What are the unusual causes of acute pancreatitis?

Unusual Causes of Acute Pancreatitis

Beyond the common culprits of gallstones and alcohol, unusual causes of acute pancreatitis include drug-induced pancreatitis, hypertriglyceridemia, hypercalcemia, anatomical abnormalities (pancreas divisum), autoimmune pancreatitis, infections (including Mycoplasma pneumoniae), post-procedural injury (ERCP, colonoscopy, cardiac surgery), pancreatic tumors, and genetic mutations. 1, 2

Metabolic and Biochemical Causes

Hypertriglyceridemia

• Severe elevations in serum triglycerides (>11.3 mmol/L) can precipitate acute pancreatitis and carries a worse prognosis than other etiologies 2
• Free fatty acids released by pancreatic lipase sequester calcium intravascularly, contributing to cellular injury and systemic hypocalcemia 2
• This is the third most common cause overall but often overlooked in initial workups 2

Hypercalcemia

• Elevated calcium activates pancreatic enzymes prematurely, leading to autodigestion and inflammation 2
• Fasting calcium concentrations must be determined in all patients with acute pancreatitis, especially when gallstones and alcohol have been excluded 2
• This should be measured after the acute phase if the etiology remains unclear 3

Drug-Induced Pancreatitis

High-Risk Medications

• Azathioprine/6-mercaptopurine causes pancreatitis in approximately 4% of treated IBD patients, typically within the first 3-4 weeks of treatment, and is dose-independent 2
• Patients carrying the HLA-DQA102:01-HLA-DRB107:01 haplotype are more prone to thiopurine-induced pancreatitis 2
• 5-ASA (mesalazine) has a much lower risk than thiopurines but can still cause pancreatitis 2
• Valproic acid is another recognized trigger 1
• A detailed drug history should be obtained in all cases, as some medications cause pancreatitis shortly after initial use while others develop after years of use 3, 1

Anatomical and Structural Abnormalities

Pancreatic Duct Anomalies

• Pancreas divisum and other pancreatic duct abnormalities obstruct normal pancreatic drainage 1, 2
• ERCP should be performed in recurrent attacks to exclude anatomical variations, ampullary tumors, and common duct stones 3
• Pancreatic duct changes (main duct obstruction, severe irregularity, dilatation) can be found in patients with inflammatory bowel disease 2

Occult Malignancy

• Pancreatic tumors can occasionally present as acute pancreatitis and should be considered particularly in elderly patients with idiopathic pancreatitis 1
• When the etiology remains obscure, a CT scan should be performed (particularly in the elderly) to exclude a tumor of the pancreas 3
• If doubt remains about a tumor, an MRI scan may add further information 3

Autoimmune Causes

• Autoimmune pancreatitis is an immune-mediated form that may be associated with IgG4-related disease 1
• This has been described in IBD patients and represents a distinct pathogenic pathway 2
• Autoimmune markers should be checked in recurrent idiopathic cases 3

Infectious Etiologies

Viral and Atypical Infections

• Viral infections can occasionally trigger pancreatitis, though the value of early and convalescent viral studies is debatable 3, 1
• Mycoplasma pneumoniae has been reported to cause acute pancreatitis as an unusual extrapulmonary manifestation 4
• Helicobacter pylori infection increases relative risk (RR 1.5, attributable fraction 4-25%) 2
• HIV infection should be noted as a comorbid condition that may contribute 3
• Evidence of viral exposure through prodromal illness should be documented in the clinical history 3

Post-Procedural Causes

Iatrogenic Triggers

• Post-ERCP pancreatitis is a recognized complication 2
• Trauma or surgery, particularly after abdominal or cardiac procedures, can cause direct pancreatic injury 1, 2
• Post-operative acute pancreatitis represents a high-risk subset with worse outcomes 1
• Recurrent pancreatitis after colonoscopy has been reported, even when the procedure appears unremarkable 5
• Recent abdominal or cardiac surgery should be documented in the history 3

Genetic Factors

• Germline mutations in BRCA2, p16, ATM, STK11, PRSS1/PRSS2, SPINK1, PALB2, and DNA mismatch repair genes increase pancreatic disease risk 2
• Family history should be obtained, particularly in younger patients with recurrent episodes 3

Critical Diagnostic Approach for Unusual Causes

When to Suspect Unusual Etiologies

• No more than 20-25% of cases should be labeled as idiopathic; the aetiology should be determined in 75-80% of cases 3, 1
• At least two good-quality ultrasound examinations should be performed before labeling a case as idiopathic, as gallstones are often missed on initial imaging 3, 2

Systematic Investigation Algorithm

1. Initial phase: Document alcohol intake in units per week, detailed drug history, viral exposure, comorbid conditions (HIV, IBD), and recent procedures 3
2. Acute phase biochemistry: Measure pancreatic enzymes, liver function tests, and look for early increase in aminotransferases or bilirubin suggesting gallstones 3, 2
3. Recovery phase testing: Measure fasting plasma lipids and calcium concentrations 3, 2
4. Advanced imaging: Repeat biliary ultrasound, MRCP (97.98% sensitivity for choledocholithiasis), or CT with pancreas protocol 3, 2
5. Recurrent cases: Consider endoscopic ultrasound to detect microlithiasis, bile sampling for crystals, autoimmune markers, and sphincter of Oddi manometry in specialist units 3, 1, 2

Common Pitfalls to Avoid

• Accepting "idiopathic" diagnosis without at least two negative ultrasounds for gallstones 3
• Failing to measure calcium and lipids in the recovery phase 3, 2
• Not considering pancreatic malignancy in elderly patients with first presentation 3, 1
• Overlooking medication history, particularly recent additions or long-term therapies 3
• Missing genetic predisposition in young patients with recurrent episodes 2