Recurrent acute pancreatitis: a harbinger for irreversible chronic pancreatitis

Figures & data

Figure 1. Progression of AP to CP via RAP and ECP.

Table 1. Causes of RAP, categorized by the TIGAR-O system. CFTR = Cystic Fibrosis Transmembrane conductance Regulator, SPINK-1 = serine protease inhibitor kazal-type 1, PRSS1 = protease serine 1, IBD = inflammatory bowel disease, SLE = systemic lupus erythematosus.

Category	Causes	Clinicopathologic context and comments
Toxic/metabolic	Alcohol	Higher incidence with heavy or binge pattern drinking Up to 38% of AP cases due to alcohol consumption will be followed by recurrent episodes
	Cigarette smoking	Independent, dose dependent risk factor for both RAP and CP
	Hypercalcemia	Ductal obstruction and injury affect acinar cell calcium signaling and inappropriate intracellular Ca accumulation Hypercalcemia seen in primary hyperparathyroidism is a rare cause of AP and RAP
	Hypertriglyceridemia	Attributed to accumulation of free fatty acids which causes downstream lipotoxicity and acinar cell damage by various inflammatory pathways Typically noted at TG level >1000 mg/dl and may have additional risk factors Patients noted to have more severe disease and higher likelihood of persistent organ failure
	Medications	At least 120 different drugs are thought to be associated with development of AP Azathioprine and Didanosine appear to have a causal relationship.
	Organotin compounds	Industrial bactericides and fungicides have been shown to cause pancreatic ductal epithelial injury and cellular mitochondrial damage in animal studies.
Idiopathic (typically chronic) Pancreatitis	Early onset	<35 years old Long, painful disease course
	Late onset	>35 years old Mild, even painless disease course
	Tropical	Younger patients in temperate zones Malnutrition may play a role Many have genetic mutations listed below
Genetic	CFTR	Ion channel dysfunction leading to impaired epithelial fluid transport in many organs including lung and pancreas Reduced level of CFTR function noted in all forms of pancreatitis Correcting CFTR function could be novel therapeutic approach
	SPINK-1	Encodes a trypsin inhibitor which in mutated forms leads to trypsinogen autoactivation and resultant damage Typically young patients in their 20s 15–40% of cases of idiopathic pancreatitis
	PRSS1	Variants increase intrapancreatic trypsin by autoactivation or by inhibiting chymotrypsin C dependent trypsinogen degradation Some variants confer higher risk of pancreatic cancer
Autoimmune	Type 1 autoimmune pancreatitis (AIP) – IgG4-related	IgG4 over twice normal level Pancreatic manifestation of multiorgan disease including retroperitoneal fibrosis, thyroiditis, chronic peri-aortitis Can present with obstructive jaundice with long ductal strictures Rapid (<2 weeks) response to steroids
	Type 2 AIP	Pancreas is only organ affected although associated with Ulcerative Colitis Neutrophilic infiltration of medium and small pancreatic ducts. Rapid (<2 weeks) response to steroids
	Lupus-associated pancreatitis	1–5% of lupus patients with higher disease activity scores and multiorgan involvement Cautious use of steroids Consider plasma exchange
Obstructive	Pancreatic divisum	Majority of patients with this anatomical variant are asymptomatic A small minority of patients with RAP and this variant may be offered minor papilla therapy with sphincterotomy and/or stenting via ERCP
	Functional Pancreatic sphincter dysfunction	Biliary colic type pain post cholecystectomy and recurrent pancreatitis Sphincterotomy appears to be of limited benefit. Drugs such as CCBs, tricyclics, SNRIs, botulinum injections have been attempted.
	Cholelithiasis	Among Most common causes of RAP Pregnancy, Native American ethnicity are risk factors Early Cholecystectomy is recommended.
	Intraductal papillary mucinous neoplasm (IPMN)	Rate of AP in IPMNs range from 12% to 67% Recommendations for resection in setting of AP remains controversial.
	Pancreatic cancer	Weight loss is typical Therapy for cancer drives management
	Duodenal duplication cyst	Most cases diagnosed in infancy/childhood and can present with obstructive symptoms Surgical excision and/or drainage procedures are recommended.
	Juxtapapillary diverticulum	May presented with primary choledocholithiasis, recurrent ascending cholangitis or RAP Combined surgical and endoscopic treatments can be curative.
	Microlithiasis	Term sometimes used interchangeably with biliary sludge although latter’s crystals are microscopic in nature. Endoscopic Ultrasound is very helpful in patients who have gallbladder. Laparoscopic cholecystectomy recommended.
	Post-traumatic pancreatic duct scars	Requires careful assessment and planning in tertiary care centers as therapeutics themselves can lead to further scarring and RAP
	IBD	Rare extraintestinal manifestation of Crohn’s disease Needs to be differentiated from IBD medication (e.g. azathioprine, 5-ASA) associated disease

Figure 2. Proposed pathway to evaluate RAP. Genetic testing is particularly indicated if there is a family history of acute pancreatitis and young age of presentation; other indicators for IgG4 testing (other than HISORt criteria) include diffuse enhancement, capsular enhancement or multiple duct strictures. It is also worth noting that endoscopic ultrasound is the imaging modality of choice in patients with single or recurrent idiopathic acute pancreatitis [27].

Somani P, Sunkara T, Sharma M. Role of endoscopic ultrasound in idiopathic pancreatitis. World J Gastroenterol. 2017 [cited 2024 Apr 24];23(38):6952. doi: 10.3748/wjg.v23.i38.6952

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