REVIEW

Approach to Patients With Suspected Chronic Pancreatitis A Comprehensive Review Gyanprakash A. Ketwaroo, MD, MSc, Steven D. Freedman, MD, PhD, and Sunil G. Sheth, MD

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presenting to the emergency department with abdominal pain, comprising almost 2% to 3% of all patients. These patients are often readmitted and receive frequent nondiagnostic imaging and other evaluation.4 To prevent unnecessary testing (cross-sectional imaging, endoscopic procedures) or treatment (recurrent hospitalization, intravenous [IV] hydration, narcotic analgesia, pancreas enzyme supplementation), it is thus important to diagnose CP accurately in its early stages and distinguish such patients from those with nonspecific abdominal pain. It is also important to diagnose CP as early as possible when preventive management (such as smoking cessation, alcohol abstinence, genetic counseling in select cases, monitoring for endocrine and exocrine insufficiency, and screening for cancer)5–10 as well as early multidisciplinary management of pain, nutrition, and structural complications may improve patient care and reduce costs. It was the purpose of this review to summarize the diagnostic testing available for early CP and to present a basis for our approach in evaluating patients with suspected CP.

From the Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA. Received for publication May 31, 2014; accepted September 26, 2014. Reprints: Sunil G. Sheth, MD, Division of Gastroenterology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Rabb 423, Boston, MA 02215 (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

It is postulated that CP is initiated by clinical or subclinical episodes of acute pancreatitis with the development of pancreatic cellular necrosis or apoptosis as the first hit in a 2-hit hypothesis. This initial insult occurs in a host who is genetically susceptible and is enhanced by environmental factors. The parenchymal injury associated with acute pancreatitis may heal without consequences, but in some patients, a second hit occurs with recurrent episodes leading to sustained activation of pancreatic stellate cells and the development of fibrosis. Genetic susceptibility involves mutations in regulatory proteases and ion channels, including PRSS1, SPINK1, and CFTR (cystic fibrosis transmembrane conductance regulator).11 Environmental determinants such as alcohol and smoking also have significant impact on the development and progression of earlyonset pancreatitis.11,12 This paradigm, also known as the sentinel acute pancreatitis event hypothesis, places acute pancreatitis on one end of the spectrum and CP on the other.13,14 In a population-based study of 7456 patients, Yadav et al15 showed that after an initial attack of acute pancreatitis, alcohol, smoking, and recurrent acute pancreatitis all predispose to the development of CP. Morphologically, it is thought that CP progresses from minimal patchy focal disease characterized by mononuclear infiltrate and fibrosis to a more diffuse distribution with overt signs of chronic inflammation, such as calcifications. Clinically, patients may progress from pain to a hyperglycemic state with end-stage CP characterized by calcifications and fibrosis of pancreas tissue. After CP has been initiated, its progression is variable, and patients can be asymptomatic for long periods. For instance, in autopsy studies of chronic alcoholics, 50% had fibrosis in the pancreas, but only 10% had clinical CP.16 Disease progression is also affected by environmental toxins, such as ongoing tobacco and alcohol use.17 Chronic pancreatitis can be also classified into different clinical phenotypes. Patients, especially those with cystic fibrosis, can present with CP characterized by pancreatic insufficiency without

Abstract: Chronic pancreatitis (CP) represents a significant health care burden in the United States. Diagnosing it early and accurately is important for the efficient management of these patients. However, the early diagnosis of CP, when structural and functional pancreatic changes are subtle, remains difficult. Complicating this is the large cohort of patients with nonspecific abdominal pain who are often suspected of having early CP and who utilize significant health care resources in attempts at diagnosis and management. We present a review of the current diagnostic tests available for making an early diagnosis of CP. We further report our approach to patients suspected of having CP based on the available literature. Key Words: chronic pancreatitis, early diagnosis, secretin MRCP, pancreatic function testing, endoscopic ultrasonography, histology (Pancreas 2015;44: 173–180)

hronic pancreatitis (CP) is a progressive inflammatory disease where pancreatic parenchyma is replaced by fibrous tissue leading to a loss of acinar and islet cells. The incidence of CP is increasing worldwide, and in the United States, it is estimated at 4 per 100,000 with an overall prevalence of 42 per 100,000.1 There is a significant health care burden associated with CP, with approximately 86,000 annual admissions per year in the United States. In the United Kingdom, the cost of loss of endocrine and exocrine function is estimated at £45 to 90 million and £75 million, respectively, with chronic pain associated with CP adding a further £638 million per year in health care costs.2 In addition, CP is associated with an increased mortality. In 1 study, the standardized mortality ratio was 3.6, with a 10-year survival of 70% and a 20-year survival of 45%.3 Mortality from CP is attributed to pancreatic and extrapancreatic malignancies, as well as cardiovascular complications. Reaching the correct diagnosis is easy in most patients with long-standing CP. These patients typically have structural changes of the pancreas that can be diagnosed with standard computed tomography (CT) or magnetic resonance imaging (MRI). However, the accurate diagnosis of CP in its early stages remains difficult because early parenchymal inflammatory and fibrotic changes may be subtle. The typical patient suspected of having early CP presents with chronic upper abdominal pain, worse with eating, and in whom standard cross-sectional imaging is normal. Such patients may have normal or sometimes mildly elevated serum lipase and/or amylase levels that are of no assistance in the diagnosis. These patients may or may not have risk factors for CP (history of acute pancreatitis, history of smoking, history of alcohol use, or family history of pancreatitis). On the other hand, nonspecific abdominal pain is the most common diagnosis given to patients

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NATURAL HISTORY AND PATHOGENESIS

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pain. Significant pancreas gland atrophy is often seen on imaging. Chronic calcific pancreatitis is typically found in patients with CP secondary to significant alcohol consumption and is easily identified with x-ray or CT imaging. In early CP, sometimes referred to as minimal change CP, patients often present with abdominal pain with minimal or normal imaging findings. A proportion of such patients may never develop significant structural features such as calcifications or ductal obstruction. Given this heterogeneous initiation, patchy distribution of disease, and variable progression, diagnosing early CP in the absence of overt manifestations is difficult.

DIAGNOSIS Histology Traditionally, histology has been considered the criterion standard for diagnosing CP. The most widely used scoring system grades the severity (mild, moderate, or severe) and distribution (focal or diffuse) of intralobular and perilobular fibrosis on a scale of 0 to 12.18 Mild and focal perilobular fibrosis carries a score of 1, and diffuse perilobular and intralobular fibrosis with replacement of acinar tissue receives a score of 12. A fibrosis score of 2 or more is considered abnormal.19 Other criteria that include chronic inflammation, fibrosis, and atrophy have also been described.20 Although pathology is considered the criterion standard, there are several limitations. The diagnosis can be missed even with surgical or endoscopic biopsy because early CP is a focal patchy disease, and there can also be poor agreement among pathologists.21 False-positive results have been described with the finding of mild and bland fibrosis, that is, without significant inflammation or inactive inflammation, especially in asymptomatic elderly patients, smokers, and alcohol consumers. Furthermore, autopsy data show a high prevalence of ductal and pancreatic abnormalities in patients with no overt history of pancreatic disease.22 Considering also the risk of pancreatitis from the biopsy itself, there is a significant need for noninvasive or minimally invasive diagnostic modalities.

Traditional Imaging Tests Analyzing, the structural changes of the pancreas is well validated for diagnosing late CP using standard imaging modalities such as CT, magnetic resonance cholangiopancreatography (MRCP), and endoscopic retrograde cholangiopancreatography (ERCP). However, there is no clear consensus for such diagnosis in early CP. Rather, these modalities have significantly reduced sensitivity in diagnosing early CP. For instance, although CT is fairly sensitive for advanced CP with calcifications, atrophy, fat replacement, and ductal dilation (75%–80%), its overall sensitivity for all CP is 47%, with a specificity of 90%.23 Likewise, the sensitivity of MRCP is 75% for advanced disease but as low as 25% for early CP.24 Contrastenhanced ultrasonography has been used in diagnosing advanced CP but has not been well studied in early CP.25 Findings on ERCP using a scoring system known as the Cambridge Classification had traditionally been used as the imaging criterion standard for diagnosing CP with sensitivities ranging from 75% to 90%.26,27 However, ERCP is invasive, with a high risk of complications and reduced specificity in several conditions. Consequently, for early CP, several modalities such as pancreatic function testing (PFT), secretin MRCP (s-MRCP), and endoscopic ultrasonography (EUS) have emerged as the preferred diagnostic modalities.

Biomarkers In the search for noninvasive biomarkers of CP, proteomics research appears promising.28 Groups have characterized the differential expression of pancreatic stellate cells and other proteins in pancreatic tissue and pancreatic fluid of patients with CP as

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compared with other pancreatic disease.29–31 Others have explored metabolites in urine,32 proteins in gastroduodenal fluid,33 and oxidized fatty acids34 and des-Leu albumin in serum.35 In the future, such testing may offer an important complement to the diagnosis of CP although none is currently proven effective for clinical use.

Genetic Testing Although genetic testing does not directly lead to the diagnosis of CP, it can help in identifying the etiology of CP in a select group of patients.36 In patients with a pertinent family history of pancreatitis, testing for mutations in the PRSS1 can not only secure the cause of CP, but may alter therapeutic recommendations such as total pancreatectomy with auto islet cell transplantation. Similarly, in patients with suspected CFTR dysfunction, functional analyses through sweat chloride testing or genetic sequencing may provide a clue to the etiology of CP.

Pancreatic Function Testing Diabetes is an unfortunate complication of CP and can occur in up to 26% to 80% of patients with established CP.37–39 It is estimated that 5% to 10% of all patients with diabetes in Western populations developed this due to endocrine pancreatic insufficiency.40 Duration of disease, prior partial pancreatectomy, early onset of calcific pancreatitis, and recurrent flares of pancreatitis are risk factors for developing diabetes.37,41,42 Thus although pancreatogenic diabetes may be a useful adjunctive marker of long-standing CP, it is uncommon in early CP. Indirect PFTs are often used in the workup of CP. Such tests include measuring fecal levels of fat, chymotrypsin, or elastase. However, although these fecal tests are relatively easy to perform, they are either nonspecific or positive only in more advanced disease.43

Direct PFTs Direct testing involves measuring the pancreatic output of enzymes or bicarbonate after stimulation with hormones such as cholecystokinin (CCK) and secretin. It is thought that the decrease in maximal stimulated secretory capacity precedes secretory failure (true exocrine insufficiency) in CP. Thus these tests would be the most sensitive for detecting early CP.44 In the basal state, the pancreas secretes small amounts of protein rich in mildly alkaline fluid. Meal-related stimulation of the duodenal S-cells results in the release of secretin into the blood that activates the ductal cells of the pancreas to secrete a large volume of bicarbonate-rich fluid. Similarly, stimulated duodenal I-cells secrete CCK that signals the acinar cells of the pancreas to release enzyme-rich fluid. In CP, there is a decrease in volume of bicarbonate and enzymes in response to hormonal stimulus compared with the normal pancreas.

Cholecystokinin Pancreatic Function Test Cholecystokinin testing measures the ability of the acinar cells to secrete digestive enzymes. The original CCK stimulated test was designed at the Mayo Clinic and involves using a dual collecting and perfusion system. This system perfuses the duodenum with a nonabsorbable marker (polyethlyene glycol), and the duodenal fluid output is then collected, measured, and analyzed to calculate enzyme output. In a simplified version of the test, a peak lipase concentration cutoff of 780 IU/L was able to discriminate healthy subjects from patients with CP.45 In a subsequent study, a peak lipase concentration of less than 800 IU/L was used as the threshold in 35 patients with suspected CP. In long-term follow-up, 24 of these patients were subsequently diagnosed with CP, 23 of these 24 patients had abnormal CCK-PFTs less than 800 IU/L.27 © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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Secretin PFT The secretin tests measure the ability of the ductal cells to produce bicarbonate. A blunting of ductal bicarbonate secretion in response to secretin is thought to characterize the early development of CP.46 The original or classic secretin PFT (s-PFT) is done with the double lumen Dreiling tube with gastric and duodenal ports for aspiration. A standard esophagogastroduodenoscopy is performed, and a guide wire is placed through the endoscope under fluoroscopic guidance beyond the ligament of Treitz. The endoscope is then removed, and a double-lumen gastroduodenal Dreiling tube is placed over the wire until the tip of the tube is in the third or fourth portion of the duodenum (placement is confirmed with fluoroscopy). In the recovery room, the gastric port of the Dreiling tube is connected to suction, and the gastric aspirate is discarded. Intravenous human secretin is then administered, and duodenal fluid is continuously collected in 15-minute aliquots for 1 hour. Collected samples are then placed on ice and sent to the chemistry laboratory to analyze bicarbonate concentration. A peak bicarbonate level of less than 80 meq/L is considered diagnostic of CP. Some have modified this test using endoscopically collected duodenal fluid (e-PFT) rather than by a Dreiling tube. Studies including 24 patients with CP and 12 healthy patients showed no difference in peak values between these 2 collection methods.47,48 A follow-up study found that samples collected at 30 and 45 minutes had the closest agreement with the full 60-minute test.49 Some experts suggest that traditional PFTs detect patients with as little as 30% damage to the pancreas.44 Two older studies showed significant linear correlation between peak bicarbonate level and histological severity.50,51 Others have shown that peak bicarbonate level had an overall 86% agreement with ERCP for the diagnosis of CP.52 In a retrospective study of 116 patients with suspected CP (defined as a presence of abdominal pain, normal CT/MRI/ MRCP/EUS) who underwent s-PFT, 20 had abnormal PFTs of which 9 developed radiologic or histologic evidence of CP after a median of 4 years.53 Only 2 of the 70 patients with normal PFTs developed CP after a median of 7 years. Thus, s-PFT had a sensitivity of 82%, specificity of 86%, positive predictive value of 45%, and negative predictive value of 97% in diagnosing CP with long-term follow-up. This study suggested that s-PFT is an excellent test to rule out early CP.

Endoscopic Ultrasound Endoscopic ultrasound has emerged as an important diagnostic modality for evaluating the structural integrity of the pancreas. At EUS, the normal pancreas parenchyma appears homogenous and slightly hyperechoic, whereas the pancreatic duct is a thin anechoic structure. In disease, changes in the pancreas parenchyma and ducts can be scored to predict the likelihood of CP. There are several scoring systems that include between 9 and 12 features.54 In postmortem examinations of the pancreas of elderly patients dying of nonpancreatic causes, there was a high frequency of EUS criteria correlation with histological fibrosis.55 In 41 patients with noncalcific CP, at least 3 EUS criteria had 83% sensitivity and 80% specificity for fibrosis score greater than or equal to 2.19 For every increase of EUS score by 1, the fibrosis score increased by 0.87. However, there was no subgroup analysis of early-stage CP. Thus, although these and other studies demonstrate excellent correlation between EUS and histology in advanced CP, such data remain limited in early CP. Furthermore, the clinical significance of having fewer abnormalities on EUS is not clear. In 1 large study of 489 patients who underwent EUS for nonpancreatobiliary disease, 17% were noted to have 1 EUS feature of CP, and 4% had greater than or equal to 3 criteria.56 In a study by Sahai et al,57 319 patients with dyspepsia © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Suspected Chronic Pancreatitis

or abdominal pain and 26 asymptomatic patients with no risk factor for pancreatic disease or excess alcohol consumption underwent EUS. They found that 0 to 3 criteria were seen less in symptomatic patients compared with asymptomatic patients (46% vs 80%). Varadarajulu et al58 evaluated 42 patients undergoing resection for pancreatitis or a pancreatic mass. They found an excellent correlation for standard EUS score and fibrosis score (R = 0.85). Using 4 or more criteria, EUS had a 91% sensitivity and 86% specificity for fibrosis score greater than or equal to 6, and 12 of 14 patients with an EUS score of 0 had no fibrosis. However, we cannot generalize this study to patients with early CP because patients with masses were included. Taken altogether, these studies suggest that simply having fewer abnormalities on EUS does not necessarily represent early CP. To address these issues, an international group of experts met in the village of Rosemont near Chicago, Ill, in April 2007 to design a consensus-based scoring system, assigning weight to certain previously described criteria, and to standardize the scoring system for the diagnosis of CP (Table 1).54 They thus defined both “indeterminate for” and “suggestive of ” CP categories, either of which could apply to early CP. Some experts have also classified as early CP patients with pancreatic pain; normal CT, ERCP, and secretin test results; and indeterminate CP by Rosemont EUS criteria.59 The Japanese criteria were also recently revised to include the diagnosis of early CP by EUS.60 These included 2 of 4 clinical criteria or risk factors (repeated abdominal pain, abnormal pancreatic enzymes, abnormal pancreatic function, continued heavy alcohol drinking >80 g/d) and 2 EUS features, and it was referred to as “probable/ possible CP” in the classification. However, it must be noted that neither the Rosemont classification nor the Japanese criteria have been fully validated in patients with early CP, and their use is based on expert opinion.

Secretin-Enhanced MRCP Administration of IV secretin and then performing MRCP significantly improves the quality of the MRI images for assessing the pancreas.61,62 In particular, there is dynamic visualization of changes in the pancreatic ductal system in response to stimulation for exocrine secretion. This increases the sensitivity and negative predictive value for ductal morphology to 77% to 89% and 84% to 98%, respectively, when compared with MRCP without secretin.63 Consequently, it is postulated that s-MRCP is more sensitive to changes of early CP.

Ductal Changes In healthy patients, the main pancreatic duct is less than 3 mm in diameter, tapers smoothly to the tail, distends about 66% in response to secretin, and then returns to baseline in 10 minutes. In CP due to decreased pancreatic secretion and fibrosis, there is less distension of the pancreatic duct and also better visualization of irregularities in the side branches.

Parenchymal Changes In CP, there is gradual replacement of glandular tissue by fibrous tissue. Decreased parenchymal signal is associated with loss of acinar tissue. On T1 images after IV contrast, there is decreased intensity in arterial phase and increased intensity in early venous phase in early CP. On T2 images, there is increased enhancement indicating fibrous/fatty replacement.

Volume Changes Secretin produces water and bicarbonate-rich fluid emptying in the duodenum. Secretin MRCP can provide quantification of the volume of pancreatic juice and therefore the volume measured www.pancreasjournal.com

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TABLE 1. Rosemont Criteria for Diagnosing CP Based on EUS Findings Parenchymal features Major A: hyperechoic foci with shadowing (body, tail) Major B: lobularity with honeycombing (body, tail)

Minor: lobularity, no honeycombing (noncontiguous) Hyperechoic foci with no shadowing Cysts Stranding

Ductal features Major A: MPD calculi in (H, body, tail)

Minor: irregular MPD contour Dilated side branches MPD dilation >3.5 mm in the body, >1.5 mm in the tail Hyperehoic duct margin

Consistent with CP: 1 major A + ≥3 minor or 1 major A + major B or 2 major A. Suggestive of CP: 1 major A +

Approach to patients with suspected chronic pancreatitis: a comprehensive review.

Chronic pancreatitis (CP) represents a significant health care burden in the United States. Diagnosing it early and accurately is important for the ef...
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