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Cover
Title Page
Copyright
List of contributors
Chapter 1: Epidemiology and genetics of pancreatitis
1. Definition
2. Burden of disease
3. Clinical features
4. Diagnosis
5. Animal models of early CP
6. Genetic risk factors for CP
7. Mendelian genetic syndromes
8. A new paradigm of personalized medicine
9. References
Chapter 2: Part A: Pathobiology of the acinar cell in acute pancreatitis
1. Overview of the acinar cell morphology and function
2. Environmental and genetic stressors and the exocrine pancreatic unfolded protein response (UPR)
3. Calcium signaling and pancreatitis
4. Mitochondrial function in pancreatitis
5. Inflammatory signaling of pancreatitis
6. Summary and potential therapeutic targets
7. References
Chapter 2: Part B: Locoregional pathophysiology in acute pancreatitis: pancreas and intestine
1. Introduction
2. Pancreatic pathophysiology
3. Intestinal pathophysiology
4. Conclusion
5. References
Chapter 2: Part C: Pathophysiology of systemic inflammatory response syndrome and multiorgan dysfunction syndrome in acute pancreatitis
1. Systemic inflammatory response syndrome
2. Multiple organ dysfunction syndrome (MODS)
3. Activation of innate immune system
4. DAMPs, inflammation, and acute pancreatitis
5. Escalation of systemic inflammation
6. Inflammatory mediators in AP
7. Coagulopathy and systemic inflammation
8. Visceral adipose tissue and systemic inflammation
9. Inflammation and organ dysfunction
10. Mitochondrial dysfunction in MODS
11. Areas for future research
12. References
Chapter 3: Diagnosis, prediction, and classification
1. Introduction
2. Diagnosis
3. Prediction
4. Classification
5. Conclusion
6. References
Chapter 4: Medical treatment
1. Introduction
2. The importance of underlying etiology
3. The pancreatic microcirculation
4. Fluid resuscitation
5. Targeted pharmacologic therapy
6. Antibiotics
7. Enteral feeding
8. Conclusion
9. References
Chapter 5: Nutritional treatment in acute pancreatitis
1. Introduction
2. Type of nutrition
3. Route of enteral nutrition
4. Enteral nutrition formulations
5. Conclusion
6. References
Chapter 6: Gallstone pancreatitis: diagnosis and treatment
1. Abbreviations
2. Summary
3. Introduction
4. How is gallstone pancreatitis diagnosed?
5. What tests are available to evaluate for common bile duct stones?
6. For patients with acute gallstone pancreatitis, what is the role for ERCP in the acute setting?
7. What is the impact of cholecystectomy on the prevention of recurrent gallstone pancreatitis, and when should it be performed?
8. What is the benefit of ERCP for patients who are poor candidates for cholecystectomy?
9. Summary
10. References
Chapter 7: Treatment of local complications
1. Introduction
2. Invasive treatment
3. Which technique to choose?
4. IAP/APA guideline
5. References
Chapter 8: Treatment of systemic complications and organ failure
1. Introduction
2. Respiratory dysfunction
3. Cardiovascular dysfunction
4. Acute kidney injury
5. Coagulation abnormalities
6. Gut barrier dysfunction
7. Conclusion
8. References
Chapter 9: Specific treatment for acute pancreatitis
1. Introduction
2. Pathogenesis of acute pancreatitis
3. Lessons from animal experiments
4. Potential novel therapeutic targets
5. Lessons from clinical trials
6. Future clinical trial design
7. References
Chapter 10: Sequelae of acute pancreatitis
1. Introduction
2. Sequelae of mild acute pancreatitis
3. Sequelae of severe acute pancreatitis/necrotizing pancreatitis (SAP/NP)
4. Palliative care
5. Summary
6. References
Chapter 11: History of chronic pancreatitis
1. References
Chapter 12: Part A: Epidemiology and pathophysiology: epidemiology and risk factors
1. Introduction
2. Changing epidemiology of chronic pancreatitis
3. Disease burden
4. Risk factors
5. Etiology of chronic pancreatitis
6. Natural history
7. Evolution of chronic pancreatitis
8. Future directions
9. Conflict of interest
10. References
Chapter 12: Part B: Epidemiology and pathophysiology: genetic insights into pathogenesis
1. Introduction
2. Overview of genetics
3. Complex genetics
4. Framework for understanding genetics of pancreatitis
5. Susceptibility to AP and RAP
6. Progression from RAP to CP
7. Future directions
8. References
Chapter 12: Part C: Pancreatic stellate cells: what do they tell us about chronic pancreatitis?
1. Introduction
2. PSCs and chronic pancreatitis
3. Animal models
4. Reversal of pancreatic fibrosis in chronic pancreatitis
5. References
Chapter 12: Part D: Autoimmune pancreatitis: an update
1. Introduction
2. Consensus definition and subtypes
3. Epidemiology
4. Pathogenesis
5. Clinical profile of AIP
6. Diagnosis of AIP
7. Management and long-term outcomes
8. Lessons learnt from AIP experience
9. Summary
10. References
Chapter 12: Part E: Etiology and pathophysiology: tropical pancreatitis
1. Definition
2. Etiology
3. Malnutrition
4. Cassava toxicity (cyanogen toxicity)
5. Xenobiotics and micronutrients
6. Familial aggregation
7. Pathology of tropical pancreatitis
8. Pathophysiology
9. Pancreatic diabetes
10. Complications related to diabetes
11. Changing scenario
12. References
Chapter 12: Part F: Mechanisms and pathways of pain in chronic pancreatitis
1. Introduction
2. Manifestations and treatment of pancreatic pain
3. Components of pancreatic pain
4. Sensory neuron receptors
5. Central sensitization
6. Conclusion
7. Acknowledgment
8. References
Chapter 13: Part A: Imaging of chronic pancreatitis
1. Introduction
2. Imaging modalities
3. MRI features of chronic pancreatitis
4. Novel MRI techniques
5. Conclusion
6. References
Chapter 13: Part B: Endoscopic ultrasonography in chronic pancreatitis
1. Introduction
2. Endoscopic ultrasound features of the normal pancreas
3. Endoscopic ultrasound features of chronic pancreatitis
4. Inter- and intraobserver variability in chronic pancreatitis
5. EUS in comparison with ERCP
6. EUS versus pancreatic function testing
7. EUS in comparison to other imaging modalities
8. Therapeutic EUS
9. References
Chapter 14: Part A: Pancreatic enzyme replacement therapy (PERT)
1. Pancreatic enzyme replacement therapy
2. Diagnosis of pancreatic exocrine insufficiency
3. Consequences of pancreatic exocrine insufficiency
4. Pancreatic enzymes
5. References
Chapter 14: Part B: Nutritional treatment: antioxidant treatment
1. Introduction
2. Basis of the “oxidative stress–micronutrient antioxidant” hypothesis
3. Modern re-appraisal of the “oxidative stress–micronutrient antioxidant” hypothesis
4. Clinical trials of antioxidant therapy in chronic pancreatitis
5. Modern randomized controlled clinical trials of antioxidant therapy in chronic pancreatitis
6. Comparing and contrasting the Delhi and Manchester clinical trials
7. Risks associated with high-dose selenium therapy
8. Current recommendation for antioxidant therapy in chronic pancreatitis
9. Declaration
10. References
Chapter 14: Part C: Pancreatogenic diabetes: etiology, implications, and management
1. Introduction
2. Etiology of T3cD
3. Pancreatic polypeptide (PP) – a marker for T3cD?
4. Implications for risk for other diseases in T3cD
5. Management of T3cD
6. Summary
7. References
Chapter 14: Part D: Nutrition without a pancreas: how does the gut do it?
1. Introduction
2. Pancreatic function in normal digestion
3. Exocrine pancreatic insufficiency
4. Carbohydrate digestion
5. Protein digestion
6. Lipid digestion
7. Vitamin malabsorption
8. Nutritional issues
9. Nutritional assessment
10. Dietary recommendations
11. Pancreatic enzyme replacement therapy
12. Summary
13. References
Chapter 15: Part A: Endoscopic management of chronic pancreatitis
1. Introduction
2. Endotherapy in chronic pancreatitis
3. Pancreatic duct strictures
4. Chronic pancreatitis-induced common bile duct strictures
5. Pancreatic pseudocysts
6. Conclusion
7. References
Chapter 15: Part B: Shocking and fragmenting pancreatic ductal stones
1. Introduction
2. Modalities for stone fragmentation
3. ERCP methods
4. Extracorporeal shockwave lithotripsy (ESWL)
5. Conclusion
6. References
Chapter 15: Part C: Endoscopic management: celiac plexus blockade
1. Introduction
2. Technique
3. Conclusion
4. References
Chapter 16: Part A: A brief history of modern surgery for chronic pancreatitis
1. Pancreatic denervation
2. Pancreatic resection
3. Ductal drainage (± partial, nonanatomic resection)
4. Islet cell autotransplantation
5. Summary
6. References
Chapter 16: Part B: Surgery for chronic pancreatitis: indications and timing of surgery
1. Introduction
2. Indications for surgery
3. Timing of surgery
4. Summary and conclusion
5. References
Chapter 16: Part C: Chronic pancreatitis: surgical strategy in complicated diseases
1. Introduction
2. Pancreatic fluid collections
3. Bile duct obstruction
4. Duodenal obstruction
5. Hemorrhage
6. Overall summary
7. References
Chapter 16: Part D: Surgery for chronic pancreatitis: pancreatic duct drainage procedures
1. Introduction
2. Patient selection
3. Pancreaticojejunostomy (Partington–Rochelle procedure)
4. Results of lateral pancreaticojejunostomy (LPJ)
5. Surgical versus endoscopic drainage procedures
6. Timing for surgical drainage in relation to other procedures
7. Summary and conclusion
8. References
Chapter 16: Part E: Surgical management: resection and drainage procedures: Chronic pancreatitis – hybrid procedures
1. Introduction
2. Indications for surgery
3. Duodenum preservation or no duodenum preservation – is that the question?
4. Beger operation – duodenum-preserving pancreatic head resection
5. Frey operation – duodenum-preserving pancreatic head resection
6. Berne operation – duodenum-preserving pancreatic head resection
7. Comparison of hybrid procedures and PPPD/Whipple operation
8. References
Chapter 16: Part F: The role of pancreatoduodenectomy in the management of chronic pancreatitis
1. Introduction
2. Surgical options for management of chronic pancreatitis
3. Duodenum-preserving pancreatic head resection (Beger procedure) and local head resection of the pancreatic head and longitudinal pancreaticojejunostomy (Frey procedure)
4. Long-term follow-up of PPPD versus Beger operation for chronic pancreatitis
5. Long-term follow-up of PPPD versus Frey procedure for chronic pancreatitis
6. Differences in patient populations
7. Mayo Clinic experience with pancreatoduodenectomy for chronic pancreatitis
8. Preoperative considerations
9. Pancreatoduodenectomy for chronic pancreatitis in perspective
10. Summary
11. References
Chapter 17: Part A: Total pancreatectomy and islet cell autotransplantation: patient selection
1. Introduction
2. Correct diagnosis
3. Failure of medical and surgical therapy
4. Disability
5. Preoperative evaluation
6. Contraindications
7. References
Chapter 17: Part B: Total pancreatectomy and islet cell autotransplantation: the science of islet cell preservation, from pancreas to liver
1. Introduction
2. Islet isolation techniques for maximizing islet yield
3. Pancreas transport and pancreas trimming
4. Pancreas cannulation
5. Pancreas distention with collagenase enzymes
6. Pancreas digestion using semi-automated method
7. Tissue recombination
8. Tissue purification
9. Transplant product preparation
10. Islet infusion, from pancreas to liver
11. Islet physiology and function following TPIAT
12. Conclusions
13. References
Chapter 17: Part C: Total pancreatectomy and islet cell autotransplantation: long-term assessment of graft function
1. Introduction
2. Quality of life following total pancreatectomy with and without islet transplantation
3. Assessment of graft function
4. Clinical outcomes following total pancreatectomy and islet autotransplantation
5. Reproducible clinical success
6. What should be monitored postoperatively?
7. The future of TPIAT
8. References
Index
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List of Illustrations

Chapter 2: Part A: Pathobiology of the acinar cell in acute pancreatitis
1. Figure 2A.1 Ultrastructure of acinar and duct cells of the exocrine pancreas. The pancreatic acinar cell has prominent basally located rough endoplasmic reticulum for the synthesis of digestive enzymes and apically located zymogen granules for the storage and secretion of the digestive enzymes. The zymogen granules undergo exocytosis with stimulation of secretion. The secretion is into the lumen of the acinar formed by the apical surfaces of the acinar cells with their projecting microvilli. Not visualized because of the relatively low magnification is the subapical actin network, the tight junctions, and the gap junctions. Pancreatic duct cells contain abundant mitochondria for energy generation needed for its ion transport functions. The ductal cells also project microvilli into the luminal space.
2. Figure 2A.2 Electron micrograph of the pancreatic acinar cell. This electron micrograph shows the key cellular structures involved in synthesis, processing, and storage of digestive enzymes. On the left is the rough endoplasmic reticulum, in the middle is the Golgi complex, and on the right are zymogen granules.
3. Figure 2A.3 Potential therapeutic targets. (−1) UPR activators to enhance the adaptive response to injurious agents; (1) inhibitors of Ca²⁺ influx to prevent the effect of increased [Ca²⁺]_i on mitochondrial function and inflammatory signaling; (2) mitochondrial depolarization inhibitors to prevent cellular ATP depletion; (3) inflammatory signal inhibitors to attenuate the inflammatory response and its effect on promoting further cellular injury; (4) leukocyte inhibitors to prevent infiltration and/or activation of leukocytes to prevent their injurious effects on the acinar cell; (5) specific vasoactive agents to both prevent inflammatory cell infiltration and promote the microcirculation which is compromised during pancreatitis.
Chapter 2: Part B: Locoregional pathophysiology in acute pancreatitis: pancreas and intestine
1. Figure 2B.1 Complex interactions between the pancreas and the intestine in the pathogenesis of severe acute pancreatitis. [1. Reflex vasoconstriction can be increased by nonselective inotropes; 2. fluid resuscitation can promote reperfusion injury; 3. experimental evidence suggests that altered mesenteric lymph can promote necrosis, but this requires confirmation.]
2. Figure 2B.2 CT images of interstitial edematous (a) and necrotizing pancreatitis (b).
3. Figure 2B.3 Changes in the superior mesenteric artery (SMA) flow and in microcirculatory blood flow (MF) in the jejunal mucosa and in the pancreas after hemorrhage and after retransfusion of shed blood. (*P < 0.05 compared with baseline.)
4. Figure 2B.4 Timing of diagnosis of infections (pneumonia, bacteremia, and infected necrosis) in 173 patients during a first episode of acute pancreatitis.
5. Figure 2B.5 Intravital microscopy sodium taurocholate model of acute pancreatitis effect on erythrocyte velocity (mm/s) with intestinal ischemia. (*P < 0.05 for difference between IV with both V and VI).
Chapter 2: Part C: Pathophysiology of systemic inflammatory response syndrome and multiorgan dysfunction syndrome in acute pancreatitis
1. Figure 2C.1 Representation of different mechanisms of organ failure during early and late phases of acute pancreatitis due to sterile inflammation and sepsis, respectively.
2. Figure 2C.2 Schematic representation of activation of immune cells by damage-associated molecular pattern (DAMP) through pattern recognition receptors (PRRs) and release of inflammatory mediators.
3. Figure 2C.3 Drivers of systemic inflammation in acute pancreatitis: apart from the pancreas itself, intestine and adipose tissue play major roles in the development of MODS.
Chapter 6: Gallstone pancreatitis: diagnosis and treatment
1. Figure 6.1 Confirming a diagnosis of gallstone pancreatitis. TUS, transabdominal ultrasound; CT, computed tomography; CCY, cholecystectomy; GS, gallstone; GB, gallbladder; MRCP, magnetic resonance cholangiopancreatography; EUS, endoscopic ultrasound; ULN, upper limit normal; AP, acute pancreatitis; ALT, alanine transaminase.
2. Figure 6.2 Recommended algorithm for diagnosing choledocholithiasis. TUS, transabdominal ultrasound; CCY, cholecystectomy; IOC, intraoperative cholangiogram; MRCP, magnetic resonance cholangiopancreatography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; CBD, common bile duct. IOC is an option; the CBD should be imaged by some modality, that is, MRCP, ERCP, and IOC. ^¥Being highly operator dependent, the best strategy between laparoscopic and endoscopic stone extraction will be determined by the availability of local expertise and technology.
3. Figure 6.3 Indications and timing of ERCP in acute biliary pancreatitis. *Early ERCP is defined as ERCP within 72 hours of clinical presentation. AP, acute pancreatitis; ERCP, endoscopic retrograde cholangiopancreatography.
Chapter 7: Treatment of local complications
1. Figure 7.1 Contrast-enhanced CT scan of a patient with infected necrotizing pancreatitis. A single large percutaneous drain was placed through the left retroperitoneum. The patient recovered fully after the drainage procedure without additional drainage procedures and without necrosectomy.
2. Figure 7.2 Percutaneous catheter drainage and video-assisted retroperitoneal debridement. (a) A transverse cross-sectional image as can be seen on a contrast-enhanced CT image of a patient with necrotizing pancreatitis. The preferred route for catheter drainage is through the left side of the retroperitoneum. (b) More detail on the drained area. (c) A small subcostal incision is made near the puncture site of the percutaneous drain. The drain is used as a guide through the retroperitoneum to the necrotic collection. All visible necrosis is removed directly. (d) A videoscope is introduced and further debridement is performed with laparoscopic instruments.
3. Figure 7.3 Endoscopic transluminal drainage and endoscopic transluminal necrosectomy. Endoscopic transluminal intervention through the posterior wall of the stomach. (a) The necrotic collection is punctured through the stomach wall, and a guidewire is placed in the collection, if needed under the guidance of endoscopic ultrasound. The tract is balloon dilated over the guidewire. Two pigtail drains and a nasocystic catheter are placed into the collection for continuous lavage. (b) The cystogastrostomy is further dilated and the collection is entered by an endoscope. Under direct vision a necrosectomy can be performed.
Chapter 9: Specific treatment for acute pancreatitis
1. Figure 9.1 Pathogenesis of acute pancreatitis. In response to pancreatitis-associated toxins the release of Ca²⁺ from endoplasmic reticulum (ER) causes a delayed activation of sustained Ca²⁺ influx through store-operated Ca²⁺ entry (SOCE) channels and cytosolic Ca²⁺ overload. Mitochondrial injury characterized as ΔΨ_m depletion and impaired ATP production is the key determinant of AP severity, mediated through mediating cell death pathway activation. Intracellular trypsinogen and nuclear factor-κB (NF-κB) are activated independently and in parallel at an early stage during AP. Injured pancreatic acinar cells (PACs) activate innate and adaptive immunity. The release of inflammatory mediators prompts inflammatory infiltration that causes further local damage, release of multiple cytokines and danger-associated molecular patterns (DAMPs) from PACs and infiltrating inflammatory cells, leading to systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF).
2. Figure 9.2 Novel drug targets for acute pancreatitis. (a) Following endoplasmic reticulum (ER) Ca²⁺ release through inositol (1,4,5)-triphosphate receptor (IP₃R) and ryanodine receptor (RyR) Ca²⁺ channels, the ER Ca²⁺ sensor protein-stromal interacting molecule 1 (STIM1) translocates to below the plasma membrane and forms puncta with SOCE channels. Sustained Ca²⁺ influx from the external environment is the rate-limiting step of cytosolic Ca²⁺ overload. Ca²⁺ release-activated Ca²⁺ (CRAC) channels, namely Orai and transient receptor potential canonical (TPRC) channels, are the principal SOCE channels in PACs. (b) In response to cytosolic Ca²⁺ overload, the mitochondrial Ca²⁺ uniporter takes up Ca²⁺ to buffer high cytosolic Ca²⁺ concentrations. Ca²⁺ overload of the mitochondrial matrix leads to mitochondrial permeability transition pore (MPTP) opening and cell death pathway activation. The exact molecular components of MPTP are not clearly defined. Cyclophilin (Cyp D) is a mitochondrial matrix protein with peptidyl-prolyl cis–trans isomerase activity encoded by the Ppif gene, a critical regulator of MPTP opening.
Chapter 10: Sequelae of acute pancreatitis
1. Figure 10.1 Disconnected pancreatic duct syndrome (DPDS) – typical computed tomography finding (coronal) of patient with DPDS 4 weeks into the course of severe acute pancreatitis. Note large peripancreatic collection in lesser sac with viable pancreatic head (long arrow) and small disconnected pancreatic tail (two short arrows).
2. Figure 10.2 Symptomatic pseudocyst (arrow) in a patient 7 years after “definitive” treatment of necrotizing pancreatitis including debridement of peripancreatic necrosis.
3. Figure 10.3 (a) Computed tomography shows surgical drain adjacent to disconnected tail (arrow). (b) Sinogram through drain illuminates pancreatic duct in the body and tail (arrow).
4. Figure 10.4 Sinogram through drain (arrowhead) illuminates duodenum (long arrow) and biliary tree (short arrows).
5. Figure 10.5 Biliary stricture during acute episode of necrotizing pancreatitis (a, arrows) resolved after 3 months of biliary stenting (b, arrows).
6. Figure 10.6 (a) Massive cavernous venous transformation (arrows) around pancreatic head in a survivor of SAP (necrosis originally involved pancreatic head). (b) Portal vein recannulation after transsplenic placement of SMV/PV stent.
Chapter 12: Part B: Epidemiology and pathophysiology: genetic insights into pathogenesis
1. Figure 12B.1 Age of onset of HP-associated symptoms. The cumulative incidence of features and complications of pancreatitis associated with mutations in the PRSS1 gene.
2. Figure 12B.2 SAPE model of chronic pancreatitis. (a) Patients may spend years with multiple susceptibility risk factors (left) but remain asymptomatic. (b) A stochastic injury to the pancreas is believed to initiate AP, which typically lasts a few days. This is critical to activating the immune system at multiple levels. The resolution phase is affected by multiple variables (yellow diamond) as genetic and environmental risk factors or modifiers that may alter the healing process, leading to progression of pathology depending on the cell type and system. (c) Pathologic variants to the biology of the stellate cell leads to fibrosis, acinar cell loss leads to PEI, islet loss lead to DM, altered neural mechanisms leads to pain syndromes, and altered DNA repair leads to metaplasia and cancer.
3. Figure 12B.3 Population-based on 7456 Allegheny County, PA, residents following their first (sentinel) episode of AP. (a) Risk of developing RAP based on etiology. (b) Risk of CP based on the presence or absence of documented RAP.
Chapter 12: Part C: Pancreatic stellate cells: what do they tell us about chronic pancreatitis?
1. Figure 12C.1 Chronic pancreatitis – a hematoxylin and eosin (H&E) stained section of the pancreas from a patient with chronic pancreatitis showing abundant fibrosis, acinar atrophy, and distorted and dilated ducts.
2. Figure 12C.2 Pancreatic stellate cells in rat pancreas stained for the selective marker desmin. (a) A representative photomicrograph of normal rat pancreas immunostained for desmin. (b) The corresponding line diagram. Desmin-positive PSCs with long cytoplasmic projections are located at the basolateral aspect of acinar cells (A).
3. Figure 12C.3 Freshly isolated pancreatic stellate cells and PSCs in early culture. (a) Cytospin of freshly isolated PSCs exhibiting desmin staining (brown) in the cytoplasm adjacent to the nucleus (blue). (b) PSCs in early culture exhibiting a flattened polygonal shape with abundant lipid droplets (containing vitamin A) in the cytoplasm, surrounding the central nucleus. (c) PSC in early culture showing positive desmin staining characteristic of a cytoskeletal protein.
4. Figure 12C.4 Human chronic pancreatitis sections. (a) Serial sections from a patient with chronic pancreatitis stained with H and E and immunostained for α-smooth muscle actin (αSMA) and glial fibrillary acidic protein (GFAP), demonstrating positive staining for the PSC activation marker αSMA and the PSC selective marker GFAP in fibrotic areas. Tahara et al., Laboratory Investigation, 2013. Reprinted with permission from Nature Publishing Group. (b) Dual staining of a human chronic pancreatitis section immunostained for the PSC activation marker αSMA and for collagen using Sirius Red. The brown staining for αSMA is colocalized with the red staining for collagen indicating the presence of activated PSCs in fibrotic areas of the pancreas.
5. Figure 12C.5 Perpetuation of PSC activation. A diagrammatic representation of the postulated pathway for a perpetually activated state for PSCs. Pancreatic stellate cells are activated via paracrine pathways by exogenous factors during pancreatic necroinflammation. Activated PSCs synthesize and secrete endogenous cytokines, which influence PSC function via autocrine pathways. It is possible that this autocrine loop in activated PSCs perpetuates the activated state of the cell, even in the absence of the initial trigger factors, leading to excessive ECM production and eventually causing pancreatic fibrosis.
6. Figure 12C.6 Rat model of alcoholic chronic pancreatitis involving chronic ethanol administration and repeated endotoxin (LPS) challenge. (a) Graphical representation of histological injury in four groups of rats as assessed by scoring for vacuolization, necrosis, inflammatory infiltrate, hemorrhage, and edema: (i) control diet–fed rat, no alcohol (C); (ii) alcohol-fed rat (A); (iii) control diet–fed rat challenged with repeated LPS injections (CL_r) ; (iv) alcohol-fed rat challenged with repeated LPS injections (AL_r). Alcohol and LPS alone caused minimal histological damage to the pancreas. AL_r animal exhibited the highest histological injury scores compared with the other three groups. 25 HPF/section, three sections per rat were examined (*P < 0.001 AL_r vs. CL_r, A and C; n = 7 rats/group). (b) Masson's trichrome staining for pancreatic connective tissue: representative micrographs from CL_r and AL_r animals showing increased fibrosis (blue Masson's staining) in the latter group. (c) αSMA staining for activated PSCs: representative micrographs from CL_r and AL_r animals showing significantly increased αSMA in the latter group.
Chapter 12: Part D: Autoimmune pancreatitis: an update
1. Figure 12D.1 AIP and other organ involvement in IgG4 related disease [6].
Chapter 12: Part E: Etiology and pathophysiology: tropical pancreatitis
1. Figure 12E.1 Photomicrographs show marked heterogeneity of pathology ranging from normal acini to ductal concretions with periductal fibrosis and lymphoid follicles indicating chronic changes. (H&E, ×10 original magnification.)
2. Figure 12E.2 Photomicrographs show dilated duct with denuded epithelium contains concretions with extensive periductal fibrosis. (H&E, ×20 original magnification.)
3. Figure 12E.3 Photomicrographs show mild peripheral lymphomononuclear infiltration with lipoid metaplasia of acinar cells, which is seen in early phase. (H&E, ×40 original magnification.)
4. Figure 12E.4 Photomicrographs show neural hyperplasia with perineural inflammation. (H&E, ×40 original magnification.)
5. Figure 12E.5 Photomicrographs show areas of acinar destruction replaced by young fibroblasts accompanied by edema separating islets of Langerhans. (H&E, ×20 original magnification.)
6. Figure 12E.6 Photomicrographs show areas of acinar destruction replaced mature adipose tissue separating islets of Langerhans. (H&E, ×40 original magnification.)
Chapter 12: Part F: Mechanisms and pathways of pain in chronic pancreatitis
1. Figure 12F.1 Pathways of pancreatic pain signal transmission in chronic pancreatitis with emphasis on mechanisms of sensitization. Peripherally, extracellular inflammatory agents including NGF, trypsin, and tryptase sensitize and activate pancreatic afferent nociceptive neurons through integrative calcium signaling pathways. Centrally, sensitization is mediated through positive feedback loops among dorsal horn neurons and the activated neuronal supporting cells, microglia and astrocytes, via Cat S-mediated cleavage and release of soluble FKN. Abbreviations: ROS, reactive oxygen species; AA, arachidonic acid metabolites; TRPV, transient receptor potential vanilloids; NGF, nerve growth factor; PAR2, protease-activated receptor 2; PLC, phospholipase C; PKC, protein kinase C; PKA, protein kinase A; DRG, dorsal root ganglia; EET, epoxyeicosatrienoic acids; TrkA, trypomyosin-related kinase A; SP, substance P; FKN, fractalkine; sFKN, soluble fractalkine; Cat S, cathepsin S; CCR2, chemokine receptor 2; CCL2, chemokine ligand 2; MAPK, map kinase pathway; ERK, extracellular signal–regulated kinase pathway.
Chapter 13: Part A: Imaging of chronic pancreatitis
1. Figure 13A.1 Normal pancreas. Axial precontrast T1W 3D gradient echo with fat saturation (3D GRE FS) (a) shows that T1 signal in the normal pancreas (arrows) is more intense than that of the liver and spleen. Axial postcontrast T1W 3D GRE FS in the arterial (b) and delayed (c) phase shows the normal peak enhancement of the pancreas, in the arterial phase, with relative decreased enhancement in the delayed phase. Axial T2W image (d) demonstrates the normal T2 signal is similar in the pancreas compared with the liver.
2. Figure 13A.2 Chronic pancreatitis, presumed due to radiation therapy for esophageal cancer. Axial precontrast T1W 3D GRE FS image (a) shows relative decreased T1 signal intensity of the pancreas (arrows) compared with the liver. Postcontrast arterial (b) and delayed phase (c) T1W images demonstrate that peak enhancement has shifted to the delayed phase. On the axial T2W fat-saturated image (d), there is uniform increased T2 signal throughout the pancreas.
3. Figure 13A.3 Chronic pancreatitis due to pancreatic ductal adenocarcinoma. Axial precontrast T1W 3D GRE FS image (a) shows decreased T1 signal throughout the pancreas (short white arrows) with peak enhancement shifted to the delayed postcontrast phase (c) compared with the arterial phase (b). The T2W fat-saturated image (d) demonstrates dilation of the pancreatic duct (red arrows). A mass in the head of the pancreas (long white arrow in b and c) was biopsied, showing ductal adenocarcinoma.
4. Figure 13A.4 Chronic pancreatitis. Axial precontrast T1W 3D GRE FS image (a) shows relative decreased T1 signal intensity of the pancreas (arrows) compared with the liver. Postcontrast arterial (b) and delayed phase (c) T1W images demonstrate that peak enhancement has shifted to the delayed phase. On the axial T2W fat-saturated image (d), there is uniform mildly increased T2 signal throughout the pancreas.
5. Figure 13A.5 Fatty infiltration of the pancreas in chronic pancreatitis. In-phase (a) and opposed-phase (b) T1W images show marked signal dropout on the opposed-phase image due to microscopic lipid throughout the pancreas (arrow).
6. Figure 13A.6 Chronic pancreatitis in a patient status post-Whipple procedure. Axial precontrast T1W 3D GRE FS image (a) shows relative decreased T1 signal intensity of the pancreas (arrow) compared with the liver. Postcontrast arterial (b) and delayed phase (c) T1W images demonstrate that peak enhancement has shifted to the delayed phase. (d) Spectroscopic analysis demonstrates hepatic lipid correlating to 11%; quantitative evaluation of hepatic lipid and iron may be routinely obtained with MRI.
Chapter 13: Part B: Endoscopic ultrasonography in chronic pancreatitis
1. Figure 13B.1 EUS features of chronic pancreatitis.
2. Figure 13B.2 Histologic correlates of EUS features of chronic pancreatitis.
3. Figure 13B.3 EUS images demonstrating normal pancreatic parenchymal and ductal anatomy in comparison to EUS features in chronic pancreatitis.
Chapter 14: Part C: Pancreatogenic diabetes: etiology, implications, and management
1. Figure 14C.1 Prevalence of types of diabetes. (a) Distribution of types of diabetes and (b) causes of type 3c (pancreatogenic) diabetes based on studies of 1922 diabetic patients reported by Hardt et al. [3].
2. Figure 14C.2 Pancreatic polypeptide. The amino acid structure of (canine) pancreatic polypeptide (PP) and the connected icosapeptide that is synthesized as a precursor molecule in PP- or F-cells of the pancreatic islets. The amino acids that differ in mammalian PPs are shown in the box. The “hairpin fold” of the peptide is conserved among all members of the PP family of peptides.
3. Figure 14C.3 Endocrine anatomy of pancreatic islets. Serial sections of a representative islet found in the head or ventral (left panel) and tail or dorsal (right panel) portions of the pancreas. (a) Tissue stained with hematoxylin and eosin. (b) β-Cells immunohistochemically stained with anti-insulin antibody. (c) α-Cells stained with antiglucagon antibody. (d) Pancreatic polypeptide (PP) cells stained with anti-PP antibody. (e) δ-Cells stained with antisomatostatin antibody. Note the differential presence of α-cells and PP-cells in the dorsal and ventral portions of the pancreas, respectively.
4. Figure 14C.4 Hepatic insulin sensitivity and glucose tolerance in patients with chronic pancreatitis before, during, and after PP administration. (a) Percent suppression of hepatic glucose production (Ra) during 2.0 mU/kg/min insulin infusion in six normal subjects (NL) and five patients with chronic pancreatitis accompanied by PP deficiency (CP), before (Study 1), during (Study 2), and 1 month after (Study 3) an 8-hour infusion of 2.0 pmol/kg/min of bovine PP. *P < 0.05 versus NL, ‡P < 0.05 versus Study 1. (b) Mean plasma glucose concentration during 180-minute oral glucose tolerance test in 6 normal subjects and 10 patients with chronic pancreatitis before (OGTT 1), 18 hours after (OGTT2), and 1 month after (OGTT3) an 8-hour infusion of 2.0 pmol/kg/min of bovine PP. Closed circles indicate normal glucose tolerance status on initial testing; open circles indicate impaired glucose tolerance or diabetes on initial glucose tolerance testing. After PP infusion, every patient with abnormal glucose tolerance demonstrated a lower mean glucose value.
5. Figure 14C.5 PP responses to oral glucose in young normal, old normal, and old diabetic subjects. Serum PP responses to 75 g glucose ingested at time 0 in 10 healthy subjects aged less than 40 years with normal glucose tolerance (Young NL), 19 healthy subjects aged greater than 65 years with normal glucose tolerance (Old NL), and 21 elderly subjects with T2D (Old DM). Data are shown as mean ± SE.
6. Figure 14C.6 Suggested algorithm for the treatment of patients with T3cD. Recommend and reinforce lifestyle changes (weight loss if obese, exercise, diet, abstention from alcohol, and smoking cessation) at every visit. Begin metformin and advance to maximum dose based on blood glucose and hemoglobin A_1c (HgbA_1c) levels. Add pancreatic enzyme replacement therapy (Panc Enz Rx) if fecal elastase C1 is less than 100 ug/g or patient has signs or symptoms of pancreatic exocrine insufficiency. If HgbA_1C levels persist above 7%, add an additional oral agent such as a thiazolidinedione (TZD), an α-glucosidase inhibitor (αGI), or a sodium glucose cotransporter-2 inhibitor. If HgbA_1c > 7% persists, add basal intermediate- or long-acting insulin. Convert to intensive (multidose) insulin treatment but continue metformin if HgbA_1c persists > 7%. Consider adjunct treatment (Adjunct Rx) such as pramlintide before escalating insulin dose if HgbA_1C > 7% persists.
Chapter 15: Part A: Endoscopic management of chronic pancreatitis
1. Figure 15A.1 (a) Main pancreatic duct stricture in the head of pancreas. (b) and (c) Multiple pancreatic stents placed. Note that a biliary stent was placed for a bile duct stricture.
2. Figure 15A.2 (a) Main pancreatic duct stricture in the head of pancreas. (b) Balloon dilation of pancreatic duct stricture in the head of pancreas. (c) Fully covered self-expandable metallic stent placement. (d) Pancreatic duct stricture resolution after temporary fully covered self-expandable metallic stent was removed.
3. Figure 15A.3 (a) Chronic pancreatitis–induced common bile duct stricture (arrow). (b) Balloon dilation of common bile duct stricture. (c) Multiple plastic stents placed.
4. Figure 15A.4 (a) Chronic pancreatitis–induced common bile duct stricture. (b) Balloon dilation of common bile duct stricture. (c) and (d) Fully covered self-expandable metallic stent placement.
5. Figure 15A.5 (a) Pancreatic pseudocyst seen on EUS. (b) Pseudocyst is punctured using a 19-guage needle. (c) and (d) Balloon dilation to enlarge the cystogastrostomy tract. (e) and (f) Two double-pigtail plastic stents placed transmurally.
6. Figure 15A.6 (a) Pancreatic pseudocyst seen on EUS. (b) Pseudocyst is punctured through the duodenal wall using a 19-guage needle. (c) A guidewire is looped twice to maintain secure access. (d) and (e) Fully covered self-expandable metallic stent placed transmurally.
Chapter 15: Part C: Endoscopic management: celiac plexus blockade
1. Figure 15C.1 The celiac ganglia, measuring 1.45 cm, is seen just anterior to the takeoff of the celiac artery from the aorta.
2. Figure 15C.2 Color Doppler shows flow in the aorta.
3. Figure 15C.3 A 19-gauge needle is inserted into the celiac ganglia.
4. Figure 15C.4 A 1-cm celiac ganglia is seen as a hypoechoic oblong structure with hyperechoic foci.
Chapter 16: Part C: Chronic pancreatitis: surgical strategy in complicated diseases
1. Figure 16C.1 Spectrum of pancreatic fluid collection in chronic pancreatitis. (a) CT: Intra-pancreatic head. (b) MRCP: pancreatic duct obstruction and lesser sac collection. (c) CT: extra-pancreatic lesser sac collection. (d) CT: extra-pancreatic tail of pancreas collection.
2. Figure 16C.2 (a) CT: pancreatic duct obstruction with ascites. (b) XR: Isolated left pleural effusion. (c) ERCP: showing an obstructed pancreatic duct with stones. (d) Endoscopy: Pancreatic duct stent.
3. Figure 16C.3 (a and b) ERCP and MRCP: high grade distal bile duct obstruction. (c). CT: grossly dilated bile duct and pancreatic duct. (d) CT: demonstrating large calcified mass in head of pancreas without dilated pancreatic duct.
4. Figure 16C.4 Management algorithm for bile duct obstruction according to the size of the main pancreatic duct.
5. Figure 16C.5 (a) ERCP: Bleeding from the ampulla of Vater. (b) CT: false aneurysm in head of pancreas. (c) Selective angiography: false aneurysm arising from gastro-duodenal artery. (d) Selective angiography: successful embolization.
Chapter 16: Part D: Surgery for chronic pancreatitis: pancreatic duct drainage procedures
1. Figure 16D.1 The longitudinal side-to-side pancreaticojejunostomy. The opened pancreatic duct with ductal mucosa. The posterior layer is sutured and a start is made for the anterior layer at the schematic drawing.
2. Figure 16D.2 The mean Izbicki Pain scores at baseline and 6 weeks up to 24 months after endoscopic and surgical drainage.
Chapter 16: Part E: Surgical management: resection and drainage procedures: Chronic pancreatitis – hybrid procedures
1. Figure 16E.1 Progression of the pancreatic head tumor 2 years after a drainage operation. Limiting the operation to the pancreatic duct in the pancreatic body and tail of the pancreas might lead to persistent symptoms due to the pacemaker function of the pancreatic head.
2. Figure 16E.2 Comparison of long- and short-term results comparing drainage procedures (D) to resection procedures (R). On the long-term procedures resecting the pancreatic head are more effective than simple drainage procedures.
3. Figure 16E.3 Randomized controlled trials comparing duodenum-preserving operations (Frey and Beger) to oncological operations (PPPD and Whipple operation). o, no difference; +, superiority of duodenum-preserving operation; p.o., postoperative; QOL, quality of life.
4. Figure 16E.4 Beger operation. After a subtotal resection of the pancreatic head two anastomoses are performed to the remaining pancreatic tail and a rim of pancreas on the duodenum. The operation can be combined with a biliary anastomosis to the intrapancreatic part of the biliary duct.
5. Figure 16E.5 Comparison of the various commonly used hybrid techniques. +, always performed; ±, sometimes performed; −, rarely performed.
6. Figure 16E.6 Frey operation. A wide excision of the pancreatic head is combined with a longitudinal drainage procedure. A laterolateral pancreaticojejunostomy is performed in a Roux-en-Y fashion.
7. Figure 16E.7 Comparison between the Frey and the Beger operations as short- and long-term observations. f/u, follow-up of the previous study; NS, no differences in pain, QOL, and endocrine and exocrine functions.
Chapter 16: Part F: The role of pancreatoduodenectomy in the management of chronic pancreatitis
1. Figure 16F.1 Pylorus-preserving pancreatoduodenectomy. Note the end-to-side mucosa-to-mucosa pancreaticojejunostomy. If the pancreatic duct in the distal pancreatic remnant is very dilated (greater than 7 mm) lateral pancreatoduodenectomy is an alternative.
2. Figure 16F.2 (a) Beger procedure with near complete resection of pancreatic head. Note the preservation of posterior capsule of pancreas and bile duct. If obstructed, the intrapancreatic portion of the common bile duct can be opened in the proximal pancreatic head remnant and included in the proximal side-to-side pancreaticojejunostomy. (b) Note two pancreatic anastomoses for reconstruction: end-to-end pancreaticojejunostomy to the distal pancreatic remnant and a-side to-side pancreaticojejunostomy to the proximal pancreatic remnant.
3. Figure 16F.3 (a) Frey procedure with filleting of the pancreas longitudinally from splenic hilum to medial wall of duodenum. The head of the gland is unroofed or “cored out.” Care needs to be taken to protect the common bile duct as it courses posteriorly. (b) Longitudinal pancreaticojejunostomy includes the filleted portion of the pancreatic duct in the neck, body, and tail as well as the excavation cavity in the head of the gland.
4. Figure 16F.4 Kaplan–Meier survival curves for 166 patients undergoing pancreatoduodenectomy at Mayo Clinic from 1976 to 2013 (blue) and for age-matched control patients with life expectancy based on US life tables (red). Survival was significantly less for patients with chronic pancreatitis.
5. Figure 16F.5 (a and b) Abdominal computed tomography with intravenous contrast in axial views reveals inflammatory pancreatic head mass and macrocalcification. Note the patency of portal vein and preservation of tissue planes between the pancreas and the peripancreatic vessels. (c) Coronal image in same subject with inflammatory head mass, macrocalcification, and moderate pancreatic duct dilation noted in proximal body of the pancreas. The patient underwent pylorus-preserving pancreatoduodenectomy with satisfactory outcome.
6. Figure 16E.6 Endoscopic retrograde cholangiopancreatography in a different patient with intractable abdominal pain, weight loss, and impending obstructive jaundice. Double duct sign suspicious for malignancy. Head mass and duodenal stenosis was present. Pylorus-preserving pancreatoduodenectomy was chosen to rule out malignancy and to treat both intractable pain and mechanical complications.
Chapter 17: Part B: Total pancreatectomy and islet cell autotransplantation: the science of islet cell preservation, from pancreas to liver
1. Figure 17B.1 Illustration of the procedure of total pancreatectomy and intraportal islet infusion. Following the complete resection of the pancreas, the islets are isolated and gently infused back into the portal vein of the patient.
2. Figure 17B.2 Islet isolation process: pancreas dissection, ductal cannulation, collagenase enzyme distention, digestion setup, and isolated islets.
3. Figure 17B.3 Proportion of patients who are insulin independent at various time points after TPIAT, by the number of islets (IEQ/kg) transplanted.
Chapter 17: Part C: Total pancreatectomy and islet cell autotransplantation: long-term assessment of graft function
1. Figure 17C.1 (a and b) Abdominal ultrasound images of two patients following a pancreatectomy and islet cell autotransplant (more than 12 months earlier). The images demonstrate nodular echogenicity of the liver found in 25% of the patients. The changes occur from 6 to 12 months following the islet infusion and are not found in patients following a total pancreatectomy alone. (c and d) The liver appearances are not associated with clinical, biochemical, or radiological evidence of liver dysfunction or progression of the appearances once established. (c and d) show the same patient with stable ultrasound appearances over a 2-year period.
2. Figure 17C.2 Number of patients who are insulin independent following pancreatectomy and islet autotransplantation in the Leicester series.
3. Figure 17C.3 C-Peptide levels at 120 minutes in patients who have had a pancreatectomy and islet autotransplant.
4. Figure 17C.4 Patient postoperative satisfaction survey.
5. Figure 17C.5 Survival in islet and islet transplant patients following total pancreatectomy.
6. Figure 17C.6 Effect of collagenase on islet isolation: Insulin-independent patients.