Introduction And Suspected Agents

Drug-induced hepatitis is a significant adverse event during anti-tubercular treatment. Prompt recognition and appropriate management are crucial to prevent severe morbidity.

Suspected Hepatotoxic Drugs

Several first-line and second-line anti-tubercular drugs are known to cause hepatotoxicity.

Clinical Presentation And Baseline Monitoring

Symptoms Of Hepatotoxicity

• Children with drug-induced hepatitis present with a range of gastrointestinal and systemic symptoms.
• Significant side effects include nausea and vomiting.
• Patients may complain of abdominal pain.
• Poor appetite is a common early indicator.
• Clinically evident jaundice may develop as the condition progresses.

Monitoring Guidelines

• Routine baseline liver function tests are not required for patients on first-line drugs without existing hepatopathy.
• Testing is indicated if a child shows symptoms or signs suggesting hepatic dysfunction.
• In children living with HIV, liver function tests should be done at baseline, day 15, month one, and month three.
• After three months, a symptom-directed approach is helpful for HIV-infected children.
• If symptoms of drug toxicity develop, a physical examination and liver enzyme measurement should be repeated.

Evaluation And Differential Diagnosis

Alternative Causes To Exclude

Before attributing hepatitis solely to anti-tubercular drugs, other causes must be eliminated.

• Enquire about the intake of other hepatotoxic medications.
• Enquire about alcohol intake, particularly in older adolescents.
• Investigate for viral hepatitis as an alternative cause.
• Hepatitis B surface antigen and other viral markers for Hepatitis A, C, and E must be checked in cases of jaundice,.

Management Strategy For Tuberculosis Hepatitis

Management Based On Illness Severity

The approach to managing hepatitis depends heavily on the clinical severity of the underlying tuberculosis disease.

Very Sick Patients

• Examples include patients with meningitis or sputum smear grade 3+.
• It is critical not to stop tuberculosis treatment entirely.
• Give a safe, non-hepatotoxic anti-tubercular treatment regimen.
• Examples of non-hepatotoxic drugs include Streptomycin, Fluoroquinolones, and Cycloserine.

Patients Not Seriously Ill

• Wait and observe the patient.
• Introduce anti-tubercular treatment only once enzyme levels return to near normal.

Severity Of Transaminitis And Required Actions

• If enzymes are more than five times the upper limit of normal, stop all hepatotoxic drugs.
• Continue with at least three non-hepatotoxic medications.
• If hepatitis worsens or does not resolve with the three-drug regimen, then stop all drugs entirely.

Reintroduction Of Anti-Tubercular Drugs

Principles Of Drug Reintroduction

• Wait for enzyme levels to decrease to <= 2 times the upper limit of normal before reintroducing drugs.
• Reintroduce remaining drugs one at a time.
• Start with the least hepatotoxic agents first.
• Monitor liver function by testing enzymes every three days after each reintroduction,.
• Ensure no deterioration occurs before re-introducing the next drug.
• If the most likely offending agent is not essential, consider not reintroducing it.

Specific Reintroduction Dosages

The reintroduction of drugs is tried from lower doses and gradually increased to the full dose.

Rifampicin Reintroduction Schedule

• Start with 150 mg.
• Repeat liver function tests after three to five days.
• If there is no enzyme increase and no symptoms, increase the dose to 300 mg.
• Repeat liver function tests again.
• Finally, increase to the full required dose.

Pyrazinamide Reintroduction Schedule

• Start with an initial dose of 250 mg.
• Gradually increase to 500 mg, then 750 mg, and then 1 gram.
• Progress to the full required dose while continuously monitoring.

Regimen-Specific Management Algorithms

Isoniazid Mono/Poly Drug-Resistant Tuberculosis Regimen

• Withhold Rifampicin and Pyrazinamide if severe or symptomatic transaminitis occurs.
• Continue with all other drugs in the regimen.
• If liver enzymes decrease to <= 2 times the upper limit of normal, restart full doses gradually.
• The order of reintroduction should be Rifampicin first, followed by Pyrazinamide.
• If either Rifampicin or Pyrazinamide cannot be given, substitute with replacement drugs.
• Extend treatment up to 9 months if bacteriological response is achieved at month five.

Multidrug-Resistant Tuberculosis Regimens

Shorter Oral Bedaquiline-Containing Regimen

• Withhold Bedaquiline, High-dose Isoniazid, Ethionamide, and Pyrazinamide during severe hepatotoxicity.
• Monitor clinical symptoms, transaminases, and bilirubin weekly.
• Restart withheld drugs gradually in the following order once enzymes normalize: Bedaquiline, High-dose Isoniazid, Pyrazinamide, then Ethionamide.
• Shift the patient to the longer oral multidrug-resistant regimen if any drug needs to be permanently stopped.

Longer Oral Multidrug-Resistant Regimen

• Withhold Bedaquiline, Pyrazinamide, Ethionamide, and P-Aminosalicylic Acid if utilized.
• Monitor clinical progress and laboratory parameters weekly.
• Restart withheld drugs gradually in the following order: Bedaquiline, Pyrazinamide, Ethionamide, then P-Aminosalicylic Acid.
• Modify the regimen from the replacement sequence if any drug must be permanently stopped.