DR. KOMALDEEP KAUR - PowerPoint Presentation

Slide1

DR. KOMALDEEP KAURJUNIOR RESIDENTT.B.HOSPITAL

ANTITUBERCULOSIS TREATMENT INDUCED HEPATOTOXICITYSlide2

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 1

st 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.Slide3

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.Slide4

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.Slide5

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

).

Hepatotoxicity

implies chemical driven liver damageSlide6

It is functionally interposed between the site of absorption and the systemic circulation The central role played by liver in the clearance and transformation of chemicals makes it susceptible to drug induced injury

Hepatotoxicity

implies chemical driven liver damage cont.Slide7

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 water-soluble 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

pyrazinamideSlide8

Anti tuberculosis drugs are among the most common causes of drug induced liver injury. The reported incidence of hepatotoxicity due to anti-TB 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%.

INCIDENCE

:Slide9

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.

Why do we need to study ATT induced

hepatotoxicity

:-Slide10

Among patients who experience elevated transaminases, approximately one-tenth may proceed to severe hepatotoxicity and liver failure if the offending drug is not stopped.

Furthermore, one-tenth of patients with liver failure may die if liver transplantation is not available.

COMPLICATIONS :Slide11

1st line drugs:-RifampicinIsoniazidPyrazinamideEthambutol and Streptomycin are not hepatotoxic among the first line drugs.

2nd line drugs :-EthionamideCycloserinePAS

Clarithromycin

Anti-TB drugs are used in combination , it may be difficult to pinpoint which drug is responsible for the reaction.

Several anti-TB agents are associated with hepatic toxicity

-Slide12

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

Pattern of of

hepatotoxic

reactions Slide13

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.

Isoniazid

Slide14

ACETYLATION HYDROLYSIS CYP-450

ISONIAZID

ACETYL ISONIAZID

ISONICOTINIC ACID

ACETYL HYDRAZINE

ISONICOTINYL GLYCINE

HYDRAZINE

DIACETYL HYDRAZINESlide15

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

.

Slow and fast

acetylators

:-Slide16

Gradually resolves within 1-4 weeks of stopping the drugIf drug is continued, pt may develop severe hepatitis including fulminant hepatic failureHistopathological picture resembles that of viral hepatitis and shows hepatocyte necrosis, ballooning degeneration, and inflammatory infiltrate.Dose related toxicityHS is considered unlikely because of delayed onset of H induced hepatotoxicity

.Characteristic features of isoniazid

induced

hepatotoxicity

:-Slide17

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.

RIFAMPICIN :-Slide18

Characteristic features of rifampicin induced hepatotoxicity:-

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.Slide19

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.

CYP-450 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

Isoniazid

and

rifampicin

:

Isoniazid

Acetyl

isoniazid

Monoacetyl

hydrazine

Toxic metabolitesSlide20

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.

PYRAZINAMIDE Slide21

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 )Slide22

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.Slide23

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.Slide24

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.

Who are at risk

:

risk factors for the development of ATT induced

hepatotoxicitySlide25

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

.

Risk factors for the development of ATT induced

hepatotoxicitySlide26

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 alcohol-induced 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.

Who are at riskSlide27

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.

Who are at riskSlide28

SYMPTOMSConstitutional 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.

CLINICAL FEATURES

:

symptoms typically precede jaundice or liver failure by only a few days..Slide29

Jaundice : evidenced by yellowing Of skin, sclera or mucous membrane. It is present in more severe cases as a late manifestation.

Right upper quadrant tenderness may occur

Hepatomegaly

may occur but

splenomegaly

and

ascites

are usually absent.

SIGNS OR PHYSICAL FINDINGSSlide30

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.

SIGNS OR PHYSICAL FINDINGSSlide31

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.Slide32

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

.

DIFFERENTIAL DIAGNOSIS

:

it is important to decide

wether

the anti-

tb

drugs are the cause of the liver damage or

wether

there are other explanations such as viral hepatitis. Differential diagnosis for anti-

tb

drugs induced liver damage include –

– Slide33

S. Bilirubin : 0.1 – 1.2 mg/dlS.G.O.T. (AST) : 6 – 40 IU/dlS.G.P.T. (ALT) : 6-40 IU/dlAlkaline phosphatase (ALP) : 28 – 111 IU/dlNormal values :Slide34

Criteria for the diagnosis of ATT induced hepatotoxicity :-

GUIDELINES ( references )ELEVATION OF TRANSAMINASES

ELEVATION OF S. BILIRUBIN

ATS

/ CDC / IDSA

Three fold increase in 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

Any increase

ERS / WHO / IUALTD

Five fold increase in ALT

over the upper normal limit

Any increaseSlide35

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.

WORK UP Slide36

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.

HEPATIC FUNCTION TESTS AND THEIR INTERPRETATION Slide37

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. 

IMAGING STUDIES Slide38

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.PROCEDURES : Slide39

Fatigue, anorexia, vomiting, jaundice, dark colored urine.History of alcohol consumption , concomitant use of other hepatotoxic drugs Jaundice , right upper quadrant tenderness

LFTS, imaging studies.

HISTORY

CLINICAL FEATURES

INVESTIGATIONS

TREATMENTSlide40

Treatment : In case hepatitis develops,

Stop all drugsStreptomycin ,

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.Slide41

Temporary regimen before reintoduction of original anti tb drugs

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 Slide42

Recommendations for re-introduction of treatment in patients with ATT induced hepatotoxicity :-Slide43

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.

Treatment in MDR treatment induced

hepatotoxicity

Slide44

Patients with abnormal liver function will be reviewed at weekly intervals.The regimen will be resumed after the liver function become normal.If the jaundice recurs after reintroduction of the allocated regimen, further management of the patient will be decided by the DOTS- plus committee. Treatment in MDR treatment induced

hepatotoxicity Slide45

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.

PREVENTION Slide46

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.

SUMMARY