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Table of Contents

Published May 12, 2005

Tyler
Stevens, MD

Department of
Gastroenterology
and Hepatology

Darwin L. Conwell, MD

Department of
Gastroenterology
and Hepatology

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     Definition

     Epidemiology

     Pathophysiology

     Causes

     Signs and
     Symptoms

     Diagnosis

Grossly, the pancreas may be enlarged or atrophic, with or without cysts or calcifications. The ducts may be dilated, irregular, or strictured. Essential pathologic features include irregular and patchy loss of acinar and ductal tissue, chronic inflammation, ductal changes, and fibrosis (Figure 1).

Several important pathogenic theories have been developed, including: (1) oxidative stress, (2) toxic-metabolic, (3) stone and duct obstruction, and (4) necrosis-fibrosis.³ The primary premise of the oxidative stress hypothesis is that reactive byproducts of hepatic mixed-function oxidase activity damage the pancreas through chronic reflux of bile into the pancreatic duct. The toxic-metabolic theory is that alcohol is directly toxic to the acinar cell through a change in intracellular metabolism. This metabolic effect produces pancreatic lipid accumulation, fatty degeneration, cellular necrosis, and eventual widespread fibrosis. Proponents of the stone and duct obstruction theory postulate that alcohol increases the lithogenicity of pancreatic juice, leading to stone formation. Chronic contact of the stones with duct epithelial cells produces ulceration and scarring. Eventually, atrophy and fibrosis result from chronic obstruction of the acini. The necrosis-fibrosis theory differs from other theories in that it emphasizes that acute and chronic pancreatitis represent a spectrum of disease. Inflammation from acute pancreatitis leads to scarring and extrinsic compression of the pancreatic ductules. Obstruction results in stasis, atrophy, and stone formation.

New discoveries about hereditary pancreatitis have supported the necrosis-fibrosis sequence.⁴ The genetic defect of hereditary pancreatitis produces recurrent acute pancreatitis beginning in early childhood, almost invariably leading to chronic pancreatitis in early adulthood.

A recent, major advance in understanding of the underlying cellular mechanisms of pancreatic fibrogenesis is in the primary role of pancreatic stellate cells. Stimulated by alcohol and oxidative stress, activated stellate cells migrate to the periacinar areas to deposit collagen and fibronectin. Stellate cells are also stimulated by specific cytokines, many of which are emitted during the inflammatory phase of acute pancreatitis. Transforming growth factor beta1 has received considerable attention in recent years as an important mediator of pancreatic fibrosis. The sentinel acute pancreatitis event hypothesis for CP pathogenesis incorporates many of these recent discoveries.⁴ Its major premise is that an episode of acute pancreatitis (the sentinel event) produces an inflammatory milieu, setting the stage for attraction of collagen-secreting stellate cells.

Heavy and prolonged alcohol use is the most common cause of CP (Figure 2). In contrast to other etiologies, alcohol-related CP is associated with more severe pain, more extensive calcification and ductal changes, and more rapid progression to endocrine and exocrine insufficiency. Most patients experience recurrent episodes of acute pancreatitis for several years before CP develops. Interestingly, only a small percentage of chronic alcoholics develop CP, implying the presence of cofactors that amplify the effect of alcohol. An increased prevalence of some genetic mutations linked with pancreatitis (cystic fibrosis transmembrane regulator [CFTR], serine protease inhibitor Kazal type-1 [SPINK-1]) has been noted among patients with alcoholic CP. A high fat diet and smoking may also contribute to pancreatic disease in alcoholics. Smoking adversely affects pancreatic bicarbonate and water secretion, induces oxidative stress, and increases the rate of pancreatic calcification.

Tropical pancreatitis (TP) is endemic to certain developing regions, such as India, Africa, and South America. Episodic abdominal pain begins in childhood and is followed by rapid progression to endocrine and exocrine insufficiency. Nutritional factors such as dietary toxins (cyanogens in the cassava plant) and micronutrient deficiencies (zinc, copper, and selenium) may be involved in the pathogenesis of tropical pancreatitis.

Causes of obstructive CP include pancreatic adenocarcinoma, neuroendocrine tumors, and intrapapillary mucinous tumor. Autoimmune chronic pancreatitis is a rare but increasingly recognized condition.⁵ It is frequently associated with other autoimmune diseases such as Sjögren's syndrome and primary sclerosing cholangitis. Laboratory features include hypergammaglobulinemia and the presence of autoantibodies, including anti-lactoferrin and anti-carbonic anhydrase I and II. Imaging features include diffuse pancreatic enlargement and a narrowed pancreatic duct. The clinical and radiographic features of the disease improve rapidly with corticosteroid therapy. The pathogenesis of autoimmune pancreatitis likely relates to an immune-mediated attack on the ductal cells.

Important recent discoveries have been made in the genetic basis of pancreatic disease.

Hereditary pancreatitis is a rare, autosomal-dominant disease producing recurrent painful episodes of acute pancreatitis in childhood, leading to CP and pancreatic cancer in adulthood. The mechanism of hereditary pancreatitis has recently been elucidated: a mutation in the cationic trypsinogen gene, leading to loss of autoregulation of activated trypsin.⁴ Additionally, recent studies have demonstrated a high prevalence of CFTR gene mutations among patients presenting with idiopathic acute and chronic pancreatitis. Although 85% of cystic fibrosis patients have the severe form of cystic fibrosis, with respiratory disease and pancreatic insufficiency, the remaining 15% possess lower sweat chloride levels and may express other phenotypes, including pancreatitis. Most patients who present with pancreatitis as the sole phenotypic feature of cystic fibrosis have one or two mild CFTR mutations. Additionally, an increased prevalence of mutations has been observed among patients with idiopathic pancreatitis. The SPINK-1 gene encodes a protein that is important in the prevention of early trypsin activation.

Severe hypercalcemia is known to trigger episodes of acute pancreatitis through trypsin-mediated mechanisms and may progress to CP. Chronic renal failure is associated with an increased prevalence of CP, perhaps related to a direct toxicity of uremia on the pancreas. Hyperlipidemia and gallstones are controversial causes of CP.

Ten to 30% of patients with chronic pancreatitis possess no clear risk factors for the disease. Idiopathic chronic pancreatitis has a bimodal age presentation. Early-onset idiopathic chronic pancreatitis presents with severe abdominal pain in childhood with relatively few structural and functional changes. Late-onset idiopathic chronic pancreatitis presents in middle and late adulthood, often with minimal pain and pronounced exocrine insufficiency.

Abdominal pain occurs in 50% to 80% of cases and is responsible for most of the hospitalizations related to this illness. Pancreatic pain is dull or boring in quality and worsens after eating. The pain is located in the epigastric area and often radiates to the back. There may be associated nausea and vomiting with exacerbations of pain. Ammann and Muellhaupt described two patterns of pain.⁶ Type A pain is characterized by short, relapsing episodes lasting days to weeks, separated by pain-free intervals. Type B pain implies prolonged, severe, unrelenting pain. Pain exacerbations are not always associated with elevations of the serum amylase and lipase. Some studies have demonstrated a gradual diminishment of pancreatic pain over years.¹⁸ Although controversial, proposed clinical predictors of this "pancreatic burnout" include calcifications, exocrine insufficiency, and endocrine insufficiency.^19,20 There are several proposed pathogenic mechanisms of abdominal pain in CP, including intraductal hypertension, neural inflammation, neurohormonal changes, concomitant gastroparesis, elevated cholecystokinin (CCK) levels, and nonvisceral pain.

Gradual pancreatic fibrosis produces a steady deterioration in enzyme output, leading to steatorrhea and weight loss. Direct pancreatic function testing (PFT) detects subtle changes in exocrine function early in the course of CP; however, clinically apparent steatorrhea does not occur until 90% of pancreatic function is lost. The sudden development of steatorrhea may suggest main pancreatic duct obstruction by inflammatory strictures or cancer. Endocrine insufficiency does not occur until late in the disease course. Pancreatic diabetes requires insulin and is typically brittle because of concomitant glucagon deficiency. Weight loss in CP is multifactorial, related to maldigestion, fear of eating, anorexia, nausea, and vomiting. Severe or rapid weight loss is a red flag for pancreatic cancer.

Complications (Table 1)
Chronic pseudocysts are benign cysts formed of pancreatic fluid and surrounded by a fibrous wall. The pathogenesis of pseudocysts in CP is thought to be ductal obstruction leading to upstream dilation and cyst formation. Endoscopic retrograde cholangiopancreatography (ERCP) may show communication of the cyst with the main pancreatic duct. The typical clinical presentation of a pseudocyst is worsening abdominal pain in the setting of known CP, with or without mild elevation in the serum amylase and lipase. Biliary obstruction and gastric outlet obstruction may occur due to compression of the bile duct and duodenum from severe fibrosis, enlarging pseudocysts, or pancreatic cancer. Pancreatic adenocarcinoma contributes substantially to mortality, developing in 4% of patients with long-standing CP. The diagnosis may be difficult but should be suspected in the setting of worsening abdominal pain, weight loss, or functional decline. Imaging tests often produce uncertainty in differentiating cancer from inflammatory masses, and brushings are frequently nondiagnostic. Definitive diagnosis might not be made until the time of surgical resection.

Pancreatic fistulas, ascites, and pleural effusions arise from a communication of pancreatic pseudocysts with adjacent cavities or from disruption of the pancreatic ducts. The diagnoses of pancreatic ascites and pleural effusions are based on the finding of elevated fluid amylase content. Endoscopic stent placement across the pancreatic duct disruption may ameliorate these complications. Splenic vein thrombosis is common and usually asymptomatic; however, recurrent bleeding from secondary gastric varices develops in some patients.

Imaging tests are frequently employed in the diagnostic workup of CP.^7,8 Although late-stage CP is often readily apparent on imaging tests, the diagnosis of early ("minimal change") CP is more challenging. When results of standard noninvasive imaging tests are negative, ERCP and endoscopic ultrasound (EUS) offer improved sensitivity for early disease at the cost of increased risk. When imaging test results are negative, pancreatic function tests are helpful to confirm or rule out the presence of pancreatic insufficiency as a surrogate marker of early CP. A brief discussion of the various imaging and functional diagnostic modalities follows (Table 2).

Contrast CT with thin cuts through the pancreas is a reliable test for diagnosis of advanced CP. The cardinal CT features of CP are pancreatic atrophy, calcifications, and main pancreatic duct dilation (Figure 3). Using these criteria, CT has sensitivity for advanced CP of 74% to 90% and specificity of 84% to 100%. Additionally, CT allows detection of CP complications including pseudocysts, splenic artery pseudoaneurysm, and biliary obstruction. The finding of pancreatic head enlargement may suggest pancreatic cancer or an inflammatory mass.

ERCP is a highly sensitive radiographic test for CP (sensitivity 71% to 93%; specificity 89% to 100%).⁹ The Cambridge classification grades ERCP changes from equivocal (class I) to severe (class IV) (Figure 4, Table 3). Although ERCP is considered sensitive for early CP, the finding of small-duct changes is not completely specific for CP because they may also be seen in old age or in resolving acute pancreatitis. As with most diagnostic tests, studies comparing ERCP to histology (the true gold standard) are lacking. Additionally, ERCP carries a 5% to 10% risk of acute pancreatitis. In recent years, the role of ERCP in diagnosis of pancreatic disease has decreased because safer and less invasive techniques have been developed.

Magnetic resonance imaging (MRI) is comparable to CT for detecting gross glandular abnormalities (atrophy, pseudocysts). Contrast-enhanced MRI may offer improved differentiation of neoplastic and inflammatory masses. Heavily T₂-weighted images produce bright enhancement of fluid-filled structures including the pancreatic duct (MR-cholangiopancreatography [MRCP]), allowing a noninvasive alternative to ERCP for imaging the pancreatic duct (Figure 5).

EUS is a minimally invasive test that allows simultaneous assessment of ductal and parenchymal structure. Eleven EUS criteria have been used to diagnose CP (Table 4). An EUS score cutoff of five criteria has been found to have good sensitivity and specificity for CP.¹⁰

Because plain films and transabdominal ultrasound are highly specific, inexpensive, and noninvasive, they are reasonable screening tests. Unfortunately, they lack sensitivity, particularly for early and moderate disease. The finding of pancreatic calcifications on abdominal plain film is nearly 100% specific but poorly sensitive (30% to 70%) for the diagnosis of CP (Figure 6). In patients with thin bodies, transabdominal ultrasound may detect parenchymal and ductal features suggestive of CP (sensitivity 60% to 70%, specificity 80% to 90%). Ultrasound also helps in ruling out other causes of abdominal pain such as gallstones.

PFTs are useful for the evaluation of steatorrhea or to diagnose exocrine insufficiency. Direct PFTs require placement of double-lumen, gastroduodenal tubes for pancreatic fluid collection after intravenous CCK or secretin stimulation (Figure 7). Pancreatic fluid is subsequently analyzed for enzyme and bicarbonate production. Direct tests are sensitive for early CP because they detect subtle changes in pancreatic function before the development of overt steatorrhea. Because of the cumbersome nature of placing gastroduodenal tubes, direct PFTs are not widely available. It is hoped that newer endoscopic PFT methods will increase availability of these valuable tests (Figure 8).¹¹

Several noninvasive, indirect tests of pancreatic function are also available, including fecal fat analysis, fecal chymotrypsin, and fecal elastase.¹ The bentiromide tests and pancreolauryl tests are no longer available in the United States. These tests are sensitive for moderate and late-stage exocrine insufficiency but lack sensitivity for early disease.

Three components are essential to the optimal management of CP: (1) control of pain, (2) improvement of maldigestion, and (3) management of complications.

Abdominal Pain
The management of chronic pancreatic pain is challenging. The American Gastroenterological Association (AGA) has published an evidence-based technical review on the management of pain in CP.¹² In this review, the available medical, endoscopic, and surgical techniques for pain control are critically evaluated in the context of existing literature. The following paragraphs reflect these guidelines.

Some have advocated "supportive therapy" for abdominal pain on the premise that fibrosis and scarring ultimately progress to pancreatic burnout and spontaneous relief of pain. Although long-term improvement in pain is observed in some patients with CP, a significant subset continues to experience debilitating pain for decades.¹³ The AGA technical review states "a strategy of waiting for spontaneous pain relief is not reliable and may be unreasonable advice for the patient with persistent, severe pain."¹²

The AGA technical review discusses several medical options for pain relief, including abstinence from alcohol, analgesics, and pancreatic enzymes. Abstinence from alcohol is critical because continued use may hasten disease progression, aggravate chronic pain, and increase mortality. Non-narcotic analgesics (nonsteroidal anti-inflammatory agents, acetaminophen, and tramadol) are the next step in management of painful CP. If pain persists, low doses of mild narcotics (codeine 15 to 60 mg/day or propoxyphene 65 to 260 mg/day) may be added. Severe or recalcitrant pain may warrant the use of stronger opiates in select cases.

Pancreatic enzymes are presumed to improve pain by suppressing CCK release from the duodenum, leading to decreased pancreatic stimulation. The AGA review critically appraises the literature regarding the controversial use of enzymes for pain.¹² A meta-analysis of six randomized placebo-controlled trials did not reveal a statistically significant benefit for supplemental pancreatic enzyme therapy for pain relief; however, there was substantial methodologic variability among the included trials.¹⁴ Uncoated preparations may work better by enhancing delivery to the proximal small bowel. Uncoated pancreatic enzymes may be worth trying in all patients because of their safety and minimal side effects; however, the AGA technical review cautions that "additional studies are required to establish the effectiveness of this modality of treatment and to define whether certain subsets are more likely to benefit from enzyme therapy."¹²

Interestingly, many patients with CP have nonvisceral pain (central or somatosensory in origin).¹⁵ A differential nerve blockade (DNB) is helpful in determining whether there is a central or somatosensory component to the pain syndrome. A differential nerve blockade is indicated for any patient with pancreatic pain that does not respond to simple medical therapeutic measures such as non-narcotic analgesics and enzymes. Antidepressants, anticonvulsants (gabapentin), topical therapy, and psychiatric counseling may be of use for patients with nonvisceral pain. Nerve blockade may be used for select patients with visceral pancreatic pain. Limited studies suggest that a subset of patients obtain significant short-term pain relief from CT-guided celiac plexus blockade. EUS-guided celiac plexus blockade has recently emerged as an effective alternative, with a more prolonged duration of effect.¹⁶

It is generally accepted that pain in CP may result in part from obstruction of the main pancreatic duct from stones and strictures, leading to increased ductal and parenchymal pressure. Because obstruction contributes to pain, patients with "large-duct" CP may benefit from endoscopic or surgical duct-decompression therapy. Endoscopic techniques include biliary and/or pancreatic sphincterotomy, removal of pancreatic duct stones, and placement of pancreatic stents.

Several surgical options exist for select patients with pain resulting from CP. In patients with a dilated main pancreatic duct, a side-to-side pancreaticojejunostomy (Puestow procedure) may be performed. Most studies of surgical and endoscopic decompressive therapy in CP have revealed good short-term but poor long-term pain control. The AGA technical review states that these procedures are best performed based on "need for long-term narcotic therapy, marked diminution of the quality of life because of intractable pain, or major nutritional consequences of pain."¹²

Pancreatic resection is reserved for patients with small-duct disease and pain unresponsive to medical therapy. The Whipple procedure and distal pancreatectomy have been used in the past for treatment of patients with small-duct CP. Newer resection techniques offer substantial relief of pain related to an inflamed and scarred gland, with preservation of surrounding structures. For example, the Beger procedure involves resection of the inflamed pancreatic head with careful sparing of the duodenum; the Frey procedure adds a longitudinal duct decompression to the pancreatic head resection. The AGA technical review cites several potential drawbacks of resection procedures, including: (1) paucity of randomized trials, (2) loss of exocrine and endocrine function including diabetes (3) technical expertise required for organ-sparing methods, and (4) lack of pain relief in some patients, even after total pancreatectomy.¹² In spite of these drawbacks, resection may offer significant relief to a subset of carefully chosen patients, particularly if performed in high-volume centers.

The AGA medical position statement for treatment of pain in CP provides a stepwise algorithm for use of the above-stated therapeutic modalities.¹²

Maldigestion
Pancreatic enzymes are used for treatment of maldigestion in CP. Exogenous pancreatic enzymes are safe, well tolerated, and produce few side effects. There are a multitude of available pancreatic enzyme preparations (Table 5); they differ based on enzyme content, the use of microspheres versus microtablets, and the presence of a coating for delayed release. Lipase is the most important determinant of the effectiveness of individual preparations. A minimum of 30,000 USP units of lipase per meal allows adequate intraluminal digestion of fat and protein in most patients. The dose may need to be titrated to as much as 60,000 to 80,000 USP units lipase per meal because not all the lipase may reach the proximal small intestine in active form. Enzymes may be taken entirely at the onset of each meal; however, dosing is more physiologic if one-half the amount is taken at the onset and one-half approximately 15 minutes into the meal.

Because the enzyme "microspheres" contained in most coated preparations are typically released too distally in the small bowel, uncoated preparations are optimal for management of maldigestion. Alternatively, patients may break open coated capsules and sprinkle the microspheres over food to ensure proper delivery to the proximal bowel. Because uncoated preparations are more easily denatured by gastric acid, acid suppression with either a proton-pump inhibitor (eg, omeprazole 20 mg once daily) or histamine-receptor antagonist (eg, famotidine 20 mg twice daily) is required.

Response to enzyme therapy may be monitored through an assessment of symptoms or, more objectively, through 72-hour stool fat quantification. A poor response to pancreatic enzymes may suggest one of several possibilities (Table 6). A daily proton-pump inhibitor may be added for those refractory to therapy because gastric acid may denature exogenous enzymes. A general approach to treatment of maldigestion in CP is shown in Figure 9.

Management of Complications
Large or symptomatic pseudocysts may be drained endoscopically through transmural or transpapillary approaches (Figure 10). Large pseudocysts may also be definitively drained surgically through cyst-gastrostomy. Biliary and gastric outlet obstructions are best managed through surgical decompression. Complications of pancreatic duct disruption or fistulae (pancreatic ascites or pleural effusions) are managed by prolonged pancreatic rest (parenteral nutrition) and endoscopic placement of pancreatic duct stents.

The Cleveland Clinic Approach
Because of the significant challenges inherent in the management of this disease, we have developed a multidisciplinary approach¹⁷ that is similar to the AGA algorithm.¹² Patients first undergo a diagnostic and staging evaluation (Figure 11). Most patients undergo CT and/or MRCP to evaluate the pancreatic ducts and parenchyma. Secretin-stimulated direct PFT, ERCP, and EUS are used as second-line tests to diagnose early CP in patients in whom initial imaging is negative.

Once the diagnosis of CP has been established, patients with severe pancreatic pain refractory to initial conservative management are referred for a differential nerve blockade to clarify the origin of their pain syndrome (Figure 12). Patients with nonvisceral pain are referred for psychotherapy and chemical dependency treatment. Patients with visceral pain are first given a trial of conservative medical management. If pain persists, patients with large-duct disease or pseudocysts are referred for surgical management or endoscopic therapy. Patients with small-duct disease are referred for anesthesia pain management for a visceral pain block. Minimal-change disease that fails to respond to nerve blocks may be considered for resection or experimental drug trials. Patients who fail to improve with these medical and surgical therapies may benefit from thorascopic splanchnicectomy.

Return to Medicine Index

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