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ANTITUBERCULOSIS
TREATMENT
INDUCED
HEPATOTOXICITY
DR. KOMALDEEP KAUR
JUNIOR RESIDENT
T.B.HOSPITAL
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Tuberculosis is a disease caused by
Mycobacterium tuberculosis, a bacteria that is
passed between people through the air.
The disease can be cured with proper drug
therapy, but because the bacteria may become
resistant to any single drug, combinations of anti
tuberculosis drugs are used to treat tuberculosis
(TB) are normally required for effective treatment.
In the present era, short course ATT with standard
1st line drugs namely H, R, Z, E &/or S is the norm
and these drugs constitute the essential
components of DOTS strategy for control of TB
endorsed by WHO.
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Anti tuberculosis combinations are products with
more than one drug, given simultaneously to treat
tuberculosis.
The different drugs have different mechanisms of
action and are given together to avoid emergence
of drug resistant strains of the Mycobacterium
tuberculosis.
Using medications with different mechanisms of
action also targets the bacteria in different ways
and makes treatment more effective.
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Anti TB drugs may result in adverse effects
involving almost all systems in the body
including GIT, liver, kidneys, skin, nervous
system , oto vestibular apparatus and eyes.
Of these, DIH is an important and commonly
encountered adverse effect.
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The human body identifies almost all drugs as foreign
substances (i.e. xenobiotis) and subjects them to
various chemical processes (i.e. metabolism) to make
them suitable for elimination.
Although almost all tissues in the body have some
ability to metabolise chemicals , SER in the liver is the
principal “metabolic clearing house” for both
endogenous chemicals ( eg: cholesterol, steroid
hormones, fatty acids and proteins) and exogenous
substances ( eg: drugs, alchol).
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It is functionally interposed between the site of
absorption and the systemic circulation
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The central role played by liver in the clearance and
transformation of chemicals makes it susceptible to
drug induced injury
 ATT
with R,H,Z & E/S is very effective but the first three
drugs are hepatotoxic.
 Most
anti tuberculosis drugs are liposoluble and their
elimination requires biotransformation into more watersoluble compounds. This is mostly performed by hepatic
phase I and phase II biotransformation enzymes.
 The
utilization of multidrug regimen for the treatment of
TB such as combination of H,R&Z have been associated
with an increased risk of DIH. Rifampicin may potentiate
the toxicity of isoniazid and pyrazinamide
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Anti tuberculosis drugs are among the most common
causes of drug induced liver injury.
The reported incidence of hepatotoxicity due to antiTB drugs varies from 2.5% to 34.9%. However , this
often includes mild elevation of transaminases.
Serious liver injury occurs in less than 5% of cases.
Definite change in anti- TB drugs is necessary in only
1-2%.
A major adverse reaction to one of the first line anti
tuberculosis drugs , which result in discontinuation of
that drug, has several implications:
 There may be considerable morbidity, even mortality,
particularly with drug induced hepatitis.
 This may incur substantial additional costs because
of added outpatient visits, tests, and in more serious
instances hospitalizations.
 Alternative agents may have greater problems with
toxicity, and are often less effective, so that
treatment must be prolonged which may reduce
compliance.
 As a result the risk of treatment failure and relapse
are higher.
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Among patients who experience elevated
transaminases, approximately one-tenth may proceed
to severe hepatotoxicity and liver failure if the
offending drug is not stopped.
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Furthermore, one-tenth of patients with liver failure
may die if liver transplantation is not available.
1st line drugs: Rifampicin
 Isoniazid
 Pyrazinamide
Ethambutol and Streptomycin are not hepatotoxic
among the first line drugs.
2nd line drugs : Ethionamide
 Cycloserine
 PAS
 Clarithromycin
Anti-TB drugs are used in combination , it may be
difficult to pinpoint which drug is responsible for the
reaction.
Direct or predictable
Indirect or unpredictable
or idiosyncratic
When drug or or one of its metabolite is
either directly toxic to liver or lowers host
immune response.
When drug or one of its metabolite acts
as a hapten and induces hypersensitivity
in the host.
Dose dependent
Independent of dose and is
immune mediated
Predominant pattern of liver injury
is Zonal hepatocellular necrosis
Biopsy specimen reveal cholestasis
n there is evidence of monocytic or
eosinophillic infiltrates.
Systemic signs of hypersensitivity
are rare.
Usually associated with classic
symptoms of hypersensitivity
including fever and rash
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Is bactericidal drug and inhibits the enzyme
required for mycolic acid synthesis , an
essential component of mycobacterial cell
wall.
It is bacteriostatic against resting and
bactericidal against rapidly multiplying
organisms.
Is effective against intra as well as
extracellular mycobacteria.
Action is most marked against rapidly
multiplying bacilli (less effective against slow
multipliers)
Is effective orally and metabolized by
ACETYLATION which is genetically controlled.
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ACETYLATION
ACETYL ISONIAZID
ISONIAZID
HYDROLYSIS
ISONICOTINIC ACID
CYP-450
ACETYL HYDRAZINE
DIACETYL
HYDRAZINE
ISONICOTINYL
GLYCINE
HYDRAZINE
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An individual’s rate of acetylation is genetically
determined.
Europeans and southern Indians are predominantly slow
acetylators, with a mean serum half life for Isoniazid of
about 3h.
Japanese, Korean and Eskimo populations have a majority
of rapid acetylators, with an Isoniazid half life of about
1.4h.
The rate of acetylation has not been shown to significantly alter
the effectiveness of Isoniazid. However, slow acetylation may
lead to higher blood concentrations with chronic administration of
the drug, with an increased risk of toxicity. Fast acetylation leads
to higher blood levels of the toxic metabolite acetylisoniazid and
thus to an increase in toxic reactions - hepatitis which is 250
times more common than in slow acetylators.
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Gradually resolves within 1-4 weeks of
stopping the drug
If drug is continued, pt may develop severe
hepatitis including fulminant hepatic failure
Histopathological picture resembles that of
viral hepatitis and shows hepatocyte necrosis,
ballooning degeneration, and inflammatory
infiltrate.
Dose related toxicity
HS is considered unlikely because of delayed
onset of H induced hepatotoxicity.
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It is bactericidal to mycobacterium and acts
by inhibiting DNA dependent RNA
polymerase.
It is equally effective against intra and extra
cellular bacilli.
It is the only bactericidal drug active against
dormant bacteria in solid caseous lesions.
Apart from TB , it is also used in leprosy.
Rifampicin is an inducer of drug metabolizing
enzymes and enhances the metabolism of
many drugs.
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Abnormalities in the LFTs are common in pts
receiving R and these resolve even while the drug
continues to be used.
Occurs earlier as compared to that of Isoniazid.
Produces a patchy cellular abnormality with marked
peri-portal inflammation.
Has been postulated to occur as a part of systemic
allergic reaction
Elevation of S. bil and Alk. PO4 levels are
characteristics with R treatment.
Unconjugated hyperbilirubinemia occurs a result of
competition with bilirubin for uptake at hepatocyte
plasma membrane.
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DIH occurs with greater frequency and may be
more severe when isoniazid and rifampicin are
administered in combination than when either
drug is given alone.
The answer probably lies in the interaction
between isoniazid and rifampicin metabolism.
Isoniazid
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Acetyl
isoniazid
CYP-450
Monoacetyl
hydrazine
Toxic
metabolites
Rifampicin is an enzyme inducer. It interacts with DNA
and increases the synthesis of microsomal enzyme
protein, specially CYP-450. As a result, metabolism of
inducing drug itself and/or other drugs is induced
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Is weakly bactericidal drug but is more active in
acidic media (intracellular sites and at the sites of
inflammation).
It is effective only against intracellular
mycobacteria.
Hepatotoxicity is the most serious side effect of
pyrazinamide treatment. The drug should be
administered with caution to those with a history
of liver or biliary tract disease.
In 40% of the patients it causes non-gouty
arthralgia. Other side effects are porphyria and
photosensitivity.
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It appears to be a dose related side effect of
pyrazinamide.
The exact pathogenetic mechanism of
pyrazinamide induced hepatic damage has
not been clarified as yet. In pts receiving a
combination of H,R & Z , two patterns of
fulminant liver injury have been observed.
Early increase in serum transaminases ( by R
induced H toxicity )
Late increase in serum transaminases ( Z
induced hepatotoxicity )
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ETHAMBUTOL : is a bacteriostatic agent for
mycobacterium and acts by inhibiting the
synthesis of arabinogalactan ( a component
of cell wall) due to inhibition of arabinosyl
transferase .
It causes dose dependent and reversible
visual disturbances like optic neuritis, red
green colour blindness and retinal damage.
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STREPTOMYCIN : is a tuberculocidal
aminoglycoside
It is not absorbed orally and must be
administered by i.m. injection.
It is active only against extracellular bacteria.
It is NOT hepatotoxic.
Other aminoglycosides used for treatment of
TB are amikacin , kanamycin and
capreomycin.
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Race: Some drugs appear to have different toxicities
based on race. For example, blacks and Hispanics
may be more susceptible to isoniazid (INH) toxicity.
The rate of metabolism is under the control of P-450
enzymes and can vary from individual to individual.
Alcohol ingestion: Alcoholic persons are susceptible
to drug toxicity because alcohol induces liver injury
and cirrhotic changes that alter drug metabolism.
Alcohol causes depletion of glutathione
(hepatoprotective) stores that make the person more
susceptible to toxicity by drugs.
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Sex: Although the reasons are unknown, hepatic drug
reactions are more common in females.
Age: Elderly persons are at increased risk of hepatic injury
because of
Decreased clearance
Drug-to-drug interactions
Reduced hepatic blood flow
Variation in drug binding
Lower hepatic volume.
In addition, poor diet, infections, and multiple
hospitalizations are important reasons for drug-induced
hepatotoxicity.
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Underlying Liver disease:
Hepatitis B or c are common causes of chronic liver disease.
Several studies show that hepatitis b and C coinfection increase the
risk of ATDH.
Smoking: A toxic air pollutant formed by smoking such as acrolein
was reported to induce hepatotoxicity through direct mitochondrial
damage. Moreover, smoking may induce CYP isoform (CYP2E1)
and could contribute to drug induced hepatotoxicity and alcoholinduced liver disease.
Concomitant use of other hepatotoxic drugs : pts on ART (
Abacavir, nevirapine , Lamivudine and Zidovudine ), anticonvulsants
(Valproic acid,Phenytoin ) ,antifungals (Itraconazole ,Ketoconazole,
Fluconazole), Methotrexate for connective tissue disease,
Anti-inflammatory drugs, nonsteroidal (NSAIDS), Anabolic steroids.
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Genetic factors: A unique gene encodes each
P-450 protein. Genetic differences in the P-450
enzymes can result in abnormal reactions to
drugs, including idiosyncratic reactions.
Other comorbidities: Persons with
moderately /far advanced /extensive disease
(pulm TB) , AIDS, persons who are
malnourished, and persons who are fasting may
be susceptible to drug reactions because of low
glutathione stores.
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SYMPTOMS
Constitutional symptoms : fatigue , anorexia,
nausea, myalgia and arthralgia
Symptoms due to liver failure: jaundice, dark
colored urine, light colored stools, bleeding
diathesis , pruritis , confusion and coma.
Symptoms due to hepatic inflammation : right
upper quadrant tenderness and gastrointestinal
distress.
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Jaundice : evidenced by yellowing Of skin, sclera or
mucous membrane. It is present in more severe
cases as a late manifestation.
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Right upper quadrant tenderness may occur
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Hepatomegaly may occur but splenomegaly and
ascites are usually absent.
4.In advanced cases, patients may exhibit bleeding from
the gingiva or echymosis or have other manifestations
of coagulopathy.
5.Stigmata of chronic liver disease typically are absent
unless prior liver disease exists.
6.Hepatic encephalopathy or coma may develop after
onset of other symptoms of severe disease.
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The cause of hepatitis during TB treatment
can either be the anti tuberculosis drugs or
something else, so the other possibilities
have to be excluded before deciding that the
hepatitis is drug induced.
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INFECTIOUS CAUSES:
Viral infections : hepatitis A,B OR C, yellow fever virus, epstein barr
virus and cytomegalovirus.
Bacterial infections : pneumococci and leptospira.
Parasite infections : malaria, schistosomiasis, a number of ther flukes,
as well as ascaris lumbricoides, which can obstruct the bile ducts.
Even TB iself can affect the liver.
NON – INFECTIOUS CAUSES :
Alcohol abuse.
Concomitant use of other hepatotoxic drugs
Liver enzymes rise due to some obstructive causes like cholelithiasis ,
bile duct stones , some tumours.
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S. Bilirubin : 0.1 – 1.2 mg/dl
S.G.O.T. (AST) : 6 – 40 IU/dl
S.G.P.T. (ALT) : 6-40 IU/dl
Alkaline phosphatase (ALP) : 28 – 111 IU/dl
GUIDELINES
( references )
ELEVATION OF
TRANSAMINASES
ELEVATION OF S.
BILIRUBIN
ATS / CDC / IDSA
Three fold increase in Any increase
ALT over the upper
normal limit in
patients reporting
jaundice &/or hepatitis
symptoms such as
nausea, vomiting,
abdominal pain,
unexplained fatigue.
Five fold increase in
ALT over the upper
normal limit in the
absence of symptoms
ERS / WHO / IUALTD
Five fold increase in
ALT over the upper
normal limit
Any increase
Performing laboratory tests to assess and diagnose the
effects of the suspected medication is essential.
 Patients with a hepatocellular process generally have a
disproportionate elevation in serum aminotransferase
levels compared with alkaline phosphatase levels, while
those with cholestasis have the opposite findings.
 Hepatitis B and C serology should be performed to exclude
an infectious etiology.
 ANA testing may help in cases of possible autoimmune
hepatitis. The presence of antibodies to specific forms of
CYP has been associated with hypersensitivity to some
drugs.
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S. bilirubin : to diagnose jaundice and to assess its severity.
Unconjugated bilirubin : to assess for haemolysis .
Alkaline phosphatase : to diagnose cholestasis and
infiltrative disease.
AST / SGOT : to diagnose hepatocellular disease and assess
progression of disease.
ALT/ SGPT : relatively lower value than AST.
S. albumin & prothrombin time : to assess severity of liver
injury. HIV infection and malnutrition may confound this.
Gamma globulin : large elevations are suggestive of
autoimmune hepatitis , other typical increase observed in
persons with cirrhosis.
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USG : is inexpensive as compared to CT scanning and MRI.
USG is effective to evaluate the gall bladder, bile duct
pathologies and also to rule out hepatic tumours.
CT scanning : CT scanning can help in detecting focal
hepatic lesions 1cm or larger and some diffuse conditions.
It can also be used to visualize adjacent structures in the
abdomen.
MRI : MRI provides excellent contrast resolution. It can be
used to detect cysts, hemangiomas, and primary or
secondary tumours. The portal vein , hepatic vein and
biliary tract can be visualized without contrast injections.
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LIVER BIOPSY : histopathological evaluation is an
important tool in diagnosis. A liver biopsy is not
essential in every case but a morphological pattern
consistent with the expected pattern provides
supportive evidence.
HISTORY
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Fatigue, anorexia, vomiting, jaundice, dark
colored urine.History of alcohol consumption
, concomitant use of other hepatotoxic drugs
CLINICAL
FEATURES
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Jaundice , right upper quadrant tenderness
INVESTIGATIONS
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LFTS, imaging studies.
TREATMENT
Treatment :
In case hepatitis develops,
•Stop all drugs
•Streptomycin ,Ethambutol and a fluoroquinolone may
be started after appropriate checks on renal function
and visual acuity.
• After complete resolution of transaminases, most
antituberculosis drugs can be safely restarted in a
phased manner i.e. the drugs are started one by one to
identify the culprit, which should never be used again,
while the other drugs found safe should be continued.
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If the patient is severely ill , the patient may
die if left without treatment until the hepatitis
resolves.
In such patients, treatment should be given
with two or three of the least hepatotoxic
drugs, which are Streptomycin , Ethambutol
and one of the Fluoroquinolones (Ofloxacin) .
The regimen would be sufficient to control
the infection temporarily
Restart with rifampicin
LFTs remain mormal
Period one week
Add Isoniazid
LFTs remain normal
Period one week
Add Pyrazinamide
If recurrence of symptoms or deterioration of
liver function
The last added drug should be stopped
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If the patient presents with symptoms/signs
of hepatitis ( anorexia, nausea, vomiting ,
abdominal discomfort , and/or dark colored
urine ) he/she will be examined for clinical
jaundice and liver enlargement .
If there is icterus , anti – TB drugs will be
witheld and the patient reviewed with the
results of the liver function tests.
If the results are abnormal , ethionamide and
pyrazinamide are to be witheld, and the other
drugs continued.
If the results of the liver function tests are
normal, the treatment will be resumed.
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Patients with abnormal liver function will be
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The regimen will be resumed after the liver
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reviewed at weekly intervals.
function become normal.
If the jaundice recurs after reintroduction of
the allocated regimen, further management
of the patient will be decided by the DOTSplus committee.
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Clinical monitoring with atleast monthly questions on
hepatotoxicity related symptoms is advised. If available it
is recommended to perform blood tests for
transaminases at baseline for at least high risk patients if
not all.
If a patient has had hepatitis and an offending drug has
been identified, this should be documented in the
patient’s record and the patient should be properly
informed about this, preferably in writing, and should
not be given this drug again.
In summary
 TB should be treated under supervision of a qualified
physician.
 Patients should be advised to seek medical care if they
experience any signs or symptoms of hepatotoxicity (i.e.
jaundice, malaise, nausea and vomiting).
 They should be advised not to drink alcohol during TB
treatment.
 The patient should keep motivated to continue treatment
even when he is feeling better.
 In the case of signs or symptoms of hepatotoxicity, the liver
function should be examined.
 In the case of confirmed moderate or severe drug-induced
hepatotoxicity, treatment should be interrupted and
reintroduced after the hepatotoxicity has resolved.