Collapse in a Patient on Anti-Tuberculous Therapy
A 34-year-old man from a rural district is admitted with 3 weeks of cough, evening fevers, and 6 kg weight loss. Sputum is smear-positive for acid-fast bacilli. He was started 10 days ago on weight-based standard first-line therapy (isoniazid, rifampicin, pyrazinamide, ethambutol). Today he reports dark urine and yellowing of the eyes. Temperature 37.6 C, BP 100/60 mmHg, pulse 96/min. He is jaundiced. Total bilirubin 88 micromol/L (mostly conjugated), ALT 640 U/L (baseline was 22), INR 1.9, serum creatinine 90 micromol/L. He denies alcohol use, paracetamol, or herbal remedies. Viral hepatitis serology is negative.
1. Is this drug-induced liver injury, and how would you grade its severity? What features in this case drive your grading?
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Yes - a hepatocellular-pattern injury (ALT far above the normal range with a conjugated hyperbilirubinemia) arising 10 days after starting a regimen containing three hepatotoxic drugs, with competing causes (viral hepatitis, alcohol, paracetamol) excluded, fits drug-induced liver injury.
Grading should consider:
- ALT elevation (~29x upper limit) - moderate to severe elevation.
- Bilirubin more than 2x ULN with ALT elevation is the concerning 'Hy's law' pattern, which predicts a higher risk of severe outcome.
- INR 1.9 indicates synthetic liver dysfunction - this is the feature that pushes the case from 'moderate' toward 'severe/life-threatening.'
The combination of jaundice plus coagulopathy means this patient cannot simply be observed; he needs the offending drugs stopped and close monitoring for progression to hepatic failure.
2. Which drugs should be stopped and which, if any, can safely be continued? Justify each decision.
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- Stop isoniazid, rifampicin, and pyrazinamide immediately. All three are hepatotoxic; rifampicin also worsens cholestasis and induces enzymes. Continuing them risks fulminant hepatic failure, especially with an INR of 1.9.
- Ethambutol is essentially non-hepatotoxic and can be continued to maintain some mycobacterial cover while the liver recovers.
- Once ALT falls to roughly twice the upper limit and bilirubin normalizes, a sequential reintroduction is standard: usually rifampicin first (least hepatotoxic of the three), then isoniazid, then pyrazinamide if tolerated - with monitoring between steps. If the patient's disease is severe (smear-positive, cavitary, symptomatic), bridging therapy with non-hepatotoxic agents (e.g., an aminoglycoside plus a fluoroquinolone plus ethambutol) may be considered after specialist input.
Key point: never restart all three simultaneously; a graded reintroduction identifies the culprit and avoids a second severe injury.
3. The patient deteriorates: INR rises to 2.6 and he becomes drowsy. What is your immediate priority and how does it change your antituberculous plan?
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This is evolving acute liver failure - coagulopathy plus encephalopathy. Immediate priorities:
- Airway and consciousness monitoring, transfer to a facility with critical care and, ideally, liver transplant capability.
- Do not give vitamin K blindly as a 'fix' - it may partially correct the INR and mask worsening synthetic function; if given, interpret cautiously.
- Avoid hepatotoxic and sedating drugs, correct hypoglycemia, monitor for cerebral edema.
- Permanently discontinue the hepatotoxic regimen; TB treatment now requires a specialist-designed non-hepatotoxic regimen (e.g., aminoglycoside, fluoroquinolone, ethambutol, and possibly others), recognizing that this is a second-line approach with longer duration and greater toxicity.
This is a case where the exam wants you to recognize that 'stop the drugs' is not enough - the presence of encephalopathy changes the trajectory and the whole treatment plan.