Fatty Liver Disease. Mark Thursz. Imperial College
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1 Fatty Liver Disease Mark Thursz Imperial College
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![Non-Alcoholic Fatty Liver Disease UK adult obesity (BMI>30) 1980: 6% [M], 8% [F].](/docs-images/92/108956139/images/6-0.jpg "1997: 17% [M], 20% [F]. By 2004, 23.6% of men and 23.")
6 Non-Alcoholic Fatty Liver Disease UK adult obesity (BMI>30) 1980: 6% [M], 8% [F]. 1997: 17% [M], 20% [F]. By 2004, 23.6% of men and 23.8% of women were obese in England and Wales.
7 Obesity in Africa
8 Causes of Death in NAFLD Patients Hagstrom J. Hep 2017
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10 NAFLD Associates with CVD Independent of other CVD risk factors Amongst diabetics NAFLD increases risk of Coronary artery disease Cerebrovascular disease Peripheral vascular disease More severe coronary disease NASH increases risk more than steatosis Increased carotid intimal thickness Coronary artery calcification Impaired flow mediated vasodilation Increased arterial stiffness Carotid artery inflammation Byrne. J.Hep 2015
11 Genetics Determinants PNPLA3 TM6SF2 Romeo Nat Gen 2008 & Liu Nat Comm 2014
12 NORMAL DISEASE PROGRESSION 12-20% STEATOSIS 5-15% NASH BMI DM-II Waist circumference Sedentary lifestyle 0-12% Inflammation on histology CIRRHOSIS PNPLA3 & TM6SF2 genotypes (Day, Liver Int., 2006)
13 NAFLD is the most important cause of abnormal LFTs with normal serology Final Diagnosis % NASH 34 Steatosis 32 Cryptogenic hepatitis 9 DILI 7.6 Normal 5.9 Autoimmune 1.9 Granulomas/Sarcoid 1.7 PBC 1.4 PSC 1.1 Skelly J.Hep 2001
14 Secondary Hepatic Steatosis Macrovesicular Alcohol Hepatitis C (Gt3) Wilson s disease Lipodystrophy Starvation Parenteral nutrition Abetalipoproteinaemia Drugs Amiodarone, methotrexate, tamoxifen, corticosteroids Microvesicular Reye s syndrome Drugs Valproate, ART Acute fatty liver of pregnancy Genetic disorders (eg Lysosomal acid lipase deficiency)
15 IS A BIOPSY ALWAYS NECESSARY? Not always necessary but may be helpful. Exclude alternative/secondary pathology Stratify disease progression risk
16 NON-ALCOHOLIC FATTY LIVER DISEASE: A SPECTRUM OF CLINICAL AND PATHOLOGICAL SEVERITY (Matteoni et al, 1999: Gastroenterology 116: ) Retrospective analysis of 132 patients followed for up to 18 years. Steatosis? NASH NASH Liver related deaths highest in groups 3 and 4.
17 Non-Invasive Diagnosis of NASH Steatohepatitis CK18 fragments Feldstein 2009 Methacetin breath test Ferritin Fibrosis Markers PIIINP ELF Fibrotest Fibroscan
18 Prognosis Depends on Fibrosis Stage Overall Survival Development of Severe Liver Disease Hagstrom J. Hep 2017
19 NAFLD FIBROSIS SCORE NAFLD Fibrosis Score= x Age (years) x BMI (kg/m2) x IFG/diabetes (yes = 1, no = 0) x AST/ALT ratio x platelet (x109/l) x Albumin (g/dl). A score of less than excludes fibrosis (NPV 88-93%). A score of greater than predicts fibrosis (PPV 82-90%). Angulo et al, Hepatology, 2007
20 European Liver Fibrosis Panel (ELF) TIMP1, Hyaluronic acid, Procollagen III peptide Guha. Hepatology 2008
21 FIBROSCAN
22 Elastography Diagnostic Performance AUROC SSI FS ARFI AUROC SSI FS ARFI 0.84 Cassinotto Hepatology 2016 AUROC SSI FS ARFI 0.87
23 THERPEUTIC TARGETS 1. Weight loss 2. Control metabolic syndrome & optimise management of components Hypertension Dyslipidaemia Insulin resistance/type 2 Diabetes mellitus 3. Prevent progression of fibrosing steatohepatitis
24 LIFESTYLE MODIFICATION Weight Loss Dietary modification Dietician in clinic Diabetes sister for advice Exercise Pedometers Subsidised gym in hospital for group get fit sessions Behavioural Therapy Clear Targets Positive Feedback
25 Effect of Weight Loss on ALT Suzuki et al. J. Hepatol 2005
26 Regular Exercise Fatty Liver assessment by spectrometry Exercising improves - Insulin resistance - Steatosis - Independently from the weight loss n= 7 n= 12 Johnson,Hepatology 2009 Helmerhost, Diabetes 2009
27 Exercise & Visceral Fat Keating J. Hep 2015
28 TREATING OBESITY Central appetite suppressants Rimonabant (Acomplia) Cannaboid receptor antagonist No longer available Slowing absorption Orlistat (Xenical) Lipase inhibitor Reduces dietary fat absorption BMI >30 or >28 plus Metabolic Syndrome May cause steatorrhoea Bariatric Surgery
29 Bariatric Surgery and NAFLD NAS Score Fibrosis Score Lassailly. Gastro 2015
30 THERPEUTIC TARGETS 1. Weight loss 2. Control metabolic syndrome & optimise management of components Hypertension Dyslipidaemia Insulin resistance/type 2 Diabetes mellitus 3. Prevent progression of fibrosing steatohepatitis
31 Statins and LFTs Statins do cause ^LFTs Statins do not cause liver failure Statins are not contraindicated in patients with ^LFTs Cirrhosis NASH Statins are contraindicated in decompensated liver disease Check LFTs before starting statin therapy Do not monitor LFTs Do as patients to report jaundice, fatigue, malaise An Assessment of Statin Safety by Hepatologists. Am.J. Cardiol 2006:
32 THERPEUTIC TARGETS 1. Weight loss 2. Control metabolic syndrome & optimise management of components Hypertension Dyslipidaemia Insulin resistance/type 2 Diabetes mellitus 3. Prevent progression of fibrosing steatohepatitis
33 DRUG THERAPY Available Now Insulin sensitising agents Metformin Glitazones (PPARg agonists) Anti-oxidant therapy Vitamin E Bile Acid Metabolism Ursodeoxycholic acid In Development Insulin sensitising agents PPAR a/d agonists GLP-1 agonists Bile Acid Metabolism FXR agonists Anti-inflammatory CCR2/CCR5 Inhibition Anti-fibrotics Lysyl Oxidase antibody
34 Metformin & Liver Cancer Franciosi et al. PLOS One 2014
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36 PIVENS: ALT, AST, Insulin Resistance, and Weight, According to Study Group. Sanyal AJ et al. N Engl J Med 2010;362:
37 PIVENS: Histological Outcomes. Sanyal AJ et al. N Engl J Med 2010;362:
38 Why not Pioglitazone/Vitamin E for All NAFLD Patients? Neither drug tested in diabetics No data on efficacy/safety in cirrhotics Vitamin E Increased risk of haemorrhagic stroke Increased risk of prostate cancer Increased overall mortality Pioglitazone Increased weight Long term safety questions
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40 FXR Agonists
41 Neuschwander-Tetri. Lancet 2015 FXR Agonist in NASH Flint trial Key side effects Pruritus Increased LDL cholesterol
42 PPARA/d Agonist Elafibrinor
43 Elafibranor in NASH Ratziu Gastro 2016
44 ACTIONS OF GLUCAGON-LIKE PEPTIDE 1 Drucker DJ (2005) Biologic actions and therapeutic potential of the proglucagon-derived peptides Nat Clin Pract Endocrinol Metabol 1: doi: /ncpendmet0017
45 Newsome Lancet 2016
46 Summary NAFLD is not a benign disease Increased liver mortality Increased cardiovascular disease Full assessment requires Evaluation of fibrosis Identification of all clinical manifestations of metabolic syndrome Management should focus on Weight loss Cardiovascular / Cerebrovascular risk factors Drug therapy
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