Abnormal Liver Function. Dr William Alazawi MA(Cantab) PhD MRCP Senior Lecturer and Consultant in Hepatology Queen Mary, University of London

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1 Abnormal Liver Function Dr William Alazawi MA(Cantab) PhD MRCP Senior Lecturer and Consultant in Hepatology Queen Mary, University of London

2 Does Liver Disease Matter?

3 Mortality in England & Wales

4 Liver-related mortality in under 65s

5 Does Liver Disease Matter? Between 2000 and 2009, deaths from chronic liver disease and cirrhosis in the under 65s increased by around 20% while they fell by the same amount in most EU countries. And all 3 major causes of liver disease - obesity, undiagnosed infection, and, increasingly, harmful drinking - are preventable. Dame Sally Davis Chief Medical Officer

6 Liver Function Tests Bilirubin Aspartate aminotransferase (AST) Alanine aminotransferae (ALT) Alkaline phosphatase Gamma glutamyl transpeptidase (GGT)

7 Liver Function Tests Bilirubin Aspartate aminotransferase (AST) Alanine aminotransferae (ALT) Alkaline phosphatase Gamma glutamyl transpeptidase (GGT)

8 Jaundice Pre-Hepatic Hepatic Post-Hepatic Patients with jaundice should be assessed urgently

9 Liver Tests ALT /AST = hepatatic Alk Phos / γgt = cholestatic

10 Population Study Total for 3 Boroughs n=813,700 White Indian Pakistani Bangladeshi Asian Other Black African Black Caribbean Other How much liver disease is out there? How much has been worked up

11 Study Design Cross sectional study using the east London GP Database 690,683 adults registered in 150 coterminus GP practices LFTs requested in a 2 year period

12 Results 218,032 adults had LFTs tested (31.6%) 31,672 (14.5%) at least 1 abnormal results ALT or AST

13 Risk of Abnormal LFTs Multivariate analysis Alazawi et al, BJGP 2014

14 LFTs - something and nothing?

15 Normal LFTs adults years 8 years follow-ip Kim HC et al. BMJ. 2004;328(7446):983

16 Prevalence of Liver Diagnoses NAFLD Hepatitis B Acute Viral Hepatitis C ALD Inherited Pregnancy-related Autoimmune Venous Thrombosis - 2,000 4,000 6,000 N=690,683 Alazawi et al, 2014

17 Undiagnosed Liver Disease in Primary Care Total Abnormal n=31,672 Undiagnosed Diagnosed n=27,895 n=3,687 88% no liver diagnosis 12,687 (38%) Drugs (including statins) 3,372 (11%) Excess alcohol consumption 6,026 (19%) Safe alcohol & viral tests (negative) 6,300 (20%) No viral tests

18 Abnormal liver function tests and/or ultrasound showing fatty liver Primary Care: Symptoms & comorbidities Detailed drug history Careful family history Alcohol review AUDIT-C Abnormalities resolve AUDIT-C Positive Brief Intervention Repeat tests in 3 months Abnormalities persist Hepatology Metabolic risk factors inc BMI Blood Tests*: Viral hepatitis HBV & HCV FBC, U&E, INR, TFT LFTs inc AST / GGT Lipid profile Ferritin Autoantibodies Immunoglobulins Consider need for ultrasound All patients with clinical jaundice or bilirubin >40 should be referred urgently for assessment *A complete liver screen would additionally include testing for alpha1-antitrypsin, caeruloplasmin and alphafetoprotein. Chronic viral infection should be excluded by testing for hepatitis B virus surface antigen and antibodies against hepatitis C virus. If abnormalities are acute, exclude hepatitis A and hepatitis E virus infection.

19 Abnormal liver function tests and/or ultrasound showing fatty liver Primary Care: Symptoms & comorbidities Detailed drug history Careful family history Alcohol review AUDIT-C Abnormalities resolve AUDIT-C Positive Brief Intervention Repeat tests in 3 months Abnormalities persist Hepatology Metabolic risk factors inc BMI Blood Tests*: Viral hepatitis HBV & HCV Screen Positive or uncertain FBC, U&E, INR, TFT LFTs inc AST / GGT Lipid profile Ferritin Autoantibodies Immunoglobulins Consider need for ultrasound All patients with clinical jaundice or bilirubin >40 should be referred urgently for assessment *A complete liver screen would additionally include testing for alpha1-antitrypsin, caeruloplasmin and alphafetoprotein. Chronic viral infection should be excluded by testing for hepatitis B virus surface antigen and antibodies against hepatitis C virus. If abnormalities are acute, exclude hepatitis A and hepatitis E virus infection.

20 Abnormal liver function tests and/or ultrasound showing fatty liver Primary Care: Symptoms & comorbidities Detailed drug history Careful family history Alcohol review AUDIT-C Metabolic risk factors inc BMI Blood Tests*: Viral hepatitis HBV & HCV FBC, U&E, INR, TFT LFTs inc AST / GGT Lipid profile Ferritin Autoantibodies Immunoglobulins Consider need for ultrasound Abnormalities resolve AUDIT-C Positive Brief Intervention Repeat tests in 3 months Screen Positive or uncertain Negative or Metabolic Risk NAFLD Abnormalities persist Hepatology All patients with clinical jaundice or bilirubin >40 should be referred urgently for assessment *A complete liver screen would additionally include testing for alpha1-antitrypsin, caeruloplasmin and alphafetoprotein. Chronic viral infection should be excluded by testing for hepatitis B virus surface antigen and antibodies against hepatitis C virus. If abnormalities are acute, exclude hepatitis A and hepatitis E virus infection.

21 Non-Alcoholic Fatty Liver Hepatic fat on biopsy or imaging No other cause for fat including alcohol Metabolic Syndrome

22 Age (continuous) Male <0.001 Diabetes <0.001 Hypertension <0.001 Cardiovascular Disease BMI Category BMI underweight BMI normal (ref) BMI overweight <0.001 BMI obese <0.001 Independent Risk Factors for NAFLD Explanatory Variable Odds 95% CI P value Ratio Ethnic Group Bangladeshi Indian Pakistani White (reference cat) African <0.001 Caribbean <0.001

23 Not the whole story Mean age % not diabetic 48% not obese

24 Non-Alcoholic Fatty Liver Disease

25 How common is NAFLD? Depends on population and definition Histology 20 51% 1,2 US 17 46% 3 MR Spectroscopy 31% 4 ALT 7 11% 3 Overall: NAFLD 20% (6.3 33%) 5 1 Lee J et al. J Hepatol. 2007;47(2):239-44; 2 Marcos A et al. Transplantation. 2000;69: ; 3 Vernon G et al. Aliment Pharmacol Ther Aug;34(3):274-85; 4 Browning JD et al. Hepatology. 2004;40(6): ; 5 Chalasani N et al. Gastroenterology ;142(7):

26 NAFLD is associated with mortality P=0.02

27 Mortality in NAFLD Adams et al 2005

28 Non-Alcoholic Fatty Liver Disease FAT INFLAMMATION

29 NASH and liver mortality NASH - OR 5.71 ( ) 1 NASH + Fibrosis - OR ( ) Survival of 129 / 212 patients with NASH 2 P= Musso Ekstedt Ekstedt 2015

30 NASH vs Fat Retrospective series - biopsies from 1980s N=118 NAFLD Söderberg C et al. Hepatology. 2010;51(2):

31 NAFLD and Liver Cancer 34.8% ALD NAFLD HCV HBV Cirrhotic Non-Cirrhotic 23% of NAFLD are non-cirrhotic Newcastle MDM data Dyson et al 2013 J Hepatol

32 The Prevalence of NASH Brooke Medical Center 12.2% Williams et al, 2011

33 Progression of NAFLD 30% of population has NAFLD 10% of NAFLD develop NASH 25% of NASH develop cirrhosis 10-25% of cirrhosis develop HCC Siegel & Zhu 2009

34 Does SS Progress to NASH? 9-20% NASH progress to cirrhosis 1-3 SS stable over time Olmsted 420 cohort; 7.6 yr follow up No SS deaths 35% NASH died 3 1 Harrison Ong Adams 2005

35 Does SS Progress to NASH? Patients with >1 biopsy Median follow-up 6.6 yr Progressors increase T2DM (65% vs 48%) TOTAL McPherson et al, J Hep 2015

36 Risk Factors for NASH Age / Male Gender? / Hispanic ethnicity Diet Fructose Corn Syrup / Coffee Microbiome Firmicutes -?ethanol-producing Genetics PNPLA3, TM6SF2 steatosis and fibrosis Metabolic syndrome Obesity Diabetes Hyperlipidaemia

37 Liver Biopsy PROs CONs Staging Invasive Grading Cost Diagnosis Sampling Co-Pathology Reluctance Static information 30 % pain / % bleeding Pathologist - dependent 10-30% false negative for cirrhosis

38 Non-Invasive Tests of Fibrosis Blood Tests Elastography Ideally: Accurate Available Stage and Grade Valid (numbers and aetiologies)

39 Non-Invasive Tests of Fibrosis Blood Tests Elastography Ideally: Accurate Available Stage and Grade Valid (numbers and aetiologies)

40 Gressner et al, 2009

41 Assessing risk of fibrosis NAFLD-FS Age / BMI / DM / AST:ALT / Plt / Albumin APRI AST / Plt FIB-4 Age / AST / ALT / Plt BARD BMI / DM / AST:ALT

42 NAFLD fibrosis score 733 patients 480 training, 253 validation Rochester / Newcastle / Sydney / Italy 90% Caucasian BMI 32.2 DM / IFG 69% NPV 88% 60% of patients could avoid biopsy PPV 78% 25% of patients indeterminate

43 Composite Scores Retrospective N= months (3-317) 92% White 36% Diabetic 31% BMI>35 51% Fibrosis ¾ 13% Death or OLT Angulo et al 2013 J Hepatol

44 Abnormal liver function tests and/or ultrasound showing fatty liver Primary Care: Symptoms & comorbidities Detailed drug history Careful family history Alcohol review AUDIT-C Abnormalities resolve AUDIT-C Positive Brief Intervention Repeat tests in 3 months Abnormalities persist Hepatology Metabolic risk factors inc BMI Blood Tests*: Viral hepatitis HBV & HCV FBC, U&E, INR, TFT LFTs inc AST / GGT Lipid profile Ferritin Autoantibodies Immunoglobulins Consider need for ultrasound Screen Positive or uncertain Negative or Metabolic Risk: Likely NAFLD: Calculate NAFLD Fibrosis Score Behaviour / lifestyle advice Alcohol Exercise Diet Cardiovascular risk factors I / H risk Low risk Follow-up in Primary Care Annual review All patients with clinical jaundice or bilirubin >40 should be referred urgently for assessment *A complete liver screen would additionally include testing for alpha1-antitrypsin, caeruloplasmin and alphafetoprotein. Chronic viral infection should be excluded by testing for hepatitis B virus surface antigen and antibodies against hepatitis C virus. If abnormalities are acute, exclude hepatitis A and hepatitis E virus infection. The Diagnostic Liver Clinic will return patients to GP with a diagnosis and advice on future management

45 Treatment in NAFLD? Follow-up metabolic syndrome: Correct hyperlipidaemia Diet Statins monitor change from baseline Glitazones not soundly proven; use if indicated for hyperlipidaemia Other CV risk factors Hypertension Smoking cessation Insulin Resistance

46 Exercise Low/moderate intensity (n=141) 9x more likely to exercise >1hr/week 150 mins / week or increase by >60mins improvement in ALT Metabolic indices (HOMA-IR) Independent of weight loss St George et al, 2009

47 Weight loss improves histology Musso et al, 2009

48 Weight loss improves histology 293 patients with NASH 40% male BMI week lifestyle 750kcal/day deficit 64% fat 22% fat Walk 200 mins / week 8, 16, 24, 32, 40 weeks Vilar-Gomez 2015

49 The NASH pipeline Lomb & Tetri 2015

50 Ongoing work at Barts Health Clinical trials LOXL2 Cenicriviroc Obeticholic acid Observational studies Immune and inflammatory response Diabetes & NAFLD Basic science studies Mechanisms of disease Therapeutic targets

51 Primary Care & Commissioning A pathway for abnormal LFTs? Avoid unnecessary repetition of tests One-stop clinics? Risk stratification Access to behaviour and lifestyle services

52 Abnormal liver function tests and/or ultrasound showing fatty liver Management in Primary Care Referral Primary Care: Abnormalities resolve Diagnosis and Symptoms & Advice comorbidities AUDIT-C Positive Detailed drug history Brief Intervention Careful family history Abnormalities Repeat tests in 3 persist Alcohol review AUDIT-C months Diagnostic Liver Clinic Metabolic risk factors inc Bart s Health Hepatology BMI Screen Blood Tests*: Positive or Viral hepatitis HBV & uncertain HCV Behaviour / FBC, U&E, INR, TFT lifestyle advice Likely NAFLD: LFTs inc AST / GGT Negative Alcohol I / H risk or Calculate Lipid profile Exercise NAFLD Metabolic Ferritin Fibrosis Score Diet Low risk Risk: Cardiovascular Autoantibodies risk factors Immunoglobulins Annual review Consider need for ultrasound All patients with clinical jaundice or bilirubin >40 should be referred urgently for assessment Follow-up in Primary Care *A complete liver screen would additionally include testing for alpha1-antitrypsin, caeruloplasmin and alphafetoprotein. Chronic viral infection should be excluded by testing for hepatitis B virus surface antigen and antibodies against hepatitis C virus. If abnormalities are acute, exclude hepatitis A and hepatitis E virus infection. The Diagnostic Liver Clinic will return patients to GP with a diagnosis and advice on future management