A comprehensive approach to drug-induced liver injury based on recently released guidelines from the American College of Gastroenterology

1. Drug-Induced Liver Injury
 DILI
Mario U. Mondelli
Research Laboratories, Department of Infectious Diseases,
Fondazione IRCCS Policlinico San Matteo and Department of Internal
Medicine, University of Pavia, Italy.
IASL Satellite Conference, Beijing, September 13, 2014

2. A Multidisciplinary Perspective on the Management of HCC
Characterization of DILI
 Intrinsic: Drugs that predictably cause liver injury in humans or in animal models
when given in sufficiently high doses (eg acetaminophen)
 Common
 Consistent clinical presentation
 Dose-related
 Idiosyncratic:
 Rare
 Recent data indicated incidences of 14-19 cases/100,000 person-years in the West
 Susceptible individuals
 Less consistent relationship to dose
 Variable clinical presentation, latency and course
 Chronic: Failure of LFTs to return to pre-DILI baseline and or other signs or
symptoms of ongoing liver disease 6 mos after DILI onset

3. A Multidisciplinary Perspective on the Management of HCC
Idiosyncratic Drug Reaction
 Rare adverse drug reaction which can lead to jaundice, liver
failure, or death.
 Antimicrobials and herbal and dietary supplements (HDS)
most common cause of DILI in the Western world.
 Anti-TB drugs and HDS most common cause of DILI in the
developing world
ACG Clinical Guideline Am J Gastroenterol 2014; 109:950–966

4. Incidence and Outcomes of DILI in
Western Patients
Iceland1 France2 USA3 Spain4
Recruitment
method
Prospective
population-based
Prospective
population-based
Prospective
registry
Prospective
registry
Years 2010-2012 1997-2000 2003-2007 1994-2004
N. of cases 96 34 300 461
Follow-up 13 months ‒ 6 months 6 months
Females (%) 56 65 60 49
% died (liver-related
death %)
11.5 (9.1) 5.8 (100) 8 (44) 5.2 (75 incl. OLT)
Major implicated
agents
(Appendix 1)
Antibiotics*,
NSAIDs, HDS
Antibiotics,
psychotropic
drugs, lipid-lowering,
NSAIDs
Antibiotics,
CNS agents,
HDS
Antibiotics, CNS
agents, NSAIDs
*: Amoxicilline-clavulanate mostly implicated
Modified from Björnsson ES. Clin Liver Dis 2014;4:9-11.
1. Björnsson ES, et al. Gastroenterology 2013;144:1419-25. 2. Sgro C, et al. Hepatology 2002;36:451-5.
3. Chalasani N, et al. Gastroenterology 2008;135:1924-34. 4. Andrade RJ, et al. Gastroenterology 2005;129:512-21.

5. A Multidisciplinary Perspective on the Management of HCC
Pathogenesis of Idiosyncratic DILI
A complex interplay among host, drug, and environmental factors
Maddukuri VC and Bonkowsky HL Clin Liver Dis 2014;4:1-3.

6. A Multidisciplinary Perspective on the Management of HCC
Characterization of Idiosyncratic DILI
 Latency
 Pattern of injury (R-value)
 Mortality risk (Hy’s law)
 Outcome (resolution vs chronicity)

7. A Multidisciplinary Perspective on the Management of HCC
Factors that May Predispose to Idiosyncratic DILI
Host Factors Environmental Factors Drug-Related Factors
Age Smoking Daily dose
Gender Alcohol Metabolic profile
Pregnancy Infection Class effect and cross
sensitization
Malnutrition Drug interactions and
polypharmacy
Obesity
Diabetes
Underlying liver disease
Indications
Previous DILI
ACG Clinical Guideline Am J Gastroenterol 2014; 109:950–966

8. A Multidisciplinary Perspective on the Management of HCC
Risk Factors and Hepatotoxic Drugs
 Age:
 Children: valproate, propylthiouracil, aspirin (Reye’s syndrome)
 Elderly: INH, amoxicillin – clavulanate, nitrofurantoin
 Gender:
 minocycline, diclofenac, methyl-DOPA, nitrofurantoin (AIH); nevirapine
 Pregnancy:
 methyldopa and hydralazine, antimicrobials including antiretroviral agents,
propylthiouracil
 Diabetes:
 methotrexate and anti-TB medicines
 Alcohol:
 APAP, methotrexate, INH
 Drug-drug interactions:
 valproate, anti-TB drugs

9. A Multidisciplinary Perspective on the Management of HCC
Diagnosing DILI
 Diagnosis of exclusion
 History and physical examination
 Medication exposure and onset and course of altered LFTs (usually DILI
occurs during thr first 6 mos after starting a new medication except
nitrofurantoin, minocycline, statins)
 Antibiotics and antiepileptics account for > 60 % of DILI
 HDS crucial
 Diagnostic evaluation:
 Tailored according to R-value
 Abdominal imaging
 Liver biopsy: supplementary but usually not revealing
 Differential diagnosis:
 Exclude competing etiologies
 Hepatocellular injury: viral hepatitis (HEV !), AIH, Wilson’s disease…, etc.
 Cholestatic injury: intrahepatic and extrahepatic

10. A Multidisciplinary Perspective on the Management of HCC
When Is Liver Biopsy Indicated?
 Persistence of altered LFTs after wash-out
 Weakens the case for DILI or suggests chronic DILI
 Consider biopsy if:
 continued use or re-exposure to the implicated agent is expected
 unresolved acute hepatocellular at 60 d and for cholestatic DILI at 180 d
after exposure
 cholestatic DILI takes longer to resolve
 Move-up or defer biopsy if LFTs trend up or down, respectively
 Risk stratification based on degree of necrosis and fibrosis
 Eosinophils and less degree of necrosis indicate  likelihood of recovery
 DD with AIH
 Minocycline, nitrofurantoin may have AIH-like features

11. A Multidisciplinary Perspective on the Management of HCC
Characterizing DILI by Pattern of Injury
R-Value.
 ALT / ULN ÷ AP / ULN. Used to define
hepatotoxicity injury patterns:
 Hepatocellular ( R > 5),
Mixed (2 < R < 5),
 Cholestatic ( R < 2)
Kaplowitz N . Nat Rev Drug Discov 2005;4:489 -99.

12. A Multidisciplinary Perspective on the Management of HCC
DILIN Observational Study: Histology
 Most common histological patterns:
 Acute (21%) and chronic hepatitis (14%)
 Acute (9%) and chronic cholestasis (10%)
 Cholestatic hepatitis (29%)
 Hepatocellular injury: more severe inflammation and lobular
disarray
 Cholestatic injury: bile plugs and duct paucity
 Severe or fatal hepatic injury associated with higher
degrees of necrosis, fibrosis stage, microvesicular
steatosis, and ductular reaction
 Eosinophils and granulomas were found more often in
those with milder injury
Kleiner DE, et al (DILIN). Hepatology 2014;59:661-670

13. Acute Cholestatic Injury Resulting from an Anabolic Steroid
Kleiner DE, et al (DILIN). Hepatology 2014;59:661-670

14. Chronic Cholestatic Injury Resulting from
Amoxicillin Clavulanate
Kleiner DE, et al (DILIN). Hepatology 2014;59:661-670

15. Acute Hepatitic Injury Resulting from Ciprofloxacin
Kleiner DE, et al (DILIN). Hepatology 2014;59:661-670

16. Chronic Hepatitic Injury Resulting from Isoniazid
Kleiner DE, et al (DILIN). Hepatology 2014;59:661-670

17. Cholestatic Hepatitic Injury Resulting from Duloxetine
Kleiner DE, et al (DILIN). Hepatology 2014;59:661-670

18. A Multidisciplinary Perspective on the Management of HCC
Causality Assessment
 Consensus expert opinion following a thorough evaluation
for competing etiologies is the current gold standard
 RUCAM1,2. Most commonly used score.
 Score from − 9 to + 10 grouped into likelihood levels of “excluded”
(score  0), “unlikely” (1 – 2), “possible” (3 – 5), “probable” (6 – 8),
“highly probable” (> 8)
 Divided into hepatocellular vs. cholestatic/mixed
 Based on timing of exposure, LFT washout, risk factors for DILI,
competing medications, competing diagnoses, and rechallenge
information (if any)
 Useful but should not be used as the sole diagnostic tool, not
validated
1. Roussel Uclaf Causality Assessment Method. Danan G , Benichou C. J Clin Epidemiol 1993;46:1323-30. 2. Benichou et al. J Clin Epidemiol
1993;46:1331-6. APPENDIX 2.

19. A Multidisciplinary Perspective on the Management of HCC
Prognosis in Idiosyncratic DILI
 Variable severity and evolution at 6 mos. (DILIN, n=660)1
  10% develop ALF
  20% have persistent liver injury
 Unrelated to dose, route, or duration of drug administration
 Cholestatic DILI fares better than hepatocellular
 OLT-free survival for ALF due to DILI 23 %, with 40 %
undergoing OLT (overall 58 % lower than APAP)2
 DILIN patients receiving liver biopsy (n=249)3:
 33 % hospitalized
 15 % considered severe
 6 % died or OLT
1. Fontana RJ, et al. Gastroenterology 2014; 147:96-108. 2. Reuben A, et al. Hepatology 2010;52:2065-76.
3. Kleiner DE, et al (DILIN). Hepatology 2014;59:661-670.

20. A Multidisciplinary Perspective on the Management of HCC
Hy’s Law
1 in 10 mortality risk of DILI if:
Serum ALT or AST > 3 × ULN
Serum total Bil > 2 × ULN, with no  Alk Phos
No other reason for  ALT, AST, Bil or
preexisting or acute liver disease
Temple R. Pharmacoepidemiol Drug Saf 2006;15:241-243.

21. A Multidisciplinary Perspective on the Management of HCC
Rising Incidence of HDS Hepatotoxicity
Maddukuri VC and Bonkowsky HL Clin Liver Dis 2014;4:1-3.

22. A Multidisciplinary Perspective on the Management of HCC
Reasons for Consuming HDS in Patients
Enrolled into the US DILIN Network
Navarro VJ, et al. (DILIN). Hepatology 2014, in press.

23. A Multidisciplinary Perspective on the Management of HCC
Herbal and Dietary Supplement Hepatotoxicity
 HDS second most common cause of DILI in the US1 and
increasing
 Supplements used for body building and weight loss are
mostly implicated
 HDS do not undergo preclinical and clinical toxicology
safety testing, nor clinical trials for safety or efficacy.
 Problems with:
 Batch to batch variation
 Myriad ingredients
 Unlabeled contaminants or adulterants, e.g. microbials2,3 or heavy
metals4,5
 RUCAM score useless because of absence of labeled
warnings on HDS
1) Chalasani N, et al. Gastroenterology 2008;135:1924 – 34. 2) Kneifel W, et al. Planta Med 2000;68 5 – 15. 3) Stickel F. J Hepatol
2009;50:111 – 7 . 4) Ernst E. Eur J Clin Pharmacol 2002;57:891 – 6. 5) Saper RB, et al. JAMA 2008;300:915 – 23.

24. A Multidisciplinary Perspective on the Management of HCC
Diagnosing HDS
 Physicians must specifically query patients for HDS
consumption because of underreporting
 Same approach as for conventional drugs
 Most HDS cause hepatocellular-type liver injury (R > 5)
 Only a few agents show repeating patterns of injury, eg:
 Anabolic steroids: cholestatic hepatitis
 Pyrrolizidine alkaloids: sinusoidal obstruction

25. Etiology of Severe DILI in China
Etiology N. (%)
Chinese herbal medicine 203 (42.6)
Anti-TB drugs 83 (17.4)
Antibiotics 42 (8,8)
NSAID 24 (5)
Antithyroid agents 22 (4.6)
Psychotropic 15 (3.1)
Wang G-Q, et al. Clin Liver Dis 2014;4:26-9
Death rate: 18%
Improved: 62%
Worsened: 20%

26. A Multidisciplinary Perspective on the Management of HCC
Rechallenge
Best avoided!
 Reintroducing a medication in this context may be
associated with a more rapid return of injury than initially
experienced, and a more severe and possibly fatal reaction
 Exception: cases of life-threatening situations where there
is no suitable alternative

27. A Multidisciplinary Perspective on the Management of HCC
Treatment
 Withdrawal of the offending medication (the earlier the
better)
 UDCA: efficacy not established
 Steroids: no controlled trials
 N-Acetylcysteine (NAC): no improvement in overall survival
 In early stage ALF: 58% OLT-free survival vs 27% placebo1
 FDA has not approved NAC for non-APAP ALF
1. Bechmann LP, et al. J Hepatology 2010;53:639 – 47

28. A Multidisciplinary Perspective on the Management of HCC
Follow-Up
 Chronic DILI occurs in about 15 – 20 % of cases of acute
DILI and requires long-term follow-up
 Subjects who presented with cholestatic DILI are more
likely to develop chronic DILI
 Chronic DILI resembles AIH and might respond to steroids

29. A Multidisciplinary Perspective on the Management of HCC
DILI in patients with CLD
 The DILIN prospective study has demonstrated that at least
6 % of enrolled patients had pre-existing CLD1
 There is little evidence of increased risk of DILI in patients
with CLD
 Patients with chronic HBV with INH hepatotoxicity have
more severe hepatocellular injury compared with uninfected
patients, and HAART-related liver injury is more severe in
patients with viral hepatitis2,3
 ARVs4 and INH2,3 may cause hepatotoxicity in HIV/HBV or
HCV-coinfected patients
 Difficult to distinguish a spontaneous disease flare from a
bona fide DILI episode
1. Fontana RJ, et al. Gastroenterology 2014;147:96-108. 2. Nunez M. Hepatology 2010;52:1143 – 55. 3. Ungo JR, et al. Am J Resp Crit Care
Med 1998;157:1871 – 6. 4. Wong WM, et al. Hepatology 2000;31:201 – 6.

30. A Multidisciplinary Perspective on the Management of HCC
Summary & Conclusions
 Idiosyncratic DILI is rare and unpredictable
 Antimicrobials and HDS ( incidence) most commonly involved
 DILI is rarely fatal although ALF and emergency OLT is a
possible outcome in about 10% of cases
 Host and environmental factors may predispose to DILI
 Pattern of liver injury only rarely linked to a specific compound
 Causality assessment mainly relies on consensus expert opinion
but scores may help
 Cholestatic DILI fares better than hepatocellular but may more
often become chronic
 CLD does not per se increase the risk of DILI, although ARVs
and INH may cause severe liver injury in HBV or HIV-coinfection
 Avoid rechallenge