DILI

Drug-Induced Liver Injury

DILI

Mario U. Mondelli

Research Laboratories, Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo and Department of InternalMedicine, University of Pavia, Italy.

IASL Satellite Conference, Beijing, September 13, 2014

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


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

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

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.

*: Amoxicilline-clavulanate mostly implicated


Pathogenesis of Idiosyncratic DILIA complex interplay among host, drug, and environmental factors

Maddukuri VC and Bonkowsky HL Clin Liver Dis 2014;4:1-3.


Characterization of Idiosyncratic DILI

Latency

Pattern of injury (R-value)

Mortality risk (Hy’s law)

Outcome (resolution vs chronicity)


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


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


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 exceptnitrofurantoin, 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


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


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.


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, microvesicularsteatosis, 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


Acute Cholestatic Injury Resulting from an Anabolic Steroid


Chronic Cholestatic Injury Resulting from

Amoxicillin Clavulanate


Acute Hepatitic Injury Resulting from Ciprofloxacin


Chronic Hepatitic Injury Resulting from Isoniazid

Cholestatic Hepatitic Injury Resulting from Duloxetine



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 rechallengeinformation (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.


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.


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.


Rising Incidence of HDS Hepatotoxicity

Maddukuri VC and Bonkowsky HL Clin Liver Dis 2014;4:1-3.


Reasons for Consuming HDS in Patients

Enrolled into the US DILIN Network

Navarro VJ, et al. (DILIN). Hepatology 2014, in press.


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 labeledwarnings 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.


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

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%


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


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


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


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 patientswith 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.


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

Health & Medicine

DILI