Anti-Tuberculosis: Hepatotoxicity of Drugs

Established chronic liver disease

• In patients with unstable or advanced liver disease, baseline liver function tests should be done at the begining of treatment.
• Regular monitoring at weekly/biweekly intervals for the initial two months should be done and followed by more widely spaced assessments allthrough the rest of treatment
• If baseline liver enzyme, alanine aminotransferase (ALT), is more than three times upper limit of normal before the initiation of treatment, one of the following antiTB regimens should be considered. 

1. Two hepatotoxic drugs (rather than three in the standard regimen)

• 9 months of isoniazid and rifampicin, plus ethambutol (until or unless isoniazid susceptibility is documented)
• 2 months of isoniazid, rifampicin, streptomycin and ethambutol, followed by 6 months of isoniazid and rifampicin;
• 6 - 9 months of rifampicin, pyrazinamide and ethambutol.

2. One hepatotoxic drug

• 2 months of isoniazid, ethambutol and streptomycin, followed by 10 months of isoniazid and ethambutol.

3. No hepatotoxic drugs

• 18 - 24 months of streptomycin, ethambutol and fluoroquinolones*.
• Newer fluoroquinolones such as levofloxacin and moxifloxacin are preferred over the older generations

Drug Induced Liver Injury

• Isoniazid, rifampicin and pyrazinamide are all associated with hepatitis. 
• rifampicin is least likely to cause hepatocellular damage, although the drug is associated with cholestatic jaundice
• pyrazinamide is the most hepatotoxic.
• Ethambutol (EMB) can be used safely in patients with hepatic disease.
• Nearly 20% of patients treated with the standard four- drug regimen show asymptomatic increase in AST concentration. It usually occurs during the first 3 months of treatment. 
• Symptoms: unexplained anorexia, nausea, vomiting, dark urine, yellow skin or eyes, fever, persistent fatigue, abdominal tenderness especially right upper quadrant discomfort. 

Patients at high risk for hepatotoxicity: 

• HIV
• Pregnant or postpartum (3 months of delivery). 
• History or at risk of chronic liver disease (daily use of alcohol, IV drug users, hepatitis, liver cirrhosis)
• Patients who are taking liver toxicity inducing drugs for chronic medical conditions. 
• Incidence of liver toxicity increases with age (>35 years old)

Liver Function Test

• Routine baseline liver function test (LFT) is recommended prior to starting the standard four-drug therapy for suspect or active TB disease
• Drug induced hepatotoxicity is defined as AST/ALT >= 3x ULN with the presence of symptoms; or AST/ALT >5x ULN in the absence of symptoms; or disproportional increase in alkaline phosphatase (ALP) and total bilirubin
• If LFT (AST/ALT) <5x ULN and no symptoms, continue with the regimen and increase monitoring frequency
• If alkaline phosphatase and bilirubin are disproportionally increased, this pattern is more consistent with Rifampin hepatotoxicity. Rifampin may be stopped. Recheck LFTs.

If LFT>=3x upper limit of normal PLUS symptoms; or LFT >=5x ULN with or without symptoms:

• STOP immediately all antituberculosis drugs. 
• Consult with an expert who is familiar with the management of hepatotoxicity. 
• Perform serologic testing for Hepatitis A, B, and C on patients who are high risk for hepatitis. 
• Rule out other causes (hepatotoxic medications, alcohol consumption, etc.) and treat accordingly. 
• In acutely ill and acid-fast stain positive patients, three “liver friendly” drugs such as Levofloxacin, Ethambutol (EMB), and Streptomycin should be started until diagnosis of liver toxicity causes are identified. 

Rechallenge Therapy

• Once drug-induced hepatitis has resolved, the drugs are reintroduced one at a time. 
• If symptoms recur or liver function tests become abnormal as the drugs are reintro¬duced, the last drug added should be stopped. 
• Some advise starting with rifampicin because it is less likely than isoniazid or pyrazinamide to cause hepatotoxicity and is the most effective agent
• After 3–7 days, isoniazid may be reintroduced. 
• In patients who have experienced jaundice but tolerate the reintroduction of rifampicin and isoniazid, it is advisable to avoid pyrazinamide

Hepatotoxicity in latent TB

• may occur with all currently recommended regimens for the treatment of latent TB infection (LTBI), including isoniazid for 6 to preferably 9 months, rifampin for 4 months, or isoniazid and rifampin for 4 months

References:

1. Management of Tuberculosis (3rd edition)
2. http://health.utah.gov/epi/diseases/TB/resources/treatment/management_common_side
3. https://www.thoracic.org/statements/resources/mtpi/hepatotoxicity-of-antituberculosis-therapy
4. http://apps.who.int/iris/bitstream/10665/44165/1/9789241547833_eng.pdf?ua=1&ua=1