Diagnostic evaluation of suspected

Drug-Induced Liver Injury

Ynto de Boer, MD

Department of Gastroenterology and Hepatology

Disclosure

No disclosures

Drug-induced liver injury

?

Outline

What is DILI?

What, other than the drug, causes DILI?

How to diagnose DILI?

Resources

Drug-induced liver injury

Hepatotoxicity:

Hepatocytes ALT/AST elevation

Cholangiocytes Alk Phos elevation

Direct toxicity, dose dependent (eg. Paracetamol; ~50%

of DILI)

Idiosyncratic injury

Drug-induced liver injury

Kleiner et al. Hepatology 2014

Ciprofloxacin -

Acute hepatitic

injury

Isoniazid -

chronic

hepatitic injury

Anabolic steroid

- Acute

cholestatic injury

Amox-clav -

Chronic

cholestatic injury

Duloxetine -

Cholestatic

hepatitis injury

Mechanisms

Cell death: apoptosis and necrosis

Reactive metabolite formation/bioactivation

Drug transporter–mediated drug-induced

hepatotoxicity

Immune-mediated response

Mitochondrial dysfunction

Activation of stress signaling pathways

Shesu et al. Clin Liv Dis 2017

Mechanisms

Shesu et al. Clin Liv Dis 2017

Genetics - Flucloxacillin

HLA-B*57:01

Daly et al. Nat Genet 2009

Genetics – overall

864 cases of DILI without amox/clav and fluclox

Nicolleti et al. Gastroenerology 2016

Genetics

Association Effect Size of rs72631567, A*33:01, and rs28521457 Across Different Liver Injury Patterns

CohortAssociatedvariant OR 95% CI P value

AF cases AF controls

Entire DILI cohort rs72631567 2.0 1.6−2.5 9.7 × 10−9 0.05 0.03

A*33:01 2.6 1.8−3.7 7.0 × 10−8 0.02 0.01

rs28521457 1.5 1.3−1.9 7.0 × 10−8 0.06 0.04

Cholestatic and mixed DILI cohort rs72631567 2.4 1.7−3.4 9.5 × 10−7 0.06 0.03

A*33:01 5.0 3.3−7.9 4.2 × 10−13 0.04 0.01

rs28521457 1.0 0.7−1.5 .9 0.04 0.04

Hepatocellular DILI cohort rs72631567 1.6 1.2−2.3 2.5 × 10−3 0.04 0.03

A*33:01 1.5 0.8−2.6 .19 0.01 0.011

rs28521457 2.1 1.6−2.7 4.8 × 10−9 0.08 0.040

Nicolleti et al. Gastroenerology 2016

Epidemiology

Ahmad et al. Clin Liv Dis 2017

Idiosyncratic DILI

National studies of drug-induced liver injury incidence

Country Iceland France Korea United Kingdom Spain Sweden

Years of study 2010–2011 1997–2000 2005–2007 1994–1999 2004–2009 1995–2005

Study type Prospective Prospective Prospective Retrospective Retrospective Retrospective

Number of DILI cases 96 34 371 128 57 77

Crude DILI incidencerate/100,000 per year 19.1 13.9 12 2.4 3.01 2.3

Ahmad et al. Clin Liv Dis 2017

Idiosyncratic DILI

Drug-induced liver injury registries across the world

Country United States Spain Korea

Years of study 2004–2013 1994–2004 2005–2007

Study type Prospective Prospective Prospective

Number of DILI cases 899 461 371

Antimicrobials (% of total) 45.3% 32% —

HDS (% of total) 16.1% — 73%

Ahmad et al. Clin Liv Dis 2017

Idiosyncratic DILI

Chalasani et al. Gastroenterology 2015

Prospective US DILIN study in 899 patients 2004 – 2014:

Idiosyncratic DILI

Chalasani et al. Gastroenterology 2015

Therapeutic classes n Individual agents n

1 Antimicrobials 408 1 Amoxicillin-clavulanate 91

2 Herbal and dietary supplements 145 2 Isoniazid 48

3 Cardiovascular agents 88 3 Nitrofurantoin 42

4 Central nervous system agents 82 4 Sulfamethoxazole/trimethoprim 31

5 Anti-neoplastic agents 49 5 Minocycline 28

6 Analgesics 33 6 Cefazolin 20

7 Immunomodulatory 27 7 Azithromycin 18

8 Endocrine 20 8 Ciprofloxacin 16

9 Rheumatologic 13 9 Levofloxacin 13

10 Gastrointestinal 12 10 Diclofenac 12

Prospective US DILIN study in 899 patients 2004 – 2014:

Clinical presentation

Mild transaminase elevation Acute liver failure

Bilirubinemia

Up to 51% of transplantation for acute liver failure is due

to DILI

Ostapowicz et al. Ann Intern Med 2002

Augmentin

Mild transaminase elevation Acute liver failure

Bilirubinemia

Up to 51% of transplantation for acute liver failure is due

to DILI

livertox.nih.gov

64 year old man

Minocycline

Mild transaminase elevation Acute liver failure

Bilirubinemia

Up to 51% of transplantation for acute liver failure is due

to DILI

livertox.nih.gov

64 year old man55 year old woman

Unexplained liver test abnormalities

Ascertain the type of injury

Exclusion of other etiologies:

obstruction, (acute) viral hepatitis, (non-)alcoholic

hepatitis, shock liver, autoimmune liver disease

History of exposure to drugs, herbals and dietary

supplements?

Look for typical/distinguishing features:

immunoallergic or autoimmune features

Hepatocellular vs cholestatic: the R-ratio

Normalised ALT/ALP ratio:

(ALT/ULN) ÷ (Alk Phos/ULN)

>5: hepatocellular

2–5: mixed hepatic injury

<2: cholestatic

Characteristics for causality assessment

Time to onset/latency

Course

Risk factors

Concomitant drugs

Nondrug causes of liver injury

Previous information on the hepatotoxicity of the drug

Response to rechallengeDanan et al. Clin Epidemiol 1993

Risk factors

Age:

exposure, multiple drugs

Gender:

metabolism, exposure

Alcohol

Other liver disease

Ethnicity/Genetics:

Asian ethnicity

HLA genotypesDanan et al. Clin Epidemiol 1993

Phenotypes

Autoimmune (ANA, SMA, IgG):

nitrofurantoin, minocycline, hydralazine, methyldopa

Immunoallergic (rash, fever, eosinophilia):

aromatic anticonvulsants, allopurinol, sulfonamides

and fluoroquinolones

Drug specific phenomena:

icterus in anabolic steroids

Diagnostic scores: RUCAM

Roussel-Uclaf Causality Assessment Method:

The individual points range from -3 to +3

The total possible score ranges from -9 to +14.

0 or less “excluded”

1 to 2 “unlikely”

3 to 5 “possible”

6 to 8 “probable”

>8, “highly probable”

Danan et al. Clin Epidemiol 1993

Diagnostic scores: RUCAM

Danan et al. Clin Epidemiol 1993

Liver biopsy

Can be helpful, but

is usually not necessary

Exclusion of

other etiologies

Distinctive patterns

can be recognised

Kleiner et al. Hepatology 2014

Liver biopsy – DILI and AIH

Suzuki et al. Hepatology 2011

Histologic features AIH DILI

Severe portal inflammation (≥grade 2) *

Prominent intra-acinar lymphocytes *h

Prominent intra-acinar eosinophils *

Cholestasis canalicular *h, *c

Prominent portal plasma cells *

Rosette formation *

Any levels of fibrosis (≥grade 1) *

Prominent port neutrophils *c

Hepatocellular cholestasis *c

Severer focal necrosis (≥grade 4) *

Autoimmune features in DILI

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De Boer et al. Clin Gastroenterol Hepatol 2017

nitrofurantoin, minocycline, methyldopa and hydralazine

Hy’s Law

Hyman Zimmerman: “drug-induced hepatocellar

jaundice is a serious lesion, with mortality from 10 to 50%”

Bob Temple:

Hepatocellular-type injury (ALT > 3 upper limit of

normal: ULN)

Bilirubin >2x ULN, no evidence of obstruction (> Alk

Phos) or Gilbert’s syndrome

Exclude other causesTemple Pharmacoepidemiol Drug Saf 2006

Outcome

US DILIN outcome data

Characteristics Antimicrobials

(n = 408)

Cardiovascular

(n = 88)

CNS agents

(n = 82)

Antineoplastics

(n = 49)

Analgesics

(n = 33)

Fatal, (%) 6.9 5.7 6 10 3

Death, at any time (%) 5.1 5.7 6.1 29 3

Liver transplantation (%) 3.9 2.3 3.7 0 0

Chalasani et al. Gastroenterology 2015

Outcome

Iceland

Björnsson et al. Gastroenterology 2013

Herbal and dietary supplements

De Boer et al. Clin Liv Dis 2017

The incidence of HDS-ILI is rising

Ask, and ask again

Herbal and dietary supplements

De Boer et al. Clin Liv Dis 2017

Livertox

adslkf

livertox.nih.gov

Conclusion

DILI can mimic any other liver disease and diagnosis is

based on careful history and pattern of injury

Liver biopsy may be helpful but generally not necessary

HDS product are often not perceived as drugs or

potentially dangerous: Ask and ask again

A helpful resource: livertox.nih.gov

Thank you for your attention!