Mechanistic insights into pancreatic duct pressure: from basic physiology to translational implications

Abstract

Purpose of review

This review summarizes recent advances in pancreatic ductal hypertension (PDH), emphasizing its pathophysiological mechanisms, clinical relevance across pancreatic diseases, and progress in noninvasive assessment. The aim is to highlight translational insights that may improve patient selection for intervention and guide long-term management strategies.

Recent findings

Evidence indicates that PDH contributes not only to pain in chronic pancreatitis but also to exocrine insufficiency, diabetes, and complications such as post-ERCP pancreatitis (PEP) and recurrent acute pancreatitis (RAP). Pancreatic stellate cells (PSCs) are central to fibrosis and are directly activated by pressure, reinforcing disease progression. Traditional methods of measuring pancreatic duct pressure rely on invasive manometry, microtransducer catheters, or pancreatic fistulae, all with inherent risks. Recent translational advances, particularly magnetic resonance cholangiopancreatography (MRCP) integrated with computational fluid dynamics modeling, have demonstrated the feasibility of noninvasive pancreatic duct pressure (PDP) estimation with strong concordance to endoscopic retrograde cholangiopancreatography-based manometry and symptom relief.

Summary

These advances emphasize the critical role of accurate pressure assessment in identifying patients with true ductal hypertension who are most likely to benefit from decompression. Noninvasive measurement offers a promising strategy to limit unnecessary interventions and to delineate the direct contribution of ductal pressure to exocrine, endocrine, and related disorders. Validation in larger cohorts and high-risk populations will be essential.

INTRODUCTION

Worldwide, the annual incidence of chronic pancreatitis (CP) is estimated at 5–14 cases per 100 000 people, with prevalence typically ranging from 30 to 50 per 100 000. However in certain regions, reported prevalence surpasses 120 per 100 000, indicating a substantial disease burden [1].

Chronic pancreatitis is a progressive fibroinflammatory disorder initiated by acinar cell injury and sustained by recurrent inflammation. Hallmark pathology includes fibrosis, acinar loss, ductal distortion, and dilatation [2,3]. Persistent parenchymal injury drives fibrogenesis, while ductal involvement results in strictures with upstream dilatation [2]. The obstructive hypothesis further suggests that protein plug formation and calcification within ducts promote obstruction, acinar dysfunction, and atrophy [4]. Abdominal pain, the predominant symptom in CP, affects most patients and often necessitates intervention [5]. Although multifactorial, ductal hypertension, frequently driven by stones or strictures, remains a central mechanism underlying persistent and recurrent pain. While endoscopy can effectively decompress the duct, careful patient selection is essential to target those with true ductal hypertension [6]. In current clinical practice, the assessment of ductal hypertension largely relies on indirect evidence, most often ductal dilatation on imaging [7]. Given the challenges of invasive measurement due to pancreatic anatomy, recent translational advances have focused on developing noninvasive approaches. These emerging techniques, together with insights into the mechanisms of ductal hypertension, hold promise for improving precision management in pancreatic diseases. 

Box 1.

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PATHOPHYSIOLOGICAL MECHANISMS OF PANCREATIC DUCTAL HYPERTENSION

The pancreas serves dual roles in endocrine regulation and exocrine secretion. Its exocrine compartment is primarily composed of acinar cells and the branching ductal network, which conveys digestive enzymes into the duodenum via the major and minor papillae [8]. At the level of the papilla, the sphincter of Oddi functions as a dynamic regulator, coordinating the flow of bile and pancreatic secretions while preventing duodenopancreatic reflux. Transpapillary passage of pancreatic juice occurs when the pancreatic duct pressure (PDP) exceeds the basal sphincter pressure or when sphincter relaxation takes place [9]. Sphincter activity is subject to modulation by both neural pathways and hormonal signals. In addition, the rheological properties of pancreatic juice influence intraductal pressure. In conditions such as chronic pancreatitis and cystic fibrosis, increased viscosity contributes to elevated pancreatic duct pressure (PDP) [10,11]. Consequently, PDP is determined by the interaction of ductal anatomy, secretory fluid properties, and sphincteric control. In most clinical contexts, morphological alterations such as pancreatic duct dilatation are employed as indirect indicators of elevated PDP, with pancreatic fibrosis representing a pivotal underlying process.

Fibrosis represents a defining histological hallmark of CP, resulting in architectural distortion of the gland. Pancreatic stellate cells (PSCs) are central mediators in this fibrotic process. These cells are situated at the basolateral surface of pancreatic acinar cells and are also distributed around small ducts and perivascular regions [12–14]. By regulating the synthesis and degradation of extracellular matrix (ECM) proteins, including type I and type III collagen as well as fibronectin, PSCs preserve tissue organization. In the normal pancreas, PSCs remain in a quiescent state, characterized by abundant cytoplasmic vitamin A–containing lipid droplets. Quiescent PSCs express specific markers including desmin, glial fibrillary acidic protein (GFAP), vimentin, and nestin [15].

During pancreatic injury, inflammatory mediators and alterations in ductal pressure drive PSCs from a quiescent into an activated phenotype. Loss of vitamin A lipid droplets, desmin, and GFAP, together with the appearance of α-smooth muscle actin (α-SMA), constitutes a hallmark of PSC activation [16]. Once activated, PSCs acquire enhanced proliferative and migratory capacity, actively synthesize and secrete ECM proteins, and release pro-inflammatory cytokines and chemokines. In most experimental settings, resolution of injury and clearance of inflammatory stimuli result in apoptosis or reversion of activated PSCs back to quiescence, thereby preventing fibrosis [17]. However, under conditions of recurrent pancreatic injury or persistent dysregulation of repair mechanisms, PSCs remain chronically activated. This sustained activation disrupts the equilibrium between ECM production and degradation, favoring excessive matrix deposition and ultimately leading to pathological fibrosis. This paradigm aligns with the widely accepted “necrosis–fibrosis sequence” [18], whereby repeated episodes of acute pancreatitis culminate in progressive fibrotic remodeling of the pancreas.

The activity of PSCs is tightly regulated by a spectrum of cytokines and growth factors. Platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β) and its downstream mediator connective tissue growth factor (CTGF), along with pro-inflammatory signals such as tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukins including IL-1, IL-6, and IL-13, collectively drive PSC proliferation, migration, ECM synthesis, and α-SMA expression, thereby reinforcing their persistent activation and profibrogenic phenotype [19–22]. Beyond responding to paracrine cues from neighboring cells, PSCs are also capable of reinforcing their activation through autocrine signaling loops. This dual regulation may in part explain why CP can progress even after removal of the initiating insults, such as recurrent acute pancreatitis (RAP) or alcohol exposure [16]. A deeper understanding of PSC biology may thus provide a critical foundation for developing therapeutic strategies aimed at halting or reversing pancreatic fibrosis.

FROM PAST TO PRESENT: TECHNIQUES OF PANCREATIC DUCTAL PRESSURE MEASUREMENT AND THEIR CLINICAL RELEVANCE

Current methods for pancreatic duct pressure measurement

In addition to ductal caliber, PDP is influenced by multiple factors such as the rheological properties of pancreatic juice. Hence, morphological alterations cannot be equated strictly with changes in intraductal pressure, underscoring the need for more precise methods of PDP assessment.

Perfusion manometry represented the earliest approach to PDP measurement. This technique employs a catheter connected to a pneumo-hydraulic perfusion system, with the catheter inserted into the duct during surgical exploration or ERCP for direct pressure recording [23–26]. The advent of micro transducer catheters subsequently improved measurement accuracy, as the recorded pressure values are less affected by catheter dimensions or the characteristics of perfusate [27,28]. Nevertheless, the potential risk of ductal injury remains a limitation. In certain unique clinical scenarios, such as in patients with pancreatic cutaneous fistulae, direct placement of a Foley catheter into the fistulous tract has been used for PDP estimation. Although this method is less accurate compared with manometry or micro transducer systems, its clinical utility is supported by the advantage of avoiding additional invasive procedures [29].

Furthermore, pancreatic tissue pressure (PTP) measurement has been proposed as an alternative surrogate for PDP, particularly in cases where ductal cannulation is technically challenging. In this approach, a fine-bore catheter connected to a pressure transducer is inserted directly into the pancreatic parenchyma, allowing real-time pressure assessment [30–32].

Using the above-mentioned methods, resting PDP in healthy controls has been reported to range approximately from 10 to 18 mmHg. In contrast, patients with CP demonstrate significantly higher resting ductal pressures, typically between 20 and 55 mmHg, with some early studies even reporting values exceeding 200 mmHg [29].

Clinical implications of elevated/altered pancreatic duct pressure

PD and abdominal pain: abdominal pain is the most common clinical symptom of CP and is frequently associated with reduced quality of life and increased healthcare costs. The earliest pathophysiological concept attributed CP-related pain to elevated ductal pressure and pancreatic ischemia secondary to ductal strictures or intraductal calculi [33]. This hypothesis is supported by the observation that approximately 65–76% [5] of patients experience pain relief following endoscopic interventions that relieve ductal obstruction. However, about one-third of patients continue to have unsatisfactory pain improvement despite ductal decompression, and studies have reported a discordance between ductal pressure and pain severity. These findings underscore the complexity of CP-related pain mechanisms, which may also involve neuropathic components resulting from chronic inflammatory changes. Pancreatic quantitative sensory testing (P-QST) has emerged as a valuable tool for characterizing pain in CP. It enables differentiation between peripheral nociceptive pain (associated with PDH), neuropathic pain, and central sensitization–related pain, thereby informing individualized therapeutic strategies such as endoscopic decompression [endoscopic retrograde cholangiopancreatography (ERCP) or extracorporeal shock wave lithotripsy (ESWL)] for patients with peripheral nociceptive pain, and neuromodulatory agents for those with neuropathic pain or pain related to central sensitization. Integrating pancreatic ductal pressure measurements with P-QST may further enhance the accuracy of predicting pain phenotypes and treatment response [34].

PD and exocrine pancreatic insufficiency (EPI): CP is characterized by early exocrine insufficiency with diabetes developing later, reflecting extensive acinar loss alongside relative preservation of islets. Current evidence suggests that this differential injury is largely attributable to apoptosis, which preferentially affects the exocrine pancreas, while endocrine islets remain preserved for a prolonged period [35,36]. Observations from clinical cohorts further corroborate this pattern, showing that in patients with CP, loss of exocrine pancreatic function occurs earlier than loss of endocrine function [37]. Reports have indicated that exocrine dysfunction develops when more than 60% of the pancreatic duct is obstructed [38]. Moreover, patients with the large-duct type of CP have a higher risk of developing new-onset EPI compared with those with the small-duct type (hazard ratio 1.72; 95% CI [1.05–2.80]; P = 0.031) [39^▪]. These findings suggest that elevated pancreatic ductal pressure may contribute to the development or progression of EPI. However, there is currently no direct clinical evidence linking ductal pressure to EPI.

PD and diabetes: Some clinical evidence suggests a potential association between pancreatic ductal pressure and the development of diabetes. Prospective studies have shown that patients with idiopathic CP who underwent early ductal decompression experienced significantly longer diabetes-free survival compared with controls (hazard ratio [95% CI], 0.39 [0.28–0.55]; P < 0.0001) [43]. In another single-center study, early endoscopic intervention was associated with improved glycemic control in idiopathic CP patients (HbA1c, 6.38 vs. 8.07 g/dl; P < 0.001) [44]. The proposed mechanism involves an interactive cascade linking ductal hypertension, PSC activation, and islet cell injury. PSCs not only drive pancreatic fibrosis with ductal narrowing and secondary dilatation, features often interpreted as indirect evidence of elevated ductal pressure, but are also directly activated by this pressure, creating a feed-forward loop that amplifies disease progression [40,41]. Although the precise role of PSCs in pancreatogenic diabetes remains to be fully defined, experimental data suggest that intra-islet PSC activation may contribute to islet fibrosis and β-cell dysfunction in type 2 diabetes [42]. However, the overall correlation between ductal pressure and endocrine dysfunction appears modest, and several studies have failed to establish a definitive causal link between ductal obstruction and diabetes [45,46]. Future investigations should prioritize the accurate quantification of pancreatic ductal pressure, which is essential before further mechanistic studies and clinical trials can clarify its role in pancreatic cellular injury and metabolic deterioration.

PD and other diseases: In addition, PDP has been implicated in several pancreatic disorders. For instance in PEP, transient increases in ductal pressure resulting from impaired pancreatic outflow, secondary to ampullary manipulation, procedure-related edema, and contrast exposure has been postulated as key contributing mechanisms in the majority of cases, although direct intraprocedural measurements of pressure are lacking [47,48]. Pancreas divisum, an anatomic variant that can alter ductal flow dynamics, is also regarded as a potential etiology of RAP. Evidence from small cohort studies has suggested that endoscopic approaches, such as minor papilla cannulation, may reduce the risk of RAP (10% vs. 67%, P < 0.05) [49]. However, this finding has not been confirmed in larger randomized controlled trials, where the incidence of RAP was 34.7% (26/75) in the minor papillotomy group and 43.8% (32/73) in the sham group, yielding an adjusted risk difference of –9.2% (95% CI, –24.8% to 6.5%) [50].

However, apart from a few case reports in which pain symptoms were directly correlated with measured PDP values [50], most associations between PD pressure and abdominal pain, EPI, diabetes, or other disorders have been inferred indirectly. Currently available methods for monitoring PDP require invasive procedures, such as surgery, ERCP, or rely on pathological conditions such as pancreatic fistula. This limitation may potentially be overcome by developing noninvasive approaches to measure PDP, which could provide further insights into the pathophysiology of pancreatic diseases.

FROM CATHETERS TO CREATIVITY: THE RISE OF NONINVASIVE ASSESSMENT OF PANCREATIC DUCTAL PRESSURE

Recent progress in computational biomechanics and image-based flow modeling has confirmed the feasibility of deriving hemodynamic parameters directly from imaging data. Patient-specific computational fluid dynamics (CFD) has already been successfully implemented in cardiovascular [51], biliary system [52] and pulmonary systems [53], thereby enabling noninvasive pressure assessment.

Secretin-enhanced magnetic resonance cholangiopancreatography (MRCP) provides clearer visualization of the pancreatic duct and richer hemodynamic information [54], while automatic 3D reconstruction further facilitates functional assessment of the duct. Building on these advances, the Johns Hopkins team led by Venkata Akshintala and Jung-Hee Seo integrated MRCP with computational fluid dynamics modeling, developed a noninvasive tool for estimating pancreatic ductal pressure.

Based on both prospective and retrospective cohorts, a predictive model was established by using MRCP-derived three-dimensional ductal reconstructions to simulate intraductal flow and compute pressure gradients. The predictive model was preliminarily validated in a small cohort, showing good concordance between the noninvasive pressure estimates and the established gold standard of ERCP-based catheter manometry, as well as with improvements in patients’ clinical abdominal pain symptoms [55^▪▪].

In the absence of reliable noninvasive tools for assessing pancreatic ductal pressure, ductal dilatation is often used clinically as an indirect marker of pressure elevation. This practice may result in unnecessary endoscopic interventions for patients with ductal widening but without true hypertension, yielding limited improvement in pain and related symptoms [56]. Despite constraints such as sample size and image quality, this innovative noninvasive method for pressure assessment demonstrated high accuracy and a strong correlation with symptom relief, underscoring the need for validation in larger cohorts and in special populations such as pancreas divisum or postsurgical patients. Noninvasive identification of patients with genuine ductal hypertension who are most likely to benefit from endoscopic intervention may become one of the key points in the management of pancreatic diseases.

CONCLUSION

Alterations in pancreatic ductal pressure are a hallmark feature of CP and related disorders. These changes are closely associated with pathological processes such as pancreatic fibrosis and PSCs activation, contributing to pain, loss of exocrine and endocrine function, and other disease manifestations. Accurate assessment of PDP and its dynamic changes can provide important insights into disease mechanisms and guide therapeutic decision-making. At present, ductal pressure is usually inferred indirectly through morphologic features such as ductal dilation, while other measurement techniques often involve invasive procedures. A secretin-enhanced MRCP–based PDP assessment system has demonstrated promising advantages in early studies, offering a noninvasive and accurate approach for evaluating PDP.

Acknowledgements

None.

Financial support and sponsorship

This research was funded by the National Key Research and Development Program of China (grant number 2024YFA0918504), Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (grant number 2024-RW320-01), National Natural Science Foundation of China (grant number 32170788, 82460135), Beijing Natural Science Foundation (grant number 7232123, 7244390, L248074), National High Level Hospital Clinical Research Funding (grant number 2022-PUMCH-B-023), Chinese Academy of Medical Sciences & Clinical and Translational Medicine Research Program(grant number 2024-I2M-C&T-B-008).

Conflicts of interest

Jianing Li, Li Wen and Aiming Yang declare no competing interests.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest