Endoscopy in the management of chronic pancreatitis

CLINICAL UPDATE American Society for Gastrointestinal Endoscopy Editor: Grace Elta, MD

ISSN 1070-7212

Vol. 13, No. 1 July 2005

Commentary Chronic pancreatitis is a chronic inflammatory disorder characterized by intermittent or continuous abdominal and/or back pain, eventual exocrine and endocrine insufficiency, and complications ranging from biliary strictures and pancreatic pseudocysts to pseudoaneurysms of related arteries. The goals of pancreatic endotherapy include relief of chronic pain from pancreatic duct (PD) obstruction (secondary to stones, strictures, papillary stenosis, and anatomic abnormality), stent placement for ductal disruptions, and treatment of related complications, including biliary obstruction and pseudocysts. John Baillie, MD, discusses the indications for endoscopic intervention in chronic pancreatitis patients. Grace Elta, MD Editor

ENDOSCOPY IN THE MANAGEMENT OF CHRONIC PANCREATITIS John Baillie, MB, ChB, FRCP Duke University Medical Center Durham, North Carolina

The principal endoscopic procedure for patients with chronic pancreatitis is ERCP.1 EUS is a less invasive technique that is increasingly used as an alternative to ERCP for investigating pancreatic abnormalities. EUS provides accurately targeted FNA for a cytologic diagnosis of masses and cystic lesions and drainage for fluid-containing structures.2 Recently, echoendoscopes with large instrument channels have been developed to allow the placement of stents for pseudocyst drainage and to offer the possibility of performing a biopsy instead of just performing aspiration cytology of lesions. Although ERCP remains the criterion standard for imaging the pancreatic ductal anatomy, cross-sectional imaging techniques, such as helical CT and MRCP now offer noninvasive approaches to diagnosing pancreatic disease.3 MRCP after intravenous injection of syn-

thetic secretin, a gut hormone that is a pancreatic secretagogue, enhances the ductal anatomy and is especially helpful in identifying anatomic variants, such a pancreas divisum (P Div).4

PRESENTATION The principal cause of chronic pancreatitis in the United States is chronic alcohol abuse. On average, 15 to 20 years or more of regular heavy drinking are necessary to convert a normal, healthy pancreas into one that it irreversibly diseased. Although alcohol abuse is often cited as a cause of acute pancreatitis, it is doubtful if this ever occurs in the absence of underlying chronic pancreatitis (i.e., it is an acute-on-chronic disease). Rarely, hypertriglyceridemia, hypercalcemia, or chronic obstruction of the pancreatic duct (PD) can lead to

Table 1. Endoscopic interventions in chronic pancreatitis Diagnostic ERCP, including: Biopsy of ampullary masses Cytologic brushing of strictures Pancreatoscopy Pancreatic sphincter manometry Treatment of symptomatic pancreas divisum (minor papillotomy) Dilation and stent placement of benign (and occasionally) malignant PD strictures Lithotripsy and removal of PD calculi Stent placement of pancreatic fistulas Stent placement of bile-duct strictures related to chronic pancreatitis Endoscopic drainage of pancreatic pseudocysts Endoscopic Ultrasound Diagnosis of ampullary and pancreatic masses (by FNA) Diagnosis and aspiration of pancreatic cysts Chemolysis of the celiac plexus for cancer pain control PD, Pancreatic duct.

chronic pancreatitis; however, the majority of the nonalcoholic cases are idiopathic. Considerable interest has recently focused on genetic predisposition to pancreatitis, which causes familial pancreatitis, as well as an unknown number of sporadic cases.5 Patients with familial pancreatitis tend to have the onset of their disease in childhood (teens), with rapid progression to chronic disease, exocrine and endocrine failure, and pancreatic cancer. These individuals are significantly more likely (up to 100 times) to develop pancreatic cancer than the general population. Gene defects identified thus far contributing to acute and chronic pancreatitis include those involving cationic trypsinogen, the cystic fibrosis transmembrane regulator, serine protease inhibitor Kazal type 1, etc.6,7 Genetic counseling should be offered to patients before they submit to genetic testing as part of the work-up of their recurrent acute or chronic pancreatitis.

occurs in approximately 7% to 8% of Americans of European origin but in only 1% to 2% of those of African and Asia origin. A small fraction of patients with P Div suffer recurrent pancreatitis, which, inexplicably, tends to start in middle age.8 Endoscopic widening (papillotomy) of the minor duodenal papilla, through which the dominant (dorsal) PD empties, “cures” 80% or so of patients who have P Div as the cause for their acute recurrent pancreatitis. Patients who have attacks of acute pancreatitis but who also have chronic pain, do less well (perhaps 50% benefit), because they have already developed some of the changes of chronic pancreatitis. Patients who have a chronic pain syndrome only as a manifestation of their presumed chronic pancreatitis do worst of all (only 20% benefit from minor papillotomy).9

PD STRICTURES

NATURAL HISTORY OF CHRONIC PANCREATITIS

The likelihood of a PD stricture being benign vs. malignant depends on a variety of factors, including prior history (e.g., does the patient have a long history of recurrent attacks of pancreatitis?), systemic symptoms (significant weight loss raises suspicion of cancer), age (cancer unlikely under 30 years), etc. However, in any adult with a PD stricture whose cause is unknown or uncertain, cancer must be suspected and either confirmed or excluded.10 PD strictures can be brushed endoscopically for cytology, and EUS can be performed to look for and to sample masses seen in association with strictures. Neither form of sampling has 100% sensitivity; sometimes the diagnosis of cancer is only made from a surgical resection specimen. It sometimes is necessary to recommend major surgery (e.g., pancreaticoduodenectomy) to a patient in the absence of histologic or cytologic confirmation of malignancy, because of serologic data (e.g., elevated carbohydrate-associated antigen 19-9), worrying systemic symptoms, or even just a strong “hunch” that a stricture is behaving like a cancer. The radiologic finding of an enlarged pancreas (e.g., by CT) and subtle ductal irregularities (on ERCP) is typical of autoimmune pancreatitis (AIP),11 a diagnosis that should be considered before assuming malignancy is present. Patients with AIP typically have other rheumatologic disorders, ranging from sicca syndrome to systemic lupus erythematosus, and a third to a half have elevations of serum immunoglobulin G subclass 4.12 The importance of diagnosing

Although chronic pancreatitis may develop without symptoms, this is not typical. Most patients have recurrent attacks of acute pancreatitis that progress to chronic damage. Initially, they may be asymptomatic between attacks, but, as the changes of chronic disease evolve, patients often develop continuous epigastric or low thoracic back pain. One of the aims of endoscopic therapy is to intervene before the onset of chronic disease and its symptoms (principally pain). Similarly, surgery for pancreatic disease is best performed before chronic disease has become established. There is as old saying that “surgeons are too quick to intervene in acute pancreatitis, and too slow in chronic pancreatitis.” There is more than a grain of truth to this statement! Most endoscopic interventions in chronic pancreatitis are “trials of therapy”: if they fail, percutaneous drainage procedures and surgery are the “fall back” positions.

INDICATIONS FOR PANCREATIC ENDOTHERAPY Pancreas divisum Embryologically, the pancreas develops from two buds that arise from the primitive foregut and fuse in the early weeks of fetal development. Failure of fusion of these buds results in two separate and distinct parts of the pancreas (dorsal and ventral), each with its own drainage system (P Div). This abnormality

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tion, trauma, or surgery often results in a communication between the pancreas and the skin (pancreaticocutaneous fistula), internal cavities (lesser sac, pleural cavities, pericardium), and the peritoneal cavity (causing pancreatic ascites).17 Detection of high levels of amylase or lipase activity in fluid aspirated from a suspicious collection confirms the diagnosis. The fistulas themselves are hard to detect by cross-sectional imaging techniques, such as CT or MRCP; ERCP is the best way to demonstrate these often subtle abnormalities. However, in the setting of a complete ductal disruption, endoscopic pancreatography typically shows a blockage but not what is “upstream.” MRCP is an excellent way to see what is “beyond” a PD disruption, because its T2-weighted images identify fluidfilled structures. Transpapillary therapy (e.g., stent placement, nasopancreatic drainage) is rarely effective in the management of PD disruption, but, if a fistula coming off an otherwise intact duct is identified, these maneuvers may allow it to close. Because patients typically do not tolerate nasopancreatic drainage for more than a few days, stent placement is the usual approach. If the fistula leads to an established collection, such as a pseudocyst, endoscopic management of the fistula needs to be followed by endoscopic or percutaneous aspiration/drainage of the collection. Failure of these approaches leaves only surgery to “fix” the problem, usually by drainage of the collection into a loop of bowel (cystenterostomy). Pancreatic exocrine secretion may be minimized by enteral feeding beyond the duodenojejunal junction (ligament of Trietz) and synthetic somatostatin analog (Octreotide) 50-100 µg administered two or 3 times daily by subcutaneous injection. Pancreatic stents placed in an effort to heal PD fistulas should be left in place until the desired affect has been achieved or it becomes obvious that they are not helping (typically, within 1-2 weeks).

AIP is that it is potentially treatable with systemic corticosteroids. Patients whose PD strictures are presumed to be benign from the history (of a clear cause), or from long duration without change, or repeated negative histologic or cytologic sampling, can be stented to assess the effect on symptoms and on he radiologic appearances. Tight strictures may need to be dilated before stent placement. Pancreatic stents should not be left in place indefinitely, because they will eventually occlude, causing obstruction and, frequently, sepsis. Typically, they are removed after 1 to 3 months and the PD is reimaged. Repeated stent placement, sometimes with progressively larger diameter (or multiple) stents, may be performed over a prolonged period. However, if the stricture shows no sign of resolution with endotherapy, surgery usually is required. Expandable metal mesh stents have been used by a few investigators (mainly European) to treat benign PD strictures.13 One U.S. group has used them to facilitate subsequent surgery in patients with P Div who have chronic pain unresponsive to minor papillotomy.14 The stents progressively enlarge small dorsal ducts until the ducts are large enough for a surgeon to undertake a lateral drainage procedure. In the present state of development of expandable metal mesh stents, they cannot be recommended for routine use in benign pancreatic disease. Such interventions should only be undertaken in the setting of a controlled clinical trial. Biliary stents frequently are used to bridge strictures in pancreatic head cancers, but, in general, obstructed PDs are not stented in this disease. However, stent placement has been reported as useful in managing steatorrhea and pain in selected pancreatic cancer patients whose symptoms appear directly related to PD obstruction.

PANCREATIC STONES

BILE-DUCT STRICTURES COMPLICATING CHRONIC PANCREATITIS

Stones may be found to be obstructing the PD, located upstream from (proximal to) a stricture or within a related cavity, e.g., a pseudocyst.15 The exact etiology of PD stones is unclear: one theory holds that PD calculi are “epiphenomena,” reflecting poor flow through the duct system, while another considers them to be the primary pathology. Pancreatic stones may calcify, rendering them visible on plain abdominal radiograms. Although such “pancreatic calcification” used to be considered parenchymal, modern imaging has shown that these densities represent calcified stones within the PD or its branches. Pancreatic calcification is common in hereditary pancreatitis and typically is seen at a much younger age than in alcoholics with CP. Stone extraction after pancreatic sphincterotomy is technically difficult but may relieve symptoms (such as recurrent attacks of acute pancreatitis) in a subset of patients. Extracorporeal shockwave lithotripsy (ESWL) and contact lithotripsy (e.g., electrohydraulic lithotripsy) deed, after successful ESWL, it may be unnecessary to repeat ERCP to remove the stone fragments, which often pass spontaneously.16 Unfortunately, despite studies showing some symptomatic improvement after endoscopic PD stone clearance, the recurrence rate is high. The alternative to endotherapy is surgical drainage of the PD by pancreaticojejunostomy (modified Puestow procedure).

Endoscopic stent placement is an excellent way to palliate distal bile-duct strictures that are complicating chronic pancreatitis.18 Although historically this intervention has been regarded as temporizing (on the way to surgery), there have been reports of long-term benefits from endotherapy. Because alcoholics with chronic pancreatitis have an increased risk of pancreatic cancer, all biliary strictures in this setting should be regarded as malignant until proved otherwise.

PSEUDOCYSTS Although often considered a complication of only acute pancreatitis, pseudocysts can be seen in chronic pancreatitis, too. They may develop after obstruction to a PD side branch (from inflammation or a stone) or after an attack of acute-onchronic pancreatitis. The diagnosis of a pseudocyst must be questioned if there is no antecedent history of pancreatitis: cystic neoplasms of the pancreas (e.g., serocystic [microcystic], mucinous cystic), intrapancreatic mucin-secretin tumors, cystic neuroendocrine tumors, and adenocarcinomas and lymphomas undergoing cystic degeneration must be considered in the differential diagnosis. EUS is very useful in this respect. Aspiration of cyst contents for cytology, staining for mucin and assay for amylase and tumor markers (such as carcinoembryonic antigen) helps distinguish pseudocysts from cystic lesions masquerading as pseudocysts. In cases of doubt, surgical resec-

PANCREATIC FISTULAS Disruption of the pancreatic ductal system from inflamma-

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tion of the affected area of pancreas may be necessary to confirm the diagnosis. Endoscopic cyst gastrostomy and cyst enterostomy are wellestablished techniques for managing pseudocysts, with reported success rates of 60% to 80%.19 The complication rate of these procedures is not insignificant, however, at around 15%. The most feared complication is uncontrollable hemorrhage, either from varices in the wall of the pseudocyst or an undiagnosed arterial pseudoaneurysm within. EUS performed before endoscopic drainage allows the optimal “target area” to be identified.

CONCLUSIONS Diagnostic and therapeutic ERCP and EUS have major roles to play in the management of chronic pancreatitis and its complications (Table 1). Undoubtedly, these roles will increase with technologic development and refinement of endoscopes and their accessories. Minimally invasive surgical techniques that use endoscopes may one day replace the much more invasive “open” surgeries currently used in chronic pancreatitis. Laparoscopic resection of the pancreatic tail for cystic lesions is already being performed in specialist centers. EUS-targeted therapies are still in their infancy but promise to add much to the treatment of chronic pancreatitis and pancreatic cancer. Crosssectional imaging techniques, such as helical CT and MRCP, are rapidly taking the place of diagnostic ERCP, but therapeutic ERCP still has an important role to play in the management of chronic pancreatitis and its complications.

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