Acute relapsing pancreatitis (ARP) represents a challenging clinical problem in the field of hepatobiliary and pancreatic disorders. It is associated with significant morbidity, impairment in quality of life and a negative impact on medical costs. Acute pancreatitis is a common condition with a reported yearly incidence ranging between 300 and 500 patients per million per year in the Western world.¹ Without an adequate initial work-up and directed therapy, more than half of the patients with an initial attack of acute pancreatitis may suffer recurrent attacks or develop chronic pancreatitis.²

Definitions

Acute pancreatitis is defined as typical pancreatic abdominal pain (mid-epigastric with radiation to the back) persisting for several hours, associated with elevation of serum amylase or lipase (to more than three times the normal levels).

ARP is defined as two or more well-documented separate episodes of pancreatitis (pain and abnormal laboratory studies) that resolve between attacks.³ Evidence of pancreatitis should be documented by computed tomography (CT) or magnetic resonance imaging (MRI) during at least one episode.

Acute idiopathic pancreatitis is a term used when no underlying cause has been identified.

Causes of ARP

An aetiology can be found in 70% to 80% of patients after an attack of acute pancreatitis, with alcohol abuse and gallstone disease most often implicated.⁴ Causes of ARP can be classified as follows.

Toxic/Metabolic Causes

Alcohol-induced pancreatitis is easily identified based on clinical history.

Hypercalcaemia (due to hyperparathyroidism in more than 90% of cases) and hypertriglyceridaemia (>1,000mg/dl is usually necessary) are established but rare causes of ARP^.5

Many medications have been implicated as causes of acute pancreatitis with a dose-dependent or idiosyncratic mechanism for the majority of cases,⁴ but are most often associated with a single episode of acute pancreatitis rather than ARP.

Mechanical Causes

Mechanical causes can induce a persistent or transient obstruction of pancreatic juice flow into the duodenum, with a consequent rise in intraductal pancreatic pressure. Potential causes of impaired pancreatic drainage include:

• migration of biliary stones, microlithiasis (<2mm) or biliary sludge^;3,6,7

• sphincter of Oddi dysfunction (SOD);

• anatomical congenital variations of the pancreatic ductal system and of the biliopancreatic junction; and

• acquired obstructive conditions at the level of Vater’s papilla (ampullary neoplasm), the level of the pancreatic duct (pancreatic ductal adenocarcinoma, cystic neoplasms, including intraductal papillary mucinous tumours, metastatic tumours to the pancreas, islet cell tumours of the pancreas, traumatic or post-operative disruption of the main pancreatic duct) or the level of the duodenal wall (cystic dystrophy of the duodenal wall).

Biliary sludge is defined as a suspension of cholesterol monohydrate crystals, calcium bilirubinate granules or calcium carbonate salts that can be visualised through transabdominal ultrasound (U/S) in the gallbladder (as low-level echoes that layer in the dependent portion of the gallbladder without acoustic shadowing) or detected on microscopic examination of centrifuged bile aspirated from the duodenum or from the common bile duct after cholecystokinin stimulation.^7,8 SOD is defined as benign, non-calculous partial obstruction (organic or functional) of the biliary and/or the pancreatic segment of the sphincter of Oddi, giving rise to episodic upper abdominal pain or pancreatitis.⁹ Acute Relapsing Pancreatitis ¹ Biliary or pancreatic SOD are divided into the following three types:^8,10,11

• Type 1 corresponds to patients with biliary- or pancreatic-type pain, elevation of liver function tests or pancreatic hydrolases, and dilation of the common bile duct (>12mm in diameter) or the main pancreatic duct (>5mm in diameter). Type 1 is considered to be due to a chronic inflammatory process (probably secondary to passage of biliary lithiasis or microlithiasis through the sphincter), which becomes a fibrosis with subsequent stenosis of part of or the entire sphincter.

• Type 2 is considered for patients with biliary- or pancreatic-type pain and only one other criterion (abnormal laboratory tests or ductal dilation). These patients are thought to suffer from a functional alteration of the physiological motility of the sphincter that causes some delay in the passage of biliary or pancreatic juices into the duodenum.

• Type 3 is reported for patients with only typical clinical symptoms.

Pancreas divisum (PD) is the most common congenital variant of the human pancreas occurring in 5% to 10% of Caucasian individuals.^12,13 Less than 5% of the population with PD ever develop pancreatic symptoms; subsequently, PD seems to have little clinical relevance.²

Although controversial, it is postulated that a relative outflow obstruction at the site of the minor papilla overburdened by draining of the larger dorsal pancreas may be the mechanism of pancreatitis in some patients with PD and unexplained ARP^.4,14 However, the frequency of PD is similar in control patients, patients with chronic pancreatitis and patients with idiopathic pancreatitis.^12,15

Recruitment bias (greater frequency of PD diagnosis in patients referred after unsuccessful opacification of the pancreatic ductal system) may have resulted in an overestimation of the prevalence of PD in endoscopic retrograde cholangio-pancreatography (ERCP) studies investigating suspected idiopathic ARP.¹⁶ It has been shown that a persistent dilation of the main pancreatic duct greater than 3mm at 10 minutes after secretin injection assessed during secretin-enhanced magnetic resonance cholangio-pancreatography (S-MRCP) is correlated with a clinical diagnosis of papillary stenosis.^15,17 However, the frequency of such a response to secretin suggesting a functional or organic stenosis of the major or minor papilla is the same in patients with or without PD.¹⁵ Other abnormalities that have been associated with ARP include anomalous pancreaticobiliary union, choledochocele, duodenal duplication cyst and annular pancreas^.18

An isolated, unexplained pancreatic duct stricture discovered during the work-up of a first episode of acute pancreatitis in a patient over 35 years of age without predisposing cause requires exclusion of an underlying pancreatic carcinoma.⁵

Intraductal papillary mucinous tumour (IPMT) is the most frequent neoplasm associated with ARP. It is an intraductal pre-malignant lesion producing mucin that blocks the pancreatic duct, thus impeding outflow and encouraging bouts of pancreatitis. IPMT is characterised by dilation and filling defects of the main pancreatic duct or of the branch duct system (see Figure 1).¹⁹