DR. KOMALDEEP KAUR

JUNIOR RESIDENTT.B.HOSPITAL

ANTITUBERCULOSIS TREATMENT

INDUCED HEPATOTOXICITY

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.

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.

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.

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 damage

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.

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 pyrazinamide

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 :

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 :-

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 :

1st line drugs:- Rifampicin Isoniazid PyrazinamideEthambutol and Streptomycin are not hepatotoxic among

the first line drugs.

2nd line drugs :- Ethionamide Cycloserine PAS ClarithromycinAnti-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 -

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

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

ACETYLATION HYDROLYSIS

CYP-450

ISONIAZID

ACETYL ISONIAZID ISONICOTINIC ACID

ACETYL HYDRAZINE

ISONICOTINYL GLYCINE

HYDRAZINE

DIACETYL HYDRAZINE

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 :-

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.

Characteristic features of isoniazid induced hepatotoxicity:-

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 :-

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.

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 metabolites

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

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 )

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.

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.

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 hepatotoxicity

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 hepatotoxicity

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 risk

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 risk

SYMPTOMS

1. Constitutional symptoms : fatigue , anorexia, nausea, myalgia and arthralgia

2. Symptoms due to liver failure: jaundice, dark colored urine, light colored stools, bleeding diathesis , pruritis , confusion and coma.

3. 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..

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

2. Right upper quadrant tenderness may occur

3. Hepatomegaly may occur but splenomegaly and ascites are usually absent.

SIGNS OR PHYSICAL FINDINGS

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 FINDINGS

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.

INFECTIOUS CAUSES:

1. Viral infections : hepatitis A,B OR C, yellow fever virus, epstein barr virus and cytomegalovirus.

2. Bacterial infections : pneumococci and leptospira.3. Parasite infections : malaria, schistosomiasis, a number of ther flukes, as

well as ascaris lumbricoides, which can obstruct the bile ducts.4. Even TB iself can affect the liver.NON – INFECTIOUS CAUSES :

1. Alcohol abuse.2. Concomitant use of other hepatotoxic drugs

3. 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 –

–

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

Normal values :

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 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.

WORK UP

1. S. bilirubin : to diagnose jaundice and to assess its severity.2. Unconjugated bilirubin : to assess for haemolysis .3. Alkaline phosphatase : to diagnose cholestasis and infiltrative

disease.4. AST / SGOT : to diagnose hepatocellular disease and assess

progression of disease.5. ALT/ SGPT : relatively lower value than AST.6. S. albumin & prothrombin time : to assess severity of liver

injury. HIV infection and malnutrition may confound this.7. Gamma globulin : large elevations are suggestive of

autoimmune hepatitis , other typical increase observed in persons with cirrhosis.

HEPATIC FUNCTION TESTS AND THEIR INTERPRETATION

1. 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.

2. 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.

3. 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

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 :

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

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.

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

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

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

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

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

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