Jaundice Six Weeks into Antitubercular Therapy
A 42-year-old shopkeeper weighing 58 kg was diagnosed with sputum smear-positive pulmonary tuberculosis six weeks ago and started isoniazid 300 mg, rifampicin 450 mg, pyrazinamide 1500 mg and ethambutol 800 mg daily. He takes no other regular medicines but drinks 60–90 mL of country liquor most evenings. He now presents with eight days of nausea and anorexia, dark urine, and three days of yellow eyes. He is icteric, alert, with tender hepatomegaly; there is no ascites and no encephalopathy. Investigations: total bilirubin 4.2 mg/dL (direct 3.0), ALT 460 U/L (baseline 28), AST 380 U/L, alkaline phosphatase 160 U/L, INR 1.4, serum albumin 3.4 g/dL, creatinine 0.8 mg/dL. Hepatitis A IgM, HBsAg, anti-HCV and HIV are negative. Ultrasound shows normal liver echotexture with no biliary dilatation.
1. What is the diagnosis, which of the four drugs are responsible, and how do you decide that this is drug-induced rather than viral or alcoholic hepatitis?
Read the worked answer
Diagnosis: antitubercular drug-induced liver injury - hepatocellular pattern with jaundice.
Pattern: ALT 460 U/L is about 16 times the upper limit of normal, and the ALT-to-alkaline-phosphatase ratio is far above 5, so this is hepatocellular, not cholestatic. A bilirubin of 4.2 mg/dL with a hepatocellular injury pattern meets Hy's law (ALT >3 times normal plus bilirubin >2 times normal without biliary obstruction) - the combination that predicts a risk of severe or fatal liver failure, which is why he needs admission and monitoring, not outpatient review.
The diagnostic criteria for stopping therapy are already met: ALT >5 times normal even if asymptomatic, ALT >3 times normal with symptoms, or any jaundice with bilirubin >2 mg/dL.
Which drugs:
- Pyrazinamide is the most hepatotoxic of the four.
- Isoniazid causes injury through its hydrazine metabolite, with the risk higher in slow acetylators and in people who drink alcohol.
- Rifampicin is less hepatotoxic alone but is a potent enzyme inducer that increases isoniazid's hepatotoxic metabolite, so the combination is worse than either drug alone; it also competes for bilirubin excretion.
- Ethambutol is not hepatotoxic - this is the drug that can be safely continued.
Against the alternatives: HBsAg, anti-HCV, hepatitis A IgM and HIV are negative; the ultrasound shows no duct dilatation, excluding obstructive jaundice; there is no history of a binge but he is a chronic daily drinker, which acts as a co-factor rather than the sole cause - the timing six weeks into therapy and the negative viral serology point to the drugs. The rifampicin dose of 450 mg is also under-dosed for 58 kg (should be 600 mg for 55–70 kg), reflecting a common prescribing error.
2. What do you stop tonight, what do you continue, and how do you treat his tuberculosis while the liver recovers?
Read the worked answer
Tonight:
- Stop isoniazid, rifampicin and pyrazinamide immediately. There is no role for continuing any of them while the ALT is 460 U/L with jaundice.
- Continue ethambutol 800 mg daily - it is renally excreted and non-hepatotoxic, so stopping it only leaves the patient untreated with no benefit.
- Stop alcohol completely; avoid paracetamol above 2 g/day and all other hepatotoxins; give antiemetics and intravenous fluids if he cannot eat.
- Admit for monitoring - check INR, bilirubin, ALT and glucose daily; a rising INR, falling glucose, or any drowsiness means progression to acute liver failure and possible transplant referral. Do not give N-acetylcysteine routinely here except as supportive care in evolving failure.
- Screen for other causes if recovery is slow: autoimmune markers, ferritin, alpha-1 antitrypsin.
Treating the tuberculosis in the interim - do not leave a smear-positive patient untreated:
- Standard practice is to wait if the disease is mild and the liver is recovering quickly, but with smear-positive pulmonary disease a non-hepatotoxic regimen should be started: Streptomycin 0.75 g intramuscularly (15 mg/kg) daily plus ethambutol 800 mg plus levofloxacin 750 mg daily, until the liver recovers.
- Check baseline visual acuity and colour vision for ethambutol, and renal function for streptomycin (hearing and vestibular checks).
- Monitor liver function weekly; the aim is for ALT to fall below 2 times the upper limit of normal and bilirubin to normalise before rechallenge.
The judgement being tested: stopping three drugs is correct, denying the patient all treatment is not.
3. Outline the reintroduction plan once the liver recovers, and state which drug you would never rechallenge and what you would use instead.
Read the worked answer
Before rechallenge - wait for: ALT below 2 times the upper limit of normal and bilirubin normal, with the patient clinically well and eating.
Sequential reintroduction (one drug at a time, with liver function checked every 3–7 days):
- Rifampicin 600 mg first - it is the least hepatotoxic of the three caused drugs and the most important for sterilising the disease; check liver function at 3 and 7 days.
- If stable, add isoniazid 300 mg; check liver function again at 3 and 7 days.
- If the ALT doubles or symptoms recur after a specific drug, stop that drug and do not reintroduce it.
Never rechallenge pyrazinamide. Rechallenge with pyrazinamide provokes recurrence of hepatitis in a high proportion of patients and can precipitate liver failure.
Replacement regimen:
- 2 months of isoniazid + rifampicin + ethambutol + levofloxacin, followed by 7 months of isoniazid + rifampicin + ethambutol (total 9 months), because the loss of pyrazinamide (and of its early bactericidal action) requires a longer course.
- If rifampicin is also implicated and cannot be reused, give a fluoroquinolone-based regimen (levofloxacin + ethambutol + streptomycin/amikacin for the intensive phase, then levofloxacin + ethambutol), extended to 12–18 months, and take expert opinion.
Safety net before discharge: written advice to return immediately with nausea, dark urine or yellow eyes; no alcohol; monthly liver function tests during the first 3 months; and a note of the drug reaction in his records so future prescribers do not restart pyrazinamide.