Abnormal LFTs and NAFLD Dr William Alazawi MA(Cantab) PhD MRCP Senior Lecturer and Consultant in Hepatology Queen Mary, University of London
Does Liver Disease Matter?
Mortality in England & Wales
Liver-related mortality in under 65s
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
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
Study Design Cross sectional study using the east London GP Database 690,683 adults registered in 150 coterminus GP practices LFTs requested in 2011 and 2012
Results 218,032 adults had LFTs tested (31.6%) 31,672 (14.5%) at least 1 abnormal results ALT or AST
Risk of Abnormal LFTs Multivariate analysis Alazawi et al, BJGP 2014
LFTs - something and nothing?
Normal LFTs 142055 adults 35-59 years 8 years follow-ip Kim HC et al. BMJ. 2004;328(7446):983
Liver Function Tests Bilirubin Unconjugated vs conjugated Aspartate aminotransferase (AST) Mitochondrial enzyme Heart/muscle/kidney hepatitis Alanine aminotransferae (ALT) Liver specific Alkaline phosphatase Bile cannalicular + sinusoidal membranes Bone/placenta Cholestasis intra/extrahepatic Gamma glutamyl transpeptidase (GGT) Hepatocellular Cholestasis alcohol
Liver Tests Pattern of Liver tests: ALT /AST = hepatatic Alk Phos / γgt = cholestatic AST > ALT alcohol ALT > AST eg viruses / NAFLD Reverses with significant fibrosis ALT: Alcohol doesn t put ALT > 500 500 1500?autoimmune hepatitis >1500 hepatitis viruses / drugs / ischaemia
Total population (e)=690,683 Total tested = 218,032 A = Tested and normal LFTs (n= 196,360) B= Tested, abnormal LFTs, no diagnosis (n= 27,985) C D C = Tested, abnormal LFTs and liver diagnosis recorded (n = 3,687) D = Tested, normal LFTs and liver diagnosis recorded (n= 4,384) E = Not tested, liver diagnosis recorded (n=3,965) E NAFLD 43% ALD 10% HBV/HCV 40% Other 7%
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
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, in press
Liver disease and Ethnicity 5 4 % 3 2 1 Caucasian Bangladeshi Pakistan Indian African 0 NAFLD ALD HBV HCV Liver Disease
Non-Alcoholic Fatty Liver Hepatic fat on biopsy or imaging No other cause for fat including alcohol Metabolic Syndrome
Age (continuous) 0.998 0.994 1.003 0.470 Male 0.85 0.78 0.92 <0.001 Diabetes 2.25 2.08 2.44 <0.001 Hypertension 1.32 1.13 1.53 <0.001 Cardiovascular Disease 0.94 0.84 1.07 0.356 BMI Category BMI underweight 0.85 0.35 2.08 0.729 BMI normal (ref) 1.00 - - - BMI overweight 2.90 2.40 3.51 <0.001 BMI obese 5.00 4.08 6.12 <0.001 Independent Risk Factors for NAFLD Explanatory Variable Odds 95% CI P value Ratio Ethnic Group Bangladeshi 1.38 1.14 1.69 0.001 Indian 0.83 0.63 1.11 0.208 Pakistani 1.12 0.83 1.53 0.459 White (reference cat) 1.00 - - - African 0.53 0.42 0.66 <0.001 Caribbean 0.47 0.36 0.61 <0.001
Not the whole story Mean age 39.5 62% not diabetic 48% not obese Images supplied by Dr William Alazawi, Queen Mary, University of London East London Population Study;Alazawi et al [In submission]
Non-Alcoholic Fatty Liver Disease
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;69:1375 1379; 3 Vernon G et al. Aliment Pharmacol Ther. 2011 Aug;34(3):274-85; 4 Browning JD et al. Hepatology. 2004;40(6):1387-95; 5 Chalasani N et al. Gastroenterology. 2012 ;142(7):1592-609
NAFLD is associated with mortality P=0.02
Mortality in NAFLD Olmsted County Cohort 420 patients over 20 yrs (3192 p-y) Mean follow-up 7.6 yrs SMR 1.34 Adams et al 2005
Increased CV Disease Systolic BP Fasting blood glucose Total cholesterol & triglycerides Insulin resistance Decreased adiponectin Raised LDL cholesterol Yu et al 2008 Francanzani et al 2008 Fallo et al 2008 Sung et al 2008
Increased risk of HCC Chaldwell & Park, 2009
NAFLD and Liver Cancer 34.8% 200 180 160 140 120 100 80 60 40 20 0 ALD NAFLD HCV HBV Cirrhotic Non-Cirrhotic 23% of NAFLD are non-cirrhotic Newcastle MDM data Dyson et al 2013 J Hepatol
Non-Alcoholic Fatty Liver Disease FAT INFLAMMATION
NASH is not benign NASH liver mortality OR 5.71 (2.31-14.13) 1 NASH + Fibrosis OR 10.06 (4.35 22.35) Survival of 129 / 212 patients with NASH 2 P=0.001 1 Musso 2011 2 Ekstedt 2006 3 Ekstedt 2015
NASH vs Fat Retrospective series - biopsies from 1980s N=118 NAFLD Söderberg C et al. Hepatology. 2010;51(2):595-602
The Prevalence of NASH Brooke Medical Center 12.2% Williams et al, 2011
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
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 2003 2 Ong 2003 3 Adams 2005
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
Symptoms of NAFLD Asymptomatic Fatigue as much as PBC Severe impairment of QOL RUQ pain Associations include OSA and hypothyroidism
Diagnosis of NALFD Abnormal LFTs Exclude viral / EtOH / AI / HC / Drugs U/S suggests fatty infiltrate Other causes of fatty liver: Surgery TPN PCOS (FSH / LH & testosterone) Lipodystrophy Drugs Tamoxifen / methotrexate / amiodarone / HAART
Liver Biopsy PROs CONs Staging Invasive Grading Cost Diagnosis Sampling Co-Pathology Reluctance Static information 30 % pain / 0.3-0.6% bleeding Pathologist - dependent 10-30% false negative for cirrhosis
Non-Invasive Tests of Fibrosis Blood Tests Elastography Ideally: Accurate Available Stage and Grade Valid (numbers and aetiologies)
Non-Invasive Tests of Fibrosis Blood Tests Elastography Ideally: Accurate Available Stage and Grade Valid (numbers and aetiologies)
Gressner et al, 2009
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
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
Composite Scores Retrospective N=320 105 months (3-317) 92% White 36% Diabetic 31% BMI>35 51% Fibrosis ¾ 13% Death or OLT Angulo et al 2013 J Hepatol
Management of 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
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
Weight loss improves NAS Musso et al, 2009
Thiazolidinediones Stimulate nuclear PPAR-γ Induce insulin sensitising genes Reduce IR Promote favourable lipid profile Promote weight gain
Pioglitazone Placebo-controlled N=55 Hypocaloric diet Improved inflammation No change in histology Belfort et al 2007 NEJM
Rosiglitazone FLIRT Ratziu et al 2008 Gastroenterology
Pioglitazone vs Vit E vs placebo N=247 NASH 2 point reduction in NAS 43% Vitamin E 19% Placebo (pioglitazone not sig different) Improved inflammatory components No improvement in fibrosis (no worsening) Pioglitazone assoc with weight gain but improved IR Sanyal et al 2012
Obeticholic acid Farnesoid X nuclear receptor Downregulate SREBP1c Increase SIRT1 Reduces fat and fibrosis in animal models Improve hepatic insulin sensitivity Decrease steatosis Inhibit lipogenesis Cause regression of atherosclerosis Anti-fibrotic
FLINT study Phase IIb double blind placebo controlled multicentre RCT Non-cirrhotic NASH patients Histology N=283 53% diabetes Primary outcome Improvement in NAS by at least 2 points No worsening of fibrosis
Neuschwander-Tetri et al, Lancet 2014
Change in liver enzymes and weight
Ongoing work at Barts Health Clinical trials LOXL2 Cenicriviroc Observational studies Immune and inflammatory response Diabetes & NAFLD Basic science studies Mechanisms of disease Therapeutic targets
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
Barts Health Liver Network: Consultants Clinical nurse specialists Registrars & Clinical fellows Pharmacists Administrators
Primary Care & Commissioning A pathway for abnormal LFTs? Avoid unnecessary repetition of tests One-stop clinics? Risk stratification Access to behaviour and lifestyle services
Abnormal liver function tests and/or ultrasound showing fatty liver Management in Primary Care Referral 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: Abnormaliti es persist Likely NAFLD: Calculate NAFLD Fibrosis Score Diagnosis and Advice Diagnostic Liver Clinic Bart s Health Hepatology Starts April 2015 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
We are keen to do more william.alazawi@bartshealth.nhs.uk