistently associated with advanced fibrosis Soriano 2008; Blanco 2011; Mendeni 2011

16 What is NAFLD? Non-Alcoholic Fatty Liver Disease Wide disease range from simple steatosis to cirrhosis Steatosis Steatosis/inflammation Steatosis Fibrosis NASH 12-40% Cirrhosis Cirrhosis 15%

17 Non alcoholic fatty liver disease (NAFLD) Prevalence 20-25% of the general population Estimated 40-60% in patients with HIV 2-7% has steatohepatitis (NASH) Hepatic manifestation of metabolic syndrome >50% of secondary care referrals due to NAFLD

18 NAFLD: Potential consequences Kotronen, Arterioscler Thromb Vasc Biol 2008

19 Epidemiology

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21 Growing prevalence of obesity Finucane Lancet 2011

22 Increasing prevalence of MS in HIV 33,347 patients MS from 8.7% to 44.1% in 7 years Worm AIDS 2010

23 Obesity in HIV patients Crum-Cianflone 2010

24 MS more prevalent in HIV than controls Bonfanti 2007

25 NASH in HIV patients

26 NASH in HIV patients 1. HAART treatment NRTIs, thymidine analogues (mitochondrial toxicity) 2. Lipodystrophy 3. HIV virus Mitochondrial damage, lipid levels (IR), didanosine

27 NAFLD in HIV mono-infection Mitochondrial toxicity Lipids level changes Insulin resistance HAART Mitochondrial toxicity Lipids level changes Insulin resistance virus proteins NAFLD/NASH The Journal of Endocrinology and Metabolism 2003

28 Mitochondrial toxicity No evidence of mitochondrial DNA depletion Evidence of mitochondrial toxicity No relation to the type of cart used Ingiliz Hepatology 2009

29 NAFLD in HIV patients 225 mono-infected patients, NAFLD in 83 Mean BMI 23.8 kg/m2 Variable 95% CI P ALT/AST ratio 4.59 ( ) <0.001 Male sex 2.49 ( ) <0.001 Cumulative NRTI 1.12 ( ) <0.001 Waist circumference 1.07 ( ) <0.001 Guaraldi Clin Infect Disease 2008

30 NASH in HIV patients 128 consecutive HIV mono-infected patients Mean BMI 24.5 kg/m2 55% NAFLD on US 18% Fibroscan >7.4 Kpa Age and MS independent predictors of >7.4 KPa Lombardi, Digestive Liver Diseases 2016

31 NASH in HIV patients APRI>1.5 in 8.3% of 432 patients T2DM and detectable HIV viraemia independent predictors Cohort also included patients who used alcohol DallaPiazza BMC Infect Dis 2008

32 Prognosis hepatology referrals

33 Natural history of NAFLD P=NS Simple steatosis 129 patients Mean follow-up 13.7 years P=0.01 NASH Ekstedt, Hepatology 2006

34 Natural history of NASH Ekstedt Hepatology 2015

35 Factors associated with progression Age (mitochondrial dysfunction) All metabolic syndrome components - Obesity/increased WC - T2DM - Hypertension - Dyslipidaemia Smoking

36 NASH and mortality CVS main cause of death Liver disease only 3d cause of mortality Ekstedt, Hepatology 2006 Soderberg, Hepatology 2010

37 NAFLD referral pathways High prevalence, low severity No liver-specific treatment How to select patients for referral? Non-invasive fibrosis assessment

38 Simple non-invasive clinical scores for F>2 FIB4 Age, ALT, AST, PLT NAFLD fibrosis score Age, BMI, hyperglycemia, AST/ALT, PLT, albumin Angulo Hepatology 2007 Shah Clin Gastroenterol Hepatol 2009

39 Calculation of simple NITs FIB-4: NAFLD fibrosis score: Liver calculator Free application for smartphones

40 Risk classification according to simple NITs Low risk for >F2 FIB4<1.3 60% Indeterminate risk for >F2 1.3<FIB4< % High risk for >F2 FIB4>3.25 5%

41 NITs and prognosis NITs initially developed as surrogate markers of fibrosis with a view to replace LB Increasingly used to assess prognosis

42 Cumulative liver related events

43 Cumulative liver related events

44 Diagnosis of NAFLD (Negative Liver Screen & USS Fatty liver) Non-invasive fibrosis tests (one or two tiers as needed) High risk for >F2 Referral Hepatology Low risk for >F2 Management in HIV clinic

45 Summary se and sp of NIT for NAFLD TN/(TN+FN)

46 Referral rate FIB-4 F3/4 referred 76% (n=100) High risk n=5 TP=2 FP=3 Indeterminates n=24 F3/4=2, F0-2=22 Refer n=11 TP=4, FP=7 Fibroscan High risk n=6 TP=2 FP=4 11% Fibroscan 24 Cost/100 pts 4520 Low risk n=71 FN=1 TN=70 Low risk n=20 FN=0 TN=20

47 Referral rate FIB-4 F3/4 referred 78% (n=100) High risk n=5 TP=2 FP=3 Indeterminates n=24 F3/4=2, F0-2=22 Refer n=13 TP=4, FP=9 Fibrotest High risk n=8 TP=2 FP=6 13% Fibrotest 24 Cost/100 pts 4950 Low risk n=71 FN=1 TN=70 Low risk n=16 FN=0 TN=16

48 Referral rate 9% FIB-4 (n=100) F3/4 referred 76% ELF 24 Cost/100 pts 3660/ 5290 High risk n=5 TP=2 FP=3 Indeterminates n=24 F3/4=2, F0-2=22 Low risk n=71 FN=1 TN=70 ELF Refer n=9 TP=4, FP=5 High risk n=4 TP=2 FP=2 Low risk n=26 FN=0 TN=26

49 Natural history of NAFLD 87% 77% 420 patients Mean follow up 7.6 years Adams, Gastro 2005

50 Annual new cases of NAFLD in C&I *population of Camden and Islington = 400,000 Annual new primary care electronic codes for NAFLD in Camden and Islington London Boroughs 1600 New Electronic codes for NAFLD March 2012-Feb 2013 March Feb 2014 Pre-pathway March 2014 Feb 2015 Post-pathway Srivastava 2015

51 Initial impact of pathway *afterevaluation of 40% of post pathwaydata at Royal Free London 100% Composite consultant judgment 90% 80% F fibrosis 70% F fibrosis 60% 50% 40% 30% 20% 10% 0% Pre-pathway ( ) Pre-pathway Non NAFLD pathway NAFLD pathway (excluding normal LFT's) Post-pathway Srivastava 2015

52 Treatment

53 Who should be treated? Simple steatosis: Lifestyle advice, CVS factors NASH, F0-F1 fibrosis: Lifestyle advice, CVS factors, clinical trials NASH, significant fibrosis: Liver-specific interventions, clinical trials

54 Potential treatment targets Lifestyle changes Antioxidant factors Insulin resistance Fibrosis

55 Weight loss and NASH 293 patients Dietary intervention 52 weeks Vila-Gomez Gastro 2015

56 Statins in liver disease 437 patients with abnormal LFTs LFT improvement Less CVS events Athyros Lancet 2010

57 PIVENS Pioglitazone, Vitamin E or placebo 287 non-diabetic patients 2 years of treatment P= P= P=NS NAS score Vit E Pioglitazone Fibrosis Placebo Vit E Pioglitazone Placebo Sanyal NEJM 2010

58 Vitamin E: current evidence Effective in two RCTs (PIVENS, TONIC) BUT: Increased mortality in doses >400 IU/day Increased risk of prostate cancer

59 Lipid metabolism Carbohydrate metabolism Reduces lipogenesis (SREBP1c) Improves insulin sensitivity Increases fatty acid oxidation Reduces neoglucogenesis FXR nuclear receptor Liver Reduces inflammation (NF-kB) Antifibrotic

60 Obeticholic acid Farnesoid X receptor agonist Non-cirrhotic NASH Double blind, phase II, placebo controlled trial 25 mg OCA (n=141), placebo (n=142) 72 weeks Primary endpoint = 2 point improvement in NAS with no worsening of fibrosis Improvement in histology (50 OCA, 23 placebo) Increase in LDL Neuschwander-Tetri Lancet 2014

61 FLINT - histological data Feature OCA Placebo Relative Risk P value Number of patients Decrease of NAS score by points with no worsening of fibrosis 50(45%) 23(21%) 1.9 ( ) Improvement in Fibrosis 36(35%) 19(19%) 1.8( ) Improvement in Ballooning 47(46%) 30(31%) 1.5( ) 0.03 Improvement in lobular inflammation 54(53%) 34(35%) 1.6( ) Improvement in Steatosis 62(61%) 37(38%) 1.7( ) 0.001

62 LEAN liraglutide vs. placebo Feature Liraglutide (n=23) Placebo (n=22) P NASH regression 9 (39%) 2 (9%) <0.05 NAS score NS Improvement in fibrosis 6 (26%) 3 (14%) NS Improvement in ballooning 14 (61%) 7 (32%) NS Improvement in steatosis 19 (83%) 10 (45%) <0.05 Improvement in lobular inflammation 11 (48%) 12 (55%) NS Armstrong Lancet 2015

63 Treatment of metabolic syndrome components Obesity exercise and diet T2DM pioglitazone, metformin or liraglutide Hypertension ΑΑΤ2 Dyslipidaemia statins Smoking cessation

64 Management of NAFLD by the HIV physician Follow-up in HIV clinic of patients at low risk of fibrosis -Annual LFTs - >10% weight loss - Treat components of metabolic syndrome (hypertension, diabetes, hyperlipidaemia) - In 3-5 years re-assess risk of advanced fibrosis using non-invasive fibrosis assessment

65 Conclusions Transaminitis common in patients with HIV Viral hepatitis, alcohol, NAFLD, drug toxicity 10% of HIV patients might have NAFLD with fibrosis Only a minority needs hepatology referral Aggressive treatment of MS components

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