1. Help with Hepatology Spire 2013 Dr Allister J Grant Consultant Hepatologist Leicester Liver Unit University Hospitals Leicester NHS Trust

2. Abnormal LFT’s in well patients 1) Isolated raise in bilirubin 2) γGT raised 1) ALT rise predominant 2) ALP rise predominant

3. 1) Isolated raise in bilirubin  DifferentialGilberts vs Haemolysis  Gilberts- unconjugated hyperbilirubinaemia  Haemolysis- Unconjugated hyperbilirubinaemia splenomegaly, anaemia, DCT, haptoglobin, reticulocyte count, film

4. 2)  -Glutamyl transpeptidase  The high sensitivity and very low specificity seriously hampers the usefulness of this test  If ALP is elevated and GGT is elevated then the raise in ALP is likely to be hepatic in origin  Elevated in a whole host of liver diseases a whole host of liver diseases Drugs/Alcohol Drugs/Alcohol Obesity/ dyslipidaemia/ DM Obesity/ dyslipidaemia/ DM CCF CCF Kidney, Pancreas, Prostate Kidney, Pancreas, Prostate

5. The majority of abnormal LFTs in asymptomatic people occur in those with:  Diabetes or metabolic syndrome (increased risk of NAFLD)  Excessive alcohol intake  Chronic hepatitis B  Chronic hepatitis C  Drugs 2) ALT rise predominant

6. Case - Mr Z 59y Architect Type 2 DM 15 yrs on diet alone BMI 35 Hypertension Amlodipine, Ramipril Minimal Alcohol

7. Mr RP  Generally unwell for 2 years  Cytopaenia Low Hb/platelets Low Hb/platelets Normal haematological Ix (peripheral consumption) Normal haematological Ix (peripheral consumption)  May 07 LGH admission with ataxia/drowsiness LGH admission with ataxia/drowsiness Extensive Ix Extensive Ix

8. Mr RP  CT abdo cirrhotic liver, portal hypertension, splenomegaly cirrhotic liver, portal hypertension, splenomegaly  OPD referral Alb 28, Pl 65 LFT’s normal, INR 1.5 Alb 28, Pl 65 LFT’s normal, INR 1.5 Imaging compatible with cirrhosis Imaging compatible with cirrhosis Reversal of sleep pattern, lack of concentration Reversal of sleep pattern, lack of concentration Daytime somnelence, intermittant confusion Daytime somnelence, intermittant confusion OGD- varices OGD- varices

9. How common is NAFLD?  The most common cause of abnormal liver function tests in the United States.  Estimated 30.1 million with NAFLD and 8.6 million with NASH  Affects 10-24% of the population  58-74% of the obese population  Affects 2.6% of children  23-53% of obese children

10. LEICESTER

11. Steatosis Steatohepatitis Cirrhosis Hepatocellular carcinoma Non Alcoholic Fatty Liver Disease (NAFLD) Spectrum of Hepatic Pathology Non Alcoholic Fatty Liver Disease (NAFLD) Spectrum of Hepatic Pathology

13. Diseases Associated with Steatohepatitis 1.Alcoholism 2.Insulin resistance a.Metabolic Syndrome a.Metabolic Syndromei.Obesityii.Diabetesiii.Hypertriglyceridemiaiv.Hypertension b.Lipoatrophy b.Lipoatrophy c.Mauriac Syndrome c.Mauriac Syndrome d.PCOS d.PCOS 3.Disorders of lipid metabolism a.Abetalipoproteinemia a.Abetalipoproteinemia b.Hypobetalipoproteinemia b.Hypobetalipoproteinemia c.Andersen’s disease c.Andersen’s disease d.Weber-Christian syndrome d.Weber-Christian syndrome 4.Total parenteral nutrition 5. HCV (certain genotypes) 6. Untreated coeliac disease 7.Severe weight loss a.Jejuno-ileal bypass a.Jejuno-ileal bypass b.Gastric bypass b.Gastric bypass c.Severe starvation c.Severe starvation8.Iatrogenic a.Amiodarone a.Amiodarone b.Diltiazem b.Diltiazem c.Tamoxifen c.Tamoxifen d.Steroids d.Steroids e.HAART e.HAART f. tetracycline f. tetracycline g.glucosamine g.glucosamine 9.Refeeding syndrome 10.Exposure to toxic agents a.Environment a.Environment b.Workplace – Sb,Th,Ba b.Workplace – Sb,Th,Ba

14. NASH Affects 3.5-5% of the population The rates of progression to cirrhosis have been estimated at between 5% and 20% over 10 years. There aren't any non-invasive means of predicting which patients are at risk of progression, and there are no agreed guidelines on how to monitor progression.

15. Natural history  Simple steatosis: relatively benign “liver” prognosis with a risk of developing clinical evidence of cirrhosis over 15–20 years in the order of 1%–2%.  NASH and fibrosis: risk of progress to cirrhosis between 0% at 5 years to 12% over 8 years.  Cirrhotic: high risk of developing hepatic decompensation and of dying from a liver-related cause including HCC.

16. Initial Investigation  Look for risk factors BMI, DM, HBP, Lipids,FHx, Drugs, Alcohol BMI, DM, HBP, Lipids,FHx, Drugs, Alcohol  Liver screen (to exclude other diseases) Including Glc/GTT/HbA1c/Lipids/AST Including Glc/GTT/HbA1c/Lipids/AST Pl, Alb, INR Pl, Alb, INR  USS Spleen size, fatty liver, collaterals Spleen size, fatty liver, collaterals

17. Fibroscan®  Electronic platform Ultrasonic signals acquisition Ultrasonic signals acquisition Numerical signal processing Numerical signal processing  Integrated computer Stiffness measurement Stiffness measurement Examinations database Examinations database  Dedicated probes with unique technology Vibrator (50 Hz) US Transducer (3,5 MHz) Fibroscan® (Echosens, Paris, France)

18. Position of probe & explored volume Cylinder of 1 cm wide & 4 cm long From 25 mm to 65 mm below skin surface This volume is at least 100 times bigger than a biopsy sample

19. Results Stiffness (kPa) Median value of 10 shots 3.9 Kilo Pascals  At least 10 shots  Success Rate: ≥ 60%  IQR * (kPa) Interval around median Contains 50% of valid shots ≤ 25% of median value

21. NASH Management 1) All patients should be encouraged to exercise, as there is good evidence that even in the absence of weight loss exercise improves NASH. Obese Patients Weight reducing diet (aim for 10%, 1-2lb per week) In patients with BMI>28 with risk factors, or >30 without risk factors, consider treatment with Orlistat etc. 2) Diabetic Patients Good diabetic control (HbA1c <6.5%) MetforminThiazolidinediones Dietician for re-education. Diabetologist if glucose control is difficult. Diabetologist if glucose control is difficult.

22. NASH Management 3) Patients with Hyperlipidaemia and abnormal LFT’s Dyslipidaemia should be aggressively addressed Dietician Review Hypercholesterolaemia -Statins Hypertriglycerideaemia -Fibrate. Lipid Clinic Avoid Drugs Avoid Drugs amiodarone, glucocorticoids, methotrexate, nifedipine, synthetic estrogens, tamoxifen Antioxidants?

23. Alcohol Related Deaths E&W 1979-2010 http://www.statistics.gov.uk/cci/nugget.asp?id=1091

24. Monthly admission rate UHL Alcohol Admissions 2004-8

25. Spectrum of Alcoholic Liver Disease  The most common manifestations of alcoholic liver disease are: Alcoholic steato-hepatitis Alcoholic steato-hepatitis Acute alcoholic hepatitis Acute alcoholic hepatitis Cirrhosis due to alcohol Cirrhosis due to alcohol

26. Alcoholic Hepatitis  Most florid manifestation of ALD  Cholestatic liver disease associated with the long term heavy use of alcohol  Often a precursor to the development of cirrhosis  More severe forms are associated with a high mortality  1yr mortality after initial hospitalisation is 40%  Best treatment Stop drinking Stop drinking Resolution occurs within weeks-months +/- cirrhosis Resolution occurs within weeks-months +/- cirrhosis

27. Symptoms  Fever  Hepatomegaly  Jaundice  Coagulopathy  Features of hepatic decompensation  However, milder forms of alcoholic hepatitis often do not cause any symptoms

28. Investigation  Biochemistry AST/ALT ratio >1.5 AST/ALT ratio >1.5 ALT usually <100 IU/ml ALT usually <100 IU/ml Raised  GT (variable) Raised  GT (variable) Raised ALP (variable) Raised ALP (variable) Low Albumin (advanced disease) Low Albumin (advanced disease) Bilirubin (≥80 mmol/l) Bilirubin (≥80 mmol/l)  Haematology Prolonged INR (advanced disease) Prolonged INR (advanced disease) Macrocytosis / anaemia Macrocytosis / anaemia Leukocytosis Leukocytosis Thrombocytopenia (advanced disease) Thrombocytopenia (advanced disease)

29. Glasgow Alcoholic Hepatitis Score Age<50 ≥ 50 WCC(10 9 /l)<15 ≥15 Urea (mmol/l)<5 ≥5 PT ratio 2.0 Bili (  mol/l) 250 Score 1 2 3 Patients score from 5-12 points. Score >8 was used to define the high risk population and maximised sensitivity and specificity.

30. Survival from Alcoholic Hepatitis 28 day survival (%) 84 day survival(%) Day 1 GAHS <9 87 79 GAHS ≥9 46 40 Day 7 GAHS<9 93 86 GAHS ≥9 47 37 Derivation and validation datasets combined – 436 patients

31. Corticosteroids  If the patient has severe alcoholic hepatitis mDF>32, MELD >11, GAHS>8 Therapeutic trial of prednisolone 40mg PO Therapeutic trial of prednisolone 40mg PO 7 days 7 days If no improvement in bilirubin then discontinue If no improvement in bilirubin then discontinue Mathurin P Hepatol 2003;38;1363-9 Louvet A Hepatol 2008;45:1348-54

32. Pentoxifylline  PTX is a phosphodiesterase inhibitor which modulates the transcription of the TNFα-gene, lowers blood viscosity and reduces portal hypertension.  RCT 101 patients with severe alcoholic hepatitis (mDF>32). 101 patients with severe alcoholic hepatitis (mDF>32). Given 400mg tds for 28 days vs placebo Given 400mg tds for 28 days vs placebo Mortality 24% vs 46% at 28 days Mortality 24% vs 46% at 28 days Significant reduction in hepatorenal syndrome Significant reduction in hepatorenal syndrome Acriviadis E, Gastro 2000 119;1637-48

33. 3) ALP Elevated  Cholestatic Illness ( With or without jaundice) Differentiate from Bony ALP GGT, ALP iso-enzymes

34. Investigation of Cholestasis Dilated bile ducts Non-dilated bile ducts Full liver screen Raised ALP Check  GT if isolated rise 1) Stop alcohol 2) Stop hepatotoxic drugs 3) Advise weight loss if BMI>25 4) Recheck LFT’s after an interval Persistently raised ALP Consider MRCP ERCP Other imaging Diagnosis made- Treat disease Non diagnostic Ix- consider Liver biopsy

35. Liver ALP Elevated  Cholestatic Illness  Acute CBD stones/Gallstones CBD stones/Gallstones Tumours 1º or 2º Tumours 1º or 2º Pancreatic pathology Pancreatic pathology Drugs Drugs Infiltration Infiltration SOD SOD  Chronic PBC Sclerosing Cholangitis 1º or 2º NASH α-1 antitrypsin Sarcoid Amyloid HIV

36. Drug Induced Cholestasis  Intrahepatic Hepatocellular Cholestasis  Intrahepatic Ductular cholestasis  Ductopenic  Granulomatous  Allopurinol Antithyroid agents Augmentin Azathioprine Barbiturates Captopril Carbamezepine Chlorpromazine Chlorpropamide Clindamycin Clofibrate Diltiazem Erythromycin estolate Flucloxacillin Isoniazid Lisinopril Methyltestosterone Oral contraceptives (containing estrogens) Oral hypoglycemics Phenytoin Trimethoprim-sulfamethoxazole

37. The END  Allister.J.Grant@uhl-tr.nhs.uk Allister.J.Grant@uhl-tr.nhs.uk  0116 258 6630  http://hepatologist.sharepoint.com http://hepatologist.sharepoint.com