Acute biliary events during anti-tuberculosis treatment: hospital case series and a nationwide cohort study

An adverse event was considered an ABE if it met both of the following criteria: (1) abnormal liver function during anti-TB treatment; and (2) diagnosis with image confirmation, such as abdominal computed tomography or sonography.

Between 2010 and 2015, a total of 3686 patients with pulmonary TB were treated at the National Taiwan University Hospital (n = 2704) and its Hsinchu Branch (n = 982). Among them, 2879 (78.1%) had culture-confirmed pulmonary TB. Liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and total bilirubin) was evaluated at baseline and at least once during anti-TB treatment in 3675 (99.7%) patients, and significant elevation in AST and ALT levels was noted in 416 (11.3% of 3675) patients. The medical records of these 416 patients were reviewed to determine whether ABE was responsible for abnormal liver function in these patients. The diagnosis of ABE was also confirmed using imaging modalities.

An adverse event was considered an ABE if it met both of the following criteria: (1) diagnosis of cholelithiasis (ICD-9-CM code 574), acute cholecystitis (ICD-9-CM code 575.0–575.2), cholangitis (ICD-9-CM code 576.1), or obstruction of biliary tract (ICD-9-CM code 576.2); and (2) the patient had received at least one of the examinations and management therapies listed in Table 1. The primary outcome was ABEs that occurred within 180 days after commencement of anti-TB treatment.

We identified patients in the NHIRD who had been diagnosed with pulmonary TB from 1996 to 2010 (Fig. 1). Active TB was defined by the following criteria: (1) at least two outpatient records or one inpatient record with a compatible diagnosis; (2) one prescription of at least three anti-TB medications; and (3) receiving two or more anti-TB medications simultaneously over a period of 120 days within a 180-day period [9]. Patients who were diagnosed with nontuberculous mycobacterial infection (ICD-9-CM code 031) during the last 60 days of anti-TB treatment were excluded. Patients who met any of the ABE diagnostic criteria before anti-TB treatment were also excluded. Date of treatment completion was defined as the last date on which two or more anti-TB drugs were taken simultaneously without receiving any anti-TB medication in the subsequent 60 days.

Comorbid conditions—comprising diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), malignancy, end-stage renal disease, connective tissue disease, acquired immunodeficiency syndrome, liver cirrhosis, transplantation, pneumoconiosis, and low-income status—at the time TB diagnosis were identified by using previously published definitions [9, 10].

Intergroup differences were assessed by using independent-sample t tests for continuous variables and chi-square or Fisher exact tests for categorical variables. The risk factors for ABEs in patients with pulmonary TB were evaluated using logistic regression analyses. Only variables with a two-sided p < 0.05 were included in the final model. All analyses were performed using IBM SPSS Statistics Version 22 (IBM Corp., Armonk, NY, USA).

A male patient in his 80s with comorbid, medically controlled hypertension and DM received standard four-drug anti-TB treatment (isoniazid, rifampin, ethambutol, and pyrazinamide) for his smear-positive, culture-confirmed pulmonary TB. He experienced fever and chills after one week of treatment. Laboratory examinations showed elevated AST (212 IU/L) and ALT (375 IU/L) and direct-type hyperbilirubinemia (total bilirubin: 2.81 mg/dL; direct bilirubin: 2.57 mg/dL). Abdominal sonography revealed the presence of multiple gall stones and dilated intrahepatic ducts. Anti-TB treatment was discontinued and ceftazidime was prescribed. One month later, the patient underwent a laparoscopic cholecystectomy procedure, followed by the resumption of anti-TB treatment. Thereafter, ABEs were not noted.

A male patient in his 50s with comorbid, medically controlled DM and COPD was diagnosed with pulmonary TB based on a histology report of a transbronchial lung biopsy and a mycobacterial culture of bronchial washing sample. The first 3 weeks of four-drug anti-TB treatment were uneventful, but after 4 weeks of treatment, he experienced nausea and vomiting. Laboratory tests revealed elevated transaminase (AST: 144 IU/L and ALT: 358 IU/L). A minimal amount of ascites in the right subdiaphragmatic area was observed using abdominal sonography. A small amount of ascites was also observed in the perigallbladder, right anterior pararenal, and pelvic space one week later using abdominal computed tomography. The patient was diagnosed with acute cholecystitis. Anti-TB treatment was interrupted and cefmetazole was administered. After his adverse reactions had resolved, anti-TB treatment was successfully resumed.

A man in his 50s with comorbid hypertension and COPD, which were under irregular medical control, was diagnosed with smear-positive, culture-confirmed pulmonary TB. Two weeks prior to the commencement of standard anti-TB treatment, he had pneumonia with respiratory failure and septic shock. Laboratory tests demonstrated elevated transaminase levels, but normal total and direct bilirubin (AST: 144 IU/L; ALT: 358 IU/L; and total bilirubin: 0.52 mg/dL). Neither gallbladder stones nor bile duct stones were identified using computed tomography (slide thickness: 5 mm; interval: 1.2 mm). The patient was treated with courses of antibiotics, which improved his respiratory condition, hemodynamic condition, and aminotransferase levels (AST: 51 IU/L; ALT: 23 IU/L). The standard four-drug anti-TB treatment was started subsequently. However, after receiving anti-TB treatment for two weeks, his bilirubin level was increased, with a mild elevation in transaminase level (AST: 77 IU/L; ALT: 49 IU/L; total bilirubin: 4.57 mg/dL; and direct bilirubin: 3.84 mg/dL). Anti-TB treatment was halted. Multiple cholelithiasis with a dilated intrahepatic duct was diagnosed using abdominal sonography. Soon after the patient underwent the sonography procedure, he experienced another episode of pneumonia with septic shock and respiratory failure. Although bilirubin and transaminase both improved after interruption of anti-TB treatment for 10 days (AST: 61 IU/L; ALT: 38 IU/L; total bilirubin: 1.72 mg/dL; and direct bilirubin: 1.37 mg/dL), the general condition of the patient deteriorated gradually. The patient died of refractory septic shock.

A previously healthy male patient in his 20s was diagnosed with smear-positive, culture-confirmed pulmonary TB and TB pleurisy. No cholelithiasis was noted in abdominal sonographs obtained 2 years prior to the diagnosis of TB. The standard four-drug anti-TB treatment improved his TB clinical symptoms, including fever, chest pain, and left pleural effusion; however, abnormal liver function was noted (AST: 303 IU/L; ALT: 499 IU/L; and total bilirubin: 0.56 mg/dL) after 6 weeks of treatment, which resolved (ASL: 26 IU/L; ALT: 34 IU/L; total bilirubin: 0.1 mg/dL) after the interruption of anti-TB treatment. In the 18th week, anti-TB treatment with isoniazid, rifampin, and ethambutol was resumed. However, the patient experienced acute abdominal cramping pain in the following week. His aminotransferase and bilirubin level did not increase (AST: 22 IU/L; ALT: 17 IU/L; and total bilirubin: 0.57 mg/dL). Multiple small cholelithiases were discovered using abdominal sonography. Rechallenge with anti-TB treatment was complicated by recurrent abdominal cramping pain immediately after taking the anti-TB drugs. Because gastroenterologists suggested a possible diagnosis of intermittent biliary obstruction due to a passing stone, he received conservative management. The anti-TB treatment was successfully completed in the ninth month after TB diagnosis.

The demographic characteristics and clinical course of these four patients are summarized in Table 2.