ATT Induced Liver Injury Dr. Zubair Sarkar JR2,Deptt. of Medicine J.N.M.C.H. , Aligarh Muslim University
Transcript
1. ATT Induced Liver Injury Dr. Zubair Sarkar JR2,Deptt. of
Medicine J.N.M.C.H. , Aligarh Muslim University
2. Introduction Tuberculosis is one of the deadliest
communicable diseases WHO(2013) : 9 million developed TB with
mortality of 1.5 million MDRTB (3.5% of new and 20.5% of previously
treated cases) and XDR-TB (9%of MDR-TB) are rampant 1.1 million
(13%) of 9 million were HIV seropositive
3. The liver (metabolic factory of the body) is central to the
metabolism of all foreign substance including anti-tuberculosis
drugs. Drug-induced liver injury (DILI) : common, often
unrecognized cause of liver damage in treatment of
tuberculosis
4. Isoniazid, rifampicin and pyrazinamide are essential
components (First Line Drugs) of the treatment of tuberculosis and
all the three drugs have hepatotoxic potential Several second line
drugs (including ethionamide , prothionamide , few
flouro-quinolones and PAS) are potentially hepatotoxic.
5. Many ART drugs including zidovudine , didanosine , ritonavir
, indinavir , nevirapine and efavirenz are hepatotoxic. Use of ATT
and ART together in HIV-TB co-infected increases risk of DILI
Treatment of latent TB infection contributes to the pool of anti TB
DILI
6. Mechanisms of drug toxicity Direct toxicity (Dose dependent)
Idiosyncratic damage Induction of hepatic enzymes Allergic
reactions
7. Direct toxicity : Acute/subacute Dose related : increases
with escalation of dosages Free radicals mediated necrosis Usually
no extra-hepatic manifestations.
8. Idiosyncratic Reaction : Most types of DILI. Include
metabolic or hypersensitivity reactions. Largely independent of
dose May occur anytime post exposure. Result from genetic or
acquired variations in drug biotransformation pathway
9. Induction of hepatic enzymes : Alter plasma drug levels
Enhance hepatotoxicity of other drugs Associated with extra hepatic
adverse drug reactions
10. Allergic reaction : Reactive metabolite mediated Manifests
with fever , lymphadenopathy, rash and severe hepatocyte
injury
11. Specific patterns of hepatic damage : I. Disruption of
intracellular calcium homeostasis II. Cholestatic damage III.
Interruption of transport pumps and loss of villous processes IV.
Reactions involving cytochrome P-450 system
12. V. Activation of apoptotic pathways and programmed cell
death VI. Inhibition of mitochondrial function
13. Anti-tuberculosis drugs and hepatotoxicity Isoniazid (INH)
: Not well-understood. Delayed onset : weeks to months 60%
incidence in first 3 months No hepatotoxicity on re-challenge
14. Isoniazid is associated with : Reactive metabolite
Immuno-allergic injury : HLA-DQB1*0201 Mitochondrial injury
15. Acetyl-isoniazid, the principal metabolite of isoniazid, is
converted to mono-acetyl hydrazine. The microsomal p-450 enzymes
convert mono-acetyl hydrazine to other compounds resulting in
hepatotoxicity.
16. Histopathology : resembles viral hepatitis showing
hepatocyte necrosis, ballooning degeneration and inflammatory
infiltrates. Absence of symptoms associated with hypersensitivity :
rash, fever, arthralgia and eosinophilia.
17. Rifampicin (RIF) : Occurs earlier Produces a patchy
cellular abnormality with marked peri-portal inflammation.
18. Mechanisms include: 1) Conjugated hyperbilirubinemia caused
by: RIF inhibiting the major bile salt exporter pump.
Dose-dependent competition with bilirubin for clearance at
sinusoidal membrane. Impeded canalicular secretion
19. 2) Hypersensitivity reaction Rare More common with large,
intermittent doses. Hypersensitivity reactions in combination with
renal dysfunction, hemolytic anemia, or flulike syndrome
20. Pyrazinamide (PZA) : Most hepatotoxic. Half life of 10
hours : can increase to 15 hours in pre-existing liver disease
Exhibits both dose dependent and idiosyncratic hepatotoxicity. Free
radical generation.
21. There may be shared mechanisms of injury for INH and PZA :
some similarity in molecular structure. Patients with previous
hepatotoxic reactions with INH : more severe reactions with RIF and
PZA combination. May induce hypersensitivity reactions with
eosinophilia and liver injury, or a granulomatous hepatitis.
22. Isoniazid + Rifampicin : Due to the additive effect or
synergistic effect The toxicity is due to direct toxic effect of
drugs or is a hypersensitivity phenomenon.
23. Increased risk is attributed to the interaction between the
metabolism of INH and rifampicin Rifampicin enhances conversion of
INH to acetylated metabolites by microsomal p450 enzyme
induction.
24. Factors implicated in development of Anti TB DILI Ethnic
and Racial variation : More common in India (11.5% risk) compared
to western countries (4.5% risk) Age : >50 years Male Genetic :
Absence of HLA DQA1*0102 and Presence of HLA-DQB1*0201 are
independent risk factors for DILI
26. Alcoholism and underlying CLD : Both predispose to the
development of DILI Infections : Hepatitis B : independent risk
factor Hepatitis C HIV
27. Malnutrition : Poor nutritional status and Decreased serum
albumin levels (3 times UNL* and total bilirubin >2 times UNL
after excluding other potential causes *upper normal limit
38. As per ATS/CDC/IDSA guidelines: In patients receiving
anti-TB treatment for active TB disease : ALT level >5 times of
UNL or >3 times of UNL in the presence of nausea, vomiting,
jaundice , abdominal pain or fatigue in the absence of laboratory
evidence of acute viral hepatitis
39. Other criteria for diagnosis of anti-TB DILI : i. AST and
/or ALT >5 times UNL ii. Total serum bilirubin rise of 1.5mg/dl
and iii. Any increase in pre-treatment levels of AST and/or ALT
together with anorexia, nausea, vomiting and jaundice
40. WHO Classification : GRADE ALT levels I 51 to 125 IU/L or
1.25 to 2.5 times normal II 126 to 250 IU/L or 2.6 to 5.0 times
normal III 251 to 500 IU/L or 5.1 to 10.0 times normal IV >500
IU/L or >10.0 times normal or >250 IU/L if accompanied by
symptoms
41. Score for Diagnosis Roussel Uclaf Causality Assessment
Method (RUCAM) score Clinical, biochemical, serological and
radiological features of liver injury Validated, standardized tool
to assess the probability of drug relatedness for liver
injury.
42. Total range : -9 to +14 Highly probable : >8 Probable :
6 8 Possible : 3 5 Unlikely : 1 2 Excluded : 5 : Hepatocellular 25
: Mixed 5 times or >3 times in presence of symptoms i.e.
jaundice.
49. Question 2 : What drugs to be given after stopping first
line ATT? Ethambutol + Hepatosafe flouroquinolone
(Levofloxacin/Moxifloxacin/Ofloxacin/Cipr ofloxacin) +
Aminoglycoside (Streptomycin) Supportive management for hepatic
dysfunction
50. Question 3 : When to restart first line anti TB drugs? ATS
: When ALT levels are