ATT INDUCED HEPATOTOXICITY

1. ATT INDUCED HEPATOTOXICITY Dr. K. K. Sharma

2. INTRODUCTION • Drug-induced hepatotoxicity (DIH) is a problem of increasing significance, and has been a long-standing concern in the treatment of tuberculosis (TB) infection. • Identification of patients at increased risk for DIH is important because hepatotoxicity causes significant morbidity and mortality and modification of the drug regimen may be required. • Drug-induced hepatotoxicity (DIH) is ultimately a clinical diagnosis of exclusion. Other causes of liver injury, should be methodically sought, and their absence makes the diagnosis plausible.

3. Contd…. • There are few clinical or laboratory manifestations that specifically suggest a liver injury is the result of a therapeutic drug, the most important clue is the temporal relationship between initiation of a drug (or drugs) and the appearance of the injury. • Rechallenge with the suspected offending agent with more than twofold serum alanine aminotransferase (ALT) elevation, and discontinuation leading to a fall in ALT, is the strongest confirmation of the diagnosis. • The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. • The pathogenesis and types of DIH varies, ranging from hepatic adaptation to hepatocellular injury. (J Hepatology 1990;11:272–276)

4. THE LIVER: STRUCTURE AND FUNCTION • The liver is situated between the alimentary tract and the systemic circulation to maximize processing of absorbed nutrients and to minimize exposure of the body to toxins and foreign chemicals. • Consequently, the liver may be exposed to large concentrations of exogenous substances and their metabolites.

5. Hepatic Drug Metabolism • The splanchnic circulation carries ingested drugs directly into the liver, a phenomenon known as the “first pass” through the liver. • Metabolic enzymes convert these chemicals through phase 1 pathways of oxidation, reduction, or hydrolysis, which are carried out principally by the cytochrome P450 class of enzymes. • Phase 2 pathways include glucuronidation, sulfation, acetylation, and glutathione conjugation to form compounds that are readily excreted from the body. • Other subsequent steps include deacetylation and deaminidation. • Many drugs may be metabolized through alternative pathways, and their relative contributions may explain some differences in toxicity between individuals.

6. Contd…. • In phase 3 pathways, cellular transporter proteins facilitate excretion of these compounds into bile or the systemic circulation. • Transporters and enzyme activities are influenced by endogenous factors such as circadian rhythms, hormones, cytokines, disease states, genetic factors, sex, ethnicity, age, and nutritional status, as well as by exogenous drugs or chemicals. • Bile is the major excretory route for hepatic metabolites. • Compounds excreted in bile may undergo enterohepatic circulation, being reabsorbed in the small intestine and re-entering the portal circulation .

7. Mechanism of Hepatic Injury A.Direct Hepatocellular Injury B.Cholestasis due to genetic defect in transportes C.Formation of haptens or neoantigens. D.Antibody-dependent cytotoxicT-cell responses E.Apoptosis F.Metabolic idiosyncratic reactions Like mitochondirial damage

8. Pathogenesis of DIH • DIH may result from • Direct toxicity of the primary compound, • a metabolite, or • from an immunologically mediated response, affecting hepatocytes, biliary epithelial cells, and/or liver vasculature. • Mostly, the exact mechanism and factors contributing to liver toxicity remain poorly understood. • Most common types of DIH  Unpredictable or idiosyncratic reactions • These hypersensitivity or metabolic reactions occur largely independent of dose and relatively rarely for each drug, and may result in hepatocellular injury and/or cholestasis.

9. Contd…. • Hepatocyte necrosis is often distributed throughout hepatic lobules rather than being zonal. • Injurious free radicals cause hepatocyte necrosis in zones farthest from the hepatic arterioles. • In hypersensitivity reactions, immunogenic drug or its metabolites may be free or covalently bound to hepatic proteins, forming haptens or “neoantigens”. • Antibody-dependent cytotoxic, T-cell, and occasionally eosinophilic hypersensitivity responses may be evoked.

10. Contd…. • Released TNF-alpha, interleukin (IL)-12, and IFN-gamma promote hepatocellular programmed cell death (apoptosis), an effect opposed by IL-4, IL-10, IL-13, and monocyte chemotactic protein-1 . (Semin Liver Dis 2002;22:137–144). • Metabolic idiosyncratic reactions may result from genetic or acquired variations in drug biotransformation pathways, with synthesis or abnormally slow detoxification of a hepatotoxic metabolite. Metabolic idiosyncratic reactions may have a widely variable latent period, but recur within days to weeks after re-exposure

11. Types of DIH • A variety of clinical syndromes may be seen with DIH, even with a single drug. • Hepatic adaptation. • Drug-induced acute hepatitis or hepatocellular injury. • Nonalcoholic fatty liver disease. • Cholestasis. • Granulomatous hepatitis.

12. Hepatic Enzyme Measurement • Increase in serum ALT(SGPT), is more specific for hepatocellular injury than an increase in AST(SGOT), which can also signify abnormalities in muscle, heart, or kidney. • Increases in alkaline phosphatase and/or bilirubin with little or no increase in ALT indicate cholestasis. • Alkaline phosphatase concentration may also increase because of processes in bone, placenta, or intestine. An increased concentration of serum GGT is useful in distinguishing liver-related from other organ-related alkaline phosphatase increases. • Jaundice is usually detectable on the physical examination when serum bilirubin exceeds 3.0 mg/dl.

13. Clinical and Immunogenetic Risk Factors for the Development of DIH [SK Sharma,AIIMS ,American J of Res & Cri Care Med V166. pp. 916-919, (2002)] • Older age • Poor nutritional status • High alcohol intake • Female sex • Pre-existing liver disease • Patient with Viral hepatitis & HIV • Hypoalbuminaemia • Moderately / far advanced tuberculosis • Dose & Duration of therapy and acetylator status. • Patient with DQB1*0201, DRB1*0301 and DRB1*0701 haplotypes

14. Causative Agents (The use of antibiotics.5th edition.Oxford: Butterworth Heinemann, 1997.JAMA 1991;265:3323) • INH + rifampin > INH alone >> PZA alone > rifampin alone > ethionamide > PAS • Potentially hepatotoxic drugs • Isoniazid • Rifampicin, Rifabutin • Pyrazinamide • Ethionamide, Prothionamide • Para-aminosalicylic acid • Drugs with much lower or little potential for hepatotoxicity • Streptomycin, Kanamycin, Amikacin, Capreomycin • Ethambutol • Ofloxacin, Levofloxacin, Ciprofloxacin • Cycloserine

15. ISONIAZID (INH) Metabolism: • Genetic polymorphisms of NAT-2 correlate with fast and slow acetylation phenotypes. • Microsomal enzymes further metabolize INH intermediates through phase 1 pathways. • Acetylator status:In fast acetylators, > 90% of the drug is excreted as acetyl-isoniazid, • whereas in slow acetylators, 67% of the drug is excreted as acetyl-isoniazid • and rest is excreted as unchanged drug into the urine.

16. Mechanism of injury • Injury is mostly acute hepatocellular in type, though a mixed hepatocellular-cholestatic picture has been reported. • There are various metabolic products of isoniazid, including monoacetyl hydrazine, hydrazine and isonicotinic acid, which have been suggested as being hepatotoxic. • Reactive metabolites of MAH are probably toxic to tissues through free radical generation. • Histopahology: Nonspecific changes resemble those of viral hepatitis with nonzonal necrosis in up to 10% of severe cases. Subacute hepatic necrosis can be seen in 30% of cases.

17. Clinical presentation of hepatotoxicity • May be asymptomatic, • Symptomatic hepatotoxicity may occur at varying serum transaminase concentrations. • Constitutional symptoms may be seen early in severe hepatotoxicity, and may last from days to weeks. • Nausea, vomiting, and abdominal pain are seen in 50 to 75% of patients with severe illness, whereas fever is noted in 10% and rash in 5% of patients. • Overt jaundice, dark urine, and clay-colored stools are late signs of clinical worsening. • Coagulopathy, hypoalbuminemia, and hypoglycemia signify life-threatening hepatic dysfunction. • The regression of isoniazid hepatotoxicity usually takes weeks. Recovery is complete in most after discontinuation of isoniazid

18. Rate of INH-induced liver injury Hepatitis Annual Update 2004at http://clinicaloptions.com/hepatitis ■ Minor elevations in alanine aminotransferase (ALT) . Observed in 10% to 20% of patients . Within 2 months of starting treatment . Most resolve without stopping INH ■ Severe liver injury with jaundice . 1% of treated patients with INH . 4% of patients receiving rifampin and isoniazid . Rarely develops in children . Risk of hepatitis inc. with concomitant alcohol use and age > 35 years . Women at increased risk ■ Fulminant hepatic failure . 10% of persons who develop jaundice . Continued treatment during prodrome increases hepatic necrosis . Resolution in nonfatal cases

19. Onset of INH Induced Hepatotoxicity Am J Respir Crit Care Med Vol 174. pp 935–952, 2006 • Hepatotoxicity occurs generally within weeks to months. Unlike a classical hypersensitivity reaction, isoniazid rechallenge does not always elicit rapid recurrence of hepatotoxicity. • Approximately 60% of the hepatotoxicity incidence occurred in the first 3 months of treatment, and 80% of the incidence occurred in the first 6months. • A retrospective case fatality review found that the median interval from treatment initiation to symptom onset was 16 weeks. • Reintroduction of isoniazid can be performed when liver function tests have returned to normal but not if there has been symptomatic evidence of liver impairment. • Liver function tests should be performed on a weekly basis for 4 weeks,and then according to the original protocol for monitoring.

20. RIFAMPICIN (RMP) Mechanisms of hepatotoxicity: • Rifampicin probably inhibit the major bile salt exporter pump and cause Conjugated hyperbilirubinemia. • Occasionally, subclinical, unconjugated hyperbilirubinemia or jaundice without hepatocellular damage may also result from dose-dependent competition with bilirubin for clearance at the sinusoidal membrane or from impeded secretion at the canalicular level. • This may be transient and occur early in treatment or in some individuals with preexisting liver disease. • Rifampicin occasionally can cause hepatocellular injury which appears to be a hypersensitivity reaction, and it may be more common with large, intermittent doses. • Rifampicin potentiate hepatotoxicities of other anti-TB medications. This effect is thought to be due to enzyme induction.

21. Clinical presentation, Rate & Onset of hepatotoxicity. • Up to 1% of patients develop rifampin-induced hepatitis. • 4% of patients receiving both rifampin and isoniazid develop hepatitis. • Asymptomatic increases in serum transaminases may occur in the first few weeks of therapy. • Idiosyncratic hypersensitivity reaction to rifampicin, manifested as anorexia, nausea, vomiting, malaise, fever, mildly elevated ALT, and elevated bilirubin, usually occurs in the first month of treatment initiation. • Hepatotoxicity is uncommon in children.

22. Contd…. • The hyperbilirubinaemia is usually transient and due to interference with bilirubin excretion by rifampicin; it does not requires cessation of the drug. • But If the bilirubin has not decreased after 2 weeks, it would be sensible to withdraw rifampicin. • There is evidence that the dose regimen appears important; in one series of patients treated with rifampicin and isoniazid, the rate of drug-induced hepatitis was 21% when rifampicin was given daily and 5% when given twice weekly. [Eur Respir J, 1995, 8, 1384–1388].

23. PYRAZINAMIDE (PZA) Metabolism: • Pyrazinamide is de-amidated to pyrazinoic acid in the liver and subsequently metabolized to 5-hydroxy-pyrazinoic acid by xanthine oxidase, aldehyde oxidase, and xanthine dehydrogenase. • The half-life (t1/2) of pyrazinamide is notably longer than that of either isoniazid or rifampin, approximately 10 hours. • In patients with preexisting hepatic disease, t1/2 is increased to 15 hours. • The kidneys clear metabolites of pyrazinamide, requiring intermittent dosing in patients with renal insufficiency

24. Mechanism of injury • Pyrazinamide exhibit both dose dependent and idiosyncratic hepatotoxicity. • Pyrazinamide alters nicotinamide acetyl dehydrogenase levels in liver  result in generation of free radical species. • There may be shared mechanisms of injury for isoniazid and pyrazinamide, because there is some similarity in molecular structure. • Patients who previously had hepatotoxic reactions with isoniazid have had more severe reactions with rifampin and pyrazinamide. • Pyrazinamide may induce hypersensitivity reactions with eosinophilia and liver injury or granulomatous hepatitis.

25. Clinical presentation, Rate & Onset of hepatotoxicity. • Asymptomatic increases in LFTs may occur early in therapy • Studies in the 1950s suggested that elevated transaminases occurred in 20%, and overt hepatitis in 8%, of those treated with daily doses of pyrazinamide at 40 to 50 mg/kg., and a relationship to dose was noted. • Uncommon with doses of 20-30mg/kg/d or with high dose intermittent regimens • Rarely cases of fatal hepatic necrosis may occur. • Uncommon in children.

26. Prothionamide and ethionamide • DIH is uncommon • May produce elevated serum transaminases in about 10% of recipients, usually after 8–12 weeks. • Usually resolves after drug discontinuation.

27. Para-aminosalicyclic acid (PAS) • Hypersensitivity to PAS has been recorded in up to 5%. • Onset usually between 2–6 weeks after commencing treatment. (Eur Respir J, 1995, 8, 1384–1388) • Rechallenge may result in recurrence of the abnormal response.

28. Fluoroquinolones • DIH is very Rare. • The mechanism of fluoroquinolone hepatotoxicity is believed to be a hypersensitivity reaction, often manifested by eosinophilia. • Reversible transaminase elevation among the fluoroquinolones may occur in up to 2 to 3% of cases. • Severe hepatocellular injury and cholestasis have been reported to occur in less than 1% of all fluoroquinolone recipients, excluding trovafloxacin, which was withdrawn due to its hepatotoxicity. • For levofloxacin, the rate of severe hepatotoxicity was reported to be less than 1 per 1,000,000. (Eur Respir J, 1995, 8, 1384–1388)

29. Clinical monitoring 1. Face-to-face monthly assessments and patient education for adverse drug events are essential. 2. Directly observed treatment (DOT) enhances treatment adherence and monitoring. 3. The World Health Organization and the International Union Against Tuberculosis and Lung Disease (IUATLD) recommend only clinical monitoring in patients with TB in low-income developing countries like India.

30. Routine Monitoring for Hepatotoxicity in Adults 1. Obtain baseline liver function tests (LFTs) a. serum transaminase enzymes: 1) aspartate aminotransferase (AST) [normal 0-40 u/l] 2) alanine aminotransferase (ALT) [normal 0-40 u/l] b. alkaline phosphatase [normal 25-115 u/l] c. gamma glutamyl transpeptidase (GGTP) [normal 10-50 u/l] d. total bilirubin [normal 0.2-1.5 mg/dl] 2. Obtain follow-up LFTs: a. patients < 35 years old with normal baseline LFTs and without a history of hepatic disease: follow-up are not required unless the patient becomes symptomatic. b. patient > 35 years old, daily alcohol consumption, abnormal baseline LFTs, taking other potentially hepatotoxic medications, or who have viral hepatitis or history of liver disease, HIV infection, or prior TB DIH. obtain LFTs every 4-6 weeks.

31. Interventions for hepatotoxicity 1. The first-line anti-TB drugs, especially rifampin, should not be discontinued for mild gastrointestinal complaints, which may be relatively frequent in the initial weeks of anti-TB treatment. 2. If serum transaminase concentrations are more than five times the ULN (with or without symptoms) or more than three times the ULN with jaundice and/or hepatitis symptoms, then potentially hepatotoxic medications should be stopped immediately and the patient evaluated promptly. 3. Serologic tests for hepatitis A, B, and C viruses should be obtained, and the patient should be evaluated for biliary disease, use of alcohol, and other hepatotoxic drugs. 4. Some experts recommend interrupting treatment for lesser increases in patients with cirrhosis or encephalopathy. 5. If indicated, until the specific cause of abnormalities can be determined, clinicians should treat with at least three anti-TB agents that are less likely to cause hepatotoxicity.

32. Management in Adults Asymptomatic patients with an increase in LFTs from baseline: a. if the increase in LFTs is < 3-5x normal: continue the current regimen and monitor for symptoms of liver dysfunction. b. for asymptomatic patients, if the serum transaminases increases > 3-5x normal: hold INH until levels return to baseline. 1) if the patient is receiving a two drug regimen, substitute at least one other drug (e.g.ethambutol) until the INH is restarted 2) if the transaminases increase with rechallenge of INH, discontinue INH, substitute another drug (e.g. ethambutol) and adjust the treatment duration as required c. if the serum total bilirubin increases: therapy usually does not require modification (rifampin competes with bilirubin for elimination resulting in increased serum bilirubin initially; bilirubin levels usually return to normal with continued therapy)

33. Symptomatic patients a. Hold all drugs and obtain LFTs b. If LFTs are within the normal ranges, refer to the Management of Nausea/Vomiting. c. If LFTs are elevated, hold drugs until symptoms resolve and the transaminases decreases to < 2x normal. 1) ethambutol and pyrazinamide should be started if drug therapy can not be held secondary to the patient’s clinical condition a) use streptomycin if pyrazinamide is suspected to be the cause of hepatotoxicity 2) rechallenge the patient after resolution of signs and symptoms by adding drugs to the regimen every 4 days. a) rifampin for 3 days, if patients remains asymptomatic then add b) INH for 3 days, if patients remains asymptomatic then add c) pyrazinamide (15-20mg/kg/d) for 3 days 3) if signs and symptoms recur with rechallenge, discontinue the responsible drug and modify the regimen and/or duration of therapy as required

34. Rechallenge 1. After ALT returns to less than two times the ULN, rifampin may be restarted with or without ethambutol. 2. After 3 to 7 days, isoniazid may be reintroduced, subsequently rechecking ALT. 3. If symptoms recur or ALT increases, the last drug added should be stopped. 4. For those who have experienced prolonged or severe hepatotoxicity, but tolerate reintroduction with rifampin and isoniazid, rechallenge with pyrazinamide may be hazardous. • In this circumstance, pyrazinamide may be permanently discontinued.Although pyrazinamide can be reintroduced in some milder cases of hepatotoxicity, the benefit of a shorter treatment course likely does not outweigh the risk of severe hepatotoxicity from pyrazinamide rechallenge.

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