DRUG INDUCED

HEPATITIS
& ITS
MANAGEMENT
SPEAKER- ARINDAM PANDE

CHAIRPERSON- Prof. B K DEY

Prof. S B GANGULY
 INTRODUCTION

MAY FOLLOW INHALATION / INGESTION /

PARENTERAL ADMINISTRATION OF—

● INDUSTRIAL TOXINS
● BICYCLIC OCTAPEPTIDES
● PHARMACOLOGICAL AGENTS
 INCIDENCE

● 1 IN EVERY 10,000 TO 100,000

● MAY BE UNDERESTIMATION, DUE TO
--UNDERREPORTING
--DIFFICULTIES IN DETECTION /
DIAGNOSIS
--INCOMPLETE OBSEVATION OF EXPOSED
PERSONS
 Yearly incidence rate

DIH: 14/100 000 inhabitants / year

= 8 000 cases / year in France
(16-times the number reported
6% to the French Pharmacovigilance
Agency)

Fatal DIH (0.8/100 000 inhabitants/year)

Sgro, Hepatology 2002;36:451.

 FOURTH CAUSE
C O KE

BO ZE
O
Burger B L OOD
HCV
HBV D R UG
Obesity/
diabetes *Bagheri,
9%* Br J Clin Pharmac
2000;50:479.

Abnormal
liver
tests
DISPROPORTIONATE ROLE
IN FULMINANT HEPATITIS
IN THE US AND UK
 Drugs: first cause

FULMINANT HEPATITIS
in the USA
 PARACETAMOL: 40%
Intentional overdoses
DRUGS: 52% Self medication with
excessive doses in the USA
OTHER DRUGS: 12%

OTHER CAUSES: 48%

FULMINANT HEPATITIS IN THE USA

Lee WM, Sem Liver Dis, 2003;23:217

 SIGNIFICANCE….
● PREVENTABLE AND CORRECTABLE CAUSE OF
ACUTE AND CHRONIC LIVER DISEASES.
● LOW FREQUENCY(6% of all adverse drug reactions)
LEADS TO CASES BEING OVERLOOKED,THUS
DIFFICULTY IN ATTRIBUTING CAUSALITY.
● ROLE OF DRUGS IN SYNERGISTIC
HEATOTOXICITY (HIV,TB,NASH,BONE OR ORGAN
TR.)
● LEGAL AND FINANCIAL IMPLICATIONS
● MOST FREQUENT CAUSE FOR POST MARKETING
WITHDRAWAL OF DRUGS (eg. troglitazone).
 FOR THE PHYSICIAN

Continued treatment
3. Fulminant
ALT hepatitis

2. Chronic
liver
disease
5 ULN
1. Adaptation
1 ULN
DRUG
 FOR THE PHARMACEUTICAL INDUSTRY

DIH: Major cause for drug withdrawal

or prescribing restrictions

Recent cases:

Ximelagatran
Troglitazone
Bromofenac

Felbamate
Pemoline
Tolcapone
Trovafloxacin
 DEFINITION (FDA, FEB’2001)
● ALT > 3 times of UNL & Total Bilirubin > 2
times of UNL
● Further verification through analysis of
additional data
● ↑ serum enzymes ( ALT, AST, ALP)- indicator
of liver injury
● ↑ Total & Conjugatad Bilirubin – measure of
overall liver function
 PATTERN OF HEPATOTOXICITY

● PREDICTABLE / DIRECT TOXIC EFFECT

(DOSE DEPENDENT)

● UNPREDICTABLE / IDIOSYNCRATIC
(DOSE INDEPENDENT)
-- IMMUNO-ALLERGIC TYPE
-- METABOLIC IDIOSYNCRASY

● OTHER
 INTRINSIC HEPATOTOXINS

● Acute liver damage after a relatively brief

latent period in a predictable, dose-
dependent fashion
● Independent of host susceptibility factors
● Acetaminophen, CCl4, toxins of Amanita
mushroom species
 IDIOSYNCRATIC HEPATOTOXINS

● An infrequent unpredictable fashion after a

variable latent period
● Variations in the pathways of drug
biotransformation, immune mediated
hypersensitivity (drug-allergy)
● Fever, arthralgia, rash and eosinophilia
● Halothane, isoniazid, phenytoin
 CLINICAL CLASSIFICATION
wide spectrum from minor nonspecific derangements to fulminant
hepatic necrosis

Hepatocellular – acute inflammation

Cholestatic –biliary obstruction
Mixed
Fatty liver
Fibrosis, chronic hepatitis
Granuloma
Vascular damage
Tumor
Hepatitis Mixed Cholestasis

ALT x ULN
Hepatocellular Injury >5 ← → <2 Cholestasis &
and Inflammation ALP x ULN Ductular injury and
Inflammation
 Liver Injury and Its Patterns

Navarro V and Senior J. N Engl J Med 2006;354:731-739

 Hy’s rule

Mortality of drug-induced
hepatocellular jaundice: 10%

Example:
5 of 1 000 patients have
ALT > 10 ULN and bilirubin > 3 ULN
in a clinical trial

You can expect:

5 deaths with liver failure for 10 000 recipients
after marketing
 Idiosyncratic Drug Reactions and the Cells That Are Affected

Lee W. N Engl J Med 2003;349:474-485

 Effects of Increased or Cumulative Doses of Drugs

Lee W. N Engl J Med 2003;349:474-485

 Hepatic Drug Metabolism

Uptake

Efflux
(Phase III)
Metabolism

Phase I Phase II
(CYP enz) (Conjugation)

A schematic of the interplay between drug uptake,

metabolism and efflux in the hepatocyte.
 METABOLIC ACTIVATION
Drug
CYP

Reactive metabolite

(Low Amounts) (High Amounts)

Extensive
covalent
Protein
binding
 GSH
Immune reactions Direct toxicity
MITOCHONDRIAL DYSFUNCTION
Drugs

 Beta-  Respi-
oxidation ration

Steatosis Cell dysfunction

Cell death
Lactic acidosis
 Six Mechanisms of Liver Injury

Lee W. N Engl J Med 2003;349:474-485

 CLINICAL
MANIFESTATIONS OF
DRUG INDUCED HEPATITIS
 ACUTE DIH CHRONIC DIH
ACUTE HEPATITIS
Cytolytic hepatitis Subacute or chronic hepatitis
Mixed hepatitis
Cholestatic hepatitis
+ cholangi(oli)tis Vanishing bile duct syndrome

Bland cholestasis

Steatosis Steatohepatitis

Sinusoidal dilation, Peliosis,

VOD , Budd-Chiari

Hepatic adenoma, HCC

Liver-Biopsy Specimens Showing Common Histologic Features of Drug-Related Hepatotoxicity

Navarro V and Senior J. N Engl J Med 2006;354:731-739

HOW CAN THE DIAGNOSIS
BE MADE?
 DIAGNOSIS

- Always consider a possible iatrogenic cause

- Insistent questioning
(Analgesic drugs, illicit drugs, psychoactive
drugs, NSAIDs, over-the-counter drugs,
herbal remedies)
- Compatible chronology (DIH may sometimes appear
2 weeks after treatment is stopped)
-  Fever, rash, eosinophilia (immunoallergic mech.)
- Similarity to previously reported cases
- Exclusion of other causes
(obesity/diabetes, alcohol, …viral serologies,
ultrasonography)
- Deceleration after withdrawal
 Diagnosis of Drug-Related Hepatotoxicity

Navarro V and Senior J. N Engl J Med 2006;354:731-739

 Specific antibodies
Autoantibodies
Tienilic acid anti-LKM2 (anti-CYP2C) Beaune, PNAS 1987;84:551

Dihydralazine anti-LM (anti-CYP1A2) Bourdi, JCI 1990;85:1967

Halothane anti-CYP2E1 Eliasson, Mol Pharmacol 1996;50:573

Germander anti-EH de Berardinis, Mol Pharmacol 2000;58:542

Iproniazid anti-M6 (anti-MAO B) Pons, BBRC 1996;218:1118

Anti-metabolite-protein adduct antibodies

Halothane anti-TFA-protein Kenna, JPET 1998;245:1103

Tienilic acid anti-TA-protein Robin, JCI 1996;98:1471

Diclofenac anti-Diclof.-protein Aithal, Hepatology 2004;39:1430

 Lymphocyte proliferation assay

● Mononuclear cells are separated from a patient’s peripheral

blood and cultured in medium in the presence of the suspected
allergen.
● A positive result is most easily demonstrated by lymphocyte
proliferation (usually measured by the uptake of tritiated
thymidine).
● The ratio of counts per minute in the presence of antigen
compared with a control culture in its absence is expressed as the
stimulation index.
● If this value is greater than a cut-off level determined in a set of
healthy controls, then the test is considered positive, and
evidence of the presence of sensitised lymphocytes.
● Certain activation markers and adhesion molecules such as
CD11a/CD18 (LFA-1), accounts for their rapid reactivation on
re-exposure to antigen.
 Lymphocyte proliferation assay
With/without drug [3H]thymidine incorporation ratio
32
( with indomethacin to prevent
inhibitory PGE2 formation)
16
8 56%
(26%
Maria and Victorino,
without Gut 1997;41:534-540
4 indo-
meth-
acin)
2
1 34% 100% 100%
95 pts 106 35 treated pts
with DIH controls without DIH
 RECHALLENGE
1. Performing a rechallenge for the sake of
diagnosis is unethical, and is particularly risky if
immunoallergy is suspected (risk of rapid and
severe DIH).

2. However, re-introduction may be attempted if:

- the drug is required to treat a serious disease;
- other drugs are less active;
- one suspects direct toxicity (rather than
immunoallergy);
- one use lower doses (or different
co-medications…);
- and transaminases are monitored frequently.
 Management
● Discontinuing the implicated drugs
● Supportive care for acute hepatitis and hepatic failure
● Specific pharmacological intervention, e.g.
– N-acetylcystein for acetoaminophen overdose
– Carnitine in valproate overdose
● No established value of
- Corticosteroids for drug hepatotoxicity with allergic
features
- Silibinin for hepatotoxicmushroom poisoning
- Ursodeoxycholic acid for cholestatic drug hepatotoxicity
 Drug withdrawal
ALT Few
weeks

10 ULN

1 ULN
DRUG
Key Guidelines in the Recognition and Prevention of Hepatotoxicity in Clinical Practice

Navarro V and Senior J. N Engl J Med 2006;354:731-739

 ACETAMINOPHEN &
HEPATOTOXICITY:
● LEADING CAUSE OF ACUTE LIVER FAILURE IN THE WEST.
● SINGLE DOSE 15-25g may cause acute liver failure.
● LIVER INJURY IN 3 PHASES.
● Role of NAPQI (Phase 1 product), by CYP2E1
● Hepatic injury apparent after 24-48 hours
● FASTING, ALCOHOLISM, CONCURRENT INH, PHENYTOIN are
risk factors.
● ALT 2000-10,000 IU/L, ZONE 3 NECROSIS.
● Rx: Gastric lavage, activated charcoal (within 30 min)
● THIOL DONORS - NAC(16hrs), METHIONINE(10hrs)
● NAC- given if, serum level > 200mg at 4 hr or > 100 mg at 8 hr. 5% oral
solution (140mg/kg loading, then 70mg/kg 4hrly for 15-20 doses)
 ATDs & HEPATOTOXICITY:
● RISK FACTORS  ^AGE, FEMALE, MALNUTRITION,
ALCOHOLISM, NAT ACTIVITY, ACETYLATOR
PHENOTYPE.
● CRITERIA FOR ATD INDUCED H’TOXICITY (ANY
ONE)
– AT > 5 ULN
– RISE IN SERUM TOTAL BILIRUBIN > 1.5
– ANY ^AT WITH ANOREXIA, NAUSEA, VOMITING, JAUNDICE
● TREATMENT(BTS GUIDELINES):
STOP HEPATOTOXIC DRUGS--START ETHAMBUTOL,
STREPTOMCIN, QUINOLONES--AFTER COMPLETE
RESOLUTION OF TRANSAMINITIS,
REINTRODUCE---
 ATDs & HEPATOTOXICITY:

● --INH introduced at 50mg/d to 300/d over 2-

3 days---After 2-3 days, RFM introduced at
75mg/d to 450m/d--Finally PZN
reintroduced at 250 mg/d to 1500mg/day.
● RECURRENCE OF DIH AFTER RE-
INTRODUCTION OF ATDs IS 7-25%
 METHOTREXATE &
HEPATOTOXICITY:
● RISK FACTORS….Age >60, Dose(5-
15mg/wk), Alcohol, Obesity, Diabetes,
Psoriasis, NASH.
● FEATURES….Non specific, absent until
portal hypertension with liver failure develop.
● MONITORING….Procollagen 3 peptide
levels, LFT at 2 months interval, Liver biopsy
after cumulative dose of 1.5g(in psoriasis, RA).
 VALPROATE &
HEPATOTOXICITY:
● RISK FACTORS: Exclusively in children <
3yrs..Mitochondrial enzyme def, Friedreich ataxia,
Reyes syn.
● Mediated by metabolite 4 pentenoic acid
● FEATURES: Nonspecific,4-12 wks after start, Extra
hepatic features.
● Asymptomatic ALT elevation in 45% treated patients
● MANAGEMENT: Avoid VPA in combination,
Significance of warning symptoms in 1st 6 mnth, I.V.
L-Carnitine- 50mg/kg/day (if coma, rising ammonia
level, valproate level > 450mg/l)
 STATINS &
HEPATOTOXICITY:
● Very high doses of statins may cause hepatotoxicity, but typical
therapeutic doses not associated with significant liver injury.
● Hepatocellular necrosis from statins is exceptionally rare in
humans
● Asymptomatic elevations in aminotransferases are common but
they do not indicate hepatic damage, especially in the setting of
normal bilirubin levels.
● The notion that ezetimibe may have less risk of hepatotoxicity
has recently been challenged and it may not be a “safe
alternative” to statins in patients with pre-existing liver disease.
● The anti-hyperlipidemic drug with the highest potential for
hepatic injury is the sustained-release formulation of niacin
● Fenofibrate may very rarely instigate an autoimmune hepatitis-
type reaction with resultant ductopenia, chronic hepatitis, and
fibrosis, especially when used in combination with statin
medications.
 OHA & HEPATOTOXICITY:

● It is recommended that liver enzymes (ALT) should be

monitored in patients with diabetes receiving
antidiabetic drugs for which incidences of hepatotoxicity
are already reported.
 HAART &
HEPATOTOXICITY:
● NRTI’s:
● MITOCHONDRIAL TOXICITY(XCEPT LAMIVUDINE)
● MICRO/MACROVESCICULAR STEATOSIS,LACTIC
ACIDOSIS (with shock like state), LFT ABNORMALITY
● ONSET USUALLY 6 MONTHS AFTER START OF
THERAPY
● NNRTI’s:
● HEPATITIS AS A PART OF HYPERSENSITIVITY
REACTION,WITH EOSINOPHILIA, SKIN RASH,
LYMPHADENOPATHY.
● PROTEASE INHIBITORS:
● CLINICAL HEPATITIS IS INFREQUENT.
 TRANSAMINASE
MONITORING:
USEFUL OR USELESS?
 TRANSAMINASE MONITORING

2 Weeks 4 Weeks

Frequent

(e.g., tacrine)
ALT > 5 ULN Stop treatment No jaundice

Infrequent
Rather than infrequent LFT monitoring,
it’s best to
WARN THE PATIENT

“ Consult and have liver tests performed

if you don’t feel well ”

“Stop treatment immediately

should you become jaundiced”
 CAN WE PREDICT
WHICH PATIENT
WILL DEVELOP DIH?
Risk Factors
Toxic Potential
Genetic Factors
of Drug
- reactive metabolite - drug metabolism
- mitochondrial effects - detoxification
- transport
- others

Environmental Factors
- other drug
- ethanol
- age
- underlying disease
 DIH and age
High drug
consumption

Young
Old >
adults
> Children

Exceptions: Reye’s
syndrome with
 Susceptibility aspirin and Reye-like
(e.g., isoniazid) syndrome with
valproate
 DIH and gender

Incidence of DIH:
2.6-fold higher in females than males
in persons aged 50 years or more

(Same in females and males before 50)

Sgro, Hepatology 2002;36:451

 DIH in cirrhosis

CIRRHOSIS

- Does not change the incidence of DIH

- but worsens it outcome

(The same degree of liver injury, which is well tolerated in a

normal subject, can trigger liver failure, complications and
death in patients with an already impaired liver function)
 DIH and VIRAL INFECTIONS

Viral Hepatitis  DIH Paracetamol

Anti-tuberculous
drugs

HAART

Varicella, inflenza  Reye Aspirin

 ADDITIVE IMPAIRMENT OF
MITOCHONDRIAL FUNCTION

NASH,
Alcohol abuse,
DRUG(S) + OTHER Viral Infections,
CONDITION(S) Pregnancy,
Inborn b-oxidation
defects,
Mitochondrial
Additively impair cytopathies
mitochondrial function

Liver disease
 CYP INDUCTION AND/OR MALNUTRITION
CAN INCREASE THE DIRECT TOXICITY
OF REACTIVE METABOLITES

Large doses of
paracetamol Susceptibility:
CYP2E1  Alcohol abuse
Malnutrition
Large amounts
of a reactive  GSH
metabolite
Hepatitis due to
direct toxicity
THE N-ACETYL-TRANSFERASE POLYMORPHISM
CAN MODULATE AUTOIMMUNE HEPATITIS

Extensive acetylators Poor acetylators

Dihydralazine Dihydralazine
CYP1A2 NAT2 CYP1A2
Reactive metabolite Reactive metabolite

CYP1A2-metabolite adducts CYP1A2-metabolite adducts

Anti-CYP1A2 autoantibodies Anti-CYP1A2 autoantibodies

Uncommon hepatitis More frequent hepatitis

Bourdi, Mol Pharmacol 1994;45:1287
Amoxicillin & Clavulanic Acid-
Induced Hepatitis

HLA class II haplotype:

DRB1*1501-DRB5*01101-DQB1*0602

Patients: 57% Controls: 13%

Hautekeete, Gastroenterology 1999;117:1181

PREVENTION OF
RECURRENCE
- Warn the patient and his/her doctors
against using the drug again.

- Give the patient a list of all

pharmaceutical specialties containing
the drug, in order to avoid inadvertent
rechallenge.
 CONCLUSION
DIH: Difficult to avoid, predict and diagnose

TWO GOLDEN RULES

1. Always consider
the possibility of DIH

2. Immediately withdraw
all suspected drugs
in severe cases

Avoid most mishaps

THANK YOU.