Case Report

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A 31-year-old man from India presented to the emergency department with complaints of several days of weakness, fever, vomiting, and persistent pain in the epigastrium. Three weeks before this presentation, he was seen in the same hospital with complaints of persistent diarrhea, fever, and a weight loss of 7 kg. The patient had a positive tuberculin test result of 13 millimeters. Endoscopy showed aphthous ulcers in the duodenum, terminal ileum, and ileocecal valve. Antituberculous medications were begun, and his diarrhea and fever resolved. Follow-up endoscopy showed complete resolution of aphthous ulcers.

At the time of his presentation to the emergency department, the patient had received 14 days of daily rifampin (600 mg), isoniazid (300 mg), and pyrazinamide (1500 mg). He denied any history of alcohol ingestion, abdominal trauma, abnormal lipid test results, and gallbladder or pancreatic diseases. There was no family history of diabetes mellitus, lipid disorders, or pancreatitis. He had not been on any medications before the onset of pain and fever. He took a few tablets of ibuprofen after the onset of pain but this did not relieve the pain.

On physical examination, the patient appeared acutely ill with frequent vomiting. He had a temperature of 39.0 °C. The abdomen was distended and tender on deep palpation in the midepigastrium. In addition, rebound tenderness, guarding, and absent bowel sounds were noted. The laboratory test results showed serum amylase levels of 12.6 µkat/L (758 U/L), leukocyte counts of 16 x 10⁹/L (16 000 mm^–3), glucose levels of 140 mg/dL, hematocrit of 0.35, calcium levels of 1.85 mmol/L (7.4 mg/dL), and serum potassium levels of 3.0 mmol/L (mEq/L). A flat plate of the abdomen showed the "colon cut-off" sign. Ultrasound and computed tomography test results of the abdomen were consistent with the diagnosis of acute pancreatitis; the biliary tract was normal.

The clinical impression was drug-induced acute pancreatitis, perhaps related to rifampin. The patient improved quickly and was discharged on the fifth hospital day with normal laboratory test results. The following day he was restarted on isoniazid therapy alone, 300 mg. Six hours later, he awoke from sleep with severe epigastric pain radiating to the back, nausea, and vomiting. On examination, his abdomen was distended with severe tenderness and rebound in the epigastrium. Serum amylase levels were 10.3 µkat/L (620 U/L) and lipase levels were 58.1 µkat/L (3488 U/L). The pain gradually subsided, and the patient was discharged on the eighth hospital day. After discharge, he was restarted on daily rifampin (600 mg), pyrazinamide (1500 mg), and ethambutol (800 mg), without any recurrence of symptoms.

Discussion

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Since its discovery in 1952, isoniazid has remained the most valuable first-line drug in the treatment of tuberculosis. Moreover, its use as a chemoprophylactic agent plays an important role in our health care approach toward combating the current increased prevalence of tuberculosis. In 1989, the Centers for Disease Control and Prevention recommended isoniazid prophylaxis for persons positive for human immunodeficiency virus (HIV) who also have a positive tuberculin skin test result [4]. This recommendation is supported by the results of a clinical trial in persons with asymptomatic HIV infection in whom the use of isoniazid was associated with a decreased incidence of active tuberculosis and a delayed onset of HIV-related disease [5].

In a review of the literature, we could not find any patients who had been diagnosed with isoniazid-induced acute pancreatitis. In patients receiving combination chemotherapy containing isoniazid, rifampin is usually implicated as the cause of acute pancreatitis. Mattson [6] reported asymptomatic increases of amylase levels in 20 (3.7%) of 547 patients receiving intermittent rifampin and daily isoniazid for the treatment of M. tuberculosis. Nine (1.6%) patients developed abdominal pain with increases in levels of serum amylase, and 3 required discontinuation of therapy. However, these data are difficult to interpret because of incomplete information about other predisposing factors and the lack of challenge tests with the incriminating medication. In a report [7] of indomethacin-induced acute pancreatitis, the author refers to a previously described patient who had isoniazid-induced pancreatitis. However, there was no mention of isoniazid-induced toxicity in that report [8]. Moreover, large reviews [2, 3] on this topic do not mention isoniazid-induced acute pancreatitis.

Kvale [9] described a patient who had a presentation similar to that of our patient. This patient developed an acute abdomen during isoniazid chemoprophylaxis for M. tuberculosis. The symptoms resolved after discontinuation of isoniazid and recurred within 2 hours of a challenge dose. In vitro tests showed increased sensitivity of the peripheral blood lymphocytes to isoniazid. The patient was diagnosed as having drug-induced peritonitis, but unfortunately tests such as those for serum amylase and lipase and imaging studies to assess pancreatic damage were not done.

The adverse effects of isoniazid include toxic, idiosyncratic, and hypersensitivity reactions, and the patient may develop various systemic manifestations including neurologic, hematologic, rheumatic, and hepatic syndromes [3]. The present study is the first well-documented case of isoniazid-induced acute pancreatitis. This finding is important because the development of acute pancreatitis during treatment of M. tuberculosis is commonly attributed either to the underlying illness or to medications other than isoniazid. Patients with the acquired immunodeficiency syndrome (AIDS) are at an increased risk for developing acute pancreatitis, which is usually blamed on the use of medications, opportunistic infections, or HIV itself. The recognition that isoniazid-induced acute pancreatitis can occur is of particular relevance to these patients because other medications known to cause acute pancreatitis, such as pentamidine and didanosine, may be erroneously implicated and discontinued [10].

Our patient provided us with a unique opportunity to identify isoniazid as a cause of acute pancreatitis in the absence of other confounding factors. The development of pancreatitis within 6 hours of the challenge dose is consistent with a hypersensitivity reaction. It is expected that a larger number of patients with isoniazid-induced systemic reactions will be seen because of the increased use of this drug in the treatment and chemoprophylaxis of M. tuberculosis. In view of the present findings, acute pancreatitis should be considered as a possible side effect of isoniazid.