ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
Common drug induced liver injury in children -dr. harshad devarbhai
1. Common Drug-induced Liver
Injury in Children
Harshad Devarbhavi, MD, DM.
Prof & Head: Gastroenterology
St. John’s Medical College Hospital, Bangalore
2. Vignette 1
• Fifteen year old girl
• Headache, vomiting, neck-rigidity,
seizures
• CSF: Cells 8, Proteins 45, Glucose: 64
• Empirical Rx with 4-drug ATD
• Five days later: Vomiting increased,
onset of encephalopathy
3. T. proteins 6.9 6.6
Albumin 3.6 3.2
T. Bilirubin 1.1 4.2
D. Bilirubin 0.5 3.6
AST 30 155
ALT 28 237
ALP 120 104
GGT 43 134
Patient I
4. T.Proteins 6.9 6.6 5.9
Albumin 3.6 3.2 2.3
T. Bilirubin 1.1 4.2 9
D. Bilirubin 0.5 3.6 7
AST 30 155 1212
ALT 28 237 1456
ALP 120 104 123
GGT 43 134 112
Patient I
INR 4.6
5. Labs, imaging
• HAV –ve
• HBV –ve
• HCV –ve
• HEV –ve
• ANA –ve
• SMA –ve
• LKM -ve
• USG: CBD 4 mm,
• Liver 9 cm, spleen 7cm,
no ascites
6. • Child died 12 days after admission
due to hyper acute liver failure
7. Vignette 2
• Two year 7 month old girl, 11 kg
• 4-drug ATT 2 months
• Jaundice 20 days
• Irritability, altered sleep pattern, grade
III coma, 15 days
• ATT given for LRTI
21. Pediatric DILI
• Rare cause of acute and chronic liver disease
• Can cause asymptomatic elevation of liver
tests, chronic liver disease and ALF
• Acetaminophen common in west, ATT in
India
• Data are sparse in terms of clinical
characteristics and outcome
22. • Children, intrinsically to be at low risk
for DILI
– Absence of comorbidities
– Differential susceptibilities to certain
drugs
– Medications given for a shorter time
• Challenges:
– fixed drug, weight based or surface based
formulation,
– immaturity of metabolizing enzyme,
– lack of awareness of DILI
23. Pediatric DILI-ALF
• In a multicenter study of 348 children
with ALF in the US, PCT toxicity in 48
(14%)
• Idiosyncratic DILI in 5%
• Valproate (3), INH (2), and one each of
bactrim, cytoxan/dilantin, dilantin, iron,
minocycline, MTX
Squires Jr. RH. J Pediatrics 2006;148:652-658
24. Drug-related hepatotoxicity and
acute liver failure
• Twenty percent of ALF in children
• Entire spectrum: hepatitis,cholestasis,
“transaminitis”
• Potential for progression to ALF
• Most common cause of DILI-ALF is
paracetamol 15%, others (ATT/AED-
5%)
25. Drug Adults Children Recovery
APAP 39% 14% 94%
Non-APAP 13% 5% 5%
Drug-induced ALF
Squires Jr. RH. J Pediatrics 2006;148:652-658
26. Children vs adults:
pharmacokinetic and adverse –
effect differences
• In children, cytochrome P450 (CYP)-
catalyzed metabolism is increased
• UDP glucoronosyl transferase
catalyzed metabolism is not different
from adults
• Children often receive higher mg/kg
dose compared to adults
27. Valproate Hepatotoxicity: Risk
Factors
• Age < 3 years
• Patients on polytherapy
• Patients with development delay
• Mortality decreasing with rational
prescribing including monotherapy
Dreifuss FE. Neurology 1987;37:379-85
Scheffner D. Epilepsia 1988;29:530-42
Dreifuss FE. Neurology 1989;39:201-7
28. Valproate hepatotoxicity
• Occurs in children with pre-existing
mitochondrial disease or IEM
• VPA inhibition of beta-oxidation and
toxicity from VPA metabolites
• Infants and children have higher
concentration ratio of metabolites
• Polytherapy with enzyme inducers
increases formation of hepatotoxic
metabolites
29. Metabolism of antiepileptic drugs
(AED): newborn to elderly
• In general metabolic rates are fastest in children;
AED half-lives are short
• Children need larger doses on mg/kg basis than
adults
– phenytoin dosage in adults is 4-6 mg/kg, but children
need a dosage 3-5 times higher. Elderly 3-4 mg/kg
• Likewise half life of CBZ is shortest in children
and elderly
• Amount of VPA metabolized to 4-ene is > 2 fold
higher in children than adults, which may explain
the different profile of hepatotoxicity seen by age.
Epilepsia 1992;33:S32-40
32. How is hepatotoxicity defined?
Grade 3 toxicity
Grade 4 toxicity
Normal
Grade 1 or 2 toxicity
ALT or AST level
(# of times upper limit
of normal)
1
5
10
0
ULN →
“Severe
hepatotoxicity”
35. Comparison of
mechanisms of toxicity
Basis for Injury Experimental
reproducibility
Dose
dependence
Incidence
in humans
Latent
Period
Intrinsic
hepatotoxicity
Yes Yes High Often
short,
relatively
consistent
Idiosyncratic
reaction
No
No
Low Often
long and
variable
36. Idiosyncratic Hepatotoxicity
Basis for Injury Onset Dose
dependence
Rash, fever,
eosinophilia
Rechallenge
Hypersensitivity
hepatotoxicity
1-5 wk no ++ Rapid +ve
Metabolic
hepatotoxicity
2-52 wk No _ variable
37. INH-ALF in children
(Wu SS etal. Transplantation 2007;27:173-9)
• 1987-1997, 84 U.S. centers
• 20 cases
• Spontaneous recover 20%, 10 (50%)
OLT, 6 (20%) died awaiting OLT
• Mean age:9.8 y, Duration of INH 3.3 M
• Notably 5 patients with symptoms of
hepatitis were initially told not to stop
treatment
38. Incidence of clinical hepatitis
• Children
–INH+RIF = 6.9%*
–INH+RIF+PYZ= 7%**
• Adults
–2.7%*
*Steele Chest 1991
**Roy B JGH 2006