Routine liver function test monitoring is not required for all patients on isoniazid therapy for latent tuberculosis (TB) infection (strength of recommendation: B, based on case series). No clinical trials have studied the potential risks and benefits of routinely monitoring liver function tests for all patients taking isoniazid for latent TB infection. Data from 2 case series suggest that routine liver function test monitoring leads to withdrawal of isoniazid prophylaxis from about 6% of patients because of abnormal lab results.1,2 This is 10 to 60 times the hepatitis rate found in case series using a symptom-based monitoring strategy.3,6 Data are insufficient, however, to conclude that routine liver function test monitoring leads to a lower rate of fatal isoniazid hepatitis compared with a strategy of symptom-based screening. Given that complete recovery from nonfatal hepatitis is the rule, and that patients withdrawn from isoniazid prophylaxis remain at risk for developing active tuberculosis, current evidence does not support routine liver function test monitoring for all patients.
Several large population-based case series have tried to define the incidence of isoniazid-induced hepatitis and fatal hepatitis. Because these series differed in patient selection, diagnostic criteria for hepatitis, and toxicity monitoring strategies, and because their data span decades, they provide limited insight. Data from 6 large case series1,3-7 and 1 pooled compilation of published and unpublished reports8 are summarized in the Table.
Two studies1,2 that defined hepatitis as asymptomatic liver function test elevation (>5 times normal) on monthly screening found a 6% to 6.4% incidence of hepatitis, a rate 10 to 60 times higher than 4 case series3-6 that relied on symptom-based monitoring. A pooled analysis of more than 200,000 patients receiving isoniazid prophylaxis and monitored according to 1983 American Thoracic Society guidelines reported an intermediate hepatitis rate (1.2%) and only 2 deaths.8 Mortality from isoniazid hepatitis is rare, whichever monitoring strategy is selected. Some deaths attributed to isoniazid prophylaxis may also have had other contributing causes, such as unrecognized hepatitis C; most cases and deaths reported in these large series occurred before testing for hepatitis C became available in 1991.
Symptom-based monitoring strategies require stopping isoniazid promptly if symptoms of hepatotoxicity develop. In a series of 62 fatal cases of probable or possible isoniazid hepatitis, 42% had been monitored at least monthly for symptoms, and 38% stopped isoniazid within 1 week of symptom onset.9 Seven of the 8 patients receiving a liver transplant following the development of fulminant, isoniazid-related hepatitis continued to take the drug for a least 10 days after onset of symptoms of hepatotoxicity.10
Several series report increasing hepatitis risk with advancing age.1,3,5,6 In 1 series,3 rates were 3/1000 in those aged 20 to 34 years, 12/1000 in those aged 35 to 49 years, 23/1000 in those aged 50 to 64 years, and 8/1000 after age 65.
INH hepatitis incidence and mortality rates: summary of the largest case series
|Study||Time period||Monitoring strategy||Hepatitis definition||No. of patients||No. of hepatitis cases||No. of fatal cases mortality rate|
|Byrd1||~early/mid 1970s||Monthly symptom and LFT screening||AST >5x normal, with or without symptoms||1000||64 (6.4%)||0|
|Salpeter8||1983-early 1990s||Presumed to follow 1983 ATS guidelinesa||Not defined||202,497||2,459 (1.2%)||2 (0.001%)|
|Kopanoff3||July 1971 to Nov. 1972||Monthly symptom-based screening||AST ≥250 Karmen units or ALT>AST, and no other cause||13,838||92 (0.66%)||8 (0.06%)|
|IUATCP4||mid-1970s||Every-4-week symptom-based screening||Not defined||20,840||95 (0.5%)||3 (0.014%)|
|Dash4||Jan. 1973 to June 1977||Monthly symptom based screening||Jaundice, scleral icterus, or “hepatitis” notation||5300||15 (0.37%)b||1 (.019%)|
|Nolan6||Jan. 1989 to 1 December 1995||Monthly symptom-based screening||AST >5x normal with symptoms, and no other cause||11,141||11 (0.1%)||0|
|LoBue7||July 1999 to Nov. 2002||Monthly clinical monitoring, routine LFTs for patients >34 before 2000||LFTs >3x normal with symptoms, or LFTs >5x normal without symptoms||3,788||10 (0.3%)||0|
|a Withhold treatment in presence of active liver disease, limit prophylaxis of patients aged >35 to those at highest risk of developing active disease, baseline and periodic LFTs for those over 35, discontinue isoniazid if transaminases exceed 3 to 5 times normal.|
|b Calculation based on life-table analysis, because of high dropout rate during treatment LFT, liver function test; AST, aspartate transaminase; ALT, alanine transaminase; IUSTCP, International Union Against Tuberculosis Committee on Prophylaxis|