DILI is possible consequence of ingestion of OTC drugs like PCM. so it require careful clinical knowledge before taking drugs without doctors prescriptions...

1. Drug induced liver injury (DILI)
Presented by: Dr. Amrinder Singh
Junior Resident- 2
General Medicine

2. Definition
 An increase in serum alanine aminotransferase (ALT), alkaline
phosphatase (ALP), or bilirubin level, to more than twice the upper
limit of normal (ULN).
 Nature of liver injury has been characterized histologically.
 One of most common reason for withdrawl of an approved drugs.

3. Epidemiology
 Incidence 1:10000 to 1:100000.
 Overall mortality rate among hospitalized for DILI is approx. 10%
 Paracetamol is the commonest cause worldwide
 In contrast to Antitubercular drugs in India (5.7-22%)

4. Drug metabolism
 Water insoluble drugs metabolic reactions water soluble forms.
 These water soluble forms undergoes renal and biliary excretion
 Phase 1 reaction – process begins with oxidation or methylation
mediated by microsomal mixed enzyme oxygenase P-450
 Phase 2 reaction – followed by glucuronation or sulfation or
inactivation of glutathione
 Most drug hepatotoxicity is mediated by phase 1 toxic metabolites

5. Mechanism of DILI
 Rupture of cell membrane
 Injury to bile canaliculus
 P-450 drug covalent binding
 Drug adducts targeted by CTLs/ Cytokines
 Activation of apoptotic pathway by TNF- alpha
 Inhibition of mitochondrial function

6. Mechanism of DILI
Hepatotoxic
drugs
Hepatocyte Cell wall
injury
Free
radicals
Peroxidation
Of cell wall

7. Mechanism of DILI
 (expressed histologically as microvesicular steatosis).
Hepatotoxic
drugs
apoptotic
pathways
immune
response
bile excretory
pathways
Damage
Interference with
bile canalicular
pumps
Hepatocyte
injury
Endogenous
bile acidscholestasis
necrosis
lipid movement, inhibit protein
synthesis, or impair mitochondrial
Oxidation of fatty acids
Lactic acidosis

9. Risk of liver diseases caused by drugs
Factor Drugs influence
Genetic factors Phenytoin, sulphonamides,
penicillins
Valproic acid
Multiple cases in families HLA
associated
Familal cases with mitochondrial
enzyme deficiency
Age Isoniazid, nitrofurantoin
Valproic acid, salicylates
Age >60
More common in children
Gender Nitrofuratoin, minocycline,
Azathioprine, penicillins
More common in females
More common in males
Pre-existing liver
disease
Antitubercular drugs, ibuprofen Increased risk of liver injury,
Associated with HBV, HCV
History of other drug
allergy
Isoflurane,
halothane,erythromycin,NSAIDS,
sulfonamides
Due to cross sensitivity among
members of each class

10. Risk of liver diseases caused by drugs
Dose Acetaminophen, aspirin
Tetracycline, tacrine
Blood level are directly related to
hepatotoxicity
Idiosyncratic reactions
Other drugs Acetaminophen
Valproic acid
Isoniazid, zidovudine, phenytoin
lower threshold for hepatotoxicity
Other AED increase risk of
hepatotoxicity
Nutritional status
Obesity
fasting
Halothane, methotrexate,
tamoxifen
acetaminophen
hepatotoxicity, fibrosis
hepatotoxicity
Excessive alcohol intake Acetaminophen, isoniazid,
methotrexate
Lower threshold for
hepatotoxicity, fibrosis
Other disease conditions
DM
HIV/AIDS
Organ transplantation
Methotrate
Sulfonamides
azathioprine
Hepatic fibrosis
Hypersensitivity
Vascular toxicity

11. DILI severity classification

12. Chronic DILI
 Persistently elevated bilirubin (>2.8 *ULN) & ALP (>1.1*ULN) in
second month from DILI onset significantly predict chronic DILI.
 Other signs or symptoms of ongoing liver disease (e.g., ascites,
encephalopathy, portal hypertension, coagulopathy) 6 months after
DILI onset.
 Chronic DILI occurs in about 15 – 20 % of cases of acute DILI

13.  Late development to cirrhosis and its complications have been
observed, but are quite rare after acute DILI
 Chronic DILI may resemble autoimmune hepatitis and might
respond to corticosteroids.
 Serological markers and biopsy findings are suggestive of this
diagnosis.

14. Characterstic Immunologic reaction Idiosyncrastic reaction
Frequency <1 per 10000 1-50 per 10000
Gender predilection Women, often 2:1 Variable
Period of onset Constant, 2-10 weeks Variable, 2-24 weeks
Occasionally >1 year
Dose relationship none Drugs with >50 mg/d dose
Extrahepatic feature Common Rare
Eosinophilia 33-67 % <10%
Autoantibodies Often present Very rare
Interaction with other
agent
None Common with alcohol,
other hepatotoxic drugs
Example phenytoin, nitrofurantoin,
methyldopa
Isoniazid, ketoconazole,
pyrazinamide

15. R ratio
 First established by counsil for international organizations of medical science and
later modified by US FDA drug hepatotoxicity steering committee
 R ratio = (ALT of patient/ ALT ULN) / ALP of patient/ ALP ULN)
>5 2-5 <2
Hepatocellular Mixed cholestatic

18. Clinical features
 Medical history : search for any recent drug intake or therapy patient
is taking or have finished
 Case characterisation : may be asymptomatic to mild symptoms
such as nausea, vomiting, loss of appetite, rashes, pain abdomen,
pruritis, which are self limiting once drug cause DILI is withdrawn
 Severe DILI presents as Jaundice, rashes, ascites, altered sensorium,
bleeding tendencies within two weeks of drug intake

19. Stepwise approach to diagnosis of DILI

20. Investigations
Diagnosis of DILI relies on exclusion of alternative causes of liver
injury
 Complete blood count
 Liver function test, GGT
 Prothrombin test, INR
 Viral markers
 Liver imaging
 Liver biopsy
 Genetic testing for HLA genotyping

23. Liver imaging
 Ultrasonography- is typically normal in DILI
 Usually done to rule out focal locals or biliary obstruction
Additional imaging depends upon symptomatology & pattern of liver
injury
 Computed tomography
 Magnetic resonance cholangiography to rule out gall stone

24. Liver biopsy
 Integral part of specific investigation in DILI
 histological can provide information supporting diagnosis of DILI
 Histological features include infiltrations of neutrophils, eosinophils,
microvesicular necrosis, fibrosis, granuloma formation

25. Prognosis
 Histologic features indicative of prognosis
Features associated with mild or
moderate liver injury
Associated with severe liver injury
or liver transplantation or death
Presence of granuloma Neutrophilic infiltration
Eosinophilic infiltration Higher degree of necrosis
Higher degree of fibrosis
Portal venopathy
Cholangiolar cholestasis
Microvesicular steatosis

26. Newer biomarkers of DILI
Bimarker Drugs Remark
MicroRNA-122 Acetaminophen overdose Predicts the onset of DILI as
elevated before ALT
Glutamate
dehydrogenase(GLDH)
Acetaminophen induced ALF Mitochondrial enzyme confirms
hepatoceelular injury when ALT
is elevated due to extrahepatic
source
High mobility group box-1
(HMGB1)
Chromatin binding protein
released from necrotic cells
associated with molecular pattern
of injury
Cytokeratin 18 Unfavorable prognosis in DILI/
liver transplantation
osteopontin Unfavorable prognosis in DILI/
liver transplantation
Glutathione S-transferases
(GSTs)
Acetaminophen More spectic than ALT released
from cytoplasm of hepatocytes

27. Treatment of DILI
 Initial step in management of DILI is to discontinue the implicated
agent
 Spontanous recovery occurs over days to weeks.
 Improvement may not occur immediately, or worsening injury occur
despite drug withdrawl leads to hospitalization of patient
 Patient with acute liver failure or encephalopathy should be
managed conservatively

28. Two main approach for drug induced acute liver failure
I. Rapid depuration of toxic drug to stop further aggression before
agent reaches liver
II. Antidote administration to stop aggression once drug reached liver
 Charcoal depuration is mainly in acetaminophen toxicity if
administered within within 3-4 hours of acute ingestion

29. Specific therapies
Drugs Treatment
Acetaminophen N-acetylcysteine 140mg/kg loading
over 60 mins then 70 mg/kg every 4
hpurly and if sFILI
Prednisolone 1 mg/kg/d for 7 days
Terbinafine/leflunomide Cholestyramine 4gm every 6 hourly
for 2 weeks
Valproic acid (acute toxicity) Carnitine 100 mg/kg IV over 30 mins
( not > 6g) loading followed by 15
mg/kg every 4 hourly till clinical
improvement occurs
Cholestasis due to any drug Ursodeoxycholic acid

30. Liver transplantation
 Wide list for patients with DILI for liver transplantation
 Have a low sensitivity (27%) but high specificity (90%) for death
or transplantation.

31. Criteria for liver transplantation in ALF
Criteria of king’s college London
Acetaminophen cases
Arterial pH < 7.30 more than 24 hours after drug ingestion
All of the following
1) prothrombin time > 100 sec or INR >6.5
2) serum creatinine level >3.4 mg/dl or anuria
3) grade 3 to 4 encephalopathy
Non acetaminophen cases
Prothromin time > 100sec or INR > 6.7
Any three of following
Unfavourable etiology (seronegative hepatitis or drug reaction)
Age <10 or > 40 years
Acute or subacute category ( jaundiced > 7 days)
Serum bilirubin > 17.5 mg/dl
Prothromin time > 50 sec or INR > 3.5
** subsequent modification : pH <7.30 or S. lactate >3.0mmol/l

32. ATT induced hepatitis
 Isoniazid is the leading cause of liver injury & early cessation of
drugs is important
 American Thoracic Society suggest ALT monitoring during
treatment of latent TBC infection with other causes of hepatotoxicity
 Stop Isoniazid if ALT > 3 * ULN in the presence of symotoms of
hepatitis
 When ALT >5 * ULN in absence of symptoms

33.  Monthly interval has been suggested with Weekly monitoring of
ALT in case of asymptomatic > 3* ULN until resolution or
discontinuation of therapy if LFT worsen
 Patient on multidrug ATT regimens without liver injury should
undergo LFT monitoring every 2 weekly for first 8 weeks of therapy
then 4 weeks until completion of therapy
 Stop ATT if S. bilirubin >1.5 * ULN (with ALT >3* ULN) or
Prothrombin time >1.5 * ULN irrespective of presence or absence of
symptoms

34. Other antitubercular drugs
 Pyrazinamide is dose dependant hepatotoxin
 Patient taking combination of isoniazid & pyrazinamide can develop
severe liver injury
 Monitoring of ALT during therapy is recommended
 Cross reactivity among INZ, PYZ, & Ethonamide may occur
 Meta-analysis shows Pyrazinamide based regimes carried higher
risk of hepatic injury

35. Hy’s law
 Refer to a signal in trial population
 Has three component
1. Higher incidence of elevation of ALT >3* ULN compared to
placebo
2. Individual showing ALT or AST >3* ULN with T. bilirubin >2*
ULN without initial finding ofn cholestasis
3. Absence of any other cause of hepatitis

36.  Decision to stop administration of drug during clinical trial
recommended by FDA
 ALT or AST >8 *ULN
 ALT or AST >5* ULN
 ALT or AST >3* ULN (with T.Bilirubin >2* ULN or INR >1.5 )
 ALT or AST >3* ULN with symptoms of hepatitis

37. Thank you