How does tuberculosis affect the liver?

Tuberculosis Effects on the Liver

Tuberculosis can directly affect the liver in three main forms: diffuse hepatic involvement, granulomatous hepatitis, and focal tuberculoma or abscess, with the most common being diffuse involvement seen alongside pulmonary or miliary tuberculosis. 1

Direct Effects of TB on the Liver

• TB infection can cause modest elevations of hepatic transaminases (ALT/AST) even before treatment begins 2
• Diffuse hepatic involvement is the most common form, typically seen with pulmonary or miliary tuberculosis 1
• Granulomatous hepatitis represents the second form of hepatic TB involvement 1
• Focal tuberculoma or abscess is the rarest form of hepatic TB 1
• Tuberculosis itself may involve the liver, causing abnormal liver function that will improve with effective treatment 3

TB Treatment and Hepatotoxicity

• Drug-induced hepatitis is the most frequent serious adverse reaction to first-line TB drugs 3
• Isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) can all cause drug-induced liver injury (DILI) 3
• DILI is suspected when ALT levels are ≥3 times the upper limit of normal with hepatitis symptoms, or ≥5 times the upper limit of normal without symptoms 3
• Severe and sometimes fatal hepatitis associated with isoniazid therapy has been reported and may occur even after many months of treatment 4
• The risk of isoniazid-related hepatotoxicity increases with age: less than 1 per 1,000 for persons under 20 years, rising to 23 per 1,000 for persons aged 50-64 years 4

Risk Factors for TB-Related Liver Injury

• Pre-existing liver disease significantly increases the risk of hepatotoxicity during TB treatment 2
• Daily alcohol consumption substantially increases hepatotoxicity risk 4, 5
• Advanced age is associated with higher risk of liver dysfunction during TB treatment 6
• Female sex, particularly in Black and Hispanic women, may have increased risk of fatal hepatitis with isoniazid 4
• The postpartum period may be associated with increased hepatotoxicity risk 4
• HIV co-infection requires additional monitoring due to increased hepatotoxicity risk 2

Monitoring Recommendations

• Liver function should be checked before starting TB treatment 3, 2
• For patients aged 35 and older, hepatic enzymes (AST/ALT) should be measured prior to starting isoniazid therapy and periodically throughout treatment 4
• Regular monitoring of liver function (weekly for two weeks then two-weekly for the first two months) is required for patients with known chronic liver disease 3, 2
• For patients without pre-existing liver disease and normal pre-treatment liver function, routine monitoring is not required, but liver function should be checked if symptoms develop 3
• Patients should be advised about symptoms of liver dysfunction (unexplained anorexia, nausea, vomiting, dark urine, jaundice, persistent fatigue) and instructed to stop medication and seek medical attention if these occur 3, 4

Management of Hepatotoxicity

• If AST/ALT rises to five times the upper limit of normal or if bilirubin rises, hepatotoxic drugs should be stopped immediately 3, 4
• If the patient is not acutely ill and TB is non-infectious, treatment can be paused until liver function normalizes 3
• For ill patients or those with infectious TB, alternative non-hepatotoxic drugs (streptomycin and ethambutol) should be used until liver function normalizes 3
• When reintroducing drugs after hepatotoxicity, they should be introduced sequentially in small, gradually increasing doses (isoniazid first, then rifampin, then pyrazinamide) with daily monitoring of clinical condition and liver function 3
• Alcohol consumption should be avoided during TB treatment due to increased hepatotoxicity risk 2, 4

Treatment Adaptation for Liver Disease

• For patients with unstable or advanced liver disease, regimens with fewer potentially hepatotoxic agents should be considered 3
• Options for patients with liver disease include:
  • Regimen with RIF, PZA, and EMB followed by continuation phase of RIF, EMB, and PZA (retains 6-month duration but includes two hepatotoxic drugs) 3
  • Regimen with INH, RIF, and EMB for 2 months followed by INH and RIF for 7 months (total 9 months) 3
  • For advanced liver disease, a regimen with only one potential hepatotoxic drug (typically retaining RIF) plus EMB, a fluoroquinolone, cycloserine, or injectable agents for 12-18 months 3
  • For severe unstable liver disease, a regimen with no hepatotoxic agents might be necessary (e.g., streptomycin, EMB, a fluoroquinolone, and another second-line oral drug) 3

Severe Cases and Outcomes

• Despite significant elevations in liver enzymes (approximately 6 times upper limit of normal), TB drugs can be continued or reintroduced in full in most cases with careful monitoring 5
• In rare cases, TB treatment can cause fulminant hepatic failure requiring liver transplantation 7
• After liver transplantation for TB drug-induced hepatic failure, non-hepatotoxic anti-tuberculous therapy (cycloserine, ciprofloxacin, streptomycin, and ethambutol) can be used successfully 7