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EUS pancreatic function testing and dynamic pancreatic duct evaluation for the diagnosis of exocrine pancreatic insufficiency and chronic pancreatitis

      Background and Aims

      EUS and endoscopic pancreatic function tests (ePFTs) may be used to diagnose minimal-change chronic pancreatitis (MCCP). The impact of evaluation for exocrine pancreatic insufficiency (EPI) and real-time assessment of EUS changes after intravenous secretin on the clinical diagnosis of MCCP is unknown.

      Methods

      Patients with suspected MCCP underwent baseline EUS assessment of the pancreatic parenchyma and measurement of the main pancreatic duct (B-MPD) in the head, body, and tail. Human secretin 0.2 μg/kg was given intravenously followed 4, 8, and 12 minutes later by repeat MPD (S-MPD) measurements. Duodenal samples at 15, 30, and 45 minutes were aspirated to assess bicarbonate concentration. Endoscopists rated the percentage clinical likelihood of chronic pancreatitis (1) before secretin; (2) after secretin but before aspiration; and (3) after bicarbonate results.

      Results

      A total of 145 consecutive patients (mean age, 44±13 years; 98 females) were diagnosed with EPI (n = 32; 22%) or normal exocrine pancreatic function (n = 131, 78%). S-MPD/B-MPD ratios in the tail 4 and 8 minutes after secretin were higher in the group with normal exocrine function. Ratios at other times, locations, and duodenal fluid volumes were similar between the 2 groups. A statistically significant change in the median percentage likelihood of chronic pancreatitis was noted after secretin in all groups. The sensitivity and specificity of EPI for the EUS diagnosis of chronic pancreatitis (≥5 criteria) were 23.4% (95% confidence interval, 12.3-38.0) and 78.6% (95% confidence interval, 69.1-86.2), respectively.

      Conclusion

      Real-time EUS findings and ePFTs have a significant impact on the clinical assessment of MCCP. The diagnosis of EPI shows poor correlation with the EUS diagnosis of MCCP. (Clinical trial registration number: NCT01997476.)

      Graphical abstract

      Abbreviations:

      AP (anteroposterior), B-MPD (baseline main pancreatic duct diameter), CI (confidence interval), ePFTs (endoscopic pancreatic function tests), EPI (exocrine pancreatic insufficiency), EUS-CP− (absence of EUS diagnosis of chronic pancreatitis), EUS-CP+ (EUS diagnosis of chronic pancreatitis), MCCP (minimal-change chronic pancreatitis), MPD (main pancreatic duct), PBC (peak bicarbonate concentration), S-MPD (secretin main pancreatic duct diameter), sEUS (EUS after secretin stimulation), sPFTs (secretin-stimulated endoscopic pancreatic function tests)

      Introduction

      Chronic pancreatitis is an irreversible, fibrosing disease caused most commonly by chronic use of alcohol or tobacco, genetic predisposition, and recurrent acute pancreatitis.
      • Majumder S.
      • Chari S.T.
      Chronic pancreatitis.
      Symptoms almost always include pain, and later exocrine pancreatic insufficiency (EPI) with malabsorption may occur with progressive fibrosis. The diagnosis of chronic pancreatitis with extensive calcifications, gland atrophy, or pancreatolithiasis is relatively straightforward. However, early or minimal-change chronic pancreatitis (MCCP) is more difficult to detect due to a lack of radiologic findings, laboratory parameters, and classic symptomatology. Additional diagnostic tools to permit accurate early detection before extensive fibrosis of the pancreas would be a major advance.
      The use of EUS for the diagnosis of chronic pancreatitis has historically used parenchymal and ductal abnormalities
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      Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis.
      with diagnostic certainty increasing as more abnormalities are identified. More recently, the Rosemont classification was proposed giving greater weight to some EUS features and assigned major and minor criteria for the diagnosis.
      • Catalano M.F.
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      EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification.
      However, the use of EUS for diagnosing chronic pancreatitis does have some limitations. First, it is generally accepted that ≥5 EUS features maximizes specificity for the diagnosis but certainty remains less clear in patients with fewer features.
      • Sahai A.V.
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      Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography.
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      Second, although EUS findings are speculatively correlated with a histologic abnormality, it is unclear which feature is pathologic or seen in normal human aging.
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      Third, the relative value of assigning more importance to any EUS criteria remains doubtful over the traditional scoring system.
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      Multicenter comparison of the interobserver agreement of standard EUS scoring and Rosemont classification scoring for diagnosis of chronic pancreatitis.
      Finally, interobserver agreement for the diagnosis among experts assessed retrospectively using videotaped examinations remains poor.
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      The reliability of EUS for the diagnosis of chronic pancreatitis: interobserver agreement among experienced endosonographers.
      Hormone-stimulated pancreatic function tests (PFTs) to evaluate for EPI have long been considered the nonhistologic reference standard for the diagnosis of chronic pancreatitis. Traditionally, these were performed by aspirating fluid from the small bowel after insertion of a double-lumen (Dreiling) collection tube.
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      However, use of this tube has largely been replaced by endoscopic PFTs (ePFTs), which use intravenous sedation and a gastroscope to improve patient comfort. Currently used secretin-stimulated endoscopic pancreatic function tests (sPFTs) collect duodenal fluid at timed intervals for at least 45 minutes after hormone administration
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      • et al.
      The efficiency of endoscopic pancreatic function testing is optimized using duodenal aspirates at 30 and 45 minutes after intravenous secretin.
      and use a peak bicarbonate concentration (PBC) of ≤80 mEq/L to diagnose EPI.
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      • et al.
      Cholecystokinin-stimulated peak lipase concentration in duodenal drainage fluid: a new pancreatic function test.
      sPFTs provide similar accuracy to PFTs done with the Dreiling tube
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      • Zuccaro Jr., G.
      • et al.
      A randomized crossover study of secretin-stimulated endoscopic and Dreiling tube pancreatic function test methods in healthy subjects.
      and demonstrate a sensitivity of 66% to 71% and specificity of 67% to 98% for the diagnosis of chronic pancreatitis.
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      Evaluation of duct-cell and acinar-cell function and endosonographic abnormalities in patients with suspected chronic pancreatitis.
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      Endoscopic ultrasound, secretin endoscopic pancreatic function test, and histology: correlation in chronic pancreatitis.
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      • et al.
      A study of the clinical utility of a 20-minute secretin-stimulated endoscopic pancreas function test and performance according to clinical variables.
      Hormone stimulation of pancreatic secretion may also produce variations in main pancreatic duct (MPD) compliance,
      • Catalano M.F.
      • Lahoti S.
      • Alcocer E.
      • et al.
      Dynamic imaging of the pancreas using real-time endoscopic ultrasonography with secretin stimulation.
      ,
      • Gardner T.B.
      • Purich E.D.
      • Gordon S.R.
      Pancreatic duct compliance after secretin stimulation: a novel endoscopic ultrasound diagnostic tool for chronic pancreatitis.
      duodenal fluid volumes,
      • Lara L.F.
      • Takita M.
      • Burdick J.S.
      • et al.
      A study of the clinical utility of a 20-minute secretin-stimulated endoscopic pancreas function test and performance according to clinical variables.
      and possibly sonographic changes in patients with or without chronic pancreatitis or EPI. A small single-center study of 35 patients demonstrated that EUS morphologic evaluation of the pancreas with secretin stimulation (sEUS) and sPFTs can be performed safely simultaneously, and MPD compliance may be greater in the pancreatic tail in normal individuals.
      • Gardner T.B.
      • Purich E.D.
      • Gordon S.R.
      Pancreatic duct compliance after secretin stimulation: a novel endoscopic ultrasound diagnostic tool for chronic pancreatitis.
      In this prospective study, we hypothesized that EUS, sEUS, and sPFTs in patients with suspected MCCP could be performed safely in a larger patient population. Secondary objectives were to evaluate differences in duodenal fluid volumes, pancreatic sonographic features, and main duct compliance. Finally, we sought to study the sequential impact of findings from EUS alone, sEUS changes and results of sPFTs on the suspected clinical diagnosis of MCCP, and the test characteristics of the diagnosis of EPI compared with the EUS diagnosis of MCCP.

      Methods

      Patient selection and study design

      The investigator-initiated protocol was originally intended to be a prospective multicenter study. However the Intuitional Review Board at only one invited center (Indiana University Health Medical Center, Indianapolis) approved the protocol and supporting documents (ClinicalTrials.gov Identifier: NCT01997476, registered November 13, 2013). After discussion with the senior investigator (T.G.), it was decided to continue as a single-center study. Before enrollment, all patients underwent screening with medical history and physical examination to determine eligibility. Eligible patients signed informed consent before enrollment. Inclusion criteria included patients aged 18 to 80 years with clinical suspicion of chronic pancreatitis with or without EPI in whom ePFTs were planned for structural and functional evaluation of the exocrine pancreas. They were also required to be capable of undergoing sedation and willing/capable of signing informed consent. Exclusion criteria included severe cardiopulmonary or renal disease, ongoing illicit drug use/abuse, moderate to severe alcohol use (<30 g/day), pregnancy or nursing, known allergy to secretin, use of any medication within the previous 30 days that could cause pancreatitis or interfere with interpretation of PFTs, or use of an anticholinergic medication within 48 hours of enrollment. Patients were also excluded if they had undergone previous pancreatic surgery or sphincterotomy, had known pancreatolithiasis or pancreatic calcifications, suspected or proven sphincter of Oddi dysfunction, symptoms of acute pancreatitis within the previous 60 days, a new abdominal pain or exacerbation of chronic pain within 30 days, or the presence of a condition that may interfere with exocrine pancreatic functioning, including celiac disease, type 1 diabetes, previous gastrectomy, cystic fibrosis, or severe malnutrition (body mass index, <18 kg/m2).

      Combined EUS, e-PFT, and sEUS testing procedure

      All endoscopic procedures were performed by 1 of 3 experienced endosonographers using propofol sedation administered by an anesthesiologist. EGD was performed initially to exclude an alternative cause for symptoms. An electronic radial EUS echoendoscope (Olympus GF-UE160-AL5; Olympus America; Center Valley, Pa, USA) was used to assess for abnormal pancreatic parenchymal (hyperechoic foci ≥2 mm, hyperechoic strands ≥3 mm, lobularity, cysts ≥3 mm) and ductal (main duct irregularity, hyperechoic margins, shadowing stones, and dilated side branches) findings in the head, body, and tail. The baseline main pancreatic duct (B-MPD) diameter was measured in all 3 locations and recorded. Finally, the baseline anteroposterior diameter of the pancreas anterior to the splenoportal confluence was measured. The contents of the gastric and duodenal lumens were then aspirated completely by the echoendoscope and discarded.
      The synthetic human secretin (ChiRhoStim; ChiRhoClin Inc, Burtonsville, Md, USA) used in this study is supplied as 16 μg of secretin, 1.5 mg of l-cysteine hydrochloride, and 20 mg of mannitol as a lyophilized powder per vial. It was reconstituted in 8 mL of sterile NaCl such that each 1 mL of the resulting solution contained 2 μg of secretin. At study commencement, a test dose of 0.2 μg (0.1 mL) was recommended before the full treatment dose to exclude an allergic reaction. If no allergic reaction was noted after 1 minute, the remaining full dose of secretin 0.2 μg/kg was given intravenously over 1 minute. During the study, a communication from the U.S. Food and Drug Administration removed the requirement for the test dose, and thereafter only the full 0.2 μg/kg secretin dose was given to the remaining study patients.
      At 4, 8, and 12 minutes after administration of secretin, real-time dynamic EUS measurement of the secretin-stimulated MPD (S-MPD) was re-measured in the head, body, and tail. Ten minutes after secretin administration, the anteroposterior (AP) gland diameter was also re-measured, and evaluation of all parenchymal and ductal features were assessed for increased visibility or prominence. After the measurements, the echoendoscope was used to aspirate the gastric contents, and any residue in the suction tubing was also aspirated. The gastroscope was then placed in the proximal duodenum at or distal to the major papilla. At 15, 30, and 45 minutes after secretin administration, collection of at least 3 mL of duodenal fluid was attempted through the suction channel of the gastroscope. The procedure was then completed and the patient brought to recovery. Duodenal collection samples were placed on ice and brought immediately to the hospital chemistry laboratory for evaluation of bicarbonate concentration using the hospital autoanalyzer. No additional therapeutic maneuvers were performed during EUS to minimize confounding variables contributing to potential adverse events.
      The endoscopist performing the EUS rated the percentage likelihood of chronic pancreatitis clinically at 3 time points during the study: (1) after history, physical examination, and EUS but before secretin; (2) after secretin, repeat pancreatic duct, and parenchymal measurements but before duodenal fluid collection, and (3) after all duodenal bicarbonate results were available.

      Definitions

      The highest bicarbonate concentration from the 3 samples was considered the peak concentration. A PBC ≥80 mEq/L from secretin ePFT was considered normal. Exocrine pancreatic insufficiency (EPI) was defined as all 3 bicarbonate values <80 mEq/L. The EUS diagnosis of chronic pancreatitis (EUS-CP+) or absence of chronic pancreatitis (EUS-CP−) was defined as the presence of ≥5 parenchymal and/or ductal criteria or ≤4 criteria, respectively.
      • Sahai A.V.
      • Zimmerman M.
      • Aabakken L.
      • et al.
      Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography.
      ,
      • Catalano M.F.
      • Sahai A.
      • Levy M.
      • et al.
      EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification.
      Adverse events related to secretin administration and EUS were evaluated. These were classified as (1) expected versus unexpected; (2) serious adverse event versus important but not serious adverse event; (3) no reasonable possibility (where a medical condition or other cause for the event is identified); and (4) reasonable possibility. Serious adverse events were considered to be any undesirable sign, symptom, or medical condition that was fatal, life-threatening, required inpatient hospitalization ≥24 hours, resulted in persistent or significant disability/incapacity, or was medically significant and which the investigator regarded as serious based on clinical judgment.

      Statistical analysis

      Based on previous studies using ERCP as a reference standard, we estimated that the sensitivity and specificity of EUS using ≥5 features of chronic pancreatitis for the detection of EPI were at least 70% and 80%, respectively. Based on these assumptions, enrollment of 800 patients would permit estimation of sensitivity and specificity with confidence limits of 10%. As only 1 study center (Indiana University Health Medical Center, Indianapolis) approved the protocol and supporting documents, it was decided to continue at that single center with a suggested enrollment of about 150 patients. This enrollment size is the value recruited at the outset that would have been expected from each center if approval from all Intuitional Review Boards was possible.
      Analyses were performed to determine associations between outcomes of interest for 2 population groups: (1) normal exocrine pancreatic function versus EPI; and (2) ≥5 EUS features of chronic pancreatitis (EUS-CP+) versus ≤4 features of chronic pancreatitis (EUS-CP−). Student t tests were used to compare continuous variables between groups, and chi-squared tests were used to analyze homogeneity between groups for categorical variables. The Fisher exact test was used to verify the results if numerical values were small. Correlation analyses were performed when analyzing the association between outcome variables of interest when all were continuous. When data were nonlinear, nonparametric tests were performed using the Wilcoxon rank sum test and Spearman’s correlation analysis. All analyses were performed using SAS v9.4 (SAS Institute, Cary, NC, USA).

      Results

      Study population and dynamic EUS measurements

      Between December 2013 and November 2017, 169 consecutive patients were evaluated, and 5 failed screening due to refusal to take a pregnancy test (n = 1), body mass index <18 kg/m2 (n = 1), previous Roux-en-Y gastric bypass (n = 1), use of sandostatin (n = 1), and diagnosis of acute pancreatitis (n = 1). Of the 164 patients who gave consent, 19 were excluded due to discovery of a pancreatic cyst (suspected intraductal papillary mucinous neoplasm) or solid mass requiring biopsy (n = 6), gastric bezoar (n = 3), prolonged hypoxia or difficulty with sedation (n = 3), inability to complete the procedure due to time constraints or other emergency procedure (n = 3), failure to maintain intravenous access (n = 1), identification of fatty pancreas with nonvisible pancreatic duct (n = 1), autoimmune pancreatitis (n = 1), and pancreatic calcifications precluding further evaluation of features of chronic pancreatitis (n = 1).
      The remaining 145 patients (mean age, 44 ± 14 years; 98 females) were diagnosed with EPI (n = 32; 22%) or normal exocrine pancreatic function (n = 131, 78%). The EPI group had a more frequent diagnosis of diabetes (44%) compared those without EPI (16%; P = .009, Table 1). Baseline demographics and the frequency of EUS-CP+ (34% vs 32%; P = .75) were otherwise similar (Table 2). The ratio of the secretin-stimulated main pancreatic duct (S-MPD) to baseline (B-MPD) measurements (S-MPD/B-MPD) in the tail at 4 minutes (P = .01) and 8 minutes (P = .02) after secretin were higher in patients with normal exocrine function but were similar at other times and sites in the pancreas. Duodenal fluid quantities aspirated at all 3 times were also similar between the 2 groups. In 18 patients, the diagnosis of normal exocrine pancreatic function was made only after the 45-minute collection.
      Table 1Baseline demographic and clinical data and results of dynamic EUS measurements and pancreatic fluid collection before and after secretin for the 145 patients with exocrine pancreatic insufficiency (n = 32) and normal exocrine pancreatic function (n = 113)
      Overall (n = 145)Exocrine pancreatic insufficiency (n = 32)Normal exocrine pancreatic function (n = 113)P value
      Age (years), mean (SD)44.0 (13.5)47.8 (13.6)43.0 (13.3).07
      Female, n (%)98 (68.1)24 (75.0)74 (66.1).34
      Body mass index (kg/m2), median (range)26.3 (15.2-52.3)29.1 (19.1-40)25.9 (15.2-52.3).09
      Tobacco user, n (%)59 (41.0)15 (46.9)44 (39.3).44
      Alcohol user, n (%)17 (11.8)4 (12.5)13 (11.6).89
      Diabetic, n (%)32 (22.2)14 (43.8)18 (16.1).0009
      Number of EUS features for chronic pancreatitis, n (%)
       ≤498 (67.6)21 (65.6)77 (68.1).79
       ≥547 (32.4)11 (34.4)36 (31.9)
      S-MPD/B-MPD, mean (SD)
       Head at 4 minutes1.30 (1.19)1.28 (0.33)1.30 (1.34).87
       Body at 4 minutes1.35 (0.43)1.34 (0.44)1.36 (0.42).83
       Tail at 4 minutes1.31 (0.47)1.12 (0.37)1.36 (0.49).01
       Head at 8 minutes1.31 (1.36)1.21 (0.29)1.33 (1.53).41
       Body at 8 minutes1.25 (0.40)1.29 (0.55)1.24 (0.35).59
       Tail at 8 minutes1.32 (0.46)1.18 (0.32)1.36 (0.49).02
       Head at 12 minutes1.32 (0.62)1.26 (0.31)1.33 (1.82).67
       Body at 12 minutes1.24 (0.40)1.25 (0.40)1.24 (0.40).85
       Tail at 12 minutes1.28 (0.42)1.23 (0.40)1.29 (0.43).44
      S-AP/B-AP, mean (SD)1.05 (0.65)1.03 (0.17)1.06 (0.73).67
      HCO3 (mmol/L) at 15 minutes, mean (SD)75.1 (18.3)57.1 (16.8)80.2 (15.3)<.0001∗
      HCO3 (mmol/L) at 30 minutes, mean (SD)80.9 (19.7)59.2 (19.1)87.1 (14.9)<.0001∗
      HCO3 (mmol/L) at 45 minutes, mean (SD)82.3 (18.3)58.8 (17.4)89.0 (11.9)<.0001∗
      Volume (mL) of duodenal fluid at 15 minutes11.8 (6.4)13.1 (7.6)11.4 (6.0).18
      Volume (mL) of duodenal fluid at 30 minutes, mean (SD)11.9 (6.3)11.3 (6.3)12.1 (6.3).49
      Volume (mL) of duodenal fluid at 45 minutes, mean (SD)10.9 (7.3)11.3 (8.7)10.8 (6.9).71
      Exocrine pancreatic insufficiency was defined as all bicarbonate values <80 mEq/L. Normal exocrine pancreatic function had at least 1 value >80 mEq/L. The EUS diagnosis of chronic pancreatitis (EUS-CP+) or absence of chronic pancreatitis (EUS-CP−) was defined as the presence of ≥5 parenchymal or ductal criteria or ≤4 criteria, respectively.
      SD, Standard deviation; S-MPD, secretin main pancreatic duct diameter; B-MPD, baseline main pancreatic duct diameter; S-AP, anteroposterior diameter after secretin; B-AP, baseline anteroposterior diameter.
      Table 2Baseline demographic and clinical data and results of dynamic EUS measurements and pancreatic fluid collection before and after secretin for the 145 patients with EUS evidence of chronic pancreatitis (≥5 criteria, EUS-CP+) and ≤4 criteria (EUS-CP−)
      EUS-CP+ (n = 47)EUS-CP− (n = 98)P value
      Age (years), mean (SD)44 (14.5)44 (13.0).99
      Female, n (%)30 (65.2)68 (69.4).62
      Body mass index (kg/m2), median (range)26.6 (17.3-52.3)26.2 (15.2-47.1).88
      Tobacco user, n (%)22 (47.8)37 (37.8).25
      Alcohol user, n (%)6 (13.0)11 (11.2).75
      Diabetic, n (%)10 (21.7)22 (22.5).92
      Exocrine pancreatic insufficiency, n (%)11 (23.4)21 (21.4).79
      S-MPD/B-MPD, mean (SD)
       Head at 4 minutes1.2 (0.3)1.4 (1.4).31
       Body at 4 minutes1.3 (0.4)1.4 (0.4).26
       Tail at 4 minutes1.3 (0.5)1.3 (0.5).30
       Head at 8 minutes1.4 (0.3)1.3 (1.7).60
       Body at 8 minutes1.3 (0.4)1.2 (0.4).39
       Tail at 8 minutes1.4 (0.5)1.3 (0.5).39
       Head at 12 minutes1.2 (0.3)1.4 (2.0).46
       Body at 12 minutes1.27 (0.4)1.23 (0.4).52
       Tail at 12 minutes1.33 (0.4)1.3 (0.5).32
      S-AP/B-AP, mean (SD)1.02 (0.1)1.07 (0.8).053
      HCO3 (mmol/L) at 15 minutes, mean (SD)74.70 (21.8)75.3 (16.5).88
      HCO3 (mmol/L) at 30 minutes, mean (SD)81.15 (23.4)80.7 (17.8).93
      HCO3 (mmol/L) at 45 minutes, mean (SD)80.04 (22.1)83.42 (16.1).35
      Volume (mL) of duodenal fluid at 15 minutes, mean (SD)12.26 (6.2)11.51 (6.5).51
      Volume (mL) of duodenal fluid at 30 minutes, mean (SD)12.26 (6.4)11.79 (6.3).68
      Volume (mL) of duodenal fluid at 45 minutes, mean (SD)11.06 (6.1)10.81 (7.9).84
      Exocrine pancreatic insufficiency was defined as all bicarbonate values <80 mEq/L. Normal exocrine pancreatic function had at least 1 value >80 mEq/L. The EUS diagnosis of chronic pancreatitis (EUS-CP+) or absence of CP (EUS-CP−) was defined as the presence of ≥5 parenchymal or ductal criteria or ≤4 criteria, respectively.
      SD, Standard deviation; S-MPD, secretin main pancreatic duct diameter; B-MPD, baseline main pancreatic duct diameter; S-AP, anteroposterior diameter after secretin; B-AP, baseline anteroposterior diameter.
      Using ≥5 EUS criteria as diagnostic for chronic pancreatitis, we determined that 47 of 145 patients (32%) were EUS-CP+, and the remaining 98 of 145 patients (68%) were EUS-CP− (≤4 EUS criteria). Baseline demographics, frequency of EPI, mean S-MPD/B-MPD at all sites and times, mean ratio of AP diameter after secretin to diameter at baseline, and duodenal fluid quantities aspirated at all 3 times were also similar between the 2 groups (Table 2).

      Assessment of parenchymal and ductal features after secretin

      During the evaluation 10 minutes after secretin, those with normal exocrine pancreatic function (Table 3) had more visible parenchymal hyperechoic foci (P = .023), hyperechoic strands (P = .019), and echogenic MPD walls (P = .002) compared with the EPI group. The remaining parenchymal and ductal changes and the AP gland diameter were similar between the 2 groups. For the EUS-CP+ group, the mean gland AP diameter (P = .03), parenchymal lobularity (P = .01), and duct side branches (P = .03) were more visible after secretin compared with the EUS-CP− group (Table 4). The remaining features were similar between the 2 groups.
      Table 3EUS pancreatic parenchymal and ductal changes after human secretin in patients with exocrine pancreatic insufficiency and normal exocrine pancreatic function
      Exocrine pancreatic insufficiency (n = 32)Normal exocrine pancreatic function (n = 113)P value
      Increased parenchymal features visible after secretin, n (%)
       Hyperechoic foci12 (38)68 (60).023
       Hyperechoic strands13 (41)72 (64).019
       Cysts1 (3)2 (2).53
       Lobularity1 (3)9 (8).46
      Increased ductal features visible after secretin, n (%)
       Hyperechoic walls4 (13)48 (43).002
       Side branches11 (34)39 (35).99
       Diameter1 (3)2 (2).53
       Irregularity0 (0)0 (0)n/a
       Stones1 (3.1)0 (0).22
      AP diameter (mm), mean (SD)15.8 (3.1)15.9 (3.7).79
      Exocrine pancreatic insufficiency was defined as all bicarbonate values <80 mEq/L. Normal exocrine pancreatic function had at least 1 value >80 mEq/L.
      n/a, Not applicable; SD, standard deviation; AP, anteroposterior.
      Table 4EUS pancreatic parenchymal and ductal changes after secretin in patients with EUS-CP+ (≥5 criteria) and without EUS-CP− (≤4 criteria)
      EUS-CP+ (n = 47)EUS-CP− (n = 98)P value
      Increased parenchymal features visible after secretin, n (%)
       Hyperechoic foci26 (55)54 (55).98
       Hyperechoic strands28 (60)57 (58).87
       Cysts0 (0)3 (3).55
       Lobularity7 (15)3 (3).01
      Increased ductal features visible after secretin, n (%)
       Hyperechoic margins20 (43)32 (33).26
       Dilated side branches22 (47)28 (29).03
       Diameter1 (2)2 (2)1.0
       Main duct irregularity0 (0)0 (0)n/a
       Intraductal stones0 (0)1 (1)1.0
      Anteroposterior diameter (mm), mean (SD)16.8 (3.5)15.5 (3.5).03
      n/a, Not available; SD, standard deviation; EUS-CP+, EUS findings of chronic pancreatitis; EUS-CPL−, EUS findings of no chronic pancreatitis (EUS-CP−).

      Endoscopist’s clinical assessment of the likelihood of chronic pancreatitis

      There were 21 (14%) patients with EPI and EUS-CP− and 77 (53%) with normal exocrine function and EUS-CP−. Of the remaining patients, there were 11 (8%) with EPI and EUS-CP+ and 36 (25%) with normal exocrine function and EUS-CP+. The clinical assessment of the percentage likelihood of chronic pancreatitis in all 4 groups at all 3 time points evaluated is shown in Table 5. For all groups, there was a statistically significant change in the median percentage likelihood before, during, and after secretin administration.
      Table 5Endoscopist assessment of percentage certainty of chronic pancreatitis pre-secretin, post-secretin, and after duodenal bicarbonate results (final certainty) in patients with exocrine pancreatic insufficiency, normal exocrine pancreatic function, and EUS criteria with (EUS-CP+) or without (EUS-CP−) evidence of chronic pancreatitis
      Final diagnosisMedian pre-secretin certainty of CP, % (range)Median post-secretin/pre-sPFTs certainty of CP, % (range)Median final certainty of CP after sPFTs, % (range)P value
      EUS-CP− and EPI (n = 21)0 (0-50)20 (0-50)70 (20-100).009
      EUS-CP− and normal exocrine pancreatic function (n = 77)20 (0-75)20 (0-100)0 (0-100).028
      EUS-CP+ and EPI (n = 11)60 (20-100)60 (20-100)90 (80-100).023
      EUS-CP+ and normal exocrine pancreatic function (n = 36)60 (15-100)57.5 (20-100)32.5 (0-100).0009
      The endoscopist performing the EUS rated the percentage likelihood of chronic pancreatitis clinically at 3 time points during the study: (1) pre-secretin: after history, physical examination, and EUS but before secretin administration; (2) post-secretin/pre-sPFTs: after secretin administration with repeat pancreatic duct and parenchymal sonographic assessment but before timed duodenal fluid collections; and (3) final: after all duodenal bicarbonate results were available. Exocrine pancreatic insufficiency (EPI), peak bicarbonate concentration <80 mEq/L; normal exocrine pancreatic function, peak bicarbonate concentration ≥80 mEq/L; EUS findings of chronic pancreatitis (EUS-CP+), ≥5 criteria; EUS findings of no chronic pancreatitis (EUS-CP−), <4 criteria.
      CP, Chronic pancreatitis; sPFTs, secretin-stimulated endoscopic pancreatic function tests; EPI, exocrine pancreatic insufficiency.

      Performance of pancreatic function testing for the EUS diagnosis of chronic pancreatitis

      There was no association between the number of EUS criteria identified and the frequency of EPI (P = .94, Table 6). For the 47 EUS-CP+ patients, 11 (23%) had EPI and 36 (77%) had normal exocrine function. For the 98 EUS-CP− patients, 21 (21%) had EPI and 77 (79%) had normal exocrine function. The diagnosis of EPI had a sensitivity, specificity, positive and negative predictive value, and accuracy of 23.4% (95% confidence interval [CI], 12.3-38.0), 78.6% (95% CI, 69.1-86.2), 34.4% (95% CI, 21.6-49.9), 68.1% (95% CI, 63.9-72.1), and 60.7 (95% CI, 52.2-68.7), respectively, for the EUS diagnosis of chronic pancreatitis using ≥5 criteria (EUS-CP+).
      Table 6Relationship between number of EUS criteria for chronic pancreatitis for the 145 patients with exocrine pancreatic insufficiency (n = 32) and exocrine pancreatic sufficiency (n = 113)
      Number of EUS criteria for the diagnosis of chronic pancreatitisOverall (n = 145), n (%)Exocrine pancreatic insufficiency (n = 32), n (%)Normal exocrine pancreatic function (n = 113), n (%)P value
      013 (9.0)3 (9.4)10 (8.9).9367
      14 (2.8)2 (6.3)2 (1.8)
      225 (17.2)5 (15.6)20 (17.7)
      336 (24.8)8 (25.0)28 (24.8)
      420 (13.8)3 (9.4)17 (15.0)
      530 (20.7)7 (21.9)23 (20.4)
      611 (7.8)3 (9.4)8 (7.1)
      75 (3.5)1 (3.1)4 (3.5)
      80 (0)0 (0)0 (0)
      91 (0.7)0 (0)1 (0.9)
      Exocrine pancreatic insufficiency, peak bicarbonate concentration <80 mEq/L; normal exocrine pancreatic function, peak bicarbonate concentration ≥80 mEq/L.
      If ≥4 criteria were used for the EUS diagnosis of chronic pancreatitis, 67 patients were EUS-CP+, including 14 (21%) with EPI and 53 (79%) with normal exocrine function. For the 78 patients who were EUS-CP−, 18 (23%) had EPI and 60 (77%) had normal exocrine function. When ≥4 criteria were used, the diagnosis of EPI had a sensitivity, specificity, positive and negative predictive value, and accuracy of 20.9% (95% CI, 11.9-32.6), 76.9% (95% CI, 66.0-85.7), 43.8% (95% CI, 29.6-59.1), 53.1% (95% CI, 48.8-57.3), and 51.0% (95% CI, 42.6-59.4), respectively, for the diagnosis of chronic pancreatitis.

      Adverse events

      Three of the 169 (1.7%) patients who gave consent had repeated or prolonged hypoxia requiring early termination of the procedure and were therefore excluded from the data analysis. None of these 3 patients required application of positive pressure ventilation and were classified as expected, with important but not serious adverse events.

      Discussion

      In this study, we found that same-session EUS morphologic evaluation, dynamic measurement of MPD compliance (sEUS), and collection of duodenal fluid (sPFTs) were feasible and safe in a large prospective single-center cohort. These results confirm the findings of a previous smaller study.
      • Gardner T.B.
      • Purich E.D.
      • Gordon S.R.
      Pancreatic duct compliance after secretin stimulation: a novel endoscopic ultrasound diagnostic tool for chronic pancreatitis.
      Furthermore, parenchymal and ductal findings from sEUS and duodenal bicarbonate findings from ePFTs had a significant impact on the clinical diagnosis of chronic pancreatitis in patients with and without EUS-CP (≥5 features). To our knowledge, this is the first prospective evaluation of the impact of ePFT findings on the clinical suspicion of chronic pancreatitis in these patients.
      Administration of secretin and the resultant increase in pancreatic fluid secretion theoretically increases MPD diameter and duodenal fluid volume in normal individuals. MPD compliance
      • Balci N.C.
      • Smith A.
      • Momtahen A.J.
      • et al.
      MRI and S-MRCP findings in patients with suspected chronic pancreatitis: correlation with endoscopic pancreatic function testing (ePFT).
      • Madzak A.
      • Olesen S.S.
      • Haldorsen I.S.
      • et al.
      Secretin-stimulated MRI characterization of pancreatic morphology and function in patients with chronic pancreatitis.
      • Madzak A.
      • Olesen S.S.
      • Lykke Poulsen J.
      • et al.
      MRI assessed pancreatic morphology and exocrine function are associated with disease burden in chronic pancreatitis.
      and duodenal (pancreatic) fluid volume measurements
      • Lara L.F.
      • Takita M.
      • Burdick J.S.
      • et al.
      A study of the clinical utility of a 20-minute secretin-stimulated endoscopic pancreas function test and performance according to clinical variables.
      ,
      • Tirkes T.
      • Fogel E.L.
      • Sherman S.
      • et al.
      Detection of exocrine dysfunction by MRI in patients with early chronic pancreatitis.
      after secretin have therefore been evaluated as alternative measures for exocrine pancreatic function. Gardner et al
      • Gardner T.B.
      • Purich E.D.
      • Gordon S.R.
      Pancreatic duct compliance after secretin stimulation: a novel endoscopic ultrasound diagnostic tool for chronic pancreatitis.
      found that duct compliance measured by EUS was higher in the pancreatic tail after secretin in normal individuals. Similarly, we found that duct compliance (S-MPD/B-MPD) was higher in the pancreatic tail at 4 and 8 minutes (but not 12 minutes) after secretin in those with normal exocrine function compared with the EPI group. However, there was no difference in duct compliance in the head or body at any time after secretin between these 2 groups and also no difference in duct compliance in the head, body, or tail in the EUS-CP+ group compared the EUS-CP− group. Furthermore, duodenal volumes aspirated at 15, 30, and 45 minutes after secretin were the same in all groups. These findings suggest that EUS measurement of duct compliance and duodenal volumes after secretin may not be useful for the diagnosis of EPI or chronic pancreatitis.
      Early research noted that output from the pancreas peaked 30 minutes after hormone stimulation.
      • Wormsley K.G.
      The response to infusion of a combination of secretin and pancreozymin in health and disease.
      • Sun D.C.
      The use of pancreozymin-secretin test in the diagnosis of pancreatitis and tumors of the pancreas.
      • Go V.L.
      • Hofmann A.F.
      • Summerskill W.H.
      Simultaneous measurements of total pancreatic, biliary, and gastric outputs in man using a perfusion technique.
      Thus, sampling of duodenal fluid by the Dreiling tube to test physiologic function typically occurred up to 60 minutes after stimulation.
      • Chowdhury R.
      • Bhutani M.S.
      • Mishra G.
      • et al.
      Comparative analysis of direct pancreatic function testing versus morphological assessment by endoscopic ultrasonography for the evaluation of chronic unexplained abdominal pain of presumed pancreatic origin.
      ,
      • Ketwaroo G.
      • Brown A.
      • Young B.
      • et al.
      Defining the accuracy of secretin pancreatic function testing in patients with suspected early chronic pancreatitis.
      Current variations of ePFTs include testing only up to 45 minutes after secretin
      • Stevens T.
      • Conwell D.L.
      • Zuccaro G.J.
      • et al.
      The efficiency of endoscopic pancreatic function testing is optimized using duodenal aspirates at 30 and 45 minutes after intravenous secretin.
      or administering secretin 30 minutes before sedation for endoscopy.
      • Lara L.F.
      • Takita M.
      • Burdick J.S.
      • et al.
      A study of the clinical utility of a 20-minute secretin-stimulated endoscopic pancreas function test and performance according to clinical variables.
      In the current study, the first collection occurred 15 minutes after sedation in order to complete sEUS morphologic evaluation but continued to 45 minutes to ensure that PBC was approximated. We found that in 18 patients, the diagnosis of normal exocrine function was made only on the results of the 45-minute collection, which confirm the necessity of this timed collection during ePFTs.
      Because magnetic resonance imaging with intravenous contrast may produce or detect abnormalities such as signal differences on T1 imaging, gland atrophy, and irregular outer margins,
      • Tirkes T.
      • Fogel E.L.
      • Sherman S.
      • et al.
      Detection of exocrine dysfunction by MRI in patients with early chronic pancreatitis.
      ,
      • Tirkes T.
      • Shah Z.K.
      • Takahashi N.
      • et al.
      Reporting standards for chronic pancreatitis by using CT, MRI, and MR cholangiopancreatography: the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer.
      we postulated that the pancreatic duct and parenchyma may produce sonographic changes after secretin. In patients with normal exocrine function, post-secretin imaging showed parenchymal hyperechoic foci and strands, and MPD echogenic walls were more visible compared with the EPI group. For the EUS-CP+ group, parenchymal lobularity and duct side branches were more visible after secretin compared with the EUS-CP− group. These findings may represent sonographic imaging of increased fluid secretion from ductal cells, but as noted above, these changes did not generally translate into differences in duct compliance or duodenal volumes sampled in patients with or without EPI or EUS-CP.
      The development of pancreatic fibrosis in alcoholics appears to be patchy and may develop before the clinical onset of chronic pancreatitis.
      • Pitchumoni C.S.
      • Glasser M.
      • Saran R.M.
      • et al.
      Pancreatic fibrosis in chronic alcoholics and nonalcoholics without clinical pancreatitis.
      This preclinical stage of pancreatic disease before chronic pancreatitis has been termed pancreatopathy
      • Sata N.
      • Koizumi M.
      • Nagai H.
      Alcoholic pancreatopathy: a proposed new diagnostic category representing the preclinical stage of alcoholic pancreatic injury.
      and may manifest histology as parenchymal atrophy and acinar cell loss. The absence of clinical symptoms may eventually lead to MCCP, which is chronic pancreatitis in patients with abdominal pain but equivocal or absent related imaging findings.
      • Walsh T.N.
      • Rode J.
      • Theis B.A.
      • et al.
      Minimal change chronic pancreatitis.
      The findings of histology in evaluation of pancreatic disease is usually impractical unless patients undergo surgery or preoperative biopsy.
      • DeWitt J.
      • McGreevy K.
      • LeBlanc J.
      • et al.
      EUS-guided Trucut biopsy of suspected nonfocal chronic pancreatitis.
      Therefore, we attempted to use both EUS and sPFTs to identify patients with MCCP. Previous studies evaluating sPFTs demonstrate a sensitivity of 66% to 71% and specificity of 67% to 98% for the diagnosis of chronic pancreatitis (Table 7) compared with a reference standard of ≥4 EUS criteria,
      • Stevens T.
      • Dumot J.A.
      • Zuccaro Jr., G.
      • et al.
      Evaluation of duct-cell and acinar-cell function and endosonographic abnormalities in patients with suspected chronic pancreatitis.
      histopathology,
      • Albashir S.
      • Bronner M.P.
      • Parsi M.A.
      • et al.
      Endoscopic ultrasound, secretin endoscopic pancreatic function test, and histology: correlation in chronic pancreatitis.
      or clinical consensus.
      • Lara L.F.
      • Takita M.
      • Burdick J.S.
      • et al.
      A study of the clinical utility of a 20-minute secretin-stimulated endoscopic pancreas function test and performance according to clinical variables.
      We found that the diagnosis of EPI had a sensitivity, specificity, and accuracy of 23.4%, 78.6%, and 60.7%, respectively, compared with the EUS diagnosis of chronic pancreatitis using ≥5 criteria (EUS-CP+). If only ≥4 criteria were used, the diagnosis of EPI had a sensitivity, specificity, and accuracy of 20.9%, 76.9%, and 51.0%, respectively. For the current study, we estimated that the sensitivity and specificity of EUS using ≥5 features of chronic pancreatitis for the detection of EPI was at least 70% and 80%, respectively, when using ERCP as a reference standard. Our findings are significantly lower than previously reported and likely explained by over detection and mislabeling of abnormal parenchymal and ductal features in normal patients or those with MCCP and the lack of inclusion of patients with advanced disease. This phenomenon has also been described for interpretation of pancreatograms during ERCP.
      • Schmitz-Moormann P.
      • Himmelmann G.W.
      • Brandes J.W.
      • et al.
      Comparative radiological and morphological study of human pancreas. Pancreatitis like changes in postmortem ductograms and their morphological pattern. Possible implication for ERCP.
      A recent study highlighted the difficulty of EUS in the evaluation of histology findings in noncalcific chronic pancreatitis. Trikudanathan et al
      • Trikudanathan G.
      • Vega-Peralta J.
      • Malli A.
      • et al.
      Diagnostic performance of endoscopic ultrasound (EUS) for non-calcific chronic pancreatitis (NCCP) based on histopathology.
      found that compared with histology before total pancreatectomy and islet autotransplantation (TPIAT), identification of ≥4 EUS chronic pancreatitis features within 1 year of surgery showed a sensitivity, specificity, and accuracy of 61%, 75%, and 63% for the histologic diagnosis of chronic pancreatitis. These data along with the current study suggest that use of EUS alone for the diagnosis of MCCP should be discouraged and instead used along with direct testing for EPI, such as ePFTs. In our study, findings from ePFTs did increase the clinical diagnosis of chronic pancreatitis in all subgroups evaluated. A normal EUS examination alone may be sufficient to exclude chronic pancreatitis, whereas findings of advanced disease (pancreatolithiasis and calcifications) are sufficient to confirm the diagnosis.
      Table 7Published studies evaluating the test characteristics of endoscopic pancreatic function tests with secretin for the diagnosis of chronic pancreatitis
      ReferenceNo.Study designHCO3 collection times after secretin (minutes)Reference standard for diagnosis of chronic pancreatitisSensitivity (%)Specificity (%)PPV (%)NPV (%)Accuracy (%)
      Stevens et al (2009)
      • Stevens T.
      • Dumot J.A.
      • Zuccaro Jr., G.
      • et al.
      Evaluation of duct-cell and acinar-cell function and endosonographic abnormalities in patients with suspected chronic pancreatitis.
      50Single center, prospective15, 30, 45≥4 EUS criteria7192NRNRNR
      Albashir et al (2010)
      • Albashir S.
      • Bronner M.P.
      • Parsi M.A.
      • et al.
      Endoscopic ultrasound, secretin endoscopic pancreatic function test, and histology: correlation in chronic pancreatitis.
      25Single center, retrospective15, 30, 45, 60Histopathology8667NRNRNR
      Lara et al (2017)
      • Lara L.F.
      • Takita M.
      • Burdick J.S.
      • et al.
      A study of the clinical utility of a 20-minute secretin-stimulated endoscopic pancreas function test and performance according to clinical variables.
      81Multicenter, retrospective35, 40, 45, 50Clinical consensus of available studies669894.785.5NR
      Current study145Single center, prospective15, 30, 45≥5 EUS criteria23.478.634.468.160.7
      All studies cited use a peak bicarbonate concentration <80 mEq/L for the diagnosis of exocrine pancreatic insufficiency.
      PPV, Positive predictive value; NPV, negative predictive value; NR, not reported.
      We found that EUS-CP+ and EPI were diagnosed concomitantly in 11 (8%) patients, whereas EUS-CP− and normal exocrine function were found concomitantly in 77 (53%) patients, which led to median final certainties of chronic pancreatitis of 90% and 0%, respectively. The remaining 57 (39%) patients had discordant findings between EUS and sPFT results, which led to difficulty and wide-ranging certainties for the clinical diagnosis of chronic pancreatitis. It is crucial that endoscopists who perform EUS and ePFTs are aware of these possible discrepancies and how they may have an impact on clinical management. Further research is required to evaluate the test characteristics of EPI for the diagnosis of chronic pancreatitis using other criterion standards besides EUS findings.
      Our study is the first to prospectively evaluate sonographic findings of chronic pancreatitis after secretin and the impact of sEUS and ePFT findings on the subsequent clinical diagnosis. Nevertheless, our study does have 3 principal limitations. First, the study population was smaller than designed because Intuitional Review Board approval could only be obtained at one of the original participating institutions. Thus, study findings must be interpreted with caution because the sample size was only about one-fifth of the intended figure of 800 based on power calculations. However, this study is still the largest study to date to prospectively evaluate ePFTs and EUS and utilized 3 different endosonographers. We believe it is unlikely that this study will be replicated in a larger group. The second limitation is the use of EUS features of chronic pancreatitis as the criterion standard for the diagnosis of chronic pancreatitis. Although other studies have used histology, clinical follow-up, or ERCP and MRCP findings, our study design in patients with MCCP did not permit use of other surrogate tests. Finally, interpretation of pancreatic duct and parenchymal effects of secretin was not performed by endosonographers blinded to the previous ultrasonographic findings (Fig. 1).
      Figure thumbnail gr1
      Figure 1Endoscopist assessment of percentage certainty of the clinical diagnosis of chronic pancreatitis (CP) at 3 different time points: pre-secretin, post-secretin, and after duodenal bicarbonate results (final) in patients with EUS-CP+ (≥5 criteria), EUS-CP− (≤4 criteria), exocrine pancreatic insufficiency, and exocrine pancreatic sufficiency. Exocrine pancreatic insufficiency is defined as peak bicarbonate concentration <80 mEq/L; normal exocrine pancreatic function is defined as peak bicarbonate concentration ≥80 mEq/L; EUS findings of chronic pancreatitis (EUS-CP+) requires ≥5 criteria; EUS findings of no chronic pancreatitis (EUS-CP−) requires <4 criteria.
      In conclusion, same-session EUS and ePFTs are safe and feasible. Secretin causes distinct sonographic changes in patients with normal exocrine function and EUS evidence of chronic pancreatitis, but dynamic MPD ratios and duodenal volumes aspirated after secretin do not appear useful for the diagnosis of EPI. Findings from sEUS and ePFTs have a significant impact in the clinical assessment of chronic pancreatitis in patients with and without EUS-CP, but ePFT results show poor correlation to the EUS diagnosis of chronic pancreatitis. Finally, a 45-minute ePFT collection is required to confirm the diagnosis of normal exocrine function. Further studies, particularly in those with suspected MCCP, are required to evaluate the role of EUS and ePFTs.

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