Abstract
Purpose
Our purpose was to validate the T1 SIR (T1 score) as an imaging biomarker for the staging of CP in a large, multi-institutional, prospective study.
Methods
The prospective study population included 820 participants enrolled in the PROCEED study from nine clinical centers between June 2017 and December 2021. A radiologist at each institution used a standardized method to measure the T1 signal intensity of the pancreas and the reference organs (spleen, paraspinal muscle, liver), which was used to derive respective T1 scores. Participants were stratified according to the seven mechanistic stages of chronic pancreatitis (MSCP 0–6) based on their clinical history, MRCP, and CT findings.
Results
The mean pancreas-to-spleen T1 score was 1.30 in participants with chronic abdominal pain, 1.22 in those with acute or recurrent acute pancreatitis, and 1.03 in definite CP. After adjusting for covariates, we observed a linear, progressive decline in the pancreas-to-spleen T1 score with increasing MSCP from 0 to 6. The mean pancreas-to-spleen T1 scores were 1.34 (MSCP 0), 1.27 (MSCP 1), 1.21 (MSCP 2), 1.16 (MSCP 3), 1.18 (MSCP 4), 1.12 (MSCP 5), and 1.05 (MSCP 6) (p < 0.0001). The pancreas-to-liver and pancreas-to-muscle T1 scores showed less linear trends and wider confidence intervals.
Conclusion
The T1 score calculated by SIR of the pancreas-to-spleen shows a negative linear correlation with the progression of chronic pancreatitis. It holds promise as a practical imaging biomarker in evaluating disease severity in clinical research and practice.
Keywords: T1 score, Mechanistic Stages of Chronic Pancreatitis, MRI
Graphical abstract
Introduction
Chronic pancreatitis (CP) is a chronic inflammatory condition of the pancreas with clinical manifestations including abdominal pain, acute pancreatitis (AP), exocrine and/or endocrine pancreatic dysfunction (diabetes mellitus), and increased risk of pancreatic cancer [1]. The histologic hallmarks of CP include the triad of fibrosis, loss of acinar and islet cells, and ductal changes [2]. Because histology is not easily or readily available in clinical practice, cross-sectional imaging studies, such as computerized tomography (CT) and magnetic resonance imaging (MRI) with or without magnetic resonance cholangiopancreatography (MRCP), are recommended as the first-line diagnostic modalities by the American College of Gastroenterology [3]. The American Pancreatic Association guidelines suggest extrapolating findings of the Cambridge classification [4] which was designed primarily to interpret ductal changes on endoscopic retrograde cholangiopancreatography (ERCP) [5]. However, pancreatic ducts comprise only a fraction of the parenchyma, and ductal imaging does not reflect the parenchymal fibrosis or loss of acinar tissue described in the histopathology triad. Therefore, in patients who lack pancreatic calcifications on CT or moderate-to-severe ductal abnormalities on MRCP, establishing a CP diagnosis can be elusive and delayed. In addition, Cambridge classification with MRCP has variable interpretation [6] and moderate interobserver agreement (weighted kappa of 0.68) among the experienced abdominal radiologists [7, 8]. Prior reports, expert panel reviews, consensus guidelines, and histopathologic correlation studies have suggested that parenchymal MRI findings can detect CP earlier and might be better suited for the staging and longitudinal evaluation of CP [9–12].
On MRI examinations, a normal pancreas demonstrates a higher T1 signal intensity than a normal muscle or a normal spleen or liver, a difference attributed to the presence of rich proteinaceous material in the acinar cells containing abundant rough endoplasmic reticulum [13–15]. In conditions such as CP, proteinaceous material in the acini is reduced by chronic inflammation, and eventually, the acinar cells are replaced by fibrosis. Studies have reported that these changes prolong the T1 relaxation time and decrease in T1-weighted signal intensity ratio (SIR) [15–19]. The T1 SIR has also been correlated with exocrine pancreatic dysfunction [16, 20, 21] and fibrosis by histopathology [12, 22–24]. However, all of these studies were retrospective, performed at a single institution, and unable to assess the potential confounding effects of key variables.
In this multicenter, prospectively ascertained cohort study, we hypothesized that the T1 SIR of the pancreas could serve as an imaging biomarker for CP. MRI findings were captured systematically and T1 SIR correlated with different stages of CP [25]. The disease stages, which we defined according to a scale we named the “mechanistic stages of chronic pancreatitis” (MSCP), were determined by considering clinical history, ductal findings on MRCP, and calcifications on CT. The large sample size enabled us to control several confounding factors that otherwise could have weakened our ability to evaluate the relationship between the T1 SIR and stages of CP.
Materials and methods
Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) is an ongoing, longitudinal cohort study of CP in adult participants in the US (NCT# 03099850) [26]. It is one of the four major studies conducted by the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer, established by the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases [27, 28]. A detailed methodology of the PROCEED study was published previously [26]. The study was approved by the Institutional Review Board of all nine participating centers: Indiana University in Indianapolis, IN, University of Pittsburgh Medical Center in Pittsburgh, PA, The Ohio State University Wexner Medical Center in Columbus, OH, Mayo Clinic in Rochester, MN, Stanford University in Stanford, CA, Cedars-Sinai Medical Center in Los Angeles, CA, The Permanente Medical Group in San Francisco, CA, University of Florida in Gainesville, FL, and Baylor University in Houston, TX and the Data Coordinating Center in The University of Texas MD Anderson Cancer Center in Houston, TX. All the participants provided informed consent before any study procedures were performed.
Study cohort
The PROCEED cohort consists of subgroups purposefully selected based on the mechanistic definition [25] to represent our current understanding of the different stages of CP. The full details of the study can be found in the methodology publication [26]. Briefly, the PROCEED subgroups are as follows:
Healthy volunteers: no abdominal symptoms and no personal or family history of pancreatic disease (Green I). Participants were not required to have an MRI.
Chronic abdominal pain of suspected pancreatic origin and normal-appearing pancreas on both CT scan and MRI and/or MRCP (Green II)
Indeterminate CP: chronic abdominal pain with no history of AP and presence of Cambridge stage 1 or 2 on CT scan and/or MRI/MRCP (Yellow I)
One episode of AP and Cambridge stage 0, 1, or 2 on MRCP and/or CT scan (Yellow II)
Recurrent AP and Cambridge stage 0, 1, or 2 on CT scan and/or MRCP (Yellow III)
Definite CP: Cambridge stage 3 or 4 or presence of calcifications on CT scan and/or MRI/MRCP or histologic evidence of CP (Red)
All the participants in the Green II and Yellow subgroups were required to have a contrast-enhanced CT scan and an MRI/MRCP within 2 years before or 6 months after enrollment in the study. If not needed for clinical purposes, the MRI/MRCP study was performed for research purposes. A contrast-enhanced CT scan was performed on 92% (754/820) of the participants.
There were 1163 consecutive participants in the Green II through Red groups of the PROCEED study from June 2017 to December 2021. The study protocol did not require all participants to have an MRI/MRCP [26]. We found 833 qualifying MRIs prior to, or as part of their baseline assessment. A total of 820 participants were included in the analysis following excluding 13 of them for reasons listed in Fig. 1. The demographics of the three major PROCEED groups used in this study are listed in Table 1.
Fig. 1.
Participant enrollment flowchart
Table 1.
Characteristics of the participants in the analysis, summarized by the three PROCEED groups
| Chronic abdominal pain suspected of pancreatic origin (Green II, Yellow I) | Acute or recurrent acute pancreatitis (Yellow II, III) | Definite CP (Red) | p value | |
|---|---|---|---|---|
| N | 94 | 348 | 378 | |
| Age at enrollment | 49 (39, 59) | 46 (36, 57) | 53 (43, 62) | < 0.001 |
| Gender (male) | 31 (33) | 168 (48) | 190 (50) | 0.010 |
| Race | 0.975 | |||
| Black | 4 (4) | 18 (5) | 18 (4) | |
| White | 76 (84) | 285 (82) | 309 (81) | |
| Other | 10 (11) | 41 (11) | 50 (13) | |
| Body mass index (kg/m2) | 25.4 (22.2, 29.1)4 | 27.3 (23.9, 31.6)4 | 24.4 (21.4, 28.5)2 | < 0.001 |
| Tobacco use (cigarette smoking, cigar, tobacco chewing) | < 0.001 | |||
| Never | 54 (59.34)3 | 178 (53.29)14 | 114 (30.65)6 | |
| Past | 20 (21.98) | 99 (29.64) | 122 (32.80) | |
| Current | 17 (18.68) | 57 (17.07) | 136 (36.56) | |
| Cigarette smoking (Pack-years) | 18.5 (4.5, 40.0)3 | 9.2 (2.4, 21.8)22 | 19.0 (8.0, 33.0)18 | < 0.001 |
| Drinking status | 0.798 | |||
| Never | 13 (14)3 | 51 (15)14 | 49 (13)6 | |
| Past | 58 (63) | 197 (58) | 235 (63) | |
| Current | 20 (21) | 86 (25) | 88 (23) | |
| Drinking category | 0.004 | |||
| Abstainer | 13 (15)12 | 51 (17)49 | 49 (14)37 | |
| Light drinker | 28 (34) | 70 (23) | 55 (16) | |
| Moderate drinker | 16 (19) | 60 (20) | 66 (19) | |
| Heavy drinker | 14 (17) | 65 (21) | 78 (22) | |
| Very heavy drinker | 11 (13) | 53 (17) | 93 (27) | |
| Etiology | < 0.001a | |||
| Alcohol | NA | 58 (17)4 | 147 (39) | |
| Idiopathic | 194 (64) | 143 (41) | ||
| All other | 92 (30) | 88 (25) | ||
| Diabetes present | 12 (16)17 | 70 (21)22 | 135 (37)15 | < 0.001 |
| Exocrine pancreatic dysfunction | < 0.001 | |||
| Yes | 10 (11) | 41 (12) | 141 (37) | |
| No | 47 (58)13 | 168 (48) | 100 (26) | |
| Not tested | 24 (30) | 139 (40) | 137 (36) | |
| Calcification present | 0 (0) | 0 (0) | 262 (69) | N/A |
| Days between enrollment and MRI/MRCPb | − 10.5 (− 90.0, 18.0) | − 18.5 (− 132.5, 6.5) | − 95.5 (− 324.0, − 9.0) | < 0.001 |
| T1 score: pancreas-to-spleen | 1.30 (1.14, 1.45)10 | 1.22 (1.00, 1.43)37 | 1.03 (0.83, 1.27)53 | < 0.001 |
| T1 score: pancreas-to-muscle | 1.29 (0.94, 1.55)10 | 0.91 (0.61, 1.31)36 | 0.98 (0.61, 1.25)53 | < 0.001 |
| T1 score: pancreas-to-liver | 1.03 (0.89, 1.16)10 | 0.99 (0.82, 1.13)37 | 0.84 (0.69, 1.05)52 | < 0.001 |
Medians (25th, 75th quantiles) are reported for continuous variables. Counts (column percentages) are reported for categorical variables
Superscripts indicate the missing value counts and are excluded from the percentage calculation
p values are based on a comparison of the three groups
Comparing chronic abdominal pain, AP/RAP with definite CP
Negative (positive) numbers indicate that the image scan was before (after) enrollment
Before the statistical analysis, we classified participants a priori from the various PROCEED groups according to the MSCP based on their clinical history (i.e., abdominal pain suspected of pancreatic origin, AP or RAP), the Cambridge grade on MRCP, and the presence of parenchymal and/or ductal calcifications on the CT scan as seen on Table 2. The demographics of participants stratified according to the MSCP are listed in Table 3.
Table 2.
Definition of the MSCP
| MSCP | PROCEED cohort | Cambridge grade by MRCP | Calcification by CT | Sample size (n) |
|---|---|---|---|---|
| 0 | Chronic abdominal pain or indeterminate CP | 0 | − | 56 |
| 1 | Acute or recurrent AP | 0 | − | 179 |
| 2 | Chronic abdominal pain or indeterminate CP | 1 or 2 | − | 38 |
| 3 | Acute or recurrent AP | 1 or 2 | − | 169 |
| 4 | Definite CP | 0, 1, or 2 | + | 49 |
| 5 | Definite CP | 3 or 4 | − | 116 |
| 6 | Definite CP | 3 or 4 | + | 213 |
Table 3.
Participant characteristics corresponding to the MSCP
| MSCP 0 n = 56 | MSCP 1 n = 179 | MSCP 2 n = 38 | MSCP 3 n = 169 | MSCP 4 n = 49 | MSCP 5 n = 116 | MSCP 6 n = 213 | ALL n = 820 | p value | |
|---|---|---|---|---|---|---|---|---|---|
| Age at enrollment | 46.5 (34.5, 56.5) | 42.0 (33.0, 55.0) | 55.5 (48.0, 64.0) | 50.0 (40.0, 59.0) | 58.0 (46.0, 64.0) | 49.5 (43.0, 61.0) | 53.0 (43.0, 62.0) | 50.0 (40.0, 60.0) | < 0.001 |
| Gender (male) | 17 (30) | 84 (47) | 14 (37) | 84 (50) | 26 (53) | 57 (49) | 107 (50) | 389 (47) | 0.1211 |
| Race | 0.7264 | ||||||||
| Black | 2 (4) | 8 (5) | 2 (6) | 10 (6) | 0 (0) | 6 (5) | 12 (6) | 40 (5) | |
| Other | 7 (13) | 27 (15) | 3 (8) | 14 (8) | 8 (16) | 14 (12) | 28 (13) | 101 (12) | |
| White | 45 (83) | 141 (80) | 31 (86) | 144 (86) | 41 (84) | 96 (83) | 172 (81) | 670 (83) | |
| Body mass index (kg/m2) | 24.6 (22.0, 28.1)2 | 27.3 (23.9, 32.2)3 | 25.6 (22.7, 30.3)2 | 27.2 (23.9, 31.0)1 | 26.0 (22.2, 28.3)1 | 25.8 (22.2, 30.1) | 23.2 (20.7, 26.8)1 | 25.7 (22.3, 29.7)10 | < 0.001 |
| Tobacco use (Cigarette smoking, cigar, tobacco chewing) | < 0.001 | ||||||||
| Never | 35 (64)1 | 93 (56)12 | 19 (53)2 | 85 (51)2 | 20 (43)3 | 40 (35)2 | 54 (25)1 | 346 (43)23 | |
| Past | 13 (24) | 51 (31) | 7 (19) | 48 (29) | 15 (33) | 41 (36) | 66 (31) | 241 (30) | |
| Current | 7 (13) | 23 (14) | 10 (28) | 34 (20) | 11 (24) | 33 (29) | 92 (43) | 210 (26) | |
| Cigarette smoking (pack-years) | 7.4 (1.5, 15.4)1 | 8.0 (2.1, 20.0)17 | 37.0 (24.0, 42.5)2 | 19.0 (8.0, 39.8)5 | 19.0 (8.0, 39.8)4 | 14.0 (8.0, 29.0)7 | 19.5 (7.8, 34.5)7 | 15.5 (5.5, 30.0)43 | < 0.001 |
| Drinking status | 0.942 | ||||||||
| Never | 10 (18)1 | 27 (16)12 | 3 (8)2 | 24 (14)2 | 7 (15)3 | 13 (11)2 | 29 (14)1 | 113 (14)23 | |
| Past | 33 (60) | 100 (60) | 25 (69) | 97 (58) | 28 (61) | 77 (68) | 130 (61) | 490 (61) | |
| Current | 12 (22) | 40 (24) | 8 (22) | 46 (28) | 11 (24) | 24 (21) | 53 (25) | 194 (24) | |
| Drinking category | 0.0242 | ||||||||
| Abstainers | 10 (20)6 | 27 (18)27 | 3 (9)6 | 24 (16)22 | 7 (16)4 | 13 (13)12 | 29 (15)21 | 113 (16)98 | |
| Light drinkers | 17 (34) | 40 (26) | 11 (34) | 30 (20) | 6 (13) | 14 (13) | 35 (18) | 153 (21) | |
| Moderate drinkers | 8 (16) | 31 (20) | 8 (25) | 29 (20) | 10 (22) | 25 (24) | 31 (16) | 142 (20) | |
| Heavy drinkers | 9 (18) | 33 (22) | 5 (16) | 32 (22) | 11 (24) | 31 (30) | 36 (19) | 157 (22) | |
| Very heavy drinkers | 6 (12) | 21 (14) | 5 (16) | 32 (22) | 11 (24) | 21 (20) | 61 (32) | 157 (22) | |
| Etiology | < 0.001 | ||||||||
| Alcohol | NA | 28 (16) | NA | 30 (18)4 | 14 (29) | 36 (31) | 97 (46) | 205 (28)4 | |
| All others combined | 41 (23) | 51 (31) | 11 (22) | 34 (29) | 43 (20) | 180 (25) | |||
| Idiopathic | 110 (61) | 84 (51) | 24 (49) | 46 (40) | 73 (34) | 337 (47) | |||
| Diabetes present | 3 (6)5 | 36 (21)8 | 9 (35)12 | 34 (22)14 | 15 (33)3 | 32 (29)4 | 88 (43)8 | 217 (28)54 | < 0.001 |
| Exocrine pancreatic dysfunction | < 0.001 | ||||||||
| No | 36 (84)13 | 92 (51) | 11 (29) | 76 (45) | 19 (39) | 43 (37) | 38 (18) | 315 (39) | |
| Not tested | 1 (2) | 73 (41) | 23 (61) | 66 (39) | 17 (35) | 41 (35) | 79 (37) | 300 (37) | |
| Yes | 6 (14) | 14 (8) | 4 (11) | 27 (16) | 13 (27) | 32 (28) | 96 (45) | 192 (24) | |
| Calcification present | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 49 (100) | 0 (0) | 213 (100) | 262 (32) | NA |
| Days from enrollment to MRI/MRCPa | − 15.5 (− 88.0, 18.5) | − 7.0 (− 112.0, 10.0) | − 9.5 (− 99.0, 9.0) | − 27.0 (− 163.0, 2.0) | − 115.0 (− 455.0, − 38.0) | − 57.0 (− 185.5, 0.0) | − 109.0 (− 377.0, − 19.0) | 54.0 (− 197.0, 0.0) | < 0.001 |
Medians (25th, 75th quantiles) are reported for continuous variables
Counts (column percentages) are reported for categorical variables
Superscripts indicate the missing value counts and are excluded from the percentage calculation
p values are based on comparing the three groups on each characteristic
Negative (positive) numbers indicate that the image scan was before (after) enrollment
Imaging protocol
The standard imaging protocol is listed in Table 4. The MR image used for this analysis was an unenhanced T1-weighted gradient echo sequence with fat suppression. MRI/MRCP examinations were performed in 1.5 or 3T and was not selective to any specific manufacturer. Imaging performed at institutions not participating in the PROCEED study was considered acceptable if the examination had the required MR sequence.
Table 4.
Standard MRI imaging protocol of the PROCEED study
| (1) Axial T1-weighted, 3-D, 2-point Dixon gradient echo sequence capable of generating water-only and fat-only images in addition to in-phase and op-phase images |
| (2) T2-weighted images: axial, with fat suppression |
| (3) T2-weighted images (turbo-spin-echo (TSE) or a variant of TSE): axial and coronal, without fat suppression |
| (4) MRCP images: |
| (a) 2D MRCP (thick slab), 40 mm thick, 8 para coronal projections to best show the pancreatic duct from different angles |
| (b) 3D MRCP (thin slab): 2–3 mm, respiratory synchronized 3-D TSE sequence. Create MIP from source images |
| (5) T1-weighted images: Axial T1-weighted 3-D gradient echo with fat suppression |
| (a) Unenhanced |
| (b) Arterial |
| (c) Venous |
| (d) 5-min delayed |
Image analysis
Imaging data collection was performed independently by ten radiologists (TT, AKD, ZKS, STC, CAF, JRG, NK, SKV, AW, and KM) enlisted as co-investigators at nine clinical centers. The protocol for recording imaging data was developed before the initiation of this study, and a training module was completed [10, 26]. All the MR examinations were required to have an unenhanced T1-weighted gradient echo image with fat suppression to measure the T1 signal intensity. The region-of-interest measurement was obtained at a homogenous region of the pancreatic body/tail, avoiding volume averaging from the retroperitoneal fat, edema, vessels, and dilated pancreatic duct. We used the spleen, paraspinal muscle, and liver [29] as reference organs. Three T1 SIRs were calculated by dividing the SI of the pancreas by those of the three reference organs: T1 SIR = T1pancreas/T1 signalreference.
Statistical analysis
Three co-authors (LL, SL, and YY) performed the statistical analysis at the Data Coordinating Center of the CPDPC. The baseline characteristics of the study population are according to the PROCEED subgroups and the MSCP. For the continuous variables, the median, 25th and 75th quantiles and a Kruskal–Wallis test results are presented; for the categorical variables, the count, the proportion, and Fisher’s exact test results are presented. The association between the T1 SIR and the MSCP was examined with one-way analysis of variance, and its statistical significance was determined with an F-test. The distribution of the T1 SIR by each MSCP was visualized with comparative boxplots. To assess whether the MSCP had an association with the T1 SIR that was independent of patient characteristics, we performed a linear regression analysis of the T1 SIR on the MSCP, adjusting for demographics (age, gender, race, body mass index), behavioral covariates (tobacco use and drinking), and clinical covariates (diabetes and exocrine pancreatic dysfunction). We used 0.05 as the threshold of statistical significance.
Results
Study population
Baseline participant characteristics based on the three PROCEED subgroups are shown in Table 1. Compared to participants with chronic abdominal pain, AP/RAP, participants with definite CP were older (49, 46, and 53 years, respectively), had lower BMI (25, 27, and 24, respectively), were more likely to use tobacco (18%: 17/94, 16%: 57/348, and 36%: 136/378, respectively) and drink very heavily (12%: 11/94, 15%: 53/348, and 25%: 93/378 respectively). Men represented 50% (190/378) of the participants with definite CP, 48% (168/348) of the AP/RAP, and 33% (31/94) of those with chronic abdominal pain. Participants with definite CP were more likely to have alcohol etiology (39%: 147/378) than those with AP/RAP (17%: 58/344), more likely to have diabetes (37%: 135/363) than those with AP/RAP (21%: 70/326) and with chronic abdominal pain (16%: 12/77) and more likely to have confirmed exocrine pancreatic dysfunction (37%: 141/378) than those with AP/RAP (12%: 41/348) and those with chronic abdominal pain (11%: 10/94). The median time between enrollment in the PROCEED study and the qualifying MRI/MRCP examination was less than 96 days. No adverse events were reported specifically for the T1-weighted image acquisition. Calcifications were noted on CT studies in 69% (262/378) of participants with definite CP.
T1 score of pancreas-to-spleen
On univariate analysis, the pancreas-to-spleen T1 SIR decreased significantly (p < 0.001) from those with chronic abdominal pain to the AP/RAP and definite CP groups (Table 1). Similarly, a progressive decrease in the T1 score was associated with increasing MSCP (p < 0.0001) in both the unadjusted and adjusted covariate models (Table 5). Mean T1 score of the pancreas-to-spleen were 1.34 in MSCP 0, 1.27 in MSCP 1, 1.21 in MSCP 2, 1.16 in MSCP 3, 1.18 in MSCP 4, 1.12 in MSCP 5, and 1.05 in MSCP 6 (p < 0.0001) (Fig. 2a).
Table 5.
Mean T1 SIR values and differences in each MSCP groups, shown with and without adjustment for covariates using the regression model
| T1 SIR | MSCP | Mean (Q1, median, Q3) | Unadjusted mean difference (95% CI) | Adjusted mean difference (95% CI)a |
|---|---|---|---|---|
| T1 score: pancreas-to-spleen | 0 | 1.34 (1.22, 1.35, 1.51) | Reference | Reference |
| 1 | 1.27 (1.08, 1.29, 1.46) | − 0.07 (− 0.17, 0.03) | − 0.04 (− 0.15, 0.06) | |
| 2 | 1.21 (1.04, 1.19, 1.44) | − 0.13 (− 0.27, 0.01) | − 0.08 (− 0.23, 0.07) | |
| 3 | 1.16 (0.96, 1.18, 1.35) | − 0.17 (− 0.28, − 0.07) | − 0.15 (− 0.26, − 0.04) | |
| 4 | 1.18 (0.86, 1.12, 1.49) | − 0.15 (− 0.29, − 0.01) | − 0.08 (− 0.22, 0.06) | |
| 5 | 1.12 (0.86, 1.05, 1.27) | − 0.22 (− 0.33, − 0.10) | − 0.17 (− 0.29, − 0.05) | |
| 6 | 1.05 (0.82, 1.02, 1.25) | − 0.28 (− 0.39, − 0.18) | − 0.23 (− 0.34, − 0.12) | |
| p value | 0.0001 | < 0.0001 | < 0.0001 | |
| T1 score: pancreas-to-muscle | 0 | 1.28 (1.02, 1.33, 1.57) | Reference | Reference |
| 1 | 0.99 (0.62, 0.92, 1.31) | − 0.290 (− 0.43, − 0.15) | − 0.26 (− 0.408, − 0.12) | |
| 2 | 1.17 (0.85, 1.18, 1.54) | − 0.11 (− 0.31, 0.076) | − 0.12 (− 0.320, 0.08) | |
| 3 | 0.96 (0.64, 0.92, 1.32) | − 0.321 (− 0.465, − 0.17) | − 0.30 (− 0.441, − 0.15) | |
| 4 | 1.07 (0.62, 1.08, 1.50) | − 0.21 (− 0.39, − 0.02) | − 0.14 (− 0.334, 0.04) | |
| 5 | 0.98 (0.65, 1.05, 1.20) | − 0.30 (− 0.45, − 0.14) | − 0.25 (− 0.403, − 0.09) | |
| 6 | 0.95 (0.60, 0.97, 1.2) | − 0.33 (− 0.47, − 0.19) | − 0.30 (− 0.444, − 0.15) | |
| p value | 0.0001 | < 0.0001 | 0.0006 | |
| T1 score: pancreas-to-liver | 0 | 1.06 (0.93, 1.05, 1.17) | Reference | Reference |
| 1 | 1.02 (0.84, 1.01, 1.13) | − 0.03 (− 0.11, 0.05) | − 0.04 (− 0.13, 0.05) | |
| 2 | 1.00 (0.85, 0.98, 1.14) | − 0.05 (− 0.17, 0.06) | − 0.02 (− 0.14, 0.10) | |
| 3 | 0.95 (0.78, 0.96, 1.11) | − 0.10 (− 0.19, − 0.02) | − 0.10 (− 0.19, − 0.01) | |
| 4 | 0.95 (0.74, 0.93,1.15) | − 0.11 (− 0.22, 0.00) | − 0.07 (− 0.19, 0.04) | |
| 5 | 0.89 (0.70, 0.82, 1.05) | − 0.16 (− 0.25, − 0.07) | − 0.14 (− 0.24, − 0.04) | |
| 6 | 0.86 (0.67, 0.84, 1.04) | − 0.20 (− 0.28, − 0.11) | − 0.17 (− 0.26, − 0.07) | |
| p value | 0.0001 | < 0.0001 | 0.0004 |
Results are expressed as the unadjusted or adjusted mean difference in T1 score between each CP stage and the reference group (MSCP 0), along with 95% confidence intervals (CI)
The bottom row presents the p value from an overall F-test of any difference among the seven stages of CP
Covariates adjusted for are age, gender, race, body mass index, tobacco use, pack-years, drinking status, drinking category, diabetes, and exocrine pancreatic dysfunction
Fig. 2.
Distribution of the T1 SIR by the MSCP; a T1 SIR pancreas-to-spleen, b T1 SIR pancreas-to-muscle, and c pancreas-to-liver by the MSCP. The boxplots show the minimum, the 25th, 50th (median), 75th quantiles, and the maximum. The gray dots represent the mean SIR, and the empty dots represent outliers
T1 score of pancreas-to-muscle and pancreas-to-liver
Results for the T1 score of the pancreas-to-liver and pancreas-to-muscle in the MSCP with or without adjustment for covariates are shown in Table 5, and box-and-whisker plots are shown in Fig. 2b and c. Although there was a general trend towards a decline in T1 score with increasing MSCP, the trends were not as linear and had wider confidence intervals than those of the pancreas-to-spleen T1 score.
Receiver operating curve (ROC) analysis
ROC analysis comparing the AP/RAP group with the definite CP group showed an area under the curve (AUC) of 0.660 (95% CI 0.604–0.715). The results were nearly identical when participants from the chronic abdominal pain group were combined with the AP/RAP group and compared with the definite CP group (AUC: 0.657, 95% CI 0.603–0.712).
Discussion
In this large multicenter study, including prospectively enrolled participants, 820 MRI scans were systematically evaluated to demonstrate that the T1 SIR (T1 score) correlates with different stages of CP. In stark contrast to the design of prior studies, our results have high validity and generalizability attributed to the study’s large sample size and independent of confounding factors. These observations have important implications. We propose that the T1 score can serve as an imaging biomarker for the staging of CP severity. In clinical practice, the T1 score can serve as a severity metric for the mechanistic stage of chronic pancreatitis. It may also be considered as a potential outcome measure in clinical trials to assess response to drug therapies or nonsurgical interventions.
Premise
In current practice, CT, MRI with MRCP, endoscopic ultra-sound, and endoscopic pancreatic function tests are used to establish a diagnosis of CP [4]. The MRCP literature adopted the Cambridge classification to grade CP, from ERCP-based studies older than four decades [5]. Findings on the accompanying MRI of the parenchyma have yet to be incorporated into a reporting system. Our study is the first prospective, multicenter study with a large population that aims to fill this gap. The unenhanced T1-weighted gradient echo image used in this study is performed in almost all abdominal MR examinations. Our results show that the T1 score, as a quantitative metric, correlates with the CP stage as determined by either the three PROCEED groups, or a more granular seven-group subclassification (MSCP). Thus, our study validates the potential of the T1 score as a practical imaging biomarker.
The rationale for using the T1 signal of the parenchyma
The cardinal histopathologic features of CP are the triad of fibrosis, loss of acinar tissue (atrophy), and duct changes (distortion and dilatation) [2]. Ductal findings seen on MRCP primarily capture periductal fibrosis and do not reflect the loss of acinar cells or fibrosis in the rest of the parenchyma. Because the pancreatic duct comprises only 4% of the entire pancreas, [30, 31] using ductal imaging alone might delay and render the diagnosis of non-calcific CP elusive. Changes in the MRI parenchymal signal may provide a complete evaluation of CP [9–11] since acinar cells comprise 85% of the pancreas [32]. Many prior studies and consensus guidelines have noted the potential benefit of parenchymal imaging [9–11].
The pancreas is a highly productive exocrine gland of the digestive system. Each day, it secretes approximately 1–2 L of proteinaceous fluid that contains digestive enzymes and bicarbonate [33, 34]. Due to the abundance of proteinaceous material in the acinar cells, the normal pancreas shows a higher T1 SI than other solid organs in the upper abdomen [15, 22] as seen in an MSCP 0 participant in Fig. 3. Several publications have reported a correlation of the T1 SIR with the diagnosis and staging of CP using the pancreas-to-spleen, pancreas-to-paraspinal muscle, and pancreas-to-liver, all of which have been reported as useful methods for evaluation of CP [15, 19, 22, 29, 35]. Some studies have reported a correlation of the T1 SIR specifically with pancreatic exocrine dysfunction as measured by the endoscopic pancreatic function tests [16, 19]. In these studies, the decision to correlate the T1 SIR with the ductal features or exocrine function rather than histopathology reflects the challenges associated with acquiring pancreatic tissue from humans (e.g., the procedural complications of core biopsies) and interpreting the results (e.g., the absence of a universally accepted histological grading system for CP) [2]. Four recent publications have correlated the MRI parenchymal features (T1 SIR, T1 relaxation time, arterial-to-delayed venous enhancement ratio, diffusion-weighted imaging, and MR elastography) with surgical specimens [12, 22–24]. These studies reported a significant correlation of MRI parenchymal findings with the degree of fibrosis. In a recent study of 60 patients who had pancreatic resections and a preoperative MRI, the pancreas-to-spleen T1 SIR, pancreas-to-muscle T1 SIR, arterial-to-venous enhancement ratio of the parenchyma, and Cambridge grades were correlated with the fibrosis score [12]. The pancreas-to-spleen T1 SIR showed the highest correlation with fibrosis (r = − 0.54, p = 0.0001), followed by the arterial-to-venous enhancement ratio (r = − 0.39), Cambridge classification (r = 0.26), and pancreas-to-muscle T1 SIR (r = 0.19). The strongest inter-observer agreement was also with the pancreas-to-spleen T1 SIR (weighted kappa of 0.78), which was higher than what was previously reported for the Cambridge classification [7]. Histopathologic correlation studies agree that the T1 SIR as a quantitative metric can detect acinar cell replacement by the chronic fibroinflammatory process and decreased production of proteinaceous material.
Fig. 3.
T1 signal intensity of the pancreas in an MSCP 0 participant. This is an unenhanced axial T1-weighted gradient echo image with fat suppression in a 49-year-old woman with a history of abdominal pain of suspected CP origin but a normal MRCP and CT. T1 signal intensity of the pancreas (arrow) is higher than that of the spleen (S), paraspinal muscle (M), and liver (L). Circles represent region-of-interest measurements
Prior interobserver agreement studies have suggested that parenchymal features may yield a less subjective evaluation of CP. A multicenter study reported that the interobserver variability of the Cambridge classification given by experienced abdominal radiologists was moderate (weighted kappa of 0.68). Another multicenter study agreed that interobserver agreement was better for quantitative measures of the pancreas than for subjective imaging findings [8]. All things considered, we conclude that the T1 score is a practical and noninvasive imaging method for assessing CP staging and should improve the care of CP patients.
Implications for using the T1 score
A T1 score may positively impact patient care if used in clinical practice to detect parenchymal changes of non-calcific CP before moderate-to-severe ductal changes become visible with MRCP. The T1 score of the pancreas-to-spleen progressively declines from ~ 1.3 to ~ 1.0 as the CP progresses. In other words, the normal pancreas has a 30% higher T1 signal intensity than the spleen, but this signal decreases with the progression of CP. Figure 4 shows decreased T1 SIR in an MSCP 5 participant. We saw this decline whether we used the three PROCEED groups or the more granular MSCP categorization. Prior studies have reported that the T1 SIR has the potential to detect CP earlier than ductal imaging [16, 35]. This is presumably because T1 SIR correlates with exocrine pancreatic dysfunction which can occur before the periductal fibrosis becomes visible by MRCP. A recent longitudinal study confirmed that parenchymal findings to be a better imaging biomarker than ductal changes for follow-up of CP patients since the damage to the ductal anatomy might not be reversible with therapy [9]. In clinical practice, temporal changes in the T1 score may also facilitate the assessment of disease progression. In clinical trials, they may facilitate the evaluation of response to a drug or nonsurgical intervention. Longitudinal studies such as the PROCEED are currently underway to investigate this potential. Although our analysis shows that the T1 score is a valuable quantitative metric for staging the disease, the performance characteristics of the T1 score (AUC of 0.66) do not support using it as the standalone diagnostic test for CP.
Fig. 4.
T1 signal intensity of the pancreas in an MSCP 5 participant. This is an unenhanced axial T1-weighted gradient echo image in a 46-year-old woman with a history of CP (Cambridge grade 3). The T1-weighted signal intensity of the pancreas (arrow) compared to that of the spleen (S), liver (L), and paraspinal muscle (M) is lower than the case in Fig. 3
Limitations and caveats
Severe fatty replacement, heavy calcification, edema, or iron deposition of the primary (pancreas) or reference organ (spleen, paraspinal muscle, or liver) can alter the T1 signal. Clinical scenarios that can alter T1 signal are cystic fibrosis (due to severe fatty infiltration of the pancreas), hemochromatosis or hemosiderosis (iron deposition in the pancreas, spleen, or liver), acute pancreatitis (edema in the parenchyma) and segmental cholestasis in the liver [36]. It would be helpful to review the MR fat detection sequences (e.g., DIXON series) to make sure that the region-of-interest measurement is obtained from a segment of the pancreas where fatty infiltration is not present. Measurements should be made within the homogenous region of the parenchyma and avoid the edge of the organ where edge artifact can alter the T1 signal. Ideally, measurements should be performed in the head, body and tail of the pancreas and use the average of the entire pancreas or individual segments to calculate the signal intensity ratio.
Conclusion
In this multicenter prospective study, we have confirmed that the T1 score declines linearly with the progression of CP and can be used as an imaging biomarker for CP staging. For clinical practice, we suggest using the T1 score of the pancreas-to-spleen as a metric for the mechanistic staging of chronic pancreatitis. The T1 score also has the potential to be used in clinical trials to assess response to drug therapies or nonsurgical interventions, and longitudinal studies such as the PROCEED study are underway to confirm this potential.
Funding
Research reported in this publication was supported by the National Cancer Institute (NCI) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under award numbers: U01DK108288 (SSV, SKV, NT); U01DK108300 (WGP, STC); U01DK108306 (DY, AKD); U01DK108314 (AW, SJP); UO1DK108300 (CEF, JG); U01DK108323 (ELF, TT); U01DK108326 (WEF, CAF); U01DK108327 (PAH, DLC, ZKS); U01DK108328 (SL, LL). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Abbreviations
- CP
Chronic pancreatitis
- CT
Computerized tomography
- MRI
Magnetic resonance imaging
- MRCP
Magnetic resonance cholangiopancreatography
- SIR
Signal intensity ratio
- MSCP
Mechanistic stages of chronic pancreatitis
- CPDPC
The Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer
- PROCEED
Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies
Footnotes
Conflict of interest Dr. Forsmark receives consultant fee or honorarium from Nestle HealthCare Nutrition, Inc., Parexel International Corp and Medialis, Ltd., Dr. Park is a consultant for Abbvie.
References
- 1.Stevens T, Conwell DL, Zuccaro G. Pathogenesis of chronic pancreatitis: an evidence-based review of past theories and recent developments. Am J Gastroenterol. 2004;99(11):2256–70. doi: 10.1111/j.1572-0241.2004.40694.x. [DOI] [PubMed] [Google Scholar]
- 2.Esposito I, Hruban RH, Verbeke C, Terris B, Zamboni G, Scarpa A, et al. Guidelines on the histopathology of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and the European Pancreatic Club. Pancreatology. 2020;20(4):586–93. doi: 10.1016/j.pan.2020.04.009. [DOI] [PubMed] [Google Scholar]
- 3.Gardner TB, Adler DG, Forsmark CE, Sauer BG, Taylor JR, Whitcomb DC. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020;115(3):322–39. doi: 10.14309/ajg.0000000000000535. [DOI] [PubMed] [Google Scholar]
- 4.Conwell DL, Lee LS, Yadav D, Longnecker DS, Miller FH, Mortele KJ, et al. American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143–62. doi: 10.1097/MPA.0000000000000237. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Sarner M, Cotton PB. Classification of pancreatitis. Gut. 1984;25(7):756–9. doi: 10.1136/gut.25.7.756. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Swensson J, Akisik F, Collins D, Olesen SS, Drewes AM, Frokjaer JB. Is Cambridge scoring in chronic pancreatitis the same using ERCP and MRCP?: A need for revision of standards. Abdom Radiol (NY). 2021;46(2):647–54. doi: 10.1007/s00261-020-02685-2. [DOI] [PubMed] [Google Scholar]
- 7.Tirkes T, Shah ZK, Takahashi N, Grajo JR, Chang ST, Wachsman AM, et al. Inter-observer variability of radiologists for Cambridge classification of chronic pancreatitis using CT and MRCP: results from a large multi-center study. Abdom Radiol (NY). 2020;45(5):1481–7. doi: 10.1007/s00261-020-02521-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Trout AT, Abu-El-Haija M, Anupindi SA, Marine MB, Murati M, Phelps AS, et al. Interobserver Agreement for CT and MRI Findings of Chronic Pancreatitis in Children: A Multicenter Ancillary Study Under the INSPPIRE Consortium. American Journal of Roentgenology. 2022. doi: 10.2214/AJR.21.27234. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Steinkohl E, Olesen SS, Mark EB, Hansen TM, Frandsen LK, Drewes AM, et al. Progression of parenchymal and ductal findings in patients with chronic pancreatitis: A 4-year follow-up MRI study. Eur J Radiol. 2020;125:108868. doi: 10.1016/j.ejrad.2020.108868. [DOI] [PubMed] [Google Scholar]
- 10.Tirkes T, Shah ZK, Takahashi N, Grajo JR, Chang ST, Venkatesh SK, 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. Radiology. 2019;290(1):207–15. doi: 10.1148/radiol.2018181353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Frokjaer JB, Akisik F, Farooq A, Akpinar B, Dasyam A, Drewes AM, et al. Guidelines for the Diagnostic Cross Sectional Imaging and Severity Scoring of Chronic Pancreatitis. Pancreatology. 2018;18(7):764–73. doi: 10.1016/j.pan.2018.08.012. [DOI] [PubMed] [Google Scholar]
- 12.Tirkes T, Saeed OA, Osuji VC, Kranz CE, Roth AA, Patel AA, et al. Histopathologic correlation of pancreatic fibrosis with pancreatic magnetic resonance imaging quantitative metrics and Cambridge classification. Abdom Radiol (NY). 2022. doi: 10.1007/s00261-022-03532-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Balci C MRI assessment of chronic pancreatitis. Diagn Interv Radiol. 2011;17(3):249–54. doi: 10.4261/1305-3825.DIR.3889-10.0. [DOI] [PubMed] [Google Scholar]
- 14.Parakh A, Tirkes T. Advanced imaging techniques for chronic pancreatitis. Abdom Radiol (NY). 2020;45(5):1420–38. doi: 10.1007/s00261-019-02191-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Winston CB, Mitchell DG, Outwater EK, Ehrlich SM. Pancreatic signal intensity on T1-weighted fat saturation MR images: clinical correlation. J Magn Reson Imaging. 1995;5(3):267–71. doi: 10.1002/jmri.1880050307. [DOI] [PubMed] [Google Scholar]
- 16.Tirkes T, Fogel EL, Sherman S, Lin C, Swensson J, Akisik F, et al. Detection of exocrine dysfunction by MRI in patients with early chronic pancreatitis. Abdom Radiol (NY). 2017;42(2):544–51. doi: 10.1007/s00261-016-0917-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Tirkes T, Lin C, Fogel EL, Sherman SS, Wang Q, Sandrasegaran K. T1 mapping for diagnosis of mild chronic pancreatitis. J Magn Reson Imaging. 2017;45(4):1171–6. doi: 10.1002/jmri.25428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Tirkes T, Lin C, Cui E, Deng Y, Territo PR, Sandrasegaran K, et al. Quantitative MR Evaluation of Chronic Pancreatitis: Extra-cellular Volume Fraction and MR Relaxometry. AJR Am J Roentgenol. 2018;210(3):533–42. doi: 10.2214/AJR.17.18606. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Balci NC, Smith A, Momtahen AJ, Alkaade S, Fattahi R, Tariq S, et al. MRI and S-MRCP findings in patients with suspected chronic pancreatitis: correlation with endoscopic pancreatic function testing (ePFT). J Magn Reson Imaging. 2010;31(3):601–6. doi: 10.1002/jmri.22085. [DOI] [PubMed] [Google Scholar]
- 20.Alkaade S, Cem Balci N, Momtahen AJ, Burton F. Normal pancreatic exocrine function does not exclude MRI/MRCP chronic pancreatitis findings. J Clin Gastroenterol. 2008;42(8):950–5. doi: 10.1097/MCG.0b013e31812f4ef5. [DOI] [PubMed] [Google Scholar]
- 21.Bilgin M, Bilgin S, Balci NC, Momtahen AJ, Bilgin Y, Klor HU, et al. Magnetic resonance imaging and magnetic resonance cholangiopancreatography findings compared with fecal elastase 1 measurement for the diagnosis of chronic pancreatitis. Pancreas. 2008;36(1):e33–9. doi: 10.1097/mpa.0b013e318150e557. [DOI] [PubMed] [Google Scholar]
- 22.Watanabe H, Kanematsu M, Tanaka K, Osada S, Tomita H, Hara A, et al. Fibrosis and postoperative fistula of the pancreas: correlation with MR imaging findings--preliminary results. Radiology. 2014;270(3):791–9. doi: 10.1148/radiol.13131194. [DOI] [PubMed] [Google Scholar]
- 23.Trikudanathan G, Walker SP, Munigala S, Spilseth B, Malli A, Han Y, et al. Diagnostic Performance of Contrast-Enhanced MRI With Secretin-Stimulated MRCP for Non-Calcific Chronic Pancreatitis: A Comparison With Histopathology. Am J Gastroenterol. 2015;110(11):1598–606. doi: 10.1038/ajg.2015.297. [DOI] [PubMed] [Google Scholar]
- 24.Liu C, Shi Y, Lan G, Xu Y, Yang F. Evaluation of Pancreatic Fibrosis Grading by Multiparametric Quantitative Magnetic Resonance Imaging. J Magn Reson Imaging. 2021;54(5):1417–29. doi: 10.1002/jmri.27626. [DOI] [PubMed] [Google Scholar]
- 25.Whitcomb DC, Frulloni L, Garg P, Greer JB, Schneider A, Yadav D, et al. Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition. Pancreatology. 2016;16(2):218–24. doi: 10.1016/j.pan.2016.02.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Yadav D, Park WG, Fogel EL, Li L, Chari ST, Feng Z, et al. PRO-spective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies: Rationale and Study Design for PROCEED From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas. 2018;47(10):1229–38. doi: 10.1097/MPA.0000000000001170. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.The Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC) https://cpdpc.mdanderson.org (2015). Accessed.
- 28.Serrano J, Andersen DK, Forsmark CE, Pandol SJ, Feng Z, Srivastava S, et al. Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer: From Concept to Reality. Pancreas. 2018;47(10):1208–12. doi: 10.1097/MPA.0000000000001167. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Gallix BP, Bret PM, Atri M, Lecesne R, Reinhold C. Comparison of qualitative and quantitative measurements on unenhanced T1-weighted fat saturation MR images in predicting pancreatic pathology. J Magn Reson Imaging. 2005;21(5):583–9. doi: 10.1002/jmri.20310. [DOI] [PubMed] [Google Scholar]
- 30.Barreto SG, Carati CJ, Toouli J, Saccone GT. The islet-acinar axis of the pancreas: more than just insulin. Am J Physiol Gastrointest Liver Physiol. 2010;299(1):G10–22. doi: 10.1152/ajpgi.00077.2010. [DOI] [PubMed] [Google Scholar]
- 31.Tang X, Kusmartseva I, Kulkarni S, Posgai A, Speier S, Schatz DA, et al. Image-Based Machine Learning Algorithms for Disease Characterization in the Human Type 1 Diabetes Pancreas. Am J Pathol. 2021;191(3):454–62. doi: 10.1016/j.ajpath.2020.11.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Atkinson MA, Campbell-Thompson M, Kusmartseva I, Kaestner KH. Organisation of the human pancreas in health and in diabetes. Diabetologia. 2020;63(10):1966–73. doi: 10.1007/s00125-020-05203-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Ishiguro H, Yamamoto A, Nakakuki M, Yi L, Ishiguro M, Yamaguchi M, et al. Physiology and pathophysiology of bicarbonate secretion by pancreatic duct epithelium. Nagoya J Med Sci. 2012;74(1–2):1–18. [PMC free article] [PubMed] [Google Scholar]
- 34.Pandol SJ. Water and Ion Secretion from the Pancreatic Ductal System. The Exocrine Pancreas. Morgan & Claypool Life Sciences; 2010. [PubMed] [Google Scholar]
- 35.Balci NC, Alkaade S, Magas L, Momtahen AJ, Burton FR. Suspected chronic pancreatitis with normal MRCP: findings on MRI in correlation with secretin MRCP. J Magn Reson Imaging. 2008;27(1):125–31. doi: 10.1002/jmri.21241. [DOI] [PubMed] [Google Scholar]
- 36.Gabata T, Matsui O, Kadoya M, Yoshikawa J, Ueda K, Kawamori Y, et al. Segmental hyperintensity on T1-weighted MRI of the liver: indication of segmental cholestasis. J Magn Reson Imaging. 1997;7(5):855–7. doi: 10.1002/jmri.1880070513. [DOI] [PubMed] [Google Scholar]