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Surgery_Schwartz. drains, now assuming a greater role in the management of the local complications (discussed later). Magnetic resonance imaging (MRI) is superior to CT scanning in detecting any solid content within collections (Figure 33-13). And when a bleed is suspected, in association with a local complication, an arterial phase CT scan (CTa) is useful in detecting a pseudoaneurysm, active bleeding, and/or hematoma.3Brunicardi_Ch33_p1429-p1516.indd 144601/03/19 6:44 PM 1447PANCREASCHAPTER 33ABFigure 33-13. Corresponding computed tomography (CT) (A) and MR (B) images of a patient with a symptomatic pseudocyst. CT image reveals a well circumscribed homogenous collection (arrows) exerting mass effect on antrum of stomach. The T2-weighted MR image clearly distinguishes necrotic pancreas (black arrows) from fluid (white arrows). (Reproduced with permission from Bollen TL: Imaging of acute pancreatitis: update of the revised Atlanta classification, Radiol Clin North Am. 2012


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Surgery_Schwartz. pancreas (black arrows) from fluid (white arrows). (Reproduced with permission from Bollen TL: Imaging of acute pancreatitis: update of the revised Atlanta classification, Radiol Clin North Am. 2012 May;50(3):429-445.)Therapeutic Endoscopic Retrograde CholangiopancreatographyRandomized trials have demonstrated that early ERCP (within 24 or 48 hours of admission) reduce complications, but not mortality, in patients with predicted severe gallstone associated acute pancreatitis. While the benefits of this inva-sive modality are clear (e.g., treatment of cholangitis and release of impacted stone), this can be offset by the risks of increasing the severity of pancreatitis, bleeding, cholan-gitis, and perforation. More recent evidence has suggested that early ERCP confers no benefit in the absence of con-comitant cholangitis,83 as the offending common duct stone usually passes before ERCP can be performed. This may be evidenced by improvement in the liver function tests over the first 2 to


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Surgery_Schwartz. of con-comitant cholangitis,83 as the offending common duct stone usually passes before ERCP can be performed. This may be evidenced by improvement in the liver function tests over the first 2 to 3 days. If there is persistent cholestasis, an MRCP can be used to detect a common duct stone and can be used as a prerequisite for attempting an ERCP.84 Persistent cholesta-sis without cholangitis may require an ERCP but not usually in the acute setting.AntibioticsAlthough the use of broad-spectrum antibiotics to treat estab-lished infection in acute pancreatitis is a well-established prac-tice, there has been considerable controversy surrounding the use of prophylactic antibiotics.63 The overuse of antibiotics has been associated with a documented rise in fungal infec-tions and resistant organisms. Overall, it appears that the most recent and generally better designed studies do not support the use of prophylactic antibiotics to reduce the frequency of pancreatic infectious complications,


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Surgery_Schwartz. Overall, it appears that the most recent and generally better designed studies do not support the use of prophylactic antibiotics to reduce the frequency of pancreatic infectious complications, surgical intervention, and death.85Managing Local ComplicationsVigilance is required for the timely and accurate diagnosis of local complications. The decisions regarding how and when to intervene are often difficult. While guided by the information gained by cross-sectional imaging, the decision to intervene is based on the clinical status and trajectory of the patient and the poor response to maximal intensive care support. This means close monitoring of the patient by serial examination, supplemented by regular measurement of inflammatory markers (e.g., C-reactive protein) and a pancreatic protocol CT scan if a local complication is suspected and intervention considered warranted. In practice, intervention is delayed in order to allow demarcation and to reduce the risk of bleeding,


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Surgery_Schwartz. protocol CT scan if a local complication is suspected and intervention considered warranted. In practice, intervention is delayed in order to allow demarcation and to reduce the risk of bleeding, disseminated infection, and collateral damage to adjacent organs by an intervention (Figure 33-14). Appreciation of this has resulted in a notable trend toward delayed Figure 33-14. Operative view of infected acute pancreatitis. Peripancreatic infection, characterized by mucopurulent exu-date, extends far beyond the boundaries of the pancreas in the retroperitoneum.Brunicardi_Ch33_p1429-p1516.indd 144701/03/19 6:44 PM 1448SPECIFIC CONSIDERATIONSPART IIStomachPeritoneal spacePeripancreaticfluid collectionwith necrotic tissueEndoscope(with balloon dilatation)PancreasRPOSTERIORLATERAL VIEWNecrotic tissuein snareLStomachSpleenPeripancreaticfluid collectionwith necrotic tissueAccess toretroperitonealspaceCostal marginPancreasPancreasLiverNecrotictissueLong


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Surgery_Schwartz. VIEWNecrotic tissuein snareLStomachSpleenPeripancreaticfluid collectionwith necrotic tissueAccess toretroperitonealspaceCostal marginPancreasPancreasLiverNecrotictissueLong graspingforcepsLaparoscopeStomachSpleenPeripancreaticfluid collectionwith necrotic tissueEndoscopeStomach wallFluid collectionAortaPOSTERIORFigure 33-15. Two minimally invasive interventions for local complications of acute pancreatitis: A. video-assisted retroperitoneal debridement and B. endoscopic transgastric necrosectomy. (Reproduced with permission from Bakker OJ, van Santvoort HC, van Brunschot S, et al: Endoscopic transgastric vs surgical necrosectomy for infected necrotizing pancreatitis: a randomized trial, JAMA. 2012 Mar 14; 307(10):1053-1061.)intervention, now uncommon before 3 to 4 weeks from the onset of symptoms. An important emerging approach is the increasing use of percutaneous catheter drainage in patients with suspected infected collections.86 Fine-needle aspiration is now rarely used to confirm


Surgery_Schwartz

Surgery_Schwartz. An important emerging approach is the increasing use of percutaneous catheter drainage in patients with suspected infected collections.86 Fine-needle aspiration is now rarely used to confirm infection because the insertion of a needle at the time of planned drainage allows confirmation of the suspected infection. Preemptive drainage with one or more catheters often produces improvement or stabilization of the patient’s overall clinical status.87 In this way, drainage “buys time” and allows the lesion to become more walled off and safer to treat. Recent data suggests that primary percutaneous catheter drainage may be the only intervention required in a third to a half of patients and that this proportion might increase further if there were a policy of regular catheter exchange, upsizing, and irrigation.87 A proportion of patients do, however, require further treatment when they fail to respond and there is a wide array of minimally invasive options to choose from88 (Figure 33-15).


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Surgery_Schwartz. and irrigation.87 A proportion of patients do, however, require further treatment when they fail to respond and there is a wide array of minimally invasive options to choose from88 (Figure 33-15). These interventions can be classified on the basis of the method of visualization, route taken to the lesion, and the purpose of the intervention.89 In practice, the approach taken will depend on local expertise and equipment as well as the location and type of the specific local complication. A large Dutch randomized trial has shown that open surgical techniques should only be considered in those who fail to respond to the step-up approach, that is, prior percutaneous drainage and minimally invasive intervention.90 The exception is to be found in the rare situation where an abdominal compartment syndrome requires open decompression, but this is usually earlier than the optimal time to intervene for local complications. A recent landmark randomized trial has compared two minimally invasive


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Surgery_Schwartz. syndrome requires open decompression, but this is usually earlier than the optimal time to intervene for local complications. A recent landmark randomized trial has compared two minimally invasive techniques, endoscopic transgastric drainage, and the videoscope-assisted retroperitoneal debridement through a flank incision (see Figure 33-15). The data shows that the former approach is superior, although the latter has a role when the walled-off necrosis is remote from the stomach or duodenum, as in the left flank.91The management of an acute noninfected pseudocyst is usually conservative, as about half of these will resolve sponta-neously. When symptoms of pain or the inability to eat persist or infection occurs, intervention is required. The indications for intervention are therefore no longer based on size and duration alone. Pseudocysts persist because of communication with the main pancreatic duct and/or distal ductal stenosis. Percutaneous drainage should be avoided in this


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Surgery_Schwartz. no longer based on size and duration alone. Pseudocysts persist because of communication with the main pancreatic duct and/or distal ductal stenosis. Percutaneous drainage should be avoided in this situation because of the risk of external pancreatic fistula.92 EUS-guided internal drainage into stomach or duodenum or transpapillary stenting is the pre-ferred approach.Managing Organ FailureThe specific management of multiple organ failure is beyond the scope of this chapter. The early identification of organ dysfunc-tion and failure is important because it is a key determinant of severity and outcome and to facilitate the timely transfer of the patient to an intensive care unit to optimize management, pro-vide organ support and allow more intensive monitoring. The severity of organ failure can be scored (see Table 33-6). The responsiveness of organ failure to resuscitation over the first 48 hours is an important prognostic clue; those that respond have transient organ failure and have


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Surgery_Schwartz. can be scored (see Table 33-6). The responsiveness of organ failure to resuscitation over the first 48 hours is an important prognostic clue; those that respond have transient organ failure and have a better outlook than those who do not respond and have persistent organ failure.93 Organ failure that develops later in the disease course is usually Brunicardi_Ch33_p1429-p1516.indd 144801/03/19 6:44 PM 1449PANCREASCHAPTER 33Table 33-10Algorithm for the evaluation and management of acute pancreatitis 1. Diagnosis • History of abdominal pain consistent with acute pancreatitis • >3x elevation of pancreatic enzymes • CT scan if required to confirm diagnosis 2. Initial assessment/management (first 4 hrs) • Analgesia • Fluid resuscitation • Predict severity of pancreatitis • Ranson’s criteria • HAPS score • Assess systemic response • SIRS score • SOFA (organ failure) 3. Reassessment/management (4 to 6 hrs) • Assess response to fluid resuscitation • mean arterial pressure • heart


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Surgery_Schwartz. criteria • HAPS score • Assess systemic response • SIRS score • SOFA (organ failure) 3. Reassessment/management (4 to 6 hrs) • Assess response to fluid resuscitation • mean arterial pressure • heart rate • urine output • hematocrit • Determine etiology • Ultrasound for gallstones/sludge • History of alcohol consumption • Laboratory evaluation of other causes • MRCP and/or Urgent ERCP if concomitant cholangitis is present • not for cholestasis or predicted severe disease per se • Transfer to ICU or specialist center as needed • Deterioration or failure to respond to initial management • Intensive support for persistent organ failure • Commence enteral nutrition • Once normovolemia restored (usually after 6 hours) • Commence via NG tube if no gastric stasis • No prophylactic antibiotics or probiotics 4. Conservative management and monitoring (at least daily) • Clinical evaluation • Assess cardiovascular, respiratory, and renal function • Detect peritonitis and abdominal compartment


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Surgery_Schwartz. or probiotics 4. Conservative management and monitoring (at least daily) • Clinical evaluation • Assess cardiovascular, respiratory, and renal function • Detect peritonitis and abdominal compartment syndrome • Daily C-reactive protein • Classify severity (mild, moderate, severe, critical) • Detect intolerance of NG EN • Advance tube for NJ feeding if needed • Consider supplemental parenteral nutrition by day 4 5. Indications for “pancreatic protocol CT scan” (rarely in first week) • For significant clinical deterioration and elevated CRP • For suspicion of local pancreatic complications • For suspected bowel ischemia • For acute bleeding (CTa) (if stable enough and consider embolization) • For abdominal compartment syndrome 6. Invasive intervention • For deteriorating patient with suspected infected local complication • “Step up approach” with initial drain guided by current CT scan (percutaneous or endoscopic drainage) • Delay for 3 to 4 weeks with intensive care support, if


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Surgery_Schwartz. suspected infected local complication • “Step up approach” with initial drain guided by current CT scan (percutaneous or endoscopic drainage) • Delay for 3 to 4 weeks with intensive care support, if possible • If failure to respond or secondary deterioration, repeat CT scan, and select appropriate minimally invasive technique based on available expertise and equipment • Video-assisted retroperitoneal debridement or percutaneous nephroscopic debridement • Endoscopic transluminal debridement • Ongoing large bore drainage and irrigation 7. Indication for laparotomy • Failed “step-up approach” for further debridement/drainage • Acute abdomen (perforation or ischemia) • Severe abdominal compartment syndrome (rarely)secondary to infection of a local complication and should be managed accordingly (see Figure 33-9).CholecystectomyWhile it is widely accepted that cholecystectomy is essential to prevent recurrent gallstone associated pancreatitis, the ques-tion relates to the timing of it.


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Surgery_Schwartz. (see Figure 33-9).CholecystectomyWhile it is widely accepted that cholecystectomy is essential to prevent recurrent gallstone associated pancreatitis, the ques-tion relates to the timing of it. Index cholecystectomy, done in the same admission and prior to discharge, appears safe and can almost always be accomplished laparoscopically.94 But index cholecystectomy is not suitable for all patients, particu-larly some who have had local pancreatic complications, which includes a large inflammatory mass that extends into the porta hepatis. These patients may require an interval cholecystec-tomy after resolution of the inflammatory process. If surgery is required for the management of local complications, then a cholecystectomy is often performed at that time.DiabetesRecent evidence indicates that prediabetes and diabetes are com-mon after acute pancreatitis and occur in nearly 40% of patients after hospital discharge.95 The prevalence of newly diagnosed diabetes is much higher after acute


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Surgery_Schwartz. prediabetes and diabetes are com-mon after acute pancreatitis and occur in nearly 40% of patients after hospital discharge.95 The prevalence of newly diagnosed diabetes is much higher after acute pancreatitis (23%) than the prevalence of diabetes in the general population (4–9%). The risk of diabetes increases by at least twofold after 5 years as compared with 12 months. Interestingly, the severity of acute pancreatitis appears to have minimal effect on risk of diabetes.95 The implica-tion is that patients recovered from an attack of acute pancreatitis may need follow-up and screening for glucose intolerance.The management of acute pancreatitis remains a formidable challenge (Table 33-10) due to the variety and severity of the many associated complications (Table 33-11), and continues to evolve. Although specific treatments for acute pancreatitis remain elusive, progress has been made in the management of pain, fluid resuscitation, antibiotic prophylaxis, enteral nutrition,


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Surgery_Schwartz. to evolve. Although specific treatments for acute pancreatitis remain elusive, progress has been made in the management of pain, fluid resuscitation, antibiotic prophylaxis, enteral nutrition, therapeutic ERCP, and cholecystectomy. Progress has also been made in the intensive care management of systemic complications and in the development of less invasive interventions for the treatment of local complications, particularly infected pancreatic necrosis.4Brunicardi_Ch33_p1429-p1516.indd 144901/03/19 6:44 PM 1450SPECIFIC CONSIDERATIONSPART IITable 33-11Complications of acute pancreatitis I. Local A. Pancreatic phlegmon B. Pancreatic abscess C. Pancreatic pseudocyst D. Pancreatic ascites E. Involvement of adjacent organs, with hemorrhage, thrombosis, bowel infarction, obstructive jaundice, fistula formation, or mechanical obstruction II. Systemic A. Pulmonary 1. Pneumonia, atelectasis 2. Acute respiratory distress syndrome 3. Pleural


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Surgery_Schwartz. thrombosis, bowel infarction, obstructive jaundice, fistula formation, or mechanical obstruction II. Systemic A. Pulmonary 1. Pneumonia, atelectasis 2. Acute respiratory distress syndrome 3. Pleural effusion B. Cardiovascular 1. Hypotension 2. Hypovolemia 3. Sudden death 4. Nonspecific ST-T wave changes 5. Pericardial effusion C. Hematologic 1. Hemoconcentration 2. Disseminated intravascular coagulopathy D. GI hemorrhage 1. Peptic ulcer 2. Erosive gastritis 3. Portal vein or splenic vein thrombosis with varices E. Renal 1. Oliguria 2. Azotemia 3. Renal artery/vein thrombosis F. Metabolic 1. Hyperglycemia 2. Hypocalcemia 3. Hypertriglyceridemia 4. Encephalopathy 5. Sudden blindness (Purtscher’s retinopathy) G. Central nervous system 1. Psychosis 2. Fat emboli 3. Alcohol withdrawal syndrome H. Fat necrosis 1. Intra-abdominal saponification 2. Subcutaneous tissue necrosisReproduced with permission from Isselbacher KJ: Harrison’s Principles of Internal Medicine, 13th ed. New York, NY:


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Surgery_Schwartz. necrosis 1. Intra-abdominal saponification 2. Subcutaneous tissue necrosisReproduced with permission from Isselbacher KJ: Harrison’s Principles of Internal Medicine, 13th ed. New York, NY: McGraw-Hill Education; 1994.CHRONIC PANCREATITISDefinition, Incidence, and PrevalenceChronic pancreatitis is an incurable, chronic inflammatory con-dition that is multifactorial in its etiology, highly variable in its presentation, and a challenge to treat successfully. Autopsy studies indicate that evidence of chronic inflammation, such as fibrosis, duct ectasia, and acinar atrophy is seen in up to 5% of the population,96 although these data are difficult to interpret because many of these changes are also present in asymptomatic elderly patients.97 Population studies suggest a prevalence that ranges from 5 to 40 persons per 100,000 population, with con-siderable geographic variation.98 Differences in diagnostic crite-ria, regional nutrition, alcohol consumption, and medical access account for


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Surgery_Schwartz. from 5 to 40 persons per 100,000 population, with con-siderable geographic variation.98 Differences in diagnostic crite-ria, regional nutrition, alcohol consumption, and medical access account for variations in the frequency of the diagnosis, but the overall incidence of the disease has risen progressively over the past 50 years.EtiologyThere are multiple etiologies of chronic pancreatitis, includ-ing genetic mutations, alcohol exposure, duct obstruction due to trauma, gallstones, and tumors, metabolic diseases such as hyperlipidemia and hyperparathyroidism, and auto-immune dis-ease. In addition, nutritional causes include so-called tropical pancreatitis, which has been thought to result from ingestion of certain starches. A significant number of patients have no discernible cause of the disease despite extensive testing, and are said to have “idiopathic” chronic pancreatitis.Genetic CausesIn 1952, Comfort and Steinberg reported a kindred of “heredi-tary chronic relapsing


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Surgery_Schwartz. of the disease despite extensive testing, and are said to have “idiopathic” chronic pancreatitis.Genetic CausesIn 1952, Comfort and Steinberg reported a kindred of “heredi-tary chronic relapsing pancreatitis” after treating the proband, a 24-year-old woman, at the Mayo Clinic.99 Subsequently, familial patterns of chronic, nonalcoholic pancreatitis have been described worldwide, and a familiar pattern has emerged. Typically, patients first present in childhood or adolescence with abdominal pain and are found to have chronic calcific pan-creatitis on imaging studies. Progressive pancreatic dysfunction is common, and many patients present with symptoms due to pancreatic duct obstruction. The risk of subsequent carcinoma formation is increased, reaching a prevalence, in some series, of 40%, but the age of onset for carcinoma is typically >50 years old.100 The disorder is characterized by an autosomal dominant pattern of inheritance, with 80% penetrance and variable expres-sion. The


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Surgery_Schwartz. 40%, but the age of onset for carcinoma is typically >50 years old.100 The disorder is characterized by an autosomal dominant pattern of inheritance, with 80% penetrance and variable expres-sion. The incidence is equal in both sexes.Whitcomb and colleagues,101 and separately LeBodic and associates,102 performed gene-linkage analysis and identified a linkage for hereditary pancreatitis to chromosome 7q35. Subse-quently, the region was sequenced and revealed eight trypsino-gen genes. Mutational analysis revealed a missense mutation resulting in an Arg-to-His substitution at position 117 of the cat-ionic trypsinogen gene, or PRSS1, one of the primary sites for proteolysis of trypsin. This gain-of-function mutation results in an excess production of trypsinogen, which results in persistent and uncontrolled proteolytic activity and autodestruction within the pancreas.103 The position 117 mutation of PRSS1 and an addi-tional mutation, now known collectively as the R122H and N291 mutations


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Surgery_Schwartz. uncontrolled proteolytic activity and autodestruction within the pancreas.103 The position 117 mutation of PRSS1 and an addi-tional mutation, now known collectively as the R122H and N291 mutations of PRSS1, account for about two-thirds of cases of hereditary pancreatitis. Masson and associates described a gain-of-function mutation in the anionic trypsinogen gene, PRSS2, that is also present in some cases.104Similarly, SPINK1, an inflammation-induced trypsin inhibitor secreted in acinar cells, has been found to have a role in hereditary pancreatitis. SPINK1 specifically inhibits trypsin action by competitively blocking the active site of the enzyme. Witt and colleagues investigated96 unrelated children with chronic pancreatitis in Germany and found a variety of SPINK1 mutations in 23% of the patients.105 Several studies have now confirmed an association of loss-of-function SPINK1 mutations with familial and idiopathic forms of chronic pancreatitis, as well as so-called tropical


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Surgery_Schwartz. of the patients.105 Several studies have now confirmed an association of loss-of-function SPINK1 mutations with familial and idiopathic forms of chronic pancreatitis, as well as so-called tropical pancreatitis.106,107 SPINK1 mutations Brunicardi_Ch33_p1429-p1516.indd 145001/03/19 6:44 PM 1451PANCREASCHAPTER 33BasolateralmembraneAcinar callKeyZymogensClaudin-2CFTRCalcium regulationCAZymogens: Including;trypsinogens (PRSS1, PRSS2)chymotrypsin C (CTRC)(SPINK1 in“ammation-induced trypsin inhibitor)Calcium sensing receptor (CASR)CFTRDuodenumZymogensecretionAbnormalclaudin-2localizationDuct cellBicarbonateSodiumWaterTrypsinogenZymogensEKTrypsinActive digestiveenzymesCASRFigure 33-16. Schematic model of genetic causes of chronic pan-creatitis. A pancreatic acinus is portrayed showing the pathway for digestive enzymes (zymogens) to be secreted by the acinar cell into the ductal system where water, sodium, and bicarbonate are secreted by the duct and centroacinar (CA) cells. Mutations in


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Surgery_Schwartz. for digestive enzymes (zymogens) to be secreted by the acinar cell into the ductal system where water, sodium, and bicarbonate are secreted by the duct and centroacinar (CA) cells. Mutations in at least five genes have been identified as risk factors for chronic pancreatitis: gain-of function mutations in the cationic trypsinogen genes (PRSS1, PRSS2) cause hereditary pancreatitis. Cationic and anionic trypsinogen are normally active in the duodenum by entero-kinase (EK). Premature activation of the trypsin in the acinar cell leads to zymogen activation, local cellular injury, and inflamma-tion. Mutations of the trypsin inhibitors SPINK1 or chymotrypsin C (CTRC), or of the calcium sensing receptor CASR, result in pre-mature activation of trypsinogen. Mutations in the cystic fibrosis transmembrane receptor CFTR results in trypsinogen stasis within the ducts due to insufficient secretion by duct cells. A mutation in claudin-2 (CLDN2) results in abnormal expression in acinar cells,


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Surgery_Schwartz. transmembrane receptor CFTR results in trypsinogen stasis within the ducts due to insufficient secretion by duct cells. A mutation in claudin-2 (CLDN2) results in abnormal expression in acinar cells, instead of its normal location between duct cells, and is associated with the accelerated development of chronic pancreatitis in alcohol abusers. (Modified with permission from Solomon S, Whitcomb DC: Genetics of pancreatitis: an update for clinicians and genetic coun-selors, Curr Gastroenterol Rep. 2012 Apr;14(2):112-711.)are common in the general population as well, and the frequency of these mutations varies in different cohorts of idiopathic chronic pancreatitis, from 6.4% in France108 to 25.8% in the United States.109 Thus, hereditary pancreatitis results from one or more mutational defects that incapacitate an auto-protective process that normally prevents proteolysis within the pancreas.Cystic fibrosis, originally termed cystic fibrosis of the pancreas, results from a variety of


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Surgery_Schwartz. that incapacitate an auto-protective process that normally prevents proteolysis within the pancreas.Cystic fibrosis, originally termed cystic fibrosis of the pancreas, results from a variety of mutations of the cystic fibro-sis transmembrane receptor (CFTR). The CFTR is present in pancreatic duct cells and controls the amount of chloride and bicarbonate secreted into the normally alkaline pancreatic juice. The CFTR gene contains over 4300 nucleotides, divided into 24 exons, which encode a 1480-amino acid protein. Over 1000 polymorphisms have been reported, and many are common. The CFTR mutation associated with the classic pulmonary dis-ease, F508, is rarely observed in chronic pancreatitis. But other CFTR mutations have been noted to be associated with chronic idiopathic pancreatitis, auto-immune pancreatitis, and pancreas divisum, in which the pulmonary, intestinal, and cutaneous manifestations of the disease are silent.110Many studies have been undertaken to determine whether


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Surgery_Schwartz. auto-immune pancreatitis, and pancreas divisum, in which the pulmonary, intestinal, and cutaneous manifestations of the disease are silent.110Many studies have been undertaken to determine whether specific genetic abnormalities are associated with alcoholic chronic pancreatitis and which might confer susceptibility to the disease.105 In 2012, a landmark study by Whitcomb and associates demonstrated a likely genetic cause of the predisposition to alcohol-induced chronic pancreatitis in men.111 In a genome-wide association study of more than 2000 patients, these researchers discovered that a common DNA variant on the X chromosome is present in 26% of men without pancreatitis, but jumps to nearly 50% of men diagnosed with alcoholic pancreatitis. The variant involves the claudin 2 (CLDN2) gene, which encodes a tight junction protein normally present in ductal cells. In cases of chronic pancreatitis, the CLDN2 protein is abnormally expressed in acinar cells and may alter the secretory


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Surgery_Schwartz. gene, which encodes a tight junction protein normally present in ductal cells. In cases of chronic pancreatitis, the CLDN2 protein is abnormally expressed in acinar cells and may alter the secretory dynamics of enzyme release. The abnormality does not appear to cause pancreatitis, but if pancreatitis occurs for any reason in a person with the CLDN2 variant, it is more likely that the person will develop chronic pancreatitis; the risk is increased even further among alcohol users. Only 10% of women have the X chromosome–linked variant on both X chromosomes, and most women with the CLDN2 variant on one X chromosome appear to be protected from alcoholic chronic pancreatitis by the other X chromosome, if it is normal. Men, with only one X chromosome, have no protection if they inherit a CLDN2 mutation. This helps to explain the high prevalence of alcoholic chronic pancreatitis among men, although the mechanism remains unclear. This study does not demonstrate a genetic cause for all cases


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Surgery_Schwartz. mutation. This helps to explain the high prevalence of alcoholic chronic pancreatitis among men, although the mechanism remains unclear. This study does not demonstrate a genetic cause for all cases of alcohol-related chronic pancreatitis, but it shows that a genetic element contributes to many patients with the disease (Fig. 33-16).AlcoholIn 1878, Friedreich proposed that “a general chronic interstitial pancreatitis may result from excessive alcoholism (drunkard’s pancreas).”112 Since that observation, numerous studies have shown that a causal relationship exists between alcohol and chronic pancreatitis, but the prevalence of alcohol as the etiol-ogy of the disease in Western countries ranges widely, from 38% to 94%113 (Fig. 33-17).There is a linear relationship between exposure to alcohol and the development of chronic pancreatitis.114 The risk of dis-ease is present in patients with even a low or occasional expo-sure to alcohol (1 to 20 g/d), perhaps due to the CLDN2 gene mutation


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Surgery_Schwartz. and the development of chronic pancreatitis.114 The risk of dis-ease is present in patients with even a low or occasional expo-sure to alcohol (1 to 20 g/d), perhaps due to the CLDN2 gene mutation described previously, so there is no threshold level of alcohol exposure below which there is no risk of develop-ing chronic pancreatitis. Furthermore, although the risk of dis-ease is dose related and highest in heavy (>150 g/d, or about 11 1 oz shots, or 12 beers per day) drinkers, the prevalence of chronic pancreatitis among confirmed alcohol abusers is only 5% to 15%.115 However, the duration of alcohol consumption is definitely associated with the development of pancreatic dis-ease. The onset of disease typically occurs between ages 35 to 40 years, after 16 to 20 years of heavy alcohol consumption. Recurrent episodes of acute pancreatitis are typically followed by chronic symptoms after 4 or 5 years.116In their 1946 classic study, Comfort, Gambrill, and Baggenstoss proposed that chronic


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Surgery_Schwartz. Recurrent episodes of acute pancreatitis are typically followed by chronic symptoms after 4 or 5 years.116In their 1946 classic study, Comfort, Gambrill, and Baggenstoss proposed that chronic pancreatitis was the result of multiple episodes of acute inflammation, with residual and Brunicardi_Ch33_p1429-p1516.indd 145101/03/19 6:44 PM 1452SPECIFIC CONSIDERATIONSPART IITimeDegree of pancreatic damage= Episode of acute pancreatitisNecrosis-fibrosis sequenceFigure 33-18. “Multiple hit” theory of the etiology of chronic pancreatitis. Multiple episodes of acute pancreatitis cause progres-sively more organized inflammatory changes that ultimately result in chronic inflammation and scarring. (Reproduced with permission from Apte MV, Wilson JS: Alcohol-induced pancreatic injury, Best Pract Res Clin Gastroenterol. 2003 Aug;17(4):593-612.)Very heavy drinking (15%)Alcohol + genetic (3%)Idiopathic(42%)Genetic(24%)CFTR(14%)CFTR +SPINK1(3%)SPINK1(4%)PRSS1(3%)Hyperlipidemia,Autoimmune,Other


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Surgery_Schwartz. Res Clin Gastroenterol. 2003 Aug;17(4):593-612.)Very heavy drinking (15%)Alcohol + genetic (3%)Idiopathic(42%)Genetic(24%)CFTR(14%)CFTR +SPINK1(3%)SPINK1(4%)PRSS1(3%)Hyperlipidemia,Autoimmune,Other (4%)Obstructive(9%)Gallstone /severe AP(3%)Figure 33-17. Etiologies of chronic pancreatitis. (Reproduced with permission from Whitcomb DC: Going MAD: development of a “matrix academic division” to facilitate translating research to personalized medicine, Acad Med. 2011 Nov;86(11):1353-1359.)progressively increasing chronic inflammation.117 Subsequently, Kondo and associates showed that other, additional factors were necessary for repeated exposure to alcohol to cause chronic pancreatitis.118 Regardless of the requirement for other predisposing or facilitative factors, the concept that multiple episodes (or a prolonged course) of pancreatic injury ultimately leads to chronic disease is widely accepted as the pathophysiologic sequence119 (Fig. 33-18).Although direct alcohol exposure to the


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Surgery_Schwartz. episodes (or a prolonged course) of pancreatic injury ultimately leads to chronic disease is widely accepted as the pathophysiologic sequence119 (Fig. 33-18).Although direct alcohol exposure to the pancreatic ductal system, or elevated levels of alcohol in the bloodstream, has been shown to alter the integrity and function of pancreatic ducts and acini directly,120 most investigators believe that alco-hol metabolites such as acetaldehyde, combined with oxidant injury, result in local parenchymal injury that is preferentially targeted to the pancreas in predisposed individuals. Repeated or severe episodes of toxin-induced injury activate a cascade of cytokines, which, in turn, induces pancreatic stellate cells (PSCs) to produce collagen and cause fibrosis (Fig. 33-19).A high-protein, low-bicarbonate, low-volume secretory output is seen after chronic alcohol exposure, which may con-tribute to the precipitation of proteins in secondary ducts in the early stages of chronic


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Surgery_Schwartz. low-bicarbonate, low-volume secretory output is seen after chronic alcohol exposure, which may con-tribute to the precipitation of proteins in secondary ducts in the early stages of chronic pancreatitis.121 Calcium is complexed to protein plugs in small ductules, secondary ducts, and, eventu-ally, in the main ductal system, which causes ductal cell injury and obstruction of the secretory system, which further promotes an inflammatory response.Cigarette smoking has been strongly associated with chronic pancreatitis,122 but until recently it was unclear whether this was a causative risk factor. Studies have now shown that smoking actually accelerates the development of alcoholic pancreatitis,123 and the risk of cancer in chronic pancreatitis is increased significantly by smoking. In hereditary pancreatitis, smoking has been found to lower the age of onset of carcinoma by about 20 years.124 Smoking therefore appears to be an inde-pendent risk factor for the late complications of


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Surgery_Schwartz. hereditary pancreatitis, smoking has been found to lower the age of onset of carcinoma by about 20 years.124 Smoking therefore appears to be an inde-pendent risk factor for the late complications of alcoholic pan-creatitis, if not an early cofactor for the development of fibrosis.HyperparathyroidismHypercalcemia is a known cause of pancreatic hypersecretion,125 and chronic hypercalcemia caused by untreated hyperparathyroidism is associated with chronic calcific pancreatitis.126 Hypercalcemia is also a stimulant for pancreatic calcium secretion, which contributes to calculus formation and obstructive pancreatopathy. The treatment is correction of the hyperparathyroidism and assessment of any additional endocrinopathies.HyperlipidemiaIn addition to the risk of acute pancreatitis, hyperlipidemia and hypertriglyceridemia predispose women to chronic pancreatitis when they receive estrogen replacement therapy.127 Fasting tri-glyceride levels <300 mg/dL are below the threshold for this to


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Surgery_Schwartz. and hypertriglyceridemia predispose women to chronic pancreatitis when they receive estrogen replacement therapy.127 Fasting tri-glyceride levels <300 mg/dL are below the threshold for this to occur, and the mechanism of estrogen potentiation of hyperlip-idemia-induced chronic pancreatitis is unknown. It is assumed that chronic changes occur after repeated subclinical episodes of acute inflammation. Aggressive therapy of hyperlipidemia is therefore important in perior postmenopausal patients who are candidates for estrogen therapy.ClassificationA major impediment to a better understanding of the etiology, frequency, and severity of chronic pancreatitis has been the dif-ficulty with which investigators and clinicians have struggled to identify a useful classification system. Multiple classification systems have been proposed. The TIGAR-O scheme catego-rizes chronic pancreatitis according to risk factors and etiolo-gies, such as (a) toxic-metabolic, (b) idiopathic, (c) genetic, (d)


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Surgery_Schwartz. systems have been proposed. The TIGAR-O scheme catego-rizes chronic pancreatitis according to risk factors and etiolo-gies, such as (a) toxic-metabolic, (b) idiopathic, (c) genetic, (d) autoimmune, (e) recurrent and severe acute pancreatitis, or (f) obstructive.128 A recent classification system based on his-topathology as well as etiology was delineated by Singer and Chari.129Chronic Calcific (Lithogenic) PancreatitisThis type is the largest subgroup in the classification scheme proposed by Singer and Chari and includes patients with calcific pancreatitis of most etiologies. Although the majority of patients with calcific pancreatitis have a history of alcohol abuse, stone formation and parenchymal calcification can develop in a variety of etiologic subgroups; hereditary pancreatitis and tropical pan-creatitis are particularly noteworthy for the formation of stone disease. The clinician should therefore avoid the assumption that calcific pancreatitis confirms the diagnosis of alcohol


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Surgery_Schwartz. tropical pan-creatitis are particularly noteworthy for the formation of stone disease. The clinician should therefore avoid the assumption that calcific pancreatitis confirms the diagnosis of alcohol abuse.Brunicardi_Ch33_p1429-p1516.indd 145201/03/19 6:44 PM 1453PANCREASCHAPTER 33Normal pancreasAlcoholMetabolic / oxidative stressSentinel eventAcinar cell injury(+ / – Necrosis)Inflammatory response:proinflammatory(Early)Anti-inflammatory (Later)Alcoholmetabolic/oxidative stressRecurrent acute pancreatitis(RAP)Anti-inflammatoryFibrosisHealedStressRAPNormal (Recovered):Normal:Stellate cells(Inactive)CytokinesChronicpancreatitis:FibrosisEarly acutepancreatitis: NeutrophilLymphocyteMacrophageStellate cell(Active)Collagen, etc.Late acutepancreatitis:M(Anti-inflam-matory)Necrosis = Stress, ETOHxxxxxxxxxxxxxFigure 33-19. The sentinel acute pancreatitis event (SAPE) hypothesis for the development of chronic pancreatitis. A critical episode of acute pancreatitis activates cytokine-induced


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Surgery_Schwartz. ETOHxxxxxxxxxxxxxFigure 33-19. The sentinel acute pancreatitis event (SAPE) hypothesis for the development of chronic pancreatitis. A critical episode of acute pancreatitis activates cytokine-induced transformation of pancreatic stellate cells, which results in collagen production and fibrosis. ETOH = ethyl alcohol. (Adapted with permission from Schneider A, Whitcomb DC: Hereditary pancreatitis: a model for inflammatory diseases of the pancreas, Best Pract Res Clin Gastroenterol. 2002 Jun;16(3):347-363.)Chronic Obstructive PancreatitisThis refers to chronic inflammatory changes that are caused by the compression or occlusion of the proximal ductal system by tumor, gallstone, posttraumatic scar, or inadequate duct caliber (as in pancreas divisum). Obstruction of the main pancreatic duct by inflammatory (posttraumatic) or neoplastic processes can result in diffuse fibrosis, dilated main and secondary pan-creatic ducts, and acinar atrophy. The patient may have little in


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Surgery_Schwartz. duct by inflammatory (posttraumatic) or neoplastic processes can result in diffuse fibrosis, dilated main and secondary pan-creatic ducts, and acinar atrophy. The patient may have little in Brunicardi_Ch33_p1429-p1516.indd 145301/03/19 6:44 PM 1454SPECIFIC CONSIDERATIONSPART IINormal pancreasAbsence of duct of SantoriniNormal pancreaswith duct of SantoriniPancreas divisumSmall ductof WirsungPancreas divisumNo duct of WirsungABCDFigure 33-20. Pancreas divisum. Normal pancreatic duct anatomy and the variations of partial or complete pancreas divisum are shown. (Reproduced with permission from Beger HG: The pancreas: an integrated textbook of basic science, medicine, and surgery. London: Blackwell-Science; 1998.)the way of pain symptoms or may present with signs of exo-crine insufficiency. Intraductal stone formation is rare, and both functional and structural abnormalities may improve when the obstructive process is relieved or removed. Trauma to the pan-creas frequently results in


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Surgery_Schwartz. Intraductal stone formation is rare, and both functional and structural abnormalities may improve when the obstructive process is relieved or removed. Trauma to the pan-creas frequently results in duct injury and leakage, which may result in pseudocyst formation as well as local scar formation. Inadequately treated pancreatic trauma may result in persistent inflammatory changes in the distal gland.130Pancreas divisum represents a special case of obstruc-tive pancreatitis. It is the most common congenital anomaly involving the pancreas and occurs in up to 10% of children. It is thought to predispose the pancreas to recurrent acute pan-creatitis and chronic pancreatitis, due to functional obstruction of a diminutive duct of Santorini that fails to communicate with Wirsung’s duct (Fig. 33-20). However, the classic pic-ture of obstructive pancreatopathy with a dilated dorsal duct is unusual in pancreas divisum, so a decompressive opera-tion or a lesser papilla sphincteroplasty is


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Surgery_Schwartz. 33-20). However, the classic pic-ture of obstructive pancreatopathy with a dilated dorsal duct is unusual in pancreas divisum, so a decompressive opera-tion or a lesser papilla sphincteroplasty is frequently not fea-sible or unsuccessful. Endoscopic stenting through the lesser papilla may result in temporary relief of symptoms, and this response would increase the possibility that a permanent sur-gical or endoscopic intervention will be successful. Although some authors emphasize the pathologic implications of pan-creas divisum,131 others express skepticism that it represents a true risk to pancreatic secretory capacity or contributes to the development of chronic pancreatitis.132,133A recent French study reveals that pancreas divisum is equally prevalent among patients with idiopathic chronic pancreatitis and normal con-trols (7%), and is minimally increased in patients with PRSS1 and SPINK1 mutations. It is accompanied by CFTR mutations in 47% of patients, however, suggesting that


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Surgery_Schwartz. pancreatitis and normal con-trols (7%), and is minimally increased in patients with PRSS1 and SPINK1 mutations. It is accompanied by CFTR mutations in 47% of patients, however, suggesting that the presence of pancreas divisum together with mutational events may increase the susceptibility to pancreatitis.134Chronic Inflammatory PancreatitisChronic inflammatory pancreatitis is characterized by diffuse fibrosis and a loss of acinar elements with a predominant mono-nuclear cell infiltration throughout the gland.A variant of chronic pancreatitis is a nonobstructive, diffusely infiltrative disease associated with fibrosis, a mono-nuclear cell (lymphocyte, plasma cell, or eosinophil) infiltrate, and an increased titer of one or more autoantibodies.135 This type, referred to as autoimmune pancreatitis (AIP), is associated with a variety of illnesses with suspected or proven autoimmune etiology, such as Sjögren’s syndrome, rheumatoid arthritis, and type 1 diabetes mellitus. AIP has been


Surgery_Schwartz

Surgery_Schwartz. (AIP), is associated with a variety of illnesses with suspected or proven autoimmune etiology, such as Sjögren’s syndrome, rheumatoid arthritis, and type 1 diabetes mellitus. AIP has been characterized as either type I, with accompanying systemic or multiorgan dysfunction, or type II, which is restricted to the pancreas.Compressive stenosis of the intrapancreatic portion of the common bile duct is frequently seen in both types of AIP, along with symptoms of obstructive jaundice. Increased levels of serum β-globulin or immunoglobulin G4 are also present. Steroid therapy is uniformly successful in ameliorating the dis-ease, including any associated bile duct compression.136 CFTR mutations that result in dislocation of the transmembrane pro-tein have been found in AIP, and steroid therapy results in a nor-malization of the CFTR localization and a resumption of normal chloride and bicarbonate secretion.137 The differential diagnosis includes lymphoma, plasmacytoma (“pseudotumor” of the


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Surgery_Schwartz. results in a nor-malization of the CFTR localization and a resumption of normal chloride and bicarbonate secretion.137 The differential diagnosis includes lymphoma, plasmacytoma (“pseudotumor” of the pan-creas) and diffuse infiltrative carcinoma. Although the diagnosis is confirmed on pancreatic biopsy, presumptive treatment with steroids is usually undertaken, especially when clinical and lab-oratory findings, such as an elevation in IgG4 levels, support the diagnosis. Failure to obtain a cytologic specimen may lead to an unnecessary resectional procedure, and an untreated inflam-matory component may cause sclerosis of the extrahepatic or intrahepatic bile ducts, with eventual liver failure.138Brunicardi_Ch33_p1429-p1516.indd 145401/03/19 6:44 PM 1455PANCREASCHAPTER 33Tropical (Nutritional) PancreatitisChronic pancreatitis is highly prevalent among adolescents and young adults in Indonesia, southern India, and tropical Africa. Abdominal pain develops in adolescence, followed by


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Surgery_Schwartz. PancreatitisChronic pancreatitis is highly prevalent among adolescents and young adults in Indonesia, southern India, and tropical Africa. Abdominal pain develops in adolescence, followed by the development of a brittle form of pancreatogenic diabetes. Parenchymal and intraductal calcifications are seen, and the pancreatic duct stones may be quite large.139 Many of the patients appear malnourished, some present with extreme emaciation, and a characteristic cyanotic coloration of the lips may be seen.140 In addition to protein-caloric malnutrition, toxic products of some indigenous foodstuffs have also been thought to contribute to the disease. Because of the geographic concentration of this early-onset form of chronic pancreatitis, it has been termed tropical pancreatitis, although the exact etiology remains unclear.Clinically, tropical pancreatitis presents much like heredi-tary pancreatitis, and a familial pattern among cases is not unusual. SPINK1 mutations have been documented in


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Surgery_Schwartz. etiology remains unclear.Clinically, tropical pancreatitis presents much like heredi-tary pancreatitis, and a familial pattern among cases is not unusual. SPINK1 mutations have been documented in 20% to 55% of patients with tropical pancreatitis, and CFTR mutations have been reported as well.106,107 The accelerated deteriora-tion of endocrine and exocrine function, the chronic pain due to obstructive disease, and the recurrence of symptoms despite decompressive procedures characterize the course of disease. As immigrants from the tropical regions increasingly find their way to all parts of the world, an awareness of this severe form of chronic pancreatitis is helpful for those who treat patients with pancreatic disease.Asymptomatic Pancreatic FibrosisPancreatic fibrosis is seen in some asymptomatic elderly patients, in tropical populations, or in asymptomatic alcohol users. There is diffuse perilobar fibrosis and a loss of acinar cell mass, but there is not a main ductular component.


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Surgery_Schwartz. elderly patients, in tropical populations, or in asymptomatic alcohol users. There is diffuse perilobar fibrosis and a loss of acinar cell mass, but there is not a main ductular component. In addition, the presence of fibrosis and decreased exocrine function in patients with diabetes has raised the question of whether long-standing diabetes is a cause of chronic pancreatitis.141 Patients with this entity are usually asymptomatic in terms of typical pancreatic pain, and a recent histopathologic study of patients with typi-cal chronic pancreatitis and “diabetic exocrine pancreatopathy” reveals significant differences in morphology, including a virtual absence of duct distortion or obstruction (Fig. 33-21).142 It remains unknown whether this form of chronic inflammation precedes or contributes to the roughly twofold increase in the risk of pancreatic cancer in patients with long-standing diabetes.Idiopathic PancreatitisWhen a definable cause for chronic pancreatitis is lacking, the term


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Surgery_Schwartz. to the roughly twofold increase in the risk of pancreatic cancer in patients with long-standing diabetes.Idiopathic PancreatitisWhen a definable cause for chronic pancreatitis is lacking, the term idiopathic is used to categorize the illness. Classically, the idiopathic group includes young adults and adolescents who lack a family history of pancreatitis but who may represent indi-viduals with spontaneous gene mutations encoding regulatory proteins in the pancreas. A variable percentage of SPINK1 and CFTR mutations have been described in various studies. In addi-tion, the idiopathic group has included a large number of older patients for whom no obvious cause of recurrent or chronic pan-creatitis can be found.143 However, because the prevalence of biliary calculi increases steadily with age, it is not surprising that, as methods of biliary stone detection have improved, many elderly “idiopathic” pancreatitis patients are found to have bili-ary tract disease.144An increasing number of


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Surgery_Schwartz. it is not surprising that, as methods of biliary stone detection have improved, many elderly “idiopathic” pancreatitis patients are found to have bili-ary tract disease.144An increasing number of mutations of the SPINK1 and CFTR genes have been identified in association with various forms of chronic pancreatitis. However, the role of genetic analysis in the management of these patients remains unclear, as guidelines have yet to be developed to allow physicians to use the data consistently. Although the clinical management of patients who harbor a minor CFTR mutation and chronic pan-creatitis, for example, is still dictated by the clinical manifesta-tions of the pancreatitis, recent data suggest that the etiology of chronic pancreatitis, rather than the morphology, may determine the response to surgical treatment.145A shortcoming of these clinical classification systems is the lack of histologic criteria of chronic inflammation due to the usual absence of a biopsy specimen. The


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Surgery_Schwartz. response to surgical treatment.145A shortcoming of these clinical classification systems is the lack of histologic criteria of chronic inflammation due to the usual absence of a biopsy specimen. The differentiation of recurrent acute pancreatitis from chronic pancreatitis with exac-erbations of pain can be difficult to establish and is not facili-tated by the current system. Similarly, cystic fibrosis is known to cause fibrosis and acinar dysfunction but is not included in the classification despite increasing evidence for its possible role in idiopathic chronic pancreatitis.146 Therefore, further refinements in the classification system for chronic pancreatitis Interacinarfibrosis0102030405060708090100AcinaratrophyInterlobularfibrosisStromalinflammationDuctaldistortionDuctalepithelialattenuationIslet amyloidCPDEPFigure 33-21. Comparative frequencies of key histolopathologic features of chronic pancreatitis (CP n = 7) and diabetic exocrine pancrea-topathy (DEP n = 9) (Reproduced with


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Surgery_Schwartz. amyloidCPDEPFigure 33-21. Comparative frequencies of key histolopathologic features of chronic pancreatitis (CP n = 7) and diabetic exocrine pancrea-topathy (DEP n = 9) (Reproduced with permission from Majumder S, Zhang L, Philip N, et al. Exocrine Pancreatopathy (EP) Associated With Diabetes Mellitus (DM) Is Histologically Distinct From Chronic Pancreatitis (CP): An International Multi-Reader Blinded Study, Gastroenterol 2016 April;150(4) Suppl 1: S191 (abstr).)Brunicardi_Ch33_p1429-p1516.indd 145501/03/19 6:44 PM 1456SPECIFIC CONSIDERATIONSPART IIFigure 33-22. Histology of early chronic pancreatitis. High-power microscopic (40x) histology of chronic pancreatitis shows an infil-tration of mononuclear inflammatory cells throughout the inter-stitium of the pancreas, with little fibrosis. (Used with permission from Rhonda Yantiss, Weill Cornell Medical College.)Figure 33-23. Gross appearance of chronic pancreatitis. Areas of fibrosis and scarring are seen adjacent to other areas


Surgery_Schwartz

Surgery_Schwartz. (Used with permission from Rhonda Yantiss, Weill Cornell Medical College.)Figure 33-23. Gross appearance of chronic pancreatitis. Areas of fibrosis and scarring are seen adjacent to other areas within the gland in which the lobar architecture is grossly preserved. A dilated pancreatic duct indicates the presence of downstream obstruction in this specimen removed from a patient with chronic pancreatitis. (Used with permis-sion from Rhonda Yantiss, Weill Cornell Medical College.)Figure 33-24. Histology of severe chronic pancreatitis. High-power microscopic (40x) histologic appearance of advanced chronic pancre-atitis shows extensive sheets of fibrosis and loss of acinar tissue, with preservation of islet tissue in scattered areas. (Used with permission from Rhonda Yantiss, Weill Cornell Medical College.)are needed to allow a better prediction of its clinical course and a more accurate diagnosis of a likely etiologic agent.PathologyHistology. In early chronic pancreatitis, the histologic


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Surgery_Schwartz. College.)are needed to allow a better prediction of its clinical course and a more accurate diagnosis of a likely etiologic agent.PathologyHistology. In early chronic pancreatitis, the histologic changes are unevenly distributed and are characterized by induration, nodular scarring, and lobular regions of fibrosis (Fig. 33-22). As the disease progresses, there is a loss of normal lobulation, with thicker sheets of fibrosis surrounding a reduced acinar cell mass and dilatation of ductular structures (Fig. 33-23). The ductular epithelium is usually atypical and may display features of dysplasia, as evidenced by cuboidal cells with hyperplastic features, accompanied by areas of mononuclear cell infiltrates or patchy areas of necrosis. Cystic changes may be seen, but areas of relatively intact acinar elements and normal-appearing islets persist. In severe chronic pancreatitis, there is considerable replacement of acinar tissue by broad, coalescing areas of fibrosis, and the islet size and


Surgery_Schwartz

Surgery_Schwartz. acinar elements and normal-appearing islets persist. In severe chronic pancreatitis, there is considerable replacement of acinar tissue by broad, coalescing areas of fibrosis, and the islet size and number are reduced (Fig. 33-24). Small arteries appear thickened, and neural trunks become prominent.147Tropical pancreatitis and hereditary pancreatitis are histo-logically indistinguishable from chronic alcoholic pancreatitis. In obstructive chronic pancreatitis, calculi are absent, although periacinar fibrosis and dilated ductular structures are prominent. In pancreatic lobular fibrosis seen in elderly subjects, small ducts are dilated, sometimes with small calculi trapped within. Hypertrophy of ductular epithelia is thought to cause this small-duct disease, which is accompanied by perilobular fibrosis.148Fibrosis. A common feature of all forms of chronic pancreatitis is the perilobular fibrosis that forms surrounding individual acini, then propagates to surround small lobules, and


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Surgery_Schwartz. fibrosis.148Fibrosis. A common feature of all forms of chronic pancreatitis is the perilobular fibrosis that forms surrounding individual acini, then propagates to surround small lobules, and eventually coalesces to replace larger areas of acinar tissue. The pathogenesis of this process involves the activation of pancreatic stellate cells (PSCs) that are found adjacent to acini and small arteries.149 The extended cytoplasmic processes of PSCs encircle the acini but appear quiescent in the normal gland, where they contain lipid vacuoles and cytoskeletal proteins. In response to pancreatic injury, the PSCs become activated and proliferate (similarly to hepatic stellate cells), lose their lipid vesicles, and transform into myofibroblast-like cells. These cells respond to proliferative factors such as transforming growth factor ®, platelet-derived growth factor, and proinflammatory cytokines that synthesize and secrete type I and III collagen and fibronectin. Studies indicate that vitamin


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Surgery_Schwartz. such as transforming growth factor ®, platelet-derived growth factor, and proinflammatory cytokines that synthesize and secrete type I and III collagen and fibronectin. Studies indicate that vitamin A metabolites, similar to those present in quiescent PSCs, can inhibit the collagen production of activated cultured PSCs.150 This raises the possibility that early intervention may be possible to interrupt or prevent the fibrosis resulting from ongoing activation of PSCs.The overall pathogenic sequence proposed by Schneider and Whitcomb151 whereby alcohol induces acute pancreati-tis and, with ongoing exposure, promotes the development of chronic fibrosis, is summarized in Fig. 33-19. PSCs surround-ing the acinus are activated in acute pancreatitis but may be inactivated by anti-inflammatory cytokines and, in the absence of further injury, may revert to a quiescent state. The role of proinflammatory macrophages, cytokines, and PSCs in models of acute and chronic pancreatitis represents an


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Surgery_Schwartz. and, in the absence of further injury, may revert to a quiescent state. The role of proinflammatory macrophages, cytokines, and PSCs in models of acute and chronic pancreatitis represents an important area of current research.Stone Formation. Pancreatic stones are composed largely of calcium carbonate crystals trapped in a matrix of fibrillar and other material. The fibrillar center of most stones contains no Brunicardi_Ch33_p1429-p1516.indd 145601/03/19 6:44 PM 1457PANCREASCHAPTER 33calcium but rather a mixture of other metals. This suggests that stones form from an initial noncalcified protein precipitate, which serves as a focus for layered calcium carbonate precipita-tion. The same low molecular weight protein is present in stones and protein plugs and was initially named pancreatic stone pro-tein, or PSP.152 PSP was found to be a potent inhibitor of calcium carbonate crystal growth and has subsequently been renamed lithostathine.153 Independently, a 15-kDa fibrillar protein


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Surgery_Schwartz. stone pro-tein, or PSP.152 PSP was found to be a potent inhibitor of calcium carbonate crystal growth and has subsequently been renamed lithostathine.153 Independently, a 15-kDa fibrillar protein iso-lated from the pancreas was named pancreatic thread protein, and it has been shown to be homologous with lithostathine. Finally, a protein product of the reg gene, so named because it is expressed in association with regenerating islets in models of pancreatic injury, was isolated and called reg protein and was subsequently found to be homologous with lithostathine.154 The PSP/pancreatic thread protein/reg/lithostathine gene encodes for a 166-amino acid product that undergoes posttranslational modification to produce isoforms present in pancreatic juice. The protein is expressed in all rodents and mammals, both in the pancreas as well as in brain tissue, where it is found in particu-larly high concentrations in pyramidal neurons in Alzheimer’s disease and Down syndrome. It is also found


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Surgery_Schwartz. and mammals, both in the pancreas as well as in brain tissue, where it is found in particu-larly high concentrations in pyramidal neurons in Alzheimer’s disease and Down syndrome. It is also found in the renal tubules, which is consistent with its biologic action of prevent-ing calcium carbonate precipitation.Calcium and bicarbonate ions are normally present in pan-creatic juice in high concentrations, and the solubility product of calcium carbonate is greatly exceeded under normal condi-tions. Microcrystals of calcium carbonate can be seen in normal pancreatic juice but are usually clinically silent. Lithostathine is a potent inhibitor of calcium carbonate crystal formation, at a concentration of only 0.1 μmol/L. However, lithostathine con-centrations in normal pancreatic juice are in the range of 20 to 25 μmol/L, so a constant suppression of calcium carbonate crystal formation is present in the normal pancreas.In alcoholics and in patients with alcoholic chronic pan-creatitis,


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Surgery_Schwartz. in the range of 20 to 25 μmol/L, so a constant suppression of calcium carbonate crystal formation is present in the normal pancreas.In alcoholics and in patients with alcoholic chronic pan-creatitis, lithostathine expression and secretion are dramati-cally inhibited155 (Fig. 33-25). In addition, elevated levels of precipitated lithostathine in the duct fluid in chronic pancreati-tis patients suggests that the availability of the protein may be further reduced by the action of increased proteases and other proteins present in the duct fluid of alcoholic patients. Increased pancreatic juice protein levels in alcoholic men are reversible by abstinence from alcohol,156 so the availability and effectiveness of lithostathine may be restored in patients with early-stage dis-ease by timely intervention. Nevertheless, calcific stone forma-tion represents an advanced stage of disease, which can further promote injury or symptoms due to mechanical damage to duct epithelium or obstruction of the


Surgery_Schwartz

Surgery_Schwartz. Nevertheless, calcific stone forma-tion represents an advanced stage of disease, which can further promote injury or symptoms due to mechanical damage to duct epithelium or obstruction of the ductular network.Duct Distortion. Although calcific stone disease is normally a marker for an advanced stage of disease, parenchymal and ductular calcifications do not always correlate with symptoms. Obstructing main duct stones are commonly observed and are thought to be an indication for endoscopic or surgical removal. The ball-valve effect of a stone in a secreting system produces inevitable episodes of duct obstruction, usually accompanied by pain. But some patients with complete duct obstruction have prolonged periods of painlessness. Ductular hypertension has been documented in patients with proximal stenosis of the main pancreatic duct, and prolonged ductular distention after secre-tin administration is taken as a sign of ductular obstruction.157 Although calculus disease and duct


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Surgery_Schwartz. with proximal stenosis of the main pancreatic duct, and prolonged ductular distention after secre-tin administration is taken as a sign of ductular obstruction.157 Although calculus disease and duct enlargement appear together as late stages of chronic pancreatitis, controversy persists over whether they are associated, are independent events, or are caus-ally related.Radiology. Radiologic imaging of chronic pancreatitis assists in four areas: (a) diagnosis, (b) the evaluation of severity of disease, (c) detection of complications, and (d) assistance in determining treatment options.158 With the advent of cross-sectional imaging techniques such as CT and MRI, the contour, content, ductal pattern, calcifications, calculi, and cystic disease of the pancreas are all readily discernible. Transabdominal ultrasonography is frequently used as a screening method for patients with abdominal symptoms or trauma, and the extension of ultrasonic imaging to include endoscopic ultrasound (EUS) and


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Surgery_Schwartz. ultrasonography is frequently used as a screening method for patients with abdominal symptoms or trauma, and the extension of ultrasonic imaging to include endoscopic ultrasound (EUS) and laparoscopic US have resulted in the highest-resolution images that are capable of detecting very small (<1 cm) abnormalities in the pancreas. EUS is now frequently used as a preliminary step in the evaluation of patients with pancreatic disease, and magnetic resonance cholangiopancreatography (MRCP) is increasingly being used to select patients who are candidates for the most invasive imaging method, ERCP. The staging of disease is important in the care of patients, and a combination of imaging methods is usually used (Table 33-12).Ultrasonography is frequently used as an initial imaging method in patients with abdominal symptoms, and changes con-sistent with pancreatic duct dilatation, intraductal filling defects, cystic changes, and a heterogeneous texture are seen in chronic pancreatitis (Fig.


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Surgery_Schwartz. with abdominal symptoms, and changes con-sistent with pancreatic duct dilatation, intraductal filling defects, cystic changes, and a heterogeneous texture are seen in chronic pancreatitis (Fig. 33-26). The sensitivity of transabdominal ultrasonography ranges from 48% to 96%, and it is operator dependent.159 However, the contour, texture, and ductal pattern are usually quite discernible, and it is a reliable method for peri-odic reexamination to determine the efficacy of treatment.EUS has heavily impacted the evaluation and manage-ment of patients with chronic pancreatitis. Although it is more operator dependent than transabdominal ultrasonography, EUS provides not only imaging capability but also adds the capac-ity to obtain cytologic and chemical samples of tissue and fluid aspirated with linear array monitoring (Fig. 33-27). EUS images obtained through a high-frequency (7.5to 12.5-mHz) transducer are able to evaluate subtle changes in 2to 3-mm 50102030µg lithostathine/mg total


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Surgery_Schwartz. with linear array monitoring (Fig. 33-27). EUS images obtained through a high-frequency (7.5to 12.5-mHz) transducer are able to evaluate subtle changes in 2to 3-mm 50102030µg lithostathine/mg total proteinCCPAlc.OPDControlsFigure 33-25. Lithostathine levels in chronic calcific pancreatitis (CCP) patients, patients with alcohol abuse (Alc.), patients with other pancreatic disease (OPD), and controls. (Reproduced with permis-sion from Beger HG: The pancreas: an integrated textbook of basic science, medicine, and surgery. London: Blackwell-Science; 1998.)Brunicardi_Ch33_p1429-p1516.indd 145701/03/19 6:44 PM 1458SPECIFIC CONSIDERATIONSPART IITable 33-12Cambridge classification of pancreatic morphology in chronic pancreatitisCLASSIFICATIONERCP FINDINGSCT AND US FINDINGSNormalNo abnormal SBDsNormal gland size, shape; homogeneous parenchymaEquivocalMPD normalOne of the following: less than three abnormal SBDs; MPD 2–4 mm; gland enlarged more than two times normal size; heterogeneous


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Surgery_Schwartz. SBDsNormal gland size, shape; homogeneous parenchymaEquivocalMPD normalOne of the following: less than three abnormal SBDs; MPD 2–4 mm; gland enlarged more than two times normal size; heterogeneous parenchymaMildMPD normalTwo or more of the following: less than three abnormal SBDs; MPD 2–4 mm; slight gland enlargement; heterogeneous parenchymaModerate MPD changesSmall cysts <10 mm; MPD irregularitySBD changesFocal acute pancreatitis; increased echogenicity of MPD walls; gland-contour irregularitySevereAny of the above changes plus one or more of the following: cysts <10 mm; intraductal filling defects; calculi; MPD obstruction or stricture; severe MPD irregularity; contiguous organ invasion—Abbreviations: CT = computed tomography; ERCP = endoscopic retrograde cholangiopancreatography; MPD = main pancreatic duct; SBD = side-branch duct; US = ultrasound.Reproduced with permission from Beger HG: The Pancreas. London: Blackwell-Science; 1998.Figure 33-26. Sonography in chronic


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Surgery_Schwartz. MPD = main pancreatic duct; SBD = side-branch duct; US = ultrasound.Reproduced with permission from Beger HG: The Pancreas. London: Blackwell-Science; 1998.Figure 33-26. Sonography in chronic pancreatitis. Transabdomi-nal sonogram of patient with chronic pancreatitis demonstrates het-erogeneity of the pancreatic parenchyma, dilated ductal systems, and cyst formation. (Reproduced with permission from Bolondi L, Li Bassi S, Gaiani S, et al: Sonography of chronic pancreatitis, Radiol Clin North Am. 1989 Jul;27(4):815-833.)Figure 33-27. Endoscopic ultrasound of chronic pancreatitis. The endoscopic ultrasound appearance of the parenchyma is heteroge-neous, and dilated ducts are seen, indicating early obstructive pan-creatopathy. (Used with permission from Mark Topazian, Division of Digestive Diseases, Department of Medicine, Mayo Clinic.)structures within the pancreas and can detect indolent neoplasms in the setting of chronic inflammation. Small intraductal lesions, intraductal mucus,


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Surgery_Schwartz. Diseases, Department of Medicine, Mayo Clinic.)structures within the pancreas and can detect indolent neoplasms in the setting of chronic inflammation. Small intraductal lesions, intraductal mucus, cystic lesions, and subtle ductular abnormali-ties are recognizable by EUS (Table 33-13). This allows ERCP to be reserved for these patients who require therapeutic maneu-vers, or for the evaluation of more complex problems. EUS is comparable to ERCP in the detection of advanced changes in chronic pancreatitis and may be more sensitive than ERCP in the detection of mild disease.160CT scanning has affected the diagnosis of pancreatic dis-ease more broadly than any other method. With the advent of faster helical CT scanning and CT angiography, visualization of the nature, extent, location, and relative relationships of pancre-atic structures and lesions is possible with great clarity. Duct dil-atation, calculous disease, cystic changes, inflammatory events, and anomalies are all detectable


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Surgery_Schwartz. relative relationships of pancre-atic structures and lesions is possible with great clarity. Duct dil-atation, calculous disease, cystic changes, inflammatory events, and anomalies are all detectable with a resolution of 3 to 4 mm (Fig. 33-28). CT scanning has a false-negative rate of <10% for chronic pancreatitis, but early or mild chronic disease may go undetected by CT imaging. The earliest changes are dilatation of secondary ducts and heterogeneous parenchymal changes, which are detectable by EUS and ERCP. Another drawback of CT scanning is its lower sensitivity for detecting small neo-plasms, which are seen with increased frequency in chronic pancreatitis and may be invisible to all modalities except EUS.An MRI, in both the cross-sectional mode and the coro-nally oriented heavily weighted T2 or high spin ratio imaging Brunicardi_Ch33_p1429-p1516.indd 145801/03/19 6:44 PM 1459PANCREASCHAPTER 33Table 33-13Endoscopic ultrasound features of chronic pancreatitisENDOSCOPIC


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Surgery_Schwartz. weighted T2 or high spin ratio imaging Brunicardi_Ch33_p1429-p1516.indd 145801/03/19 6:44 PM 1459PANCREASCHAPTER 33Table 33-13Endoscopic ultrasound features of chronic pancreatitisENDOSCOPIC ULTRASOUND FEATUREIMPLICATIONDuctal changes Duct size >3 mmDuctal dilation Tortuous pancreatic ductDuctal irregularity Intraductal echogenic fociStones or calcification Echogenic duct wallDuctal fibrosis Side-branch ectasiaPeriductal fibrosisParenchymal changes Inhomogeneous echo patternEdema Reduced echogenic foci (1–3 mm)Edema Enhanced echogenic fociCalcifications Prominent interlobular septaeFibrosis Lobular outer gland marginFibrosis, glandular atrophy Large, echo-poor cavities (>5 mm)PseudocystReproduced with permission from Catalano MF, Lahoti S, Geenen JE, et al. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis, Gastrointest Endosc. 1998 Jul;48(1):11-17.(MRCP) that can disclose


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Surgery_Schwartz. of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis, Gastrointest Endosc. 1998 Jul;48(1):11-17.(MRCP) that can disclose fluid-filled ducts and cystic lesions, has added greatly to the imaging options for chronic pancreatitis (Fig. 33-29). The resolution of cross-sectional MRI scanning is now approaching that of CT scanning, although the availability of MRI scanners and the complexity of the images produced have limited their large-scale use for routine imaging of the pancreas. MRCP has been shown to be an effective screening technique for disclosing ductal abnormalities that correlates closely with the contrast-filled ducts imaged by ERCP.161 The advantages of MRCP include its noninvasive methodology and Figure 33-28. Computed tomographic imaging of chronic pancre-atitis. A dilated pancreatic duct is seen, with evidence of intraductal stones and parenchymal calcification. (Reproduced with permission from


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Surgery_Schwartz. 33-28. Computed tomographic imaging of chronic pancre-atitis. A dilated pancreatic duct is seen, with evidence of intraductal stones and parenchymal calcification. (Reproduced with permission from Forsmark CE: Management of chronic pancreatitis, Gastroen-terology. 2013 Jun;144(6):1282-1291.)Figure 33-29. Coronal T2-weighted magnetic resonance image showing evidence of chronic pancreatitis, including a pancreatic duct dilatation and side-branch clubbing. (Used with permission from Mellena Bridges, MD, Mayo Clinic Jacksonville, Department of Radiology.)its ability to image obstructed ducts that are not opacified by ERCP injection. It is therefore a useful screening study to detect duct abnormalities and to confirm the need for interventional procedures. Oral, IV, and intraductal contrast are unnecessary for MRCP, and its lack of ionizing radiation makes this the saf-est method to image the ductal system in high-risk patients.For the diagnosis and staging of chronic pancreatitis, ERCP is


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Surgery_Schwartz. unnecessary for MRCP, and its lack of ionizing radiation makes this the saf-est method to image the ductal system in high-risk patients.For the diagnosis and staging of chronic pancreatitis, ERCP is considered to be the gold standard. It also serves as a vehicle that enables other diagnostic and therapeutic maneu-vers, such as biopsy or brushing for cytology, or the use of stents to relieve obstruction or drain a pseudocyst (Fig. 33-30). Figure 33-30. Pancreatic duct stenting. At endoscopic retrograde cholangiopancreatography, a stent is placed in the proximal pan-creatic duct to relieve obstruction and reduce symptoms of pain. Pancreatic duct stents are left in place for only a limited time to avoid further inflammation.Brunicardi_Ch33_p1429-p1516.indd 145901/03/19 6:44 PM 1460SPECIFIC CONSIDERATIONSPART IIFigure 33-31. Pain location in chronic pancreatitis. (Reproduced with permission from Greenfield LJ, Mulholland MW, Oldham KT, et al: Surgery, Scientific Principles and


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Surgery_Schwartz. CONSIDERATIONSPART IIFigure 33-31. Pain location in chronic pancreatitis. (Reproduced with permission from Greenfield LJ, Mulholland MW, Oldham KT, et al: Surgery, Scientific Principles and Practice, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.)Unfortunately, ERCP also carries a risk of procedure-induced pancreatitis that occurs in approximately 5% of patients.161 Patients at increased risk include those with sphincter of Oddi dysfunction and those with a previous history of post-ERCP pancreatitis. Post-ERCP pancreatitis occurs after uncompli-cated procedures, as well as after those that require prolonged manipulation. Severe pancreatitis and deaths have occurred after ERCP. It should be reserved for patients in whom the diagnosis is unclear despite the use of other imaging methods, or in whom a diagnostic or therapeutic maneuver is specifically indicated.Presentation, Natural History, and ComplicationsPresenting Signs and Symptoms. Pain is the most common symptom of


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Surgery_Schwartz. methods, or in whom a diagnostic or therapeutic maneuver is specifically indicated.Presentation, Natural History, and ComplicationsPresenting Signs and Symptoms. Pain is the most common symptom of chronic pancreatitis. It is usually midepigastric in location but may localize or involve either the left or right upper quadrant of the abdomen. Occasionally, it is perceived in the lower midabdomen but is frequently described as penetrating through to the back (Fig. 33-31). The pain is typically steady and boring, but not colicky. It persists for hours or days and may be chronic with exacerbations caused by eating or drink-ing alcohol. Chronic alcoholics also describe a steady, constant pain that is temporarily relieved by alcohol, followed by a more severe recurrence hours later.Patients with chronic pancreatic pain typically flex their abdomen and either sit or lie with their hips flexed, or lie on their side in a fetal position. Unlike ureteral stone pain or biliary colic, the pain


Surgery_Schwartz

Surgery_Schwartz. with chronic pancreatic pain typically flex their abdomen and either sit or lie with their hips flexed, or lie on their side in a fetal position. Unlike ureteral stone pain or biliary colic, the pain causes the patient to be still. Nausea or vomit-ing may accompany the pain, but anorexia is the most common associated symptom.Pain from chronic pancreatitis has been ascribed to multiple etiologies. Ductal hypertension, due to strictures or stones, may predispose to pain that is initiated or exacerbated by eating. Chronic pain without exacerbation may be related to parenchymal disease or retroperitoneal inflammation with per-sistent neural involvement. Acute exacerbations of pain in the setting of chronic pain may be due to acute increases in duct pressure or recurrent episodes of acute inflammation in the set-ting of chronic parenchymal disease. Nealon and Matin have described these various pain syndromes as being predictive of the response to various surgical procedures.162 Pain that


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Surgery_Schwartz. in the set-ting of chronic parenchymal disease. Nealon and Matin have described these various pain syndromes as being predictive of the response to various surgical procedures.162 Pain that is found in association with ductal hypertension is most readily relieved by pancreatic duct decompression, through endoscopic stenting or surgical decompression.The surgical relief of pain due to obstructive pancreatopa-thy may be dependent on the degree of underlying fibrosis and the etiology of the disease rather than the presence of ductal obstruction, per se, according to a recent studies from Johns Hopkins. Cooper et al studied 35 patients with chronic pain associated with evidence of duct obstruction who were treated with local resection of the pancreatic head and longitudinal pan-creaticojejunostomy (LR-LPJ), or Frey procedure.163 The degree of pain resolution after surgery was compared to the degree of underlying parenchymal fibrosis. After a follow-up that averaged 22 months, patients


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Surgery_Schwartz. (LR-LPJ), or Frey procedure.163 The degree of pain resolution after surgery was compared to the degree of underlying parenchymal fibrosis. After a follow-up that averaged 22 months, patients with more than 80% fibrosis had 100% pain relief, whereas only 60% patients with less than 10% fibrosis experienced substantial or complete pain relief. Subsequently, this group studied 60 patients who had undergone either the Frey procedure or the Whipple procedure for refractory pain due to chronic pancreatitis.145 In addition to histopathologic findings, they also analyzed the etiology of the disease. Of patients with “toxic” etiologies of acquired disease (i.e., a history of alcohol or tobacco abuse), 89% experienced prolonged pain relief, whereas only 39% of those with hereditary or idiopathic disease achieved this result. Further, these results were independent of the degree of pancreatic fibrosis. These findings suggest that the etiology of the disease may be the most important predictor of


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Surgery_Schwartz. achieved this result. Further, these results were independent of the degree of pancreatic fibrosis. These findings suggest that the etiology of the disease may be the most important predictor of the ben-efit of a resectional or hybrid procedure, and that patients with idiopathic or hereditary disease might be considered for an alter-native approach, such as total pancreatectomy with islet auto-transplantation (see following section).The pain of chronic pancreatitis may decrease or disappear completely over a period of years, as symptoms of exocrine and endocrine deficiency become apparent.164 This is referred to as burned out pancreatitis and correlates with the progression of disease from a mild or moderate stage to severe destruction of the pancreas. Although this evolution of painful to nonpainful disease is sometimes used as a justification to avoid intervention in painful chronic pancreatitis, noninterventional approaches to the treatment of chronic pancreatitis are inevitably


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Surgery_Schwartz. to nonpainful disease is sometimes used as a justification to avoid intervention in painful chronic pancreatitis, noninterventional approaches to the treatment of chronic pancreatitis are inevitably accompanied by the development of narcotic addiction, inability to work, and the sequelae of chronic illness.Although increased ductal pressure, and therefore paren-chymal pressure, has been thought to be the cause of pain in chronic obstructive pancreatitis, the role of chronic inflamma-tion per se, and the development of actual nerve damage in the diseased gland, are also thought to contribute to pain.165 Chronic inflammation results in the infiltration of tissue by macrophages, which secrete prostaglandins and other nociceptive agents that cause chronic stimulation of afferent neural fibers. Inflamma-tory damage to the perineurial layers surrounding the unmyelin-ated pancreatic nerves and a focal infiltration of inflammatory cells around nerves suggest that neural fibers are a target


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Surgery_Schwartz. Inflamma-tory damage to the perineurial layers surrounding the unmyelin-ated pancreatic nerves and a focal infiltration of inflammatory cells around nerves suggest that neural fibers are a target for the cellular response to inflammation in the pancreas.166Strategies to relieve pain are therefore based on three approaches: (a) reducing secretion and/or decompress the secre-tory compartment, (b) resecting the focus of chronic inflamma-tory change, or (c) interrupting the transmission of afferent neural impulses through neural ablative procedures. A trial of antisecre-tory therapy or endoscopic duct drainage may select those patients who will benefit preferentially from a decompressive procedure.Brunicardi_Ch33_p1429-p1516.indd 146001/03/19 6:45 PM 1461PANCREASCHAPTER 33Central Nervous System Abnormalities• Functional reorganization• Central sensitization (cortical)Central NervousSystem Abnormalities• Central sensitization (spinal)Obstructive Abnormalities• Pancreatic duct


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Surgery_Schwartz. System Abnormalities• Functional reorganization• Central sensitization (cortical)Central NervousSystem Abnormalities• Central sensitization (spinal)Obstructive Abnormalities• Pancreatic duct hypertension• Pancreatic parenchymal hypertension• Pancreas morphologyPancreatic and extrapancreatic complications• Pseudocysts• Duodenal or/and bile duct obstruction• Peptic ulcer• Splenic vein thrombosisAdditional causes• CCK elevation• Increased norepinephrine levels• Mesenteric ischemia (Type 3c diabetes)• Diabetic neuropathy (Type 3c diabetes)Peripheral NervousSystem Abnormalities• Pancreatic nociception• Pancreatic neuropathy and neuroplasticityAdverse effects to treatment• Opioid induced bowel dysfunction• Complications to surgery and endoscopic therapy• Bacterial overgrowth due to changed bowel motilityCentral Nervous System Abnormalities• Impaired inhibitory pain modulationFigure 33-32. Pain mechanisms in chronic pancreatitis. (Reproduced with permission from Demir IE,


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Surgery_Schwartz. to changed bowel motilityCentral Nervous System Abnormalities• Impaired inhibitory pain modulationFigure 33-32. Pain mechanisms in chronic pancreatitis. (Reproduced with permission from Demir IE, Tieftrunk E, Maak M, et al: Pain mechanisms in chronic pancreatitis: of a master and his fire, Langenbecks Arch Surg. 2011 Feb;396(2):151-160.)Patients with chronic pain due to chronic pancreatitis are often treated for years with escalating doses of narcotics, which imposes the additional problem of opioid dependency on this population. Further, it is now apparent that the pain pattern of many patients may be described as being either “visceral pain,” caused by inflammation in and around the pancreas, or “central sensitization of pain,” which is a syndrome of increased pain perception and sensitivity caused by the prolonged presence of pain167 (Fig. 33-32). Recent studies have suggested a method to differentiate these pain processes and further suggest that drugs that decrease or


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Surgery_Schwartz. and sensitivity caused by the prolonged presence of pain167 (Fig. 33-32). Recent studies have suggested a method to differentiate these pain processes and further suggest that drugs that decrease or ameliorate the central sensitization of pain, such as pregabalin and tramadol, may be especially useful in chronic pancreatitis patients.168 These methods of differential diagnosis of pain syndromes now appear to offer the means by which it is possible to further identify and predict which patients will ben-efit from a surgical approach to chronic pancreatitis.169Malabsorption and Weight Loss. When pancreatic exocrine capacity falls below 10% of normal, diarrhea and steatorrhea develop170 (Fig. 33-33). Patients describe a bulky, foul-smelling, loose (but not watery) stool that may be pale in color and float on the surface of toilet water. Frequently, patients will describe a greasy or oily appearance to the stool, or may describe an “oil slick” on the water’s surface. In severe


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Surgery_Schwartz. pale in color and float on the surface of toilet water. Frequently, patients will describe a greasy or oily appearance to the stool, or may describe an “oil slick” on the water’s surface. In severe steatorrhea, an orange, 6040207010255075Fecal fat excretion (g/day)Normal lipase output (%)Figure 33-33. Relationship of lipase output to fat malabsorption. Excess fecal fat appears when the pancreatic lipase output falls below 10% of normal secretory values. (Data from DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme out-puts and malabsorption in severe pancreatic insufficiency, N Engl J Med. 1973 Apr 19;288(16):813-815.)Brunicardi_Ch33_p1429-p1516.indd 146101/03/19 6:45 PM 1462SPECIFIC CONSIDERATIONSPART IIoily stool is often reported. As exocrine deficiency increases, symptoms of steatorrhea are often accompanied by weight loss. Patients may describe a good appetite despite weight loss or diminished food intake due to abdominal pain.In severe symptomatic chronic


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Surgery_Schwartz. symptoms of steatorrhea are often accompanied by weight loss. Patients may describe a good appetite despite weight loss or diminished food intake due to abdominal pain.In severe symptomatic chronic pancreatitis, anorexia or nausea may occur with or separate from abdominal pain. The combination of decreased food intake and malabsorption of nutrients usually results in chronic weight loss. As a result, many patients with severe chronic pancreatitis are below ideal body weight.Lipase deficiency tends to manifest itself before trypsin deficiency, so the presence of steatorrhea may be the first func-tional sign of pancreatic insufficiency.171 As pancreatic exocrine function deteriorates further, the secretion of bicarbonate into the duodenum is reduced, which causes duodenal acidification and further impairs nutrient absorption.172 Pancreatic exocrine insufficiency is frequently asymptomatic, however, and pancre-atic exocrine function is difficult to measure, so a diagnosis of chronic


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Surgery_Schwartz. and further impairs nutrient absorption.172 Pancreatic exocrine insufficiency is frequently asymptomatic, however, and pancre-atic exocrine function is difficult to measure, so a diagnosis of chronic pancreatitis is sufficient to justify a trial of pancreatic enzyme supplements. Each meal should be followed by 90,000 United States Pharmacopeia units of lipase, and the metabolic and symptomatic status of the patients should be followed.173Pancreatogenic Diabetes. The islets comprise only 2% of the mass of the pancreas, but they are preferentially conserved when pancreatic inflammation occurs. In chronic pancreatitis, acinar tissue loss and replacement by fibrosis is greater than the degree of loss of islet tissue. Islets are typically smaller than normal and may be isolated from their surrounding vascular network by the fibrosis. With progressive destruction of the gland, endocrine insufficiency commonly occurs. Frank diabetes is seen initially in about 20% of patients with chronic


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Surgery_Schwartz. vascular network by the fibrosis. With progressive destruction of the gland, endocrine insufficiency commonly occurs. Frank diabetes is seen initially in about 20% of patients with chronic pancreatitis, and impaired glucose metabolism can be detected in up to 70% of patients. In a study of 500 patients with predominantly alcoholic chronic pancreatitis, diabetes developed in 83% within 25 years of the clinical onset of chronic pancreatitis, and more than half of the diabetic patients required insulin treatment.174 Ketoacidosis and diabetic nephropathy are relatively uncommon in pancreato-genic diabetes (see Table 33-3), but retinopathy and neuropathy are seen to occur with a similar frequency as in type 1 and type 2 diabetes.175Pancreatogenic diabetes is most common in cases of chronic pancreatitis, and it is often seen after surgical resec-tion for benign or malignant disease176,177 (Fig. 33-34). Distal Hemochromatosis8%Cystic ÿbrosis4%Pancreatic resection3%Chronic


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Surgery_Schwartz. of chronic pancreatitis, and it is often seen after surgical resec-tion for benign or malignant disease176,177 (Fig. 33-34). Distal Hemochromatosis8%Cystic ÿbrosis4%Pancreatic resection3%Chronic pancreatitis76%Pancreaticneoplasia9%A Distribution of T1DM, T2DM and T3cDMB Distribution of causes of T3cDMT3cDM8%T1DM12%T2DM80%Figure 33-34. Distribution of types of diabetes (A) and causes of type 3c (pancreatogenic) diabetes (B) based on studies of 1922 diabetic patients referred to an academic medical center as reported by Hardt et al. (Data from Hardt PD, Brendel MD, Kloer HU et al: Is pancreatic diabetes (type 3c diabetes) underdiagnosed and misdiagnosed? Diabetes Care. 2008 Feb;31 Suppl 2:S165-S169.)pancreatectomy and Whipple procedures have a higher inci-dence of diabetes than do drainage procedures, and the severity of diabetes is usually worse after subtotal or total pancreatec-tomy. Pancreatogenic, or type 3c diabetes (T3cDM), is seen in cystic fibrosis, in association with


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Surgery_Schwartz. procedures, and the severity of diabetes is usually worse after subtotal or total pancreatec-tomy. Pancreatogenic, or type 3c diabetes (T3cDM), is seen in cystic fibrosis, in association with pancreatic cancer, and in cases of severe hemochromatosis.178The etiology and pathophysiology of pancreatogenic diabetes is distinct from that of either autoimmune (type 1) or obesity-related (type 2) diabetes. In type 3c diabetes, the loss of functioning pancreatic tissue by disease or surgical removal results in a global deficiency of all three glucoregulatory islet cell hormones: insulin, glucagon, and PP. In addition, there is a paradoxical combination of enhanced peripheral sensitivity to insulin and decreased hepatic sensitivity to insulin.178,179 As a result, insulin therapy is frequently difficult; patients are hyper-glycemic when insulin replacement is insufficient (due to unsup-pressed hepatic glucose production) or hypoglycemic when insulin replacement is barely excessive (due to


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Surgery_Schwartz. difficult; patients are hyper-glycemic when insulin replacement is insufficient (due to unsup-pressed hepatic glucose production) or hypoglycemic when insulin replacement is barely excessive (due to enhanced periph-eral insulin sensitivity and a deficiency of pancreatic glucagon secretion to counteract the hypoglycemia). This form of diabetes is referred to as brittle diabetes and requires special attention.PP deficiency correlates with the severity of chronic pan-creatitis, and impairments in the hepatic action of insulin are reversed in PP-deficient chronic pancreatitis patients by admin-istration of PP.180 In addition, a study of type 1 and type 3c diabetic patients treated with insulin pump therapy revealed that the addition of a continuous subcutaneous infusion of PP reduced the insulin requirements needed for glycemic control.181 Studies are currently underway to identify a clinically suitable PP analog or PP receptor agonist.Laboratory Studies. The diagnosis of chronic


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Surgery_Schwartz. the insulin requirements needed for glycemic control.181 Studies are currently underway to identify a clinically suitable PP analog or PP receptor agonist.Laboratory Studies. The diagnosis of chronic pancreatitis depends on the clinical presentation, a limited number of indirect measurements that correlate with pancreatic function, and selected imaging studies (Table 33-14). The direct measurement of pancreatic enzymes (e.g., lipase and amylase) by blood test is highly sensitive and fairly specific in acute pancreatitis but is seldom helpful in the diagnosis of chronic pancreatitis. The pancreatic endocrine product that correlates most strongly with chronic pancreatitis is the PP response to a test meal (Fig. 33-35). Severe chronic pancreatitis is associated with a blunted or absent PP response to feeding but, as with many other tests, a normal PP response does not rule out the presence of early disease.14Brunicardi_Ch33_p1429-p1516.indd 146201/03/19 6:45 PM 1463PANCREASCHAPTER


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Surgery_Schwartz. response to feeding but, as with many other tests, a normal PP response does not rule out the presence of early disease.14Brunicardi_Ch33_p1429-p1516.indd 146201/03/19 6:45 PM 1463PANCREASCHAPTER 33The measurement of pancreatic exocrine secretion requires aspiration of pancreatic juice from the duodenum after nutrient (Lundh test meal) or hormonal (CCK or secretin) stimulation.182,183 Direct aspiration of pancreatic juice by endoscopic cannulation of the duct is performed in some centers, but it is not risk free, comfortable for the patient, or more sensitive than luminal intubation methods.184Indirect tests of pancreatic exocrine function are based on the measurement of metabolites of compounds that are altered (“digested”) by pancreatic exocrine products and can be quantified by serum or urine measurements. A commonly used indirect test is the bentiromide test, in which N-benzoyl-Ltyrosyl-p-aminobenzoic acid is ingested by the subject, and the urinary excretion of the


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Surgery_Schwartz. by serum or urine measurements. A commonly used indirect test is the bentiromide test, in which N-benzoyl-Ltyrosyl-p-aminobenzoic acid is ingested by the subject, and the urinary excretion of the proteolytic metabolite p-aminobenzoic Table 33-14Tests for chronic pancreatitis I. Measurement of pancreatic products in blood A. Enzymes B. Pancreatic polypeptide II. Measurement of pancreatic exocrine secretion A. Direct measurements 1. Enzymes 2. Bicarbonate B. Indirect measurement 1. Bentiromide test 2. Schilling test 3. Fecal fat, chymotrypsin, or elastase concentration 4. [14C]-olein absorption III. Imaging techniques A. Plain film radiography of abdomen B. Ultrasonography C. Computed tomography D. Endoscopic retrograde cholangiopancreatography E. Magnetic resonance cholangiopancreatography F. Endoscopic ultrasonography04080120160Time (min)206010014018004080120160200–40IR-pancreatic polypeptide (pmol/L)NLCPFigure 33-35. Pancreatic polypeptide (PP) response to a test