Azathioprine-Induced Pancreatitis in a Patient With Autoimmune Hepatitis: A Case Report

Background

Azathioprine (AZA) is a first-line medication commonly used in the management of autoimmune hepatitis (AIH). It is also widely employed in the treatment of inflammatory bowel disease (IBD), post-transplant immunosuppression, and various autoimmune disorders. Although generally well tolerated, AZA is a recognized cause of acute pancreatitis, with an estimated incidence of 1%. ¹

We describe a patient with autoimmune hepatitis who developed acute pancreatitis shortly after initiating AZA therapy. The condition was resolved following the withdrawal of the medication, highlighting the importance of early recognition and appropriate management of this rare but serious adverse effect.

Case Presentation

A 67-year-old woman with a history of autoimmune hepatitis (AIH) and hypertension presented with a three-day history of new-onset, non-radiating, stabbing suprapubic abdominal pain, and four episodes of non-bloody, non-bilious emesis. She had been diagnosed with AIH three weeks prior to presentation and was started on budesonide at that time, followed by the addition of azathioprine (AZA) two weeks later. Vital signs revealed a fever of 101.5°F, heart rate of 110 bpm, respiratory rate of 18 breaths per minute, blood pressure of 156/88 mmHg, and oxygen saturation of 96% on room air. Physical examination revealed suprapubic tenderness, but no rebound or guarding.

Laboratory studies showed WBC: 4.53 ×10³/μL (4-11), ALT 53 U/L (7-55 U/L), AST 34 U/L(8-33 U/L), lipase 2000 U/L (0-160 U/L), alkaline phosphatase 81 U/L (44-157 U/L), and lactate 1.7 mmol/L (0.5-1.5 mmol/L). Serum IgG4 was 123.6 mg/dL (<140 mg/dl). Blood cultures were obtained. Contrast-enhanced computed tomography (CECT) of the abdomen and pelvis demonstrated mild intrahepatic biliary dilation and a common bile duct diameter of up to 10 mm. Magnetic resonance cholangiopancreatography (MRCP) without contrast demonstrated peripancreatic inflammatory stranding and fluid, consistent with acute interstitial edematous pancreatitis. The patient was diagnosed with acute pancreatitis. Given the minimally elevated IgG4 and the absence of other common etiologies—including alcohol use, cholelithiasis, and hypertriglyceridemia—and in the context of recent azathioprine initiation, drug-induced pancreatitis was determined to be the most likely etiology.

The patient was managed supportively with intravenous fluids. Her clinical status improved, and she was able to tolerate oral intake. She was discharged with instructions to discontinue both azathioprine and budesonide. At follow-up with gastroenterology one week later, she was started on mycophenolate mofetil (MMF) as an alternative immunosuppressive agent. The patient’s liver enzymes normalized and remained stable while receiving MMF.

Discussion

First-line therapy for AIH typically consists of prednisone, either as monotherapy or in combination with azathioprine (AZA). In non-cirrhotic patients or those with milder disease, the combination of budesonide and AZA is an accepted alternative first-line regimen, as studies have demonstrated higher rates of biochemical remission and fewer corticosteroid-related side effects compared with prednisone-based therapy. ² Additionally, systemic corticosteroids, such as prednisone, may attenuate the T-cell–mediated hypersensitivity cascade that underlies azathioprine-induced pancreatitis. In contrast, budesonide, due to its high first-pass metabolism (90% first pass in the liver) and low systemic bioavailability, does not offer the same effect.

AZA remains the cornerstone of maintenance therapy for AIH. It is typically initiated at a low dose of 50 mg/day and titrated up to 1–2 mg/kg/day to mitigate dose-related side effects. ² Despite its efficacy, AZA intolerance presents a significant clinical challenge, affecting an estimated 10–20% of patients, although precise figures within the AIH population remain unclear. Gastrointestinal discomfort is the most commonly reported adverse effect; however, rarer but more serious complications - such as bone marrow suppression, hepatotoxicity, and acute pancreatitis - can also occur.

Among these, AIP is a significant adverse event, occurring in approximately 1% of patients. AIP is best characterized as an idiosyncratic reaction - non–dose-dependent and unpredictable. ¹ Although most frequently documented in patients with IBD, AIP can also occur in other populations treated with AZA, including individuals with AIH, transplant recipients, and those with autoimmune or vasculitic disorders. ³

The metabolism of AZA is significantly influenced by thiopurine methyltransferase (TPMT) activity, and TPMT testing is routinely performed prior to therapy initiation to identify individuals at risk for myelotoxicity. However, TPMT activity does not correlate with the risk of developing AIP, further supporting its idiosyncratic nature. This distinction highlights the need for clinical vigilance even in patients with normal TPMT function.

Recent genomic studies have provided significant insight into the idiosyncratic nature of Azathioprine-induced pancreatitis (AIP). While traditional metabolic markers like TPMT activity do not correlate with AIP risk, research involving patients with Crohn’s disease has identified a strong association between AIP and a specific HLA variant. Specifically, the HLA-DQA102:01-HLA-DQB102:02 haplotype has been linked to a significantly increased risk of developing pancreatitis upon thiopurine exposure. ⁴ This genetic association suggests that AIP is likely a Type B hypersensitivity reaction mediated by specific antigen presentation to T-cells, rather than a direct toxic effect of drug metabolites. Although these variants have been most robustly studied in IBD cohorts, their presence likely explains the unpredictable onset observed in other populations, including patients with Autoimmune Hepatitis (AIH).

The typical onset of AIP occurs within the first three to six weeks after initiating therapy. Patients usually present with abdominal pain, nausea, and elevated pancreatic enzymes. Re-exposure to AZA can lead to a more rapid recurrence of pancreatitis, underscoring the importance of early recognition and permanent discontinuation of the drug upon diagnosis. Management is supportive, focusing on symptom control and pancreatic rest, with complete resolution expected in most cases following drug withdrawal.

The development of AIP necessitates a reassessment of the immunosuppressive strategy. Although AZA is the only approved first-line agent for maintenance therapy in AIH, MMF is a viable alternative, particularly in cases of AZA intolerance. High-dose MMF has been associated with remission rates as high as 88%, though its use may be limited by gastrointestinal side effects and cost.

Conclusion

In summary, while AZA is a mainstay in the management of AIH, clinicians should remain alert to rare but serious adverse events such as pancreatitis. Early recognition and withdrawal of the offending agent are essential, and alternative immunosuppressive options like MMF should be considered to maintain disease control without compromising patient safety.