Drug- induced Liver Injury. Guruprasad P. Aithal

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1 Drug- induced Liver Injury Guruprasad P. Aithal

2 Characterising DILI Deriving case defini=ons Phenotypes and outcomes Manifesta=ons PaBerns Liver histology Cholestasis

3 Terminology Drug- induced Liver disease: includes all forms where medica=on is considered a risk factor Acute and Chronic Parenchymal and intrahepa=c biliary system Benign and malignant tumours Drug- induced Liver injury (DILI): Acute onset liver injury abributed to a medica=on taken in a therapeu=c dose that is NOT predictable by its pharmacological ac=on Acute Not an overdose Aithal. Clin Pharmacol Ther 2011; 89:

4 CIOMS Defini=on: >2 x ULN ALT 2.6% popula=on have raised ALT 25% of the popula=on have NAFLD Fast food raises liver enzymes Modest ac=vity normalises ALT Danan & Benichou. J Clin Epidemiol 1993 Kechagias. Gut 2008;57:

5 ALT rise in Clinical trials Transient ALT (liver disease excluded) in clinical trial 2 x ULN in 6-8% 5 x ULN in 1.4% Incidence of 0.4/ 100 pa=ent yrs. Incidence of ALT in predominantly women (no known liver disease) 5xULN: 0.31/ 100 pa=ent years Makar. Pharmacoepidemiol Drug Saf 2008; 17: Well. Regul Toxicol Pharmacol 2008; 52; Aithal. Clin Pharmacol Ther 2011; 89:

6 Adapta=on vs. DILI RCT Placebo (n=39) Paracetamol (n=26) opioid + PCT (n=80) ALT >3xULN 0% placebo vs. 31%- 43% with therapy Hispanic vs. others OR: 1.9 [ ] Watkins. JAMA 2006; 296(1):87-93.

7 ALT 5 x ULN Indicates acuity Raised ALT and DILI Non- specific/ unexplained in per 100 pa=ent years AST 10 x ULN Ischemic: 55%, pancreatobiliary: 25%; DILI: 9% ALT 20 x ULN Ischemic: 61%, biliary: 4.5%, DILI: 9% Makar. Pharmacoepidemiol Drug Saf 2008; 17: Well. Regul Toxicol Pharmacol 2008; 52; Whitehead. Gut 1999; 45: Galvin. Clin Med 2015;15(3):

8 Any of the following Case defini=ons 5- fold eleva=on above ULN for ALT or AST 2- fold eleva=on above ULN for ALP (& no bone- related cause) 2- fold eleva=on above ULN for bilirubin plus ALT 3 x ULN Aithal. Clin Pharmacol Ther 2011; 89:

9 Pa#erns DILI: PaBerns and Severity Severity ALT ac=vity (ALT*): Pa=ent s ALT/ upper limit of normal ALP ac=vity (ALP*): Pa=ent s ALP/ upper limit of normal ALT/ALP ra=o (R value): ALT*/ ALP* R 5: Hepatocellular R 2: cholesta=c R : mixed Raised enzymes Jaundice Acute liver failure Transplanta=on/ death Aithal. Clin Pharmacol Ther 2011; 89:

10 Epidemiology: popula=on based Drug- induced Liver Injury Prospec=ve study: All physicians in Iceland (251,000 >15 yrs) Case defini=on: >3x ULN ALT (male=70 u/l; female= 45 u/l) > 2x ULN ALP Crude incidence: 19/ 100,000/ year 22% hospitalised for symptoms 1% death Acute Liver Failure 5,484,224 Kaiser Permanente Northern California healthcare system members: ,731,307 person- years ( 18 yrs) 62 definite or possible ALF 18 acetaminophen (4 with other drugs) 14 DILI Incidence rate: 1.02 [ ] /1,000,000 person years 6 herbal, 2 an=microbials and 6 others 5 transplanted and 3 died Bjronsson. Gastroenterology 2013; 144: Goldberg. Gastroenterology. 2015;148(7): e3

11 Outcomes 1089 pa=ents 107 (9.8%) died in 2 years DILI primary cause in 68 (64%), contributory in 15 (14%) 74% had acute liver failure 13% chronic, 7% acute on chronic liver failure 6% acute cholesta=c failure. Bilirubin, coagulopathy, leucocytosis and thrombocytopenia independently associated with DILI death Hyashi. Hepatology 2017;66(4):

12 Hy or low Expert consensus of the 1978 Fogarty Conference was that 3 ULN was markedly abnormal.

13 New Hy 1089 pa=ents 107 (9.8%) died in 2 years DILI primary cause in 68 (64%), contributory in 15 (14%) nr Hy s law: Bil 2.5 mg/dl + R >5: 6 months mortality 14% vs 10% (Hy law) HR: 6.2 ( ) vs 2.2 ( ) Hyashi. Hepatology 2017;66(4):

14 Eosinophilia Favourable prognosis Eosinophilic infiltra=on Peripheral eosinophilia Hypersensi=vity features Rashes, fever, lymphadenopathy, and/or eosinophilia, (including Stevens- Johnson syndrome) Bjornsson. Aliment Pharmacol Ther 2007; 25: Devrabhavi. Hepatology 2011; 54: Andrade. Gastroenterology 2005;129:

15 Liver biopsy to phenotype To inform prognosis Eosinophil and granuloma associated with milder course Degree of necrosis and ductular reac=on in acute liver failure associated with transplanta=on or death Neutrophils, microvesicular steatosis, cholangiolar cholestasis, fibrosis, portal venopathy associated with severity or death Katoonizadeh. Liver Int 2006; 26: Bjornsson. Aliment Pharmacol Ther 2007; 25: Kleiner. Hepatology 2014; 59: Kleiner Histopathology 2017; 70:81-93.

16 Fibrosis in AIH Cholestasis in DILI AIH vs. DILI Suzuki et al. Hepatology 2011

17 Drug- induced AIH vs AIH 9% of all DILI are DI- AIH; 9% of AIH are drug- induced. No defini=ve dis=nc=on on standard liver histology Dual- staining IHC to characterise mononuclear immune cells DI- AIH predominantly CD3 + T cells I- AIH: portal CD20 + mature B cells Steroid therapy: If uncertain or no prompt improvement on drug withdrawal Withdrawal of immunosuppression on normaliza=on of ALT Monitoring: If DI- AIH no relapse on (median 4 years) follow up vs. If I- AIH 63% relapse in 1 year; 75% in 5 years. Bjornsson. Hepatology 2010; 51:2040-8, Licata. Dig Liver Dis 2014; 46: , Foureau. Clin Exp Immunol. 2015; 180(1):40-51, Czaja. Hepatology 2002; 35:890-7, Czaja. World J Gastroenterol 2010; 28:16(8):934-47, Bjornsson. Clin Gastroenterol Hepatol 2017; 15(10):

18 80% 60% 40% 20% 0% Overall survival Spontaneous MELD survival >40 survival Karkhanis. Hepatology 2014; 59(2): Risk vs benefit of steroids Drug- induced ALF Steroids No steroids 361 with acute liver failure 66 AIH (25 with steroids) 164 Indeterminate (21 with steroids) 131 DILI (16 steroids) Steroids not associated with improved overall survival (61% vs 66%, P=0.41) Steroid use was associated with diminished survival in certain subgroups MELD >40, survival 30% vs 57%, P=0.03).

19 Drug- induced Acute liver failure 100% 90% 80% TX 70% 60% 50% 40% Died 30% 20% 10% Survived 0% Schiodt et al. Liver Transpl Surg 1999 Ostapowicz et al. Ann Int Med 2002 Wei et al. J Intern Med 2007

20 Genotype and Phenotype HLA- A*33:01 associa=on with cholesta=c/mixed DILI (n=304): OR 5.2 [ ](p=5.2x10-13 ). Nicoleq*, Aithal*. Gastroenterology 2017;152(5):

21 Secondary Sclerosing Cholangi=s 102 DILI 25 had ERCP 10 SSC (all females) Co- amoxiclav (3), sevoflurane (2), atorvasta=n, venlafaxine, infliximab, amiodarone, green tea All with cholesta=c/ mixed pabern vs 56% 70% with Jaundice at presenta=on vs 23% (p = ), Higher peak ALP: 551 ( ) vs. 329 ( ) (p = 0.055) Longer =me for resolu=on 152 days ( ) vs. 62 days (36 91) (p < ). Gudnason. Digestive and Liver Disease 2015;47:502 7

22 Vanishing Bile Duct Syndrome 26/363 (7%) of biopsies: bile duct loss 10 or more portal tracts + absence of interlobar bile ducts) 14 severe: if loss >50% of portal areas Co- amoxiclav (3), temozolomide (3), herbs (3), azithromycin (2), fluroquinones (2), PPI (2), cephalsporins (2), infliximab, montelukast, mesalazaine and allopurinol. 25/26 (96%) have jaundice vs 70% in all DILI 77% with itching vs 54% all DILI chronicity (raised liver tests at 6 months) in 94% vs 47% with other histology 19% liver related mortality vs 3% in all DILI; 7.6% transplanta=on Bonkovsky. Hepatology 2017;65:

23 Summary Higher ALT threshold relates to acuity of an event and reduces non- specific signals. DILI paberns based on liver biochemistry iden=fy clinically relevant phenotypes. Jaundice and liver failure iden=fy severity and hence outcomes. Liver biopsy strengthens clinical decision making in selected circumstances Immunological characterisa=on has poten=al to refine phenotyping further.

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