Gallbladder and Pancreas

Introduction The SPINK1 gene encodes the pancreatic secretory trypsin inhibitor, a key protective molecule that prevents premature trypsin activation within the pancreas. Dysfunction of this pathway is central to the pathogenesis of chronic pancreatitis. Among genetic variants, the p.Asn34Ser mutation has long been recognized as a major risk factor, yet its exact mechanism has remained unclear despite decades of research. Problem Statement A major paradox has existed in the field: The p.Asn34Ser variant is strongly associated with chronic pancreatitis risk, yet no consistent defect at the protein level has been identified. This has raised a critical question—does the pathogenic effect lie not in protein function, but at the level of gene expression? Summary This study supports the concept that the p.Asn34Ser variant acts through reduced messenger RNA expression rather than altered protein function. The variant exists within a larger haplotype containing multiple linked regulatory changes, particularly in the 5′ region of the gene. Emerging evidence suggests that these linked variants may disrupt transcription factor binding sites, leading to decreased SPINK1 mRNA production. Reduced mRNA levels would ultimately lower effective trypsin inhibitor availability within pancreatic acinar cells, predisposing to uncontrolled trypsin activity and chronic inflammation. Importantly, prior studies showing near-normal or even elevated protein levels may reflect compensatory mechanisms or differences in systemic versus local pancreatic expression. Overall, this work shifts the understanding of SPINK1-associated pancreatitis from a structural protein defect to a regulatory gene expression disorder, offering new insights into disease mechanisms and potential therapeutic targets.

The Rome V Gallbladder and Sphincter of Oddi Disorders chapter substantially modernizes this field by moving away from historically overused functional labels and procedure-driven diagnosis toward a more restrictive, symptom-based, harm-minimizing approach. The major theme throughout the chapter is clear: these disorders have been over diagnosed, invasive interventions have been overused, and Rome V now prioritizes careful phenotyping, exclusion of structural disease, objective evidence of obstruction, and conservative management before procedural therapy.

1. Rome V Reframes Gallbladder and Sphincter Disorders as Over diagnosed, High-Risk Syndromes

One of the most important conceptual shifts in Rome V is the explicit acknowledgment that dysfunctional gallbladder disorder (DGBD) and sphincter of Oddi disorder (SOD) have historically been over diagnosed and overtreated. Rome V emphasizes that many patients previously labeled with gallbladder or sphincter dysfunction likely have a more typical disorder of gut–brain interaction (DGBI), not a primary pancreaticobiliary motor disorder.

This is a major conceptual shift because it fundamentally changes the threshold for:

diagnosing DGBD/SOD, recommending cholecystectomy, and performing ERCP.

Rome V repeatedly emphasizes minimizing harm, given that both cholecystectomy and ERCP carry meaningful procedural risk.

2. “Typical Biliary Pain” Is Now the Central Diagnostic Gatekeeper

Rome V makes typical biliary pain the cornerstone of diagnosis for both DGBD and biliary SOD.

This is arguably the single most important practical update in the chapter because symptom quality now drives diagnostic confidence more strongly than legacy functional testing.

Rome V Definition of Typical Biliary Pain

Pain in the epigastrium and/or right upper quadrant with all of the following:

acute onset, lasts ≥20 minutes to several hours, episodic (not daily continuous pain), severe enough to interrupt activities or prompt urgent evaluation, unrelated to bowel movements, not relieved by acid suppression or positional change.

Supportive features:

nausea/vomiting, radiation to back/right scapula, postprandial occurrence, nocturnal awakening.

Rome V specifically clarifies that biliary pain is typically steady, not colicky, and is often epigastric rather than strictly RUQ, correcting two longstanding clinical misconceptions. The pain-pattern figure on page 2 (Figure 1) is especially useful because it contrasts the sustained pattern of biliary pain with renal colic and intestinal colic.

3. Gallbladder Ejection Fraction (GBEF) Is No Longer a Rome Diagnostic Criterion for DGBD

This is one of the most practice-changing updates in the chapter.

Rome V removes gallbladder ejection fraction (GBEF) from the supportive diagnostic criteria for dysfunctional gallbladder disorder (DGBD) because evidence that cholescintigraphy predicts response to cholecystectomy remains weak and inconsistent.

The chapter is explicit that:

typical biliary pain predicts response to surgery better than cholescintigraphy, and GBEF should no longer be treated as a primary diagnostic determinant.

This is one of the most important Rome V departures from older surgical practice.

4. DGBD Now Requires Watchful Waiting Before Surgery

A major Rome V change is the addition of a preoperative observation period for suspected DGBD.

Rome V now recommends that symptoms should persist despite a trial of conservative/nonoperative management before cholecystectomy is considered.

This is a major shift because it explicitly discourages reflex cholecystectomy.

The rationale is highly practical:

DGBD is benign, does not cause life-threatening complications, and symptoms may resolve spontaneously in up to 50% of patients.

Rome V therefore recommends a 3–6 month period of watchful waiting in most patients to reduce unnecessary cholecystectomy.

This is one of the most important harm-reduction changes in the chapter.

5. Cholecystectomy for DGBD Is Now Reserved for Strictly Selected Patients

Rome V takes a much more restrictive approach to cholecystectomy in DGBD.

Cholecystectomy is appropriate only when:

the patient clearly meets criteria for typical biliary pain, structural disease is excluded, symptoms persist after observation, and symptom burden remains clinically meaningful.

This is a substantial narrowing of operative candidacy.

The evaluation algorithm on page 5 (Figure 3) is one of the most clinically useful additions because it formalizes:

exclusion of alternate etiologies, nonoperative trial, reassessment at 3–6 months, and only then consideration of surgery. 6. Sphincter of Oddi Manometry Is No Longer Part of Rome Criteria

One of the most important technical changes in Rome V is the removal of sphincter of Oddi manometry from diagnostic criteria.

This is a major departure from historical practice.

Rome V removes manometry because it is:

poorly reproducible, insufficiently sensitive, not reliably predictive, and no longer clinically justifiable in routine practice.

The chapter explicitly notes that sphincter manometry has now been largely abandoned in clinical practice.

This is one of the most consequential procedural de-escalations in Rome V.

7. Biliary SOD Type III Has Effectively Been Eliminated

Rome V effectively abandons Type III SOD.

This is one of the most important and practice-changing updates in the chapter.

Following the landmark EPISOD trial, patients with biliary-type pain but no objective evidence of biliary obstruction are no longer considered to have a primary sphincter disorder. Instead, these patients are now understood to most likely have another DGBI.

This is a major conceptual correction and substantially reduces inappropriate ERCP.

8. Biliary SOD Now Requires Objective Evidence of Obstruction

Rome V now applies the term biliary SOD only to patients with:

typical biliary pain, elevated liver tests and/or biliary dilation, and no stones or structural obstruction.

This is one of the most important diagnostic tightening measures in Rome V.

The implication is simple and clinically important:

No objective evidence of biliary obstruction = no biliary SOD diagnosis.

9. Supportive Tests for Biliary SOD Have Been Removed

Rome V removes the historical supportive tests for biliary SOD:

normal amylase/lipase, sphincter manometry, hepatobiliary scintigraphy.

These were removed because they lack sufficient diagnostic reliability or predictive value.

This reflects both evidence evolution and current real-world practice.

10. ERCP for Biliary SOD Is Now Far More Restrictive

Rome V strongly narrows the role of ERCP in suspected biliary SOD.

ERCP is now primarily reserved for:

patients with convincing biliary obstruction, probable SO stenosis, or clinically meaningful objective evidence suggesting true obstructive physiology.

The evaluation algorithm on page 8 (Figure 5) is especially important because it formalizes a graded approach:

exclude alternatives, determine objective evidence burden, assess confounders (opioids, somatization, intermittent vs static abnormalities), and reserve ERCP for those with higher likelihood of benefit.

This is one of the most important procedural gatekeeping changes in Rome V.

11. Chronic Opioid Use Is a Major Confounder in Suspected Biliary SOD

Rome V explicitly highlights chronic opioid use as a major diagnostic confounder in biliary SOD.

This is clinically important because opioids may cause:

bile duct dilation, sphincter spasm, and biliary-type symptoms,

without true primary sphincter disease.

This is a highly relevant real-world caution and should directly influence ERCP decision-making.

12. Pancreatic SOD Is Now Restricted to Unexplained Recurrent Acute Pancreatitis (RAP)

This is one of the most important Rome V changes.

Rome V now restricts pancreatic SOD to patients with documented recurrent acute pancreatitis (RAP) after exclusion of other etiologies.

This is a major narrowing of the diagnosis.

Rome V explicitly states there is no evidence that pancreatic SOD causes isolated pancreatic pain in the absence of pancreatitis.

This effectively eliminates “pancreatic SOD” as an explanation for unexplained pancreatic-type pain alone.

13. EUS Is Now the Preferred Test in Suspected Pancreatic SOD

Rome V strongly prioritizes EUS in unexplained recurrent acute pancreatitis.

This is one of the most important practical recommendations in the pancreatic SOD section.

EUS is now the preferred modality to exclude:

occult stones/sludge, ampullary lesions, pancreatic neoplasia, ductal abnormalities, and chronic pancreatitis.

MRCP remains complementary (or an alternative where EUS is unavailable), but EUS is now the preferred first-line advanced test.

14. ERCP for Pancreatic SOD Remains Uncertain and Highly Selective

Rome V remains cautious regarding ERCP in pancreatic SOD.

Although observational studies suggest benefit in selected patients with recurrent pancreatitis, evidence remains inconsistent and high-quality randomized data remain insufficient.

Accordingly, Rome V recommends:

individualized decision-making, conservative management when feasible, and highly selective ERCP use given procedural risk. Clinical Bottom Line

The Rome V Gallbladder and Sphincter of Oddi Disorders chapter is fundamentally a diagnostic de-escalation and procedural restraint document.

Its major advances are:

strict redefinition of typical biliary pain, removal of GBEF as a diagnostic criterion for DGBD, mandatory watchful waiting before cholecystectomy, removal of sphincter manometry, effective elimination of Type III SOD, requirement for objective biliary obstruction in biliary SOD, much stricter ERCP thresholds, recognition of opioids as a major confounder, and restriction of pancreatic SOD to unexplained recurrent acute pancreatitis.

The single most important Rome V message is this: diagnosis now depends less on legacy functional testing and far more on strict symptom phenotyping, objective evidence, and procedural restraint.

Introduction Management of necrotising pancreatitis has evolved toward a minimally invasive, step-up approach, where initial catheter drainage—either percutaneous or endoscopic—is followed by endoscopic necrosectomy only when required. A key unresolved clinical question is the optimal timing of necrosectomy after drainage, especially in patients who remain symptomatic. The goal is to balance two competing priorities: Avoid early aggressive intervention that may increase complications Prevent prolonged sepsis and clinical deterioration due to delayed source control Problem Statement Not all patients with necrotising pancreatitis improve after catheter drainage alone. A subset continues to have persistent sepsis, organ dysfunction, pain, or failure of clinical resolution, necessitating necrosectomy. The dilemma is: 👉 Should necrosectomy be performed early after drainage, or should it be delayed to allow better demarcation of necrosis? Current Understanding and Evidence-Based Approach

1. Step-Up Strategy Remains the Foundation All major data—including trials such as the PANTER trial and the TENSION trial—support a step-up approach: Start with drainage Escalate only if there is clinical non-response This principle is universally accepted.
2. Timing Is Not Fixed—It Is Clinical Condition–Driven There is no single “ideal time point” (e.g., day 7, day 14). Timing is dictated by: Persistence of sepsis or SIRS Ongoing organ failure Lack of clinical improvement after adequate drainage Imaging showing a significant solid necrotic burden 👉 Necrosectomy should be considered when drainage alone fails, rather than based on a predefined timeline.
3. Early Necrosectomy (<2 weeks) – Generally Avoided Early intervention is associated with: Poor demarcation of necrosis Increased bleeding risk Higher procedural complications Hence, necrosectomy is usually deferred until collections mature into walled-off necrosis (WON), typically around 3–4 weeks after onset.
4. Role of Catheter Drainage First Drainage achieves several key objectives: Reduces the infected fluid component Controls sepsis in a significant proportion (up to 30–50%) May avoid the need for necrosectomy altogether 👉 Patients who respond clinically should not undergo necrosectomy.
5. When to Proceed to Necrosectomy Endoscopic necrosectomy is indicated when there is: Persistent clinical sepsis despite adequate drainage Blocked or ineffective drainage due to solid debris Ongoing pain, gastric outlet obstruction, or biliary obstruction Imaging showing a large, solid necrotic burden not amenable to drainage alone
6. Optimal Practical Window In most real-world scenarios: Drainage is performed once collection is accessible (often ~3–4 weeks) Necrosectomy is performed 3–7 days after drainage if there is no improvement, or later, depending on the response 👉 The key is not too early, not unnecessarily delayed—but triggered by clinical need.
7. Endoscopic vs Surgical Timing Paradigm Compared to surgery, endoscopic necrosectomy allows: More gradual debridement Multiple staged sessions Lower physiological stress This enables a more flexible timing strategy, tailored to patient response. Practical Clinical Approach A reasonable algorithm: Diagnose infected or symptomatic necrotising pancreatitis Perform catheter drainage (endoscopic or percutaneous) Reassess clinically over 48–72 hours If improving → continue conservative management If not improving → evaluate: Drain position/function Solid necrosis burden Proceed to endoscopic necrosectomy when indicated Key Clinical Insight The concept of “optimal timing” is somewhat misleading. 👉 The real principle is: “Drain first, wait if possible, intervene when necessary.” Conclusion The timing of endoscopic necrosectomy after catheter drainage in necrotising pancreatitis is not protocol-driven but patient-driven. Early necrosectomy should be avoided unless clinically necessary, while delayed intervention should not compromise control of sepsis. The best outcomes are achieved by individualised decision-making, guided by clinical response, imaging findings, and adequacy of drainage rather than rigid timelines.

Article Type: Review — Basic and Clinical Gastroenterology & Hepatology Introduction and Summary Chronic pancreatitis is a progressive fibro-inflammatory disease characterised by recurrent or persistent abdominal pain, exocrine insufficiency, and eventual endocrine failure. Traditionally viewed as a structural disease diagnosed by ductal changes or calcification, it is now increasingly understood as a dynamic biological process beginning with acinar cell injury and evolving through inflammation to irreversible fibrosis. This review highlights a critical gap in current practice: most patients are diagnosed at an advanced stage, when structural damage is already established, and therapeutic options are largely palliative. The authors emphasise the need to shift focus toward early disease mechanisms, particularly inflammation, and to develop therapies that can alter the natural course of the disease rather than simply manage its complications. Problem Statement The major challenge in chronic pancreatitis is not just treatment—it is late recognition and lack of disease-modifying therapy. Early-stage disease remains difficult to diagnose due to the absence of validated biomarkers and limited access to histopathology. As a result, intervention typically occurs when fibrosis, ductal distortion, and calcification are already established. Current treatment strategies—primarily endoscopic or surgical—focus on relieving ductal obstruction and managing pain. However, these approaches do not address the underlying inflammatory and fibrotic pathways driving disease progression. This has limited progress in developing therapies that can prevent progression, reduce fibrosis, or preserve pancreatic function. Key Concepts for Clinicians

1. Disease Begins with Acinar Cell Injury Chronic pancreatitis starts with repeated or sustained injury to acinar cells, triggered by factors such as alcohol, smoking, genetic predisposition, or metabolic stress.
2. Inflammation Is the Central Driver Following injury, a cascade of inflammatory responses is activated. Persistent inflammation leads to recruitment of immune cells and activation of pancreatic stellate cells.
3. Stellate Cells Drive Fibrosis Activated stellate cells are central to fibrosis. They produce extracellular matrix components, leading to progressive replacement of normal pancreatic tissue with fibrotic tissue.
4. Progression Is a Continuum The disease evolves from early inflammatory changes to late-stage fibrosis, ductal abnormalities, and calcification. Importantly, early stages may be reversible or modifiable, whereas late stages are largely irreversible.
5. Diagnosis Is Biased Toward Late Disease Most diagnoses rely on imaging features such as ductal dilatation and calcification, which represent advanced disease. Early chronic pancreatitis remains underdiagnosed.
6. Lack of Biomarkers Limits Early Detection There are no widely accepted biomarkers for early disease, making it difficult to identify patients at a stage where intervention could alter progression.
7. Current Therapies Are Mostly Symptomatic Endoscopic and surgical interventions focus on ductal decompression and pain relief. They do not target the underlying inflammatory or fibrotic processes.
8. Disease-Modifying Therapy Is the Unmet Need A major focus of research is identifying therapies that can interrupt inflammation, prevent stellate cell activation, and reduce fibrosis.
9. Emerging Therapies Target Pathophysiology New strategies are exploring anti-inflammatory, anti-fibrotic, and antioxidant pathways. These include repurposed drugs and novel agents aimed at altering disease biology rather than structure.
10. Personalized Approach Is the Future Given the heterogeneity of chronic pancreatitis, a patient-tailored strategy based on aetiology, stage, and dominant pathophysiological mechanism is essential. Clinical Relevance This review reinforces a paradigm shift: chronic pancreatitis should no longer be viewed purely as a structural disease requiring mechanical intervention, but as a biological disease driven by inflammation and fibrosis. For clinicians, this means greater emphasis on: Identifying patients at earlier stages Recognising ongoing inflammation even in the absence of overt structural changes Considering therapies that target disease mechanisms rather than only symptoms It also supports ongoing efforts toward drug repurposing and translational research, particularly in targeting inflammation and fibrosis pathways. Conclusion Chronic pancreatitis is a progressive disease driven by a sequence of acinar injury, inflammation, and fibrosis. Current management remains focused on late-stage complications due to challenges in early diagnosis and a lack of effective disease-modifying therapies. Future progress depends on improving early detection, understanding inflammatory pathways, and developing targeted treatments that can halt or reverse disease progression. A patient-tailored, mechanism-based approach represents the most promising direction for improving long-term outcomes.

Introduction The SPINK1 gene encodes the pancreatic secretory trypsin inhibitor, a key protective molecule that prevents premature trypsin activation within the pancreas. Dysfunction of this pathway is central to the pathogenesis of chronic pancreatitis. Among genetic variants, the p.Asn34Ser mutation has long been recognised as a major risk factor, yet its exact mechanism has remained unclear despite decades of research. Problem Statement A major paradox has existed in the field: The p.Asn34Ser variant is strongly associated with chronic pancreatitis risk, yet no consistent defect at the protein level has been identified. This has raised a critical question—does the pathogenic effect lie not in protein function, but at the level of gene expression? Summary This study supports the concept that the p.Asn34Ser variant acts through reduced messenger RNA expression rather than altered protein function. The variant exists within a larger haplotype containing multiple linked regulatory changes, particularly in the 5′ region of the gene. Emerging evidence suggests that these linked variants may disrupt transcription factor binding sites, leading to decreased SPINK1 mRNA production. Reduced mRNA levels would ultimately lower effective trypsin inhibitor availability within pancreatic acinar cells, predisposing to uncontrolled trypsin activity and chronic inflammation. Importantly, prior studies showing near-normal or even elevated protein levels may reflect compensatory mechanisms or differences in systemic versus local pancreatic expression. Overall, this work shifts the understanding of SPINK1-associated pancreatitis from a structural protein defect to a regulatory gene expression disorder, offering new insights into disease mechanisms and potential therapeutic targets.