DR. KOMALDEEP KAUR JUNIOR RESIDENT T.B.HOSPITAL

1. DR. KOMALDEEP KAURJUNIOR RESIDENTT.B.HOSPITAL ANTITUBERCULOSIS TREATMENT INDUCED HEPATOTOXICITY

2. 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.

3. 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.

4. 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.

5. Hepatotoxicity implies chemical driven liver damage • 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).

6. Hepatotoxicity implies chemical driven liver damage cont. • 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

7. 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

8. INCIDENCE: • 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%.

9. Why do we need to study ATT induced hepatotoxicity:- 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.

10. COMPLICATIONS : • 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.

11. Several anti-TB agents are associated with hepatic toxicity - 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.

12. Pattern of of hepatotoxic reactions

13. Isoniazid • 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.

14. ISONIAZID • ACETYLATION HYDROLYSIS CYP-450 ISONICOTINIC ACID ACETYL ISONIAZID HYDRAZINE ACETYL HYDRAZINE ISONICOTINYL GLYCINE DIACETYL HYDRAZINE

15. Slow and fast acetylators:- • 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.

16. Characteristic features of isoniazid induced hepatotoxicity:- • 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.

17. RIFAMPICIN :- • 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.

18. 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. • Unconjugatedhyperbilirubinemia occurs a result of competition with bilirubin for uptake at hepatocyte plasma membrane.

19. Isoniazid and rifampicin : • 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 Acetyl isoniazid Monoacetyl hydrazine Toxic metabolites Isoniazid

20. PYRAZINAMIDE • 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.

21. 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 )

22. ETHAMBUTOL : is a bacteriostatic agent for mycobacterium and acts by inhibiting the synthesis of arabinogalactan ( a component of cell wall) due to inhibition of arabinosyltransferase . • It causes dose dependent and reversible visual disturbances like optic neuritis, red green colour blindness and retinal damage.

23. STREPTOMYCIN : is a tuberculocidalaminoglycoside • 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.

24. Who are at risk :risk factors for the development of ATT induced hepatotoxicity • 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.

25. 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.

26. Who are at risk • 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. • Concomitantuseofotherhepatotoxicdrugs : pts on ART ( Abacavir, nevirapine , Lamivudineand Zidovudine ), anticonvulsants (Valproicacid,Phenytoin ) ,antifungals (Itraconazole ,Ketoconazole, Fluconazole), Methotrexate for connective tissue disease, Anti-inflammatory drugs, nonsteroidal (NSAIDS), Anabolic steroids.

27. 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.

28. CLINICAL FEATURES: symptoms typically precede jaundice or liver failure by only a few days.. • 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.

29. SIGNS OR PHYSICAL FINDINGS • 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 • Hepatomegalymay occur but splenomegaly and ascites are usually absent.

30. 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.

31. 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.

32. – 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 – • INFECTIOUS CAUSES: • Viral infections : hepatitis A,B OR C, yellow fever virus, epsteinbarr virus and cytomegalovirus. • Bacterial infections : pneumococci and leptospira. • Parasite infections : malaria, schistosomiasis, a number of ther flukes, as well as ascarislumbricoides, 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.

33. Normal values : • 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

34. Criteria for the diagnosis of ATT induced hepatotoxicity :-

35. WORK UP • 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.

36. HEPATIC FUNCTION TESTS AND THEIR INTERPRETATION • S. bilirubin : to diagnose jaundice and to assess its severity. • Unconjugatedbilirubin : 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.

37. IMAGING STUDIES • 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. 

38. PROCEDURES : • 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.

39. HISTORY • 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. CLINICAL FEATURES INVESTIGATIONS TREATMENT

40. Treatment : • In case hepatitis develops, • Stop all drugs • Streptomycin ,Ethambutoland 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.

41. 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

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

43. Treatment in MDR treatment 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.

44. 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.

45. PREVENTION • 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.

46. SUMMARY 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.