What causes pancreatitis in a patient on anticoagulation therapy, such as apixaban?

Causes of Pancreatitis

The most common causes of acute pancreatitis are gallstones (accounting for 60-75% of cases) and alcohol consumption (20-25% of cases), with the remaining cases attributed to hypertriglyceridemia, medications, post-procedural complications, metabolic disorders, infections, autoimmune conditions, and idiopathic causes. 1, 2

Primary Etiologies

Gallstone Disease

• Gallstones are the leading cause of acute pancreatitis, representing approximately 60-75% of all cases. 1, 2
• Biliary pancreatitis occurs when stones transiently impact in the ampulla, causing pancreatic duct obstruction and ductal hypertension, or when stones pass through into the duodenum. 3
• Abdominal ultrasonography should be performed immediately at admission to identify cholelithiasis or choledocholithiasis. 4
• The diagnosis of idiopathic pancreatitis should not be accepted without at least two good quality ultrasound examinations, as repeat ultrasound remains the most sensitive test for detecting missed gallstones. 1, 2
• Microlithiasis (microscopic gallstones) may account for up to two-thirds of previously labeled "idiopathic" cases and can be detected through bile sampling or endoscopic ultrasound. 3, 2

Alcohol-Related Pancreatitis

• Alcohol abuse is the second most common cause overall, accounting for 20-25% of acute pancreatitis cases. 1
• In chronic pancreatitis, alcohol is the etiological factor in 60-70% of cases. 2
• Abstinence from alcohol is essential for preventing recurrence in patients with alcoholic pancreatitis. 2

Metabolic Causes

Hypertriglyceridemia

• Hypertriglyceridemia is the third most common cause of acute pancreatitis and typically occurs when triglyceride levels exceed 1000-2000 mg/dL. 4
• Serum triglyceride levels >11.3 mmol/L (approximately 1000 mg/dL) indicate hypertriglyceridemia as the causative etiology. 1
• Patients with severe hypertriglyceridemia (≥1,000 mg/dL) have a 14% incidence of acute pancreatitis. 2
• Fasting triglyceride level must be obtained immediately in all patients presenting with acute pancreatitis. 4
• In hypertriglyceridemia-associated pancreatitis, free fatty acids released by pancreatic lipase sequester calcium intravascularly through FFA-albumin complexes, contributing to both cellular injury and systemic hypocalcemia. 1

Hypercalcemia

• Fasting calcium concentrations must be determined in all patients with acute pancreatitis, especially when gallstones and alcohol have been excluded as causes. 1
• Hypercalcemia should be investigated as a potential cause, particularly in idiopathic cases. 1

Drug-Induced Pancreatitis

High-Risk Medications (Class I Evidence)

Class I medications have been implicated in greater than 20 reported cases with at least one documented case following reexposure: 5

• Azathioprine and 6-mercaptopurine cause pancreatitis in approximately 4% of treated IBD patients, typically occurring within the first 3-4 weeks of treatment in a dose-independent manner. 2
• Other Class I medications include: didanosine, asparaginase, valproic acid, pentavalent antimonials, pentamidine, mesalamine, estrogen preparations, opiates, tetracycline, cytarabine, steroids, trimethoprim/sulfamethoxazole, sulfasalazine, furosemide, and sulindac. 5

Moderate-Risk Medications (Class II Evidence)

Class II medications have been implicated in more than 10 cases: 5

• Rifampin, lamivudine, octreotide, carbamazepine, acetaminophen, phenformin, interferon alfa-2b, enalapril, hydrochlorothiazide, cisplatin, erythromycin, and cyclopenthiazide. 5

Clinical Approach to Drug-Induced Pancreatitis

• A detailed medication history should be obtained for all prescription and non-prescription drugs, as drug-induced pancreatitis accounts for a small but important percentage of cases. 4
• Of the top 100 most frequently prescribed medications in the United States, 44 have been implicated in acute pancreatitis, with 14 falling into Class I or II. 5
• Physicians should have a high index of suspicion for drug-induced pancreatitis, especially in geriatric patients on multiple medications, HIV+ patients, cancer patients, and patients receiving immunomodulating agents. 5
• If drug-induced pancreatitis is suspected, the offending medication must be discontinued immediately. 4

Important Caveat Regarding Anticoagulants

• There is no established direct causal relationship between anticoagulants such as apixaban and acute pancreatitis. The guidelines on endoscopy in patients on anticoagulation therapy discuss procedural bleeding risks and post-ERCP pancreatitis, but do not identify anticoagulants themselves as a cause of pancreatitis. 6

Procedural and Traumatic Causes

• Post-ERCP pancreatitis is a recognized complication of endoscopic retrograde cholangiopancreatography. 2
• Endoscopic sphincterotomy is associated with a higher incidence of post-ERCP hemorrhage (6.2% vs 0%) but a lower incidence of post-ERCP pancreatitis (3.5% vs 8.9%) compared to stent placement without sphincterotomy. 6
• Trauma and ischemia/reperfusion injury are increasingly recognized as important mechanisms in the pathogenesis of acute pancreatitis, especially in progression from mild edematous to severe necrotizing forms. 3

Autoimmune and Infectious Causes

• Autoimmune pancreatitis, including IgG4-related pancreatitis, has been described in IBD patients. 2
• Various infections, including mumps, Coxsackie B4, and others, can trigger acute pancreatitis. 2

Anatomic and Obstructive Causes

• Pancreatic duct abnormalities, such as obstruction or pancreas divisum, are recognized causes. 2
• Duodenal Crohn's disease can cause pancreatitis through direct extension or fistulizing disease. 2
• Malignancy or fibrotic sphincter of Oddi can cause obstructive pancreatitis. 3

Idiopathic Pancreatitis

• Approximately 15-20% of cases remain idiopathic despite thorough evaluation, though this percentage should be minimized through vigorous investigation. 2
• In the absence of identified gallstones or significant alcohol history, additional testing should include fasting plasma lipids and calcium levels. 1
• Repeat biliary ultrasound and endoscopic ultrasound (EUS) may detect microlithiasis in the gallbladder or common bile duct in recurrent cases with no identified cause. 1
• MRCP has a sensitivity of 97.98% and specificity of 84.4% for choledocholithiasis and should be used when ultrasound does not show gallstones but clinical suspicion remains high. 1

Pathophysiologic Mechanisms

• Intra-acinar activation of trypsinogen plays a central role in the pathogenesis, resulting in subsequent activation of other proteases causing cell damage. 3
• Increased intracellular calcium concentration mediates acinar cell damage. 3
• Oxygen-derived free radicals and cytokines (IL-1, IL-6, IL-8, tumor necrosis factor-alpha, platelet activating factor) are principal mediators in the transformation from local inflammatory process to multiorgan illness. 3