Chronic Pancreatitis (CP) is a progressive inflammatory disorder of the pancreas characterized by recurrent abdominal pain, and in later stages, exocrine and endocrine insufficiency. This condition arises from persistent inflammation and fibrosis, gradually disrupting the pancreas’s normal function. The exact mechanisms driving CP are still debated, but the necrosis-fibrosis theory, suggesting repeated acute pancreatic injuries leading to chronic changes, is widely accepted.1 However, the development of CP likely involves a complex interplay of various factors.
Diagnosing CP presents a significant challenge in clinical practice. The wide array of diagnostic tools available reflects the complexity of confirming CP, as no single test definitively establishes the diagnosis. Early Chronic Pancreatitis, sometimes referred to as minimal change chronic pancreatitis3, is particularly difficult to diagnose. Patients may exhibit symptoms suggestive of CP, yet lack clear abnormalities on imaging. Furthermore, pancreatic function tests (PFTs), which can aid in diagnosis, might remain normal for years after symptom onset. Conversely, some individuals show pancreatic fibrosis without any clinical symptoms of CP, indicating that fibrosis severity doesn’t directly correlate with pancreatic dysfunction.8 The absence of a definitive gold standard has hindered advancements in CP diagnostics. While Endoscopic Retrograde Cholangiopancreatography (ERCP) was once considered a potential gold standard, it primarily assesses ductal anatomy and can misattribute ductal changes to CP when they are due to other factors like aging or obesity.20, 21 Histology, though currently the gold standard, is not routinely obtainable in clinical practice. Even post-mortem tissue analysis can be complicated by age-related pancreatic changes that mimic CP.22 Therefore, a definitive diagnosis of chronic pancreatitis typically requires integrating clinical history, imaging results, and function test findings. Given that CP management focuses on symptom control and slowing disease progression rather than cure, accurate diagnosis is crucial before initiating long-term treatment.
Clinical Presentation and Risk Factors for Chronic Pancreatitis
Patients with chronic pancreatitis commonly present with chronic abdominal pain, steatorrhea (fatty stools), diabetes mellitus, and unexplained weight loss. The initial assessment of patients suspected of having CP should include a detailed medical history, particularly focusing on key risk factors like alcohol and tobacco use, as these significantly increase the likelihood of CP. In the United States, alcohol abuse remains the leading cause of chronic pancreatitis.6 Research by Yadav et al. demonstrated a significantly higher prevalence of heavy alcohol consumption among CP patients compared to control groups. Heavy drinking was defined as 2–5 drinks/day for men and 1–5 drinks/day for women. The study revealed odds ratios of 3.10 for heavy drinking in CP. Notably, the same study identified cigarette smoking as an independent, dose-dependent risk factor for both CP and recurrent acute pancreatitis.7 Smoking one pack of cigarettes or more daily was associated with a 3.3-fold increased risk of developing chronic pancreatitis.7
Two established classification systems, TIGAR-O and MANNHEIM (table 1), help categorize risk factors for CP and guide clinicians in determining when to initiate diagnostic testing. Current diagnostic modalities fall into two main categories: imaging (Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Endoscopic Ultrasound (EUS), ERCP) and pancreatic function tests (direct and indirect). Each test plays a specific role in establishing a CP diagnosis. A structured approach to CP evaluation is essential to avoid unnecessary tests and diagnostic errors. This section will cover initial evaluation strategies and the application of imaging and PFTs in diagnosing suspected CP.
Table 1. Major Classification Systems for Chronic Pancreatitis Etiology
| Classification for CP Etiology |
|---|
| Traditional Classification |
| Alcohol, idiopathic, hereditary, obstructive, hyperlipidemia |
| TIGAR-O Classification |
| Toxic-metabolic: alcohol, tobacco smoking, hypercalcemia, hyperlipidemia, chronic renal failure, medications, toxins |
| Idiopathic: early onset, late onset, tropical |
| Genetic mutations: PRSS1, CFTR, SPINK1, and others |
| Autoimmune: isolated, syndromic |
| Recurrent and severe AP-associated CP: postnecrotic (severe AP), vascular disease/ischemic, postirradiation |
| Obstructive: pancreas divisum, sphincter of Oddi disorders, duct obstruction (e.g., tumor), posttraumatic pancreatic duct scars |
| MANNHEIM Classification |
| M – Multiple risk factors including: |
| Alcohol consumption: excessive (>80 g/d), increased (20–80 g/d), moderate ( |
| Nicotine consumption |
| Nutritional factors: high caloric proportion of fat and protein, hyperlipidemia |
| A – Hereditary factors: hereditary, familial, idiopathic (early onset, late onset), tropical |
| N – Efferent duct factors: pancreas divisum, annular pancreas and other congenital abnormalities of the pancreas, pancreatic duct obstruction (e.g., tumors), posttraumatic pancreatic duct scars, sphincter of Oddi dysfunction |
| N – Immunological factors: autoimmune pancreatitis |
| H – Miscellaneous and rare metabolic disorders: hypercalcemia, hyperparathyroidism, chronic renal failure, drugs, toxins |
Imaging Modalities for Chronic Pancreatitis Diagnosis
Computed Tomography (CT) in CP Diagnosis
Computed tomography (CT) is often the first-line imaging modality for evaluating suspected chronic pancreatitis. CT scans offer several advantages: wide availability, detailed visualization of pancreatic morphology changes associated with CP, and effectiveness in detecting advanced disease changes. CT is also valuable for identifying extra-pancreatic conditions that may mimic CP symptoms and for detecting complications of acute and chronic pancreatitis, such as pseudocysts, biliary or duodenal obstruction, venous thrombosis, pseudoaneurysms, and pancreatico-pleural fistulas.4 Classic CT findings in CP include pancreatic duct dilatation (68%), pancreatic atrophy (54%), and pancreatic calcifications (50%).9 (See figure 1). However, it is important to note that a normal CT scan does not exclude CP, especially in early stages, making diagnosis challenging in some patients. While pancreatic atrophy is a common finding in CP, it is non-specific and can also occur with normal aging. Conversely, as shown in Figure 1, pancreatic enlargement can also be observed in chronic pancreatitis. While CT is effective in visualizing parenchymal changes in late-stage CP, it is less sensitive in detecting subtle ductal changes characteristic of early CP.
Figure 1. Computed Tomography Findings in Chronic Pancreatitis
Figure 1: Illustrative CT scan findings commonly observed in Chronic Pancreatitis, including pancreatic duct dilatation, atrophy, and calcifications.
Magnetic Resonance Cholangiopancreatography (MRCP) for CP Diagnosis
While CT technology has significantly improved, particularly in multi-detector and multi-phase imaging, it has limitations in diagnosing CP, especially in assessing pancreatic ductal anatomy and early-stage CP. Magnetic Resonance Cholangiopancreatography (MRCP) and secretin-enhanced MRCP (sMRCP) offer enhanced sensitivity and specificity for identifying characteristic CP changes. MRCP excels at visualizing both pancreatic parenchyma and ducts. Parenchymal changes detectable by MRI include pancreatic atrophy, decreased T1 signal intensity, irregular contour of the pancreatic head or body, heterogeneous parenchyma, and delayed gadolinium enhancement after contrast administration.6 Ductal changes include intraductal filling defects suggestive of calculi, main pancreatic duct dilation, side branch dilation, irregular duct contour, and reduced ductal compliance following secretin administration.6 Although standardized diagnostic criteria for CP using MRCP are still evolving, pancreatic imaging grading systems, such as the modified Cambridge Classification, help categorize findings from normal to severe CP (see table 2). With the increasing use of sMRCP, a comprehensive grading system that incorporates both parenchymal and ductal changes is needed to improve early CP diagnosis.
Table 2. M-ANNHEIM Pancreatic Imaging Criteria for Chronic Pancreatitis
| Cambridge Grading | CT, US, MRI/MRCP | EUS |
|---|---|---|
| Normal | Quality Study depicting whole gland without abnormal features (0 points) | Quality Study depicting whole gland without abnormal features (0 points) |
| Equivocal | One abnormal feature (1 point) | Four or fewer abnormal Features (no differentiation between equivocal and mild) (1 point) Five or more abnormal features (no differentiation between moderate and marked) (3 points) |
| Mild changes | Two or more abnormal features, but normal main pancreatic duct | Equivocal/Mild: Four or fewer abnormal Features (no differentiation between equivocal and mild) (1 point) |
| Moderate changes | Two or more abnormal features, including minor main pancreatic duct abnormalities (either enlargement between 2 and 4 mm or increased echogenicity of the duct wall) (3 points) | Moderate/Marked: Five or more abnormal features (no differentiation between moderate and marked) (3 points) |
| Marked changes | As above with one or more of the required features of marked changes (4 points) | Moderate/Marked: Five or more abnormal features (no differentiation between moderate and marked) (3 points) |
Abnormal Features for CT, US, MRI/MRCP: Main pancreatic duct enlargement (2–4 mm), slight gland enlargement (up to 2× normal), heterogeneous parenchyma, small cavities (≤10 mm), irregular ducts, focal acute pancreatitis, increased echogenicity of the main pancreatic duct wall, irregular head/body contour.
Marked Changes for CT, US, MRI/MRCP: Large cavities (>10 mm), gross gland enlargement (>2× normal), intraductal filling defects or calculi, duct obstruction, stricture or gross irregularity, contiguous organ invasion.
Secretin-enhanced MRCP (sMRCP) provides a non-invasive method to assess pancreatic exocrine function. Secretin, a peptide hormone, stimulates pancreatic duct cells to release bicarbonate-rich fluid into the duodenum. sMRCP uses intravenous secretin and monitors T2 intensity changes within the pancreatic duct as a surrogate marker for exocrine function.11 sMRCP offers improved visualization of pancreatic ducts and side branches compared to conventional MRCP. ERCP was previously considered the gold standard due to its ability to detect subtle ductal and side branch changes by retrograde contrast administration, causing ductal over-distension.11 While sMRCP does not cause over-distension, it still provides adequate visualization of the main pancreatic duct, side branches, and accessory ducts.11
In healthy individuals, secretin administration typically leads to pancreatic duct distension to about two-thirds of its diameter.11 This distension capacity decreases with increasing CP severity, likely due to pancreatic fibrosis.11 Pancreatic duct flow rates, another measure obtainable from sMRCP, also correlate with pancreatic function. A study evaluating 76 CP patients measured small bowel water volume changes after secretin stimulation to derive flow rates. Normal individuals had flow rates of 7.4 ± 2.9 ml/min, significantly higher than patients with severe CP (5.3 ± 2.4 ml/min), pancreatic atrophy (3.8 ± 3.1 ml/min), and stone obstruction (5.3 ± 2.4 ml/min).13 These findings indicate that pancreatic duct flow diminishes with increasing fibrosis and atrophy, suggesting sMRCP’s utility in evaluating a spectrum of pancreatic disorders, not just CP.
Endoscopic Ultrasound (EUS) in Diagnosing CP
Endoscopic Ultrasound (EUS) has become an increasingly valuable tool in the diagnostic workup for chronic pancreatitis. While diagnosing advanced CP is usually straightforward due to classic symptoms, risk factors, and evident imaging abnormalities on CT or MRCP, early CP diagnosis is often challenging and can be mistaken for other conditions. EUS is particularly useful in these early stages, while less critical in advanced CP diagnosis.
Similar to MRCP, EUS assesses both parenchymal and ductal changes in the pancreas to diagnose CP.6,14 The International Working Group has proposed nine EUS criteria (4 parenchymal and 5 ductal) for CP diagnosis.16 (See table 3). The presence of more than five criteria is considered definitive for CP, while two or fewer criteria effectively rule it out. Patients with 2–5 criteria have an indeterminate diagnosis and require further evaluation with pancreatic function testing. These nine criteria have been linked to specific histological changes observed in specimens obtained after EUS evaluation.17 However, EUS findings can be non-specific and observed in healthy individuals, as demonstrated by Rajan et al.15 Their study of 120 patients without known pancreatic disease revealed that normal aging increases the likelihood of at least one parenchymal and one ductal EUS abnormality, observed in 23% of patients over 60 years old.
Table 3. EUS Criteria for Chronic Pancreatitis and Histological Correlates
| EUS Criteria | Histologic Correlate |
|---|---|
| Parenchymal Features | |
| Hyperechoic foci | Focal Fibrosis |
| Hyperechoic strands | Bridging Fibrosis |
| Lobular contour | Interlobular Fibrosis |
| Cysts | Cyst/pseudocyst |
| Ductal Features | |
| Main duct dilation (mm) | >3 head, > 2 body, >1 tail |
| Duct irregularity | Focal dilation/narrowing |
| Hyperechoic margins | Periductal Fibrosis |
| Visible side branches | Side branch dilation |
| Stones | Calcified stones |
The interpretation of EUS findings in CP remains debated due to potential overlap with age-related changes, smoking effects, or obesity, unrelated to CP. Furthermore, EUS is operator-dependent, leading to potential inter-endosonographer variability, a major limitation for its widespread diagnostic use. A study comparing EUS interpretations by 11 experienced endosonographers showed moderate agreement on a final CP diagnosis and for duct dilation and lobularity features, but poor agreement for the other seven EUS features.18 To improve standardization, the Rosemont criteria were developed, representing a consensus among 32 endosonographers to standardize EUS interpretation in CP.14 The Rosemont criteria categorized findings into major and minor criteria. Major A criteria include hyperechoic foci with shadowing and main pancreatic duct calculi. Major B criteria include lobularity with honeycombing. Minor criteria encompass dilated ducts (>3.5 mm), pancreatic cysts, irregular pancreatic duct, dilated side branches (>1 mm), hyperechoic duct wall, strands, non-shadowing hyperechoic foci, and lobularity with noncontiguous lobules.14 Direct comparisons of Rosemont criteria to standard criteria show limited improvement in CP diagnosis compared to pancreatic function testing.
In summary, EUS is highly sensitive for detecting pancreatic abnormalities and useful in early CP diagnosis. However, limitations include interobserver variability and low specificity of some findings. The Rosemont criteria are the most widely used diagnostic criteria but have suboptimal accuracy, especially in early CP. Given the numerous potential causes for pancreatic EUS abnormalities, EUS should not be the sole basis for CP diagnosis. Future research is needed to refine EUS diagnostic accuracy, including novel techniques like EUS elastography and assessing pancreatic duct compliance after secretin stimulation.
Endoscopic Retrograde Cholangiopancreatography (ERCP) in CP Diagnosis
Endoscopic Retrograde Cholangiopancreatography (ERCP) is now rarely used for diagnosing CP. While ERCP provides detailed pancreatograms showing changes related to chronic fibrosis and atrophy, the advent of CT, MRCP, and EUS has largely relegated ERCP to therapeutic interventions rather than purely diagnostic purposes.
Historically, pancreatogram findings indicative of CP included changes in the main pancreatic duct caliber and contour, side branch visualization, intraductal filling defects, strictures, and cavity formation. A normal main pancreatic duct typically tapers smoothly from head to tail.23 Normal duct size is variable, influenced by age, race, and gender. A 1982 study reported average main duct sizes of 3.6 mm (head), 2.7 mm (body), and 1.6 mm (tail),24 with an upper normal limit of 5–6 mm. Historically, interpretation of pancreatogram findings was inconsistent. The Cambridge criteria aimed to standardize pancreatogram interpretation, classifying ductal changes as equivocal, mild, moderate, or severe (see table 5).23 A normal pancreatogram shows no MPD or side branch abnormalities; an equivocal pancreatogram shows minimal abnormalities.23
Table 5. Cambridge Criteria for ERCP in Chronic Pancreatitis Diagnosis
| Grade | Main Pancreatic Duct | Branch Ducts |
|---|---|---|
| Normal | Normal | Normal |
| Cambridge 1 (equivocal) | Normal | <3 abnormal |
| Cambridge 2 (mild) | Normal | ≥3 abnormal |
| Cambridge 3 (moderate) | Abnormal | >3 abnormal |
| Cambridge 4 (severe) | Abnormal * | >3 abnormal |
*Abnormal MPD includes large cavity >10 mm, Intraductal filling defects, duct obstruction (stricture), duct dilation or irregularity, calculi/pancreatic calcification, or contiguous organ invasion.
Despite ERCP’s sensitivity in detecting pancreatic duct changes, it has several limitations for CP diagnosis. Similar to EUS, ERCP is operator-dependent and prone to interobserver variability, affecting both pancreatogram quality and image interpretation. Pancreatograms also do not assess parenchymal changes characteristic of CP. Critically, ERCP is the most invasive diagnostic modality, carrying risks such as post-ERCP pancreatitis. Therefore, the American Society for Gastrointestinal Endoscopy (ASGE) recommends ERCP for CP diagnosis only after less invasive imaging methods are inconclusive.19
Pancreatic Function Tests (PFTs) in CP Diagnosis
Pancreatic Function Tests (PFTs) are categorized as indirect (non-invasive) or direct (invasive).32 Indirect PFTs assess exocrine function without direct pancreatic hormonal stimulation, including serum trypsinogen, fecal elastase, and fecal fat measurements. Direct PFTs involve hormonal stimulation of the pancreas with secretin or cholecystokinin (CCK).
Indirect PFTs are advantageous due to their low cost, non-invasiveness, and ease of outpatient performance. A 72-hour fecal fat collection, an indirect PFT, is more useful for quantifying steatorrhea and monitoring response to pancreatic enzyme supplementation in established CP, rather than for initial diagnosis.25 Patient cooperation and laboratory coordination challenges limit its diagnostic use. Fecal pancreatic elastase-1 is a more commonly used indirect PFT. A 1999 study by Gullo et al. measuring fecal elastase-1 levels in healthy individuals, CP patients (stratified by severity), and patients with non-pancreatic GI disorders showed that healthy subjects and most non-pancreatic GI patients had elastase levels >190 µg/g, whereas only 10 of 44 CP patients did. Notably, all 22 patients with severe CP had levels <100 µg/g.27 Fecal elastase-1 has high sensitivity (93%) and specificity (97%) for diagnosing exocrine pancreatic insufficiency.26 False positives can occur with small intestinal bacterial overgrowth or non-formed stool samples.28 Serum trypsinogen, another indirect PFT, can aid in identifying the cause of steatorrhea. Low serum trypsinogen levels (<20 ng/ml) suggest exocrine insufficiency,29 while very high levels (>150 ng/ml) may indicate active pancreatic inflammation.25 In summary, indirect PFTs are helpful adjuncts to imaging in suspected CP. Isolated abnormal indirect PFT results are not definitively diagnostic for CP.6
Direct PFTs evaluate both acinar and ductal pancreatic cells by aspirating duodenal contents after CCK or secretin stimulation, respectively.30 CCK stimulation leads to measurement of pancreatic enzymes, while secretin stimulation leads to bicarbonate concentration measurement. A large retrospective study of patients with CP-suggestive symptoms but no radiographic evidence used secretin PFTs (sPFTs) and followed patients to assess CP development. A positive sPFT was defined as <10 mEq bicarbonate output in 30 minutes.30 Of those with positive sPFTs, 9 developed CP, compared to only 2 of 70 with negative sPFTs. sPFTs showed 82% sensitivity and 86% specificity for CP diagnosis, with a 45% positive predictive value (PPV) and 97% negative predictive value (NPV).30 This indicates that secretin-stimulated PFTs are most valuable in ruling out CP in patients with suggestive symptoms like chronic abdominal pain.
Direct PFTs and EUS may be most beneficial in diagnosing early CP. PFTs can detect exocrine dysfunction suggestive of CP before imaging changes become apparent, and EUS can identify early ductal and parenchymal abnormalities. A 2009 study by Stevens et al. comparing EUS to direct PFTs in minimal change CP diagnosis showed a 72% concordance between EUS and direct PFTs. They also concluded that direct PFTs (specifically sPFT) were more likely to be abnormal earlier in the disease course compared to EUS (using >3 criteria as a cutoff).31 Combining EUS and direct PFTs may increase diagnostic specificity, with PFTs clarifying indeterminate EUS findings (2–4 EUS features).
Differential Diagnosis of Chronic Pancreatitis
Differentiating focal pancreatic abnormalities is crucial, especially between pancreatic ductal adenocarcinoma (PDAC), focal CP, and autoimmune pancreatitis (AIP). CP can develop in any pancreatic location but commonly affects the head, including groove pancreatitis, a CP variant involving the pancreatic head, duodenum, and pancreatoduodenal groove.32 Focal CP can spare parenchyma, mimicking PDAC or other pancreatic masses.33 Groove pancreatitis patients may have elevated serum CA19-9 levels due to biliary obstruction or inflammation, further complicating diagnosis. High suspicion for PDAC must be maintained, often requiring surgical resection to exclude malignancy. However, the duct-penetrating sign, a non-constricted main pancreatic duct entering the focal enlargement, suggests CP over PDAC.33 Pancreatic calcifications and irregular MPD also favor CP over PDAC.6 Patients with focal AIP may have dramatically elevated serum IgG4 levels, extrapancreatic manifestations, negative fine needle aspiration of the mass, and a dramatic response to steroids.
Summary: Diagnostic Approach to Chronic Pancreatitis
Diagnosing CP ranges from straightforward in advanced cases with CT-evident calcifications to challenging in early CP. The diagnostic workup for suspected CP should follow a step-wise approach, progressing from non-invasive to more invasive tests, based on clinical presentation and risk factors. After a thorough history and physical exam, initial labs should include lipase, amylase, metabolic panel, and indirect PFTs (fecal elastase-1, serum trypsinogen). Computed tomography is the optimal initial imaging modality due to its sensitivity for severe CP, potentially obviating further tests. In equivocal cases, MRCP provides detailed evaluation of pancreatic parenchyma and ducts. If diagnostic uncertainty persists, EUS, with or without pancreatic function testing, should be considered. ERCP should be reserved as a last-line diagnostic tool, primarily for therapeutic purposes. Future advancements should focus on refining diagnostic tools for more accurate early CP diagnosis, as early intervention may significantly impact disease progression. Combining pancreatic function testing with indeterminate EUS results is likely the most effective approach in these challenging cases. Biomarker studies of pancreatic fluid may further enhance diagnostic accuracy.
Table 4. Rosemont Criteria for EUS Diagnosis of Chronic Pancreatitis
| Rosemont Criteria Category | Criteria |
|---|---|
| Consistent with Chronic Pancreatitis | 1 Major A feature AND 3 or more minor features OR 1 Major A feature AND 1 major B feature OR 2 Major A features |
| Probable Chronic Pancreatitis | 1 Major A feature AND less than 3 minor features OR 1 Major B feature AND 3 or more minor features OR 5 or more minor features |
| Indeterminate for Chronic Pancreatitis | 3–4 minor features, no major features OR Major B feature alone or with less than 3 minor features |
| Normal Pancreas | Less than 2 minor features, no major features |
Acknowledgments
Grant Support: Research reported in this publication was supported by the National Cancer Institute and National Institute of Diabetes And Digestive and Kidney Diseases (NIDDK) under award number U01DK108327 (PH, DC). 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
CCK – Cholecystokinin
PDAC – Pancreatic Ductal Adenocarcinoma
PFT – Pancreatic Function Testing
MRCP – Magnetic Resonance Cholangiopancreatography
ERCP – Endoscopic Retrograde Cholangiopancreatogram
CT – Computed Tomography
EUS – Endoscopic Ultrasound
sMRCP – Secretin enhanced Magnetic Resonance Cholangiopancreatography
sPFT – Secretin Pancreatic Function Test
MPD – Main Pancreatic Duct
Footnotes
Potential conflicts of interest/disclosures: Hart (Abbvie, Inc., honorarium for speaking and KC Specialty Therapeutics, LLC, consulting fees)
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