32. Bell GI, Kayano T, Buse JB, et al. Molecular biology of mammalian glucose transporters. Diabetes

Care 1990;13(3):198–208.

33. Orci L, Unger RH, Ravazzola M, et al. Reduced beta-cell glucose transporter in new onset diabetic

BB rats. J Clin Invest 1990;86(5):1615–1622.

34. Ebert R, Creutzfeldt W. Gastrointestinal peptides and insulin secretion. Diabetes Metab Rev

1987;3(1):1–26.

35. Leahy JL, Bonner-Weir S, Weir GC. Abnormal glucose regulation of insulin secretion in models of

reduced B-cell mass. Diabetes 1984;33(7):667–673.

36. Mulvihill S, Pappas TN, Passaro E Jr, et al. The use of somatostatin and its analogs in the treatment

of surgical disorders. Surgery 1986;100(3):467–476.

37. Alghamdi AA, Jawas AM, Hart RS. Use of octreotide for the prevention of pancreatic fistula after

elective pancreatic surgery: a systematic review and meta-analysis. Can J Surg 2007;50(6):459–466.

38. Allen PJ, Gonen M, Brennan MF, et al. Pasireotide for postoperative pancreatic fistula. N Engl J

Med 2014;370(21):2014–2022.

39. Malleo G, Pulvirenti A, Marchegiani G, et al. Diagnosis and management of postoperative

pancreatic fistula. Langenbeck’s Arch Surg. 2014;399(7):801–810.

40. Cubilla AL, Fortner J, Fitzgerald PJ. Lymph node involvement in carcinoma of the head of the

pancreas area. Cancer 1978;41(3):880–887.

41. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy with or without distal

gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma,

part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg

2002;236(3):355–366; discussion 366–358.

42. Japanese Pancreas Society. Classification of Pancreatic Carcinoma, First English Edition. Tokyo:

Kanehara and Complany, Ltd.; 1996.

43. Ahren B, Taborsky GJ Jr, Porte D Jr. Neuropeptidergic versus cholinergic and adrenergic regulation

of islet hormone secretion. Diabetologia 1986; 29(12):827–836.

44. Havel PJ, Taborsky GJ Jr. The contribution of the autonomic nervous system to changes of

glucagon and insulin secretion during hypoglycemic stress. Endocr Rev 1989;10(3):332–350.

45. Yeo TP, Hruban RH, Leach SD, et al. Pancreatic cancer. Curr Probl Cancer 2002;26(4):176–275.

46. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas-616 patients: results,

outcomes, and prognostic indicators. J Gastrointest Surg 2000;4(6):567–579.

47. Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for

unresectable periampullary cancer? a prospective randomized trial. Ann Surg 1999;230(3):322–328;

discussion 328–330.

48. Nagaraja V, Eslick GD, Cox MR. Endoscopic stenting versus operative gastrojejunostomy for

malignant gastric outlet obstruction-a systematic review and meta-analysis of randomized and nonrandomized trials. J Gastrointest Oncol 2014;5(2):92–98.

49. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Pancreatic

Adenocarcinoma. Version I.2016. Available from:

https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 24, 2016.

50. Seicean A. Celiac plexus neurolysis in pancreatic cancer: the endoscopic ultrasound approach. World

J Gastroenterol 2014;20(1):110–117.

51. Michaels AJ, Draganov PV. Endoscopic ultrasonography guided celiac plexus neurolysis and celiac

plexus block in the management of pain due to pancreatic cancer and chronic pancreatitis. World J

Gastroenterol 2007; 13(26):3575–3580.

52. Lillemoe KD, Cameron JL, Kaufman HS, et al. Chemical splanchnicectomy in patients with

unresectable pancreatic cancer. A prospective randomized trial. Ann Surg 1993;217(5):447–455;

discussion 456–447.

53. Gao L, Yang YJ, Xu HY, et al. A randomized clinical trial of nerve block to manage end-stage

pancreatic cancerous pain. Tumour Biol 2014;35(3):2297–2301.

54. Tanaka M, Fernandez-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the

management of IPMN and MCN of the pancreas. Pancreatology 2012;12(3):183–197.

55. Chong AK, Hawes RH, Hoffman BJ, et al. Diagnostic performance of EUS for chronic pancreatitis: a

comparison with histopathology. Gastrointest Endosc 2007;65(6):808–814.

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Chapter 53

Acute Pancreatitis

Jason S. Gold and Edward E. Whang

Key Points

1 In the United States, more than 75% of cases of acute pancreatitis are attributable to either

gallstones or alcohol.

2 In general, a diagnosis of acute pancreatitis can be made with the presence of two of the following

three features: (1) characteristic abdominal pain (acute onset of severe, persistent epigastric pain

often radiating to the back); (2) serum lipase (or amylase) levels at least three times greater than

the upper limit of normal; and (3) findings of acute pancreatitis on contrast-enhanced CT or MRI.

3 Approximately 80% of cases of acute pancreatitis are mild, associated with minimal systemic

derangements, and generally resolve within 5 to 7 days, even with minimaltherapy.

4 Severe acute pancreatitis accounts for about 20% of cases and is defined as acute pancreatitis

associated with one or more of the following: pancreatic necrosis, distant organ failure, and the

development of local complications such as hemorrhage, abscess, or pseudocyst.

5 The mortality rate associated with severe acute pancreatitis ranges from 10% to 20%, with half of

the deaths in the first 2 weeks as the result of SIRS-induced multisystem organ failure and the

remaining occurring later as the result of pancreatic necrosis/infection.

6 The most important component of initial management of acute pancreatitis is fluid resuscitation.

7 Early ERCP in acute pancreatitis has been subjected to extensive study. Early ERCP with stone

extraction and sphincterotomy clearly benefits the subset of patients with gallstone pancreatitis who

have cholangitis.

8 Infection of pancreatic and peripancreatic necrosis complicates 30% to 70% of cases of acute

necrotizing pancreatitis and most commonly becomes established during the second to third weeks

after onset of disease.

9 Infected necrosis is suggested by clinical signs such as persistent fever, increasing leukocytosis, and

imaging findings such as gas in peripancreatic collections. When the necessary, infected necrosis can

be confirmed by CT-guided fine needle aspiration.

10 Invasive intervention is usually indicated in the presence of infected necrosis. In contrast, sterile

necrotic collections almost never require intervention in the acute phase of necrotizing pancreatitis.

11 Procedures for the treatment of infected necrosis are best performed when collections become

walled off and demarcated from viable pancreatic tissue with at least partial liquefaction, which

typically requires a delay of 4 to 6 weeks after disease onset.

12 Drainage alone is now the initial recommended intervention for infected pancreatic necrosis. This is

most often accomplished through a percutaneous image-guided approach. When percutaneous drains

are placed, preference should be given to a retroperitoneal approach. Drainage can also be

accomplished through an endoscopic transluminal approach.

13 When required, débridement can often be performed through minimally invasive techniques.

14 Current well-accepted indications for intervention on pseudocysts and walled-off necrosis in the

absence of infection include the presence of symptoms attributable to the collection such as

intractable pain or obstruction of the stomach, duodenum or bile duct.

15 There are multiple treatment options available for the treatment of pancreatic pseudocysts and

sterile walled-off necrosis, including percutaneous aspiration, percutaneous drainage, and internal

drainage (performed transabdominally or endoscopically).

Acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of other

regional tissues or remote organ systems.1 In the United States, more than 250,000 patients are

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hospitalized annually with acute pancreatitis as the primary diagnosis. It is the principal cause of

approximately 3,000 deaths per year and a contributing factor in an additional 2,500 deaths. The direct

cost attributable to acute pancreatitis exceeds $2.5 billion per year in the United States.2

CLASSIFICATION AND DEFINITIONS

A useful system for defining and classifying acute pancreatitis and its complications was recently

developed through an iterative process involving several national and international pancreas

organizations.3 This new system is a modification of widely accepted but outdated classification system

originally derived from a multidisciplinary symposium held in 1992.1 The clinically based definitions

reached by consensus are shown in Table 53-1.

PATHOLOGY AND PATHOPHYSIOLOGY

The typical pathologic correlate of mild acute pancreatitis is interstitial edematous pancreatitis, in which

the pancreatic parenchyma is edematous and infiltrated with inflammatory cells. Gross architectural

features are preserved. In contrast, in necrotizing pancreatitis variable amounts of pancreatic parenchyma

and peripancreatic fat have undergone tissue necrosis, with vascular inflammation and thrombosis being

prominent features.

Studies using experimental models suggest that prototypical molecular and cellular derangements lead

to pancreatic injury, regardless of the specific etiology or inciting event that triggers an episode of acute

pancreatitis. Among the earliest of these derangements appears to be abnormal activation of proteolytic

enzymes within pancreatic acinar cells.4 Under normal conditions, trypsinogen and other digestive

zymogens are stored in granules that are segregated from lysosomal enzymes (e.g., cathepsin B) and

acid. Early in the course of acute pancreatitis, cytoplasmic vacuoles containing activated proteolytic

enzymes appear. How the digestive enzymes are activated, and what role these vacuoles play has been

the subject of much investigation. In the prevailing model, trypsinogen is believed to be activated to

yield trypsin either by colocalization with the lysosomal hydrolase cathepsin B5 or through

autoactivation due to a moderately acidic pH6. It has been noted that the cytoplasmic vacuoles

appearing in the acinar cell in experimental acute pancreatitis share expression of proteins with

autophagosomes. Autophagosomes are vacuoles that degrade cellular components such as organelles in

the process of autophagy. Highlighting the possible importance of autophagy in the development of

pancreatitis, mice lacking expression of the autophagy-related gene Atg5 in the pancreas fail to exhibit

prototypical features of acute pancreatitis.7

CLASSIFICATION

Table 53-1 Terms Used in the Classification of Acute Pancreatitis

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Figure 53-1. Schematic diagram depicting activation of proteolytic enzymes, possibly through colocalization of zymogen granules

and lysosomes, and subsequent rupture of zymogen granules releasing the activated enzymes into the cytoplasm of the pancreatic

acinar cell. The activated enzymes then undergo disordered basolateral discharge from the acinar cell into the pancreatic

parenchyma.

Acinar cell injury induced by active trypsin allows it to be released into the pancreatic parenchyma

(Fig. 53-1) where it activates more trypsin and other digestive enzymes (e.g., chymotrypsin,

phospholipase, and elastase). Trypsin can also activate the complement, kallikrein-kinin, coagulation,

and fibrinolysis cascades within the pancreatic parenchyma. Activation of these enzymes is believed to

initiate a vicious cycle in which activated enzymes cause cellular injury, an event that leads to the

release of even more destructive enzymes. This cycle can overwhelm defense mechanisms that normally

serve to limit the injurious consequences of premature trypsin activation within the pancreas (e.g.,

pancreatic secretory trypsin inhibitor–mediated inhibition of trypsin activity).

An inflammatory response is then generated in response to the initial acinar cell injury. This

inflammatory response is marked by the infiltration of the pancreatic parenchyma with immune cells

such as neutrophils, macrophages, monocytes, and lymphocytes and the release of a broad range of

proinflammatory mediators such as tumor necrosis factor (TNF) α; interleukins (IL) 1β, 6, and 8;

platelet-activating factor; chemokines (i.e., CXCL2 and CCL2); prostaglandins; and leukotrienes. The

inflammatory response, to a large extent, determines the severity of pancreatitis, and the blockade of

several components of the inflammatory response ameliorates the disease and reduces mortality in

experimental models. The understanding of how the initial acinar cell injury provokes an inflammatory

response is incomplete, but it appears that reactive oxygen species (ROS) and innate molecular pattern

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The intrapancreatic location of the distal common bile duct is critical to many pancreatic disease

processes. Gallstone pancreatitis, the second most common cause of pancreatitis in the United States, is

caused by gallstones passed into the common bile duct. These gallstones can obstruct the duct distally

and lead to transient obstruction of the pancreatic duct with resulting reflux of pancreatic juice and bile

into the pancreatic duct, causing pancreatitis.

In benign pancreatic diseases such as chronic pancreatitis, disease in the pancreatic head may cause

benign biliary strictures and jaundice, whereas disease in the body and tail more often presents with

abdominal pain. Pancreatic ductal anatomy and the presence or absence of ductal dilation dictate the

choices for operative management. In the setting of a dilated pancreatic duct, drainage procedures may

impact pancreatic pain and recurrent acute episodes. Conversely, in the setting of small duct disease,

ablative therapy with resection (duodenum-preserving pancreatic head resection,

pancreaticoduodenectomy, and distal pancreatectomy) is the treatment of choice when medical

management fails.

Figure 52-11. Large pancreatic pseudocyst in the lesser sac. The pseudocyst is compressing the stomach anteriorly.

In the setting of acute or chronic pancreatitis, ductal disruption can lead to the formation of a

pancreatic pseudocyst. In many cases, these pseudocysts occur anterior to the pancreas in the lesser sac

(Fig. 52-11). This often leads to early satiety and abdominal pain. When large pseudocysts abut the

stomach, drainage can be achieved with endoscopic or operative cystgastrostomy.

Trauma and Pancreatic Injury

The pancreatic body lies anterior to the second lumbar vertebra deep in the retroperitoneum. In cases of

blunt abdominal trauma, specifically deceleration injury, the pancreatic body is crushed against the

second vertebral body and can be transected at this point. In trauma patients with elevated amylase and

lipase levels, the trauma surgeon should be aware of this possibility and obtain cross-sectional

pancreatic imaging to rule out ductal disruption. In the case of complete ductal disruption distal

pancreatectomy or drainage of the pancreas into the intestine may be necessary.

Penetrating injury to the duodenum or pancreas often involves major vascular injury and in many

cases is not survivable. In the case of injury to the IVC, the pancreas and duodenum must be mobilized

out of the retroperitoneum (Kocher maneuver) in order to expose the vessels.

DIAGNOSTIC APPROACH TO PATIENTS WITH PANCREATIC DISEASE

Pancreatic Imaging (Studies of Pancreatic Structure)

If pancreatic disease is suspected, the pancreas can be imaged by several radiographic modalities

including plain abdominal x-rays, upper gastrointestinal series, abdominal ultrasonography, CT MRCP,

endoscopic retrograde cholangiopancreatography (ERCP), and EUS.

Abdominal Plain Films

Plain films of the abdomen may be useful in patients with acute and chronic pancreatitis. In patients

with acute pancreatitis, the most common finding on plain film include a generalized ileus with air fluid

levels, a localized ileus or “sentinel loop” of jejunum or duodenum in the area of the inflamed pancreas,

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or a cutoff of the colon due to distention of the transverse colon. In the setting of acute pancreatic fluid

collections or pseudocysts, one may see an actual mass on plain film with displacement of the stomach

or duodenum.24 These findings are not sensitive or specific for acute pancreatitis, but in the setting of

elevated amylase and lipase and associated abdominal symptoms can provide support for the diagnosis

and an indication for more sensitive pancreatic imaging studies.

In the setting of chronic pancreatitis the most common finding on plain film is the presence of

calcifications within the pancreas. These are most commonly seen at the level of the second lumbar

vertebrae, where the pancreas lies in the retroperitoneum.

Upper Gastrointestinal Series

In the setting of a mass or mass effect on plain film, an upper gastrointestinal series can demonstrate

displacement of the stomach or duodenum by a retroperitoneal mass. Displacement or narrowing of the

duodenal C-loop suggests the presence of a pancreatic mass. However, the character of the mass

(inflammatory, neoplastic, cystic, etc.) cannot be further defined on upper gastrointestinal series.24 For

this reason, upper gastrointestinal series has been largely replaced by ultrasound and other crosssectional imaging modalities such as CT or MRCP.

Ultrasonography

Abdominal ultrasound can be useful in the setting of acute pancreatitis, chronic pancreatitis, pancreatic

cystic lesions, pancreatic pseudocysts, and pancreatic cancer. In acute pancreatitis, the abdominal

ultrasound may demonstrate gallstones, suggesting a potential etiology. In addition, the ultrasound can

identify an enlarged pancreas, pancreatic edema and peripancreatic fluid collections consistent with the

diagnosis of acute pancreatitis. Ultrasound can also identify pancreatic pseudocysts, cystic lesions, and

other pancreatic masses.24 Pancreatic pseudocysts usually appear as a smooth, round fluid collection

without acoustic shadowing. A pancreatic cancer is more likely to distort the underlying pancreatic

anatomy and appear as a localized, solid lesion on ultrasound, also without acoustic shadowing. Cystic

neoplasms of the pancreas can have both solid and cystic components. They can be uniloculated or

multiloculated and contain cysts of varying size. A large uniloculated neoplastic cyst is difficult to

differentiate from a pancreatic pseudocyst.

Ultrasound examination can be limited by obesity, overlying bowel gas, recently performed barium

contrast studies. Small masses or fluid collections can be easily missed. The presence of a mass on

ultrasound is an indication for more extensive workup via CT or MRCP imaging.

Computed Tomography

Contrast enhanced, multidetector helical 3D CT is the most commonly performed study for the detection

and characterization of pancreatic solid and cystic tumors. It is also useful in defining the pancreatic

anatomy in the presence of chronic pancreatitis and identifying and following the complications of acute

pancreatitis. CT is very sensitive for identifying pancreatic masses as small as 1 cm and can accurately

distinguish solid from cystic lesions. The density of the lesion on CT can provide clues as to the

diagnosis. Pancreatic adenocarcinomas are usually solid and hypodense, whereas pancreatic

neuroendocrine tumors are vascular and appear hyperdense. Both pseudocysts and cystic lesions have

components with fluid density.

CT is sensitive for the diagnosis of a malignant pancreatic adenocarcinoma. However, it is less

sensitive and accurate in the diagnosis of cystic lesions. As CT scans are more commonly performed for

a variety of indications, many cystic lesions are found incidentally. CT can be useful in identifying the

characteristics associated with malignancy including tumor size greater than 3 cm, a dilated main

pancreatic duct, and solid components within the cystic lesion.54 However, significant controversy

remains regarding observation versus resection of pancreatic cystic lesions.

Endoscopic Ultrasound

Compared to transabdominal ultrasound, EUS provides higher-resolution images of the pancreatic

parenchyma and pancreatic duct. This procedure uses a transducer fixed to an endoscope that can be

directed to the surface of the pancreas through the stomach or duodenum. EUS provides a useful adjunct

to CT in the diagnosis of mucinous cystic lesions and malignancies. Pancreatic masses and cystic lesions

can be well visualized on EUS, providing information about tumor size and invasion of major vascular

structures. While more invasive than CT, EUS can provide useful additional information. EUS allows for

fine-needle aspiration and/or biopsy, providing a tissue diagnosis, which is critical in the setting of

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planned neoadjuvant therapy for pancreatic adenocarcinoma. EUS can also provide information about

pancreatic ductal anatomy without the risk of invasive ERCP, which can cause severe pancreatitis.

A list of 11 EUS criteria has been defined for the diagnosis of chronic pancreatitis. The ductal criteria

include pancreatic duct stones, echogenic ductal walls, irregular ductal walls, pancreatic duct strictures,

visible side branches, and ductal dilatation. The parenchyma criteria include echogenic strands,

echogenic foci, calcifications, lobular contour, and pancreatic cysts. Recent studies have determined that

three or more EUS criteria provides the best balance of sensitivity and specificity for histologic

pancreatic fibrosis.55

Finally, in the setting of intractable pain in unresectable pancreatic cancer, chemical neurolysis of the

celiac ganglion can be performed under EUS guidance. As with any endoscopic procedure, the risks

include perforation of the stomach and/or duodenum.

Magnetic Resonance Cholangiopancreatography

MRCP is now being used more commonly as a noninvasive way to image both the biliary and pancreatic

ducts. MRCP can provide excellent images and detect abnormalities of the common bile duct and main

pancreatic duct, but it is more limited in its ability to detect abnormalities in the secondary ducts. This

noninvasive imaging technique is very useful in high-risk patients and pregnant patients. It is also useful

in diagnosis of persistent choledocholithiasis in the setting of gallstone pancreatitis. MRCP is most

useful in settings where intervention such as biopsy or biliary drainage are unnecessary, thereby

avoiding the risk of ERCP. MRCP can be a good modality for defining pancreatic ductal anatomy in

patients with chronic pancreatitis and pancreatic pseudocysts to help plan operative management.

Endoscopic Retrograde Cholangiopancreatography

ERCP is the gold standard for providing information about pancreatic ductal anatomy. However, it is

associated with significant complications and can often be avoided by using the previously described

noninvasive tests. Five percent to 20% of patients develop clinical pancreatitis after ERCP and 25% to

75% have elevated amylase and lipase levels.24 There is no way to prevent post-ERCP pancreatitis;

however, high-pressure injection of the pancreatic duct is thought to contribute. Perforation of the

gastrointestinal tract is a potential complication of ERCP.

ERCP is performed less commonly since much of the information can now be obtained with CT,

MRCP, and/or EUS. However, it remains the procedure of choice when there is a high likelihood for the

need of therapeutic intervention. For example, in patients with persistently elevated liver function tests

in the setting of common duct stones ERCP is both diagnostic and therapeutic.

Pancreatic cancer is characterized by obstruction or stenosis of the pancreatic duct and or common

bile duct (double-duct sign). ERCP remains the primary modality for palliation of obstructive jaundice

with endostent placement. In chronic pancreatitis, the pancreatic duct may have irregularities including

stenosis, dilation, sacculation, and ectasia. Pancreatic duct stones may be present within the pancreatic

duct. Similar ductal changes can be observed immediately following acute attacks of pancreatitis.

However, these abnormalities can be detected on MRCP or CT.

References

1. Klein SD, Affronti JP. Pancreas divisum, an evidence-based review: part II, patient selection and

treatment. Gastrointest Endosc 2004;60(4):585–589.

2. Levy MJ, Geenen JE. Idiopathic acute recurrent pancreatitis. Am J Gastroenterol 2001;96(9):2540–

2555.

3. Testoni PA. Aetiologies of recurrent acute pancreatitis: acute or chronic relapsing disease? JOP

2001;2(6):357–367.

4. Delhaye M, Engelholm L, Cremer M. Pancreas divisum: controversial clinical significance. Dig Dis

1988;6(1):30–39.

5. Delhaye M, Engelholm L, Cremer M. Pancreas divisum: congenital anatomic variant or anomaly?

Contribution of endoscopic retrograde dorsal pancreatography. Gastroenterology 1985;89(5):951–

958.

6. Cotton PB. Congenital anomaly of pancreas divisum as cause of obstructive pain and pancreatitis.

Gut 1980;21(2):105–114.

7. Khalid A, Slivka A. Approach to idiopathic recurrent pancreatitis. Gastrointest Endosc Clin N Am

1362

2003;13(4):695–716, x.

8. Manfredi R, Costamagna G, Brizi MG, et al. Pancreas divisum and “santorinicele”: diagnosis with

dynamic MR cholangiopancreatography with secretin stimulation. Radiology 2000;217(2):403–408.

9. Ravitch MM, Woods AC, Jr. Annular pancreas. Ann Surg 1950;132(6):1116–1127.

10. Theodorides T. [Annular Pancreas]. J Chir (Paris) 1964;87:445–462.

11. Chevillotte G, Sahel J, Raillat A, et al. Annular pancreas. Report of one case associated with acute

pancreatitis and diagnosed by endoscopic retrograde pancreatography. Dig Dis Sci 1984;29(1):75–

77.

12. Glazer GM, Margulis AR. Annular pancreas: etiology and diagnosis using endoscopic retrograde

cholangiopancreatography. Radiology 1979;133(2):303–306.

13. Zyromski NJ, Sandoval JA, Pitt HA, et al. Annular pancreas: dramatic differences between children

and adults. J Am Coll Surg 2008;206(5):1019–1025; discussion 1025–1017.

14. Ikeda Y, Irving IM. Annular pancreas in a fetus and its three-dimensional reconstruction. J Pediatr

Surg 1984;19(2):160–164.

15. Guillou L, Nordback P, Gerber C, et al. Ductal adenocarcinoma arising in a heterotopic pancreas

situated in a hiatal hernia. Arch Pathol Lab Med 1994; 118(5):568–571.

16. Makhlouf HR, Almeida JL, Sobin LH. Carcinoma in jejunal pancreatic heterotopia. Arch Pathol Lab

Med 1999;123(8):707–711.

17. Kleinman R, Gingerich R, Wong H, et al. Use of the Fab fragment for immunoneutralization of

somatostatin in the isolated perfused human pancreas. Am J Surg 1994;167(1):114–119.

18. Greenberger N, Toskes P. Chapter 307. Acute and chronic pancreatitis (chapter). In: Fauci AS,

Braunwald E, Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine. 17th ed: McGraw Hill:

http://www.accessmedicine.com/content.aspx?aid=2875598. Accessed January 4, 2009.

19. Valenzuela JE, Weiner K, Saad C. Cholinergic stimulation of human pancreatic secretion. Dig Dis Sci

1986;31(6):615–619.

20. Konturek SJ, Becker HD, Thompson JC. Effect of vagotomy on hormones stimulating pancreatic

secretion. Arch Surg 1974;108(5):704–708.

21. Oh HC, Kim MH, Choi KS, et al. Analysis of PRSS1 and SPINK1 mutations in Korean patients with

idiopathic and familial pancreatitis. Pancreas 2008; 38(2), 180–183.

22. Masamune A, Kume K, Shimosegawa T. Differential roles of the SPINK1 gene mutations in alcoholic

and nonalcoholic chronic pancreatitis. J Gastroenterol 2007;42 suppl 17:135–140.

23. Dreiling D, Wolfson P. New Insights into Pancreatic Disease Revealed by the Secretin Test (chapter). Vol

2. Philadelphia, PA: Lea and Febiger; 1979.

24. Toskes P, Greenberger N. Chapter 306. Approach to the patient with pancreatic disease (chapter).

In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine. 17th ed:

McGraw Hill: http:///www.accessmedicine.com/content.aspx?aID=2875521. Accessed January 4,

2009.

25. Noda A, Hayakawa T, Kondo T, et al. Clinical evaluation of pancreatic excretion test with

dimethadione and oral BT-PABA test in chronic pancreatitis. Dig Dis Sci 1983;28(3):230–235.

26. Goff JS. Two-stage triolein breath test differentiates pancreatic insufficiency from other causes of

malabsorption. Gastroenterology 1982;83(1 Pt 1):44–46.

27. Smith RC, Southwell-Keely J, Chesher D. Should serum pancreatic lipase replace serum amylase as

a biomarker of acute pancreatitis? ANZ J Surg 2005; 75(6):399–404.

28. Kemppainen E, Hedstrom J, Puolakkainen P, et al. Increased serum trypsinogen 2 and trypsin 2-

alpha 1 antitrypsin complex values identify endoscopic retrograde cholangiopancreatography

induced pancreatitis with high accuracy. Gut 1997;41(5):690–695.

29. Kemppainen EA, Hedstrom JI, Puolakkainen PA, et al. Rapid measurement of urinary trypsinogen-2

as a screening test for acute pancreatitis. N Engl J Med 1997;336(25):1788–1793.

30. Nanjo K, Sanke T, Miyano M, et al. Diabetes due to secretion of a structurally abnormal insulin

(insulin Wakayama). Clinical and functional characteristics of [LeuA3] insulin. J Clin Invest

1986;77(2):514–519.

31. Opara EC, Atwater I, Go VL. Characterization and control of pulsatile secretion of insulin and

glucagon. Pancreas 1988;3(4):484–487.

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Figure 52-8. 3D CT reconstructions of (A) Normal arterial supply to the pancreas, (B) Replaced right hepatic artery arising from

the superior mesenteric artery, (C) Replaced common hepatic artery arising from the superior mesenteric artery and (D) Replaced

left hepatic artery arising from the splenic artery.

Variations or anomalies in the pancreatic and biliary blood supply are found in 20% to 30% of people.

In most cases, all or part of the hepatic arterial blood supply does not arise from the celiac axis. As

much of the pancreatic blood supply is derived from the hepatic arterial blood supply, these variations

lead to variations in the pancreatic blood supply. In approximately 20% of patients, the replaced right

hepatic artery arises from the superior mesenteric artery (Fig. 52-8B) in the retropancreatic position and

traverses the upper edge of the uncinate process, then runs posterolateral to the portal vein. In this case,

a pulse remains in the hepatoduodenal ligament and the gastroduodenal artery can arise from the

replaced right or the left hepatic artery. The right hepatic artery can also originate from the right

gastric in 2% of cases or from the gastroduodenal artery in 6% of cases.

The entire hepatic arterial supply can be replaced, with the common hepatic artery originating from

the SMA instead of the celiac axis (Fig. 52-8C). In this case, there is no hepatic arterial pulse medially in

the hepatoduodenal ligament. The replaced common hepatic artery runs anterior to the portal vein, but

posterior to the bile duct and gives rise to a gastroduodenal branch, which is also posterior to the bile

duct. In approximately 10% of cases, the left hepatic artery can be aberrant, most commonly arising

from the left gastric artery instead of the proper hepatic artery.

Venous Drainage

The venous drainage of the pancreas follows the arterial blood supply and is eventually returned to the

portal circulation and delivered back to the liver. There are four main routes of venous drainage in the

pancreas. In the pancreatic head the superior venous arcades drain either directly into the portal vein

superiorly or laterally. The anterior and inferior pancreaticoduodenal arcades drain directly into the

infrapancreatic SMV. There are rarely any anterior branches from the pancreatic head and neck into the

1354

superior mesenteric and portal veins. When they do occur, it is most commonly at the superior border

of the pancreatic neck.

The body and tail of the pancreas has many venous tributaries that drain into the splenic vein, which

joins the SMV posterior to the pancreatic neck forming the portal vein (PV). The three named

tributaries of the splenic are the inferior pancreatic vein, the caudal pancreatic vein, and the great

pancreatic vein. The inferior mesenteric vein (IMV) does not drain the pancreas, but joins the splenic

vein posterior to the pancreatic body. The PV then drains the intestinal blood supply to the liver.

Lymphatic Drainage

Throughout the pancreas there is a rich periacinar network of lymphatic vessels which drain to five

major nodal groups: superior, inferior, anterior, posterior, and splenic.40 The superior nodal group runs

along the superior border of the pancreas and celiac trunk. They drain the superior portion of the

pancreatic head. The inferior nodal group along the inferior border of the head and body of the

pancreas drain the inferior pancreatic head and uncinate process, eventually draining to the superior

mesenteric and paraaortic lymph nodes. The anterior lymphatics drain to the prepyloric and infrapyloric

nodes. The posterior lymph nodes include the distal common bile duct and ampullary lymphatics and

drain directly into the paraaortic lymph nodes. Finally, the splenic lymph nodes drain the lymphatics of

the pancreatic body and tail into the interceliomesenteric lymph nodes.

The Japanese Pancreas Society has classified the pancreatic lymphatic drainage into 18 lymph node

stations (Table 52-5).42 The greater and lesser curves of the stomach drain into lymph node stations 1

through 4. The anterior lymphatics described above drain into lymph node stations 5 and 6. The

superior nodal group includes lymph node stations 7 through 9 along the left gastric artery, common

hepatic artery, and celiac axis. The posterior lymph nodes include lymph node stations 12 (and all

subdivisions) and 13, while the inferior nodal group comprises stations 14 through 17. The splenic

lymph node group corresponds to Japanese lymph node stations 10 and 11.

Innervation

The innervation to the pancreas is derived from the vagus and thoracic splanchnic nerves as well as

peptidergic neurons that secrete amines and peptides.43 Parasympathetic and sympathetic fibers for

ganglia along the celiac axis and superior mesenteric artery, which give rise to the pancreatic branches

reach the pancreas by passing along the arteries from the celiac axis and superior mesenteric arteries.

The parasympathetic nerves stimulate both exocrine and endocrine secretion, while the sympathetic

fibers have a predominantly inhibitory effect (Fig. 52-9).44 The peptidergic neurons secrete hormones

including somatostatin, VIP, calcitonin gene–related peptide (CGRP), and galanin. While the peptidergic

neurons influence exocrine and endocrine secretion, their precise physiologic role is unclear. The

pancreas also has a rich network of afferent sensory fibers.

Table 52-5 Japanese Lymph Node Stations

1355

SURGICAL SIGNIFICANCE OF PANCREATIC ANATOMY

10 Knowledge of the anatomy and anatomical variants can give clues to the diagnosis of pancreatic

disease based on signs and symptoms. In addition, an understanding of the pancreatic anatomy in

relation to adjacent structures is essential when performing operative procedures on the pancreas or

surrounding structures including the duodenum, bile duct, and spleen.

1356

Figure 52-9. Schematic diagram of the neurohormonal control of the exocrine cells. Visceral receptors line the ductule system and

carry the sensation of pain to the spinal cord. Sympathetic fibers first synapse in the celiac plexus after traveling through the

thoracic ganglia and splanchnic nerves. Postganglionic fibers then synapse on intrapancreatic arterioles. Parasympathetic

preganglionic fibers travel through the celiac plexus after leaving the vagus nerves and course with vessels and ducts to synapse on

postganglionic fibers near acinar cells, islet cells, and smooth muscle cells of major ducts. Stimulation of these parasympathetic

fibers results in an immediate release of pancreatic enzymes. Secretin and CCK first enter the pancreas through the capillary

network of the islet cells, and then enter the separate capillary network of the acinar tissue through the insuloacinar portal vessels.

Glucagon, somatostatin, pancreatic polypeptide, and insulin from the islets cells reach the acinar tissue immediately after release.

In this way, the islet cells can influence the acinar tissue responses to CCK and secretin.

Pancreatic Anatomy and Pancreatic Cancer

Approximately, 75% of pancreatic adenocarcinomas occur in the pancreatic head at the genu of the

pancreatic duct.45 As a result, people who develop cancer in the head of the pancreas most commonly

present with obstructive jaundice secondary to occlusion of the intrapancreatic bile duct by tumor,

leading to earlier diagnosis. People with body and tail tumors present with abdominal pain and other

vague abdominal symptoms, often leading to a delay in diagnosis. Nearly 85% of resected pancreatic

tumors are in the head, neck, or uncinate process of the pancreas.46

Similarly, patients with cancer in the pancreatic head often have invasion of the adjacent duodenum.

They may present with or develop signs and symptoms of duodenal or gastric outlet obstruction. In

patients with unresectable disease, late gastric outlet obstruction in patients requiring

gastrojejunostomy or duodenal stenting occurs in 10% to 20% of patients. A prospective, randomized

trial demonstrated that the addition of prophylactic gastrojejunostomy in addition to

hepaticojejunostomy significantly reduced gastric outlet obstruction in patients with unresectable

disease undergoing open biliary bypass.47 However, in the modern era, biliary stenting is so effective

that operative hepaticojejunostomy for unresectable disease is rarely indicated. In the setting of isolated

gastric outlet obstruction in unresectable disease, duodenal stenting is an option. When successful this

can avoid surgery and its negative impact on the remaining quality of life. In a meta-analysis of trials

1357

comparing endoscopic stenting to gastrojejunostomy, stenting was associated with shorter time to oral

intake and shorter length of stay, with similar complication rates, and decreased mortality.48

11 The ability to resect a pancreatic cancer depends on the presence or absence of metastatic disease

and the extent of local vascular involvement. Pancreatic cancers are classified as resectable, borderline

resectable, or unresectable (including locally advanced unresectable disease and metastatic disease).

Table 52-6 shows the 2014 National Comprehensive Cancer Network definitions for resectable,

borderline resectable, and unresectable disease.49 Tumors are considered resectable if they have: (1) no

distant metastases, (2) no radiographic evidence of SMV or PV distortion, and (3) clear fat planes

around the celiac axis, hepatic artery, and SMA (Fig. 52-10A).

Table 52-6 Criteria for Resectability in Pancreatic Cancer

Tumors are considered borderline resectable if they have: (1) no distant metastases, (2) venous

involvement of the SMV or PV with distortion or narrowing of the vein or occlusion of the vein with

suitable vessel proximal and distal, allowing for safe resection and replacement, (3) gastroduodenal

artery encasement up to the hepatic artery with either short segment encasement or direct abutment of

the hepatic artery, without extension to the celiac axis, and (4) tumor abutment of the SMA not to

exceed greater than 180 degrees of the circumference of the vessel wall (Fig. 52-10B).

Tumors are considered to be locally unresectable if there is: (1) no distant metastatic disease, (2)

greater than 180 degrees SMA encasement, (3) any celiac axis abutment, (4) unreconstructable

SMV/portal occlusion, (5) invasion or encasement of the aorta or inferior vena cava (IVC), and (6)

nodal involvement outside the field of resection. Patients with any distant metastatic disease, most

commonly to the liver or lymph nodes outside the field of resection, or the presence of peritoneal

carcinomatosis are considered unresectable.

Pancreatic head cancers may also involve adjacent organs including the hepatic flexure of the colon,

the gallbladder, or the stomach. If there are no distant metastases, resection of these organs en bloc is

indicated. For cancers in the body and tail without distant metastasis, involvement of the splenic artery

and/or vein does not preclude resection as these vessels are normally taken during the operation.

However, involvement of the celiac axis or superior mesenteric artery precludes resection. Involvement

of adjacent organs including the left kidney, left adrenal, spleen, and left colon can be resected if

involved with tumor and there is no distant disease.

Knowledge of the normal pancreatic blood supply is critical in order to perform an adequate cancer

operation. As the duodenum and head of pancreas share a blood supply, it is necessary to remove these

organs en bloc when performing an operation for carcinoma. While the duodenum can be preserved in

resections performed for benign disease (duodenum-preserving pancreatic head resection), this is not

the case in patients with cancer. Likewise, for cancers in the body and tail of the pancreas it is necessary

1358

to resect the spleen and its blood supply since it shares a blood supply with the tail of the pancreas. For

benign diseases of the pancreatic tail, the spleen can be preserved.

There has been significant debate regarding the extent of lymph node dissection necessary in patients

undergoing curative resection for pancreatic cancer. Table 52-5 shows the difference in extent of

lymphadenectomy between the standard and radical procedure. The standard procedure includes the

bile duct (station 12b2) and cystic duct lymph nodes (station 12c), the posterior (station 13) and

anterior (station 17) pancreaticoduodenal lymph nodes, the SMV nodes (station 14v), and the nodes on

the right side of the superior mesenteric artery (station 14b). Radical resection adds a distal

gastrectomy (stations 3, 4, 5, and 6) and a retroperitoneal dissection extending from the right renal

hilum to the left lateral border of the aorta horizontally with samples of celiac nodes, and from the

portal vein to below the third portion of the duodenum vertically (lymph node stations 16a1, 16b2, and

9). In the United States, standard resection is most commonly performed.

Figure 52-10. A: Resectable pancreatic head cancer. There is a clear plane between the tumor and both the superior mesenteric

artery and superior mesenteric vein. B: Borderline resectable pancreatic cancer. Involvement of the superior mesenteric vein with

distortion and narrowing; tumor abutment of the superior mesenteric artery less than 80 degrees of the circumference.

Awareness of the common anatomic variants in biliary and pancreatic arterial supply is necessary to

prevent major vascular injury and damage to the hepatic blood supply during pancreatic resection. The

gastroduodenal artery is the largest named artery taken during pancreaticoduodenectomy. In the case of

a replaced right hepatic artery arising from the superior mesenteric artery, the gastroduodenal artery

can arise from this replaced vessel and enter the pancreas posterior to the bile duct. In addition, this

replaced right hepatic artery courses to the liver lateral to the bile duct and can easily be injured during

dissection of the pancreatic uncinate process off of the superior mesenteric vessels. A replaced right

hepatic artery often supplies the entire right lobe of the liver causing significant hepatic ischemia if

injured. In the case of a replaced right hepatic artery, there will still be a pulse medially in the

hepatoduodenal ligament from the left hepatic artery, but this will supply only the left lobe of the liver.

In the case of a replaced common hepatic artery, the entire hepatic blood supply will be from the

SMA. There will be no pulse medially in the hepatoduodenal ligament. The replaced vessel will again be

posterior and lateral to the bile duct and at risk of injury if not correctly identified. Given the closer

proximity of the replaced vessels to the pancreatic head and uncinate process, these replaced vessels

may also be more prone to direct involvement by tumor. If injured or involved with tumor and

resected, these often require reconstruction to restore adequate hepatic blood supply.

Due to the rich afferent sensory fiber network within the pancreas, abdominal pain and back pain are

common presenting symptoms in patients with pancreatic cancer. As pancreatic cancer progresses, the

nervous plexuses along the celiac axis in the retroperitoneum can be invaded by a tumor causing the

characteristic intractable back pain. In this setting, celiac ganglion blockade (sympathectomy) or

neurolysis using alcohol can provide significant pain relief by interrupting these somatic fibers. A celiac

block can be performed endoscopically,50 percutaneously, or intraoperatively. Endoscopic ultrasound

(EUS)- or CT-guided celiac plexus neurolysis should be considered first-line therapy in patients with pain

secondary to unresectable, locally advanced pancreatic cancer.51 Celiac blockade has been shown to

reduce pain in patients with unresectable pancreatic cancer undergoing operative bypass procedures for

obstructive jaundice and duodenal obstruction.52,53

Pancreatic Anatomy and Pancreatitis

1359

 

data from randomized trials failed to show any advantage of somatostatin analogs for accelerating

fistula closure after pancreatic surgery.39

Pancreatic Polypeptide Synthesis, Secretion, and Action

Pancreatic polypeptide is a 36-amino-acid polypeptide secreted by the F cells of the pancreatic islet. The

physiologic role of pancreatic polypeptide remains unclear. It has been shown to inhibit pancreatic

exocrine secretion and gallbladder emptying. Cholinergic innervation predominantly regulates

pancreatic polypeptide secretion. In diabetes and normal aging pancreatic polypeptide secretion is

increased resulting in increased circulating pancreatic polypeptide levels.

Other Peptide Products

Other peptides are secreted within the pancreatic islet. These include neuropeptides such as VIP,

galanin, amylin, pancreastatin, chromogranin A, and serotonin, which are believed to play a role in the

regulation of islet cell secretion. Amylin, a 36-amino-acid polypeptide, is secreted by the B cells, but not

in equimolar amounts to proinsulin. Amylin inhibits secretion of insulin and its uptake in the periphery.

Amylin has been found to be deposited in the pancreas of patients with type II diabetes and has been

implicated in the pathogenesis of the disease. Pancreastatin is another peptide found in large amounts in

the pancreas. It is a derivative of chromogranin A, but its physiologic significance is unknown.

Chromogranin A is produced by most neuroendocrine tumors and is a good marker for diagnosis and

recurrence of pancreatic neuroendocrine tumors.

Tests of Pancreatic Endocrine Function

The most widely used tests of pancreatic endocrine function measure the body’s ability to utilize

glucose. The oral glucose tolerance test provides an indirect assessment of the insulin response to an

oral glucose load; it measures the glucose profile and not the actual insulin response. After an overnight

fast, two basal blood samples are drawn and glucose levels are analyzed. Patients are then given an oral

glucose load of 40 g/m2 over 10 minutes. Blood samples are then drawn every 30 minutes for 2 hours.

The fasting glucose level should be less than 110 mg/dL. Fasting levels between 110 and 126 mg/dL are

considered borderline, and fasting levels above 126 mg/dL are diagnostic of diabetes. The 2-hour

glucose level should be below 140 mg/dL. Two-hour levels between 140 and 200 mg/dL are borderline,

and 2-hour levels over 200 mg/dL are again diagnostic of diabetes mellitus. The test takes into account

the gastrointestinal influences of glucose metabolism and can be affected by antecedent diet, drug use,

exercise, and patient age.

The intravenous glucose tolerance test can be used to eliminate gastrointestinal influences on glucose

metabolism. After basal glucose levels are obtained, this test is performed in similar fashion to the oral

glucose tolerance test, except the glucose load is delivered as an intravenous bolus of 0.5 g/kg over 2 to

5 minutes. Blood is then drawn every 10 minutes for an hour. The disappearance of glucose per minute

(K value) is calculated. A K value of 1.5 or higher is normal. The results are age adjusted, as the

response to the intravenous glucose load decreases with age.

An insulinoma is a pancreatic neuroendocrine tumor that secretes insulin. The gold standard for

diagnosis of insulinoma is the 72-hour monitored fast. This test documents Whipple triad of

hypoglycemia, neuroglycopenic symptoms concurrent with hypoglycemia, and resolution of symptoms

with administration of glucose. It also allows the clinic to rule out surreptitious administration of

exogenous insulin. Within the B cell, proinsulin is cleaved into insulin and C-peptide prior to secretion.

Therefore, both insulin and C-peptide levels can be measured in the blood stream and should be present

in a 1:1 ratio. Surreptitious administration of exogenous insulin can be differentiated from insulinoma

by the absence of C-peptide in the case of the exogenously administered insulin. Patients are fasted in a

monitored setting. All nonessential medications are stopped and patients can only drink water, black,

decaffeinated coffee, and diet sodas. Glucose and insulin levels as well as neuroglycopenic symptoms

are closely monitored. The criteria for discontinuing the fast include serum glucose levels less than 45

mg/dL and the patient must be symptomatic. The 72-hour fast is highly sensitive for insulinoma and a

patient rarely finishes this test without an unequivocal diagnosis. Urine should also be screened for the

presence of sulfonylureas and other oral hypoglycemic medications.

The intravenous arginine test and tolbutamide response test are used to help in diagnosis of more rare

hormone-secreting pancreatic neuroendocrine tumors. After an overnight fast, a patient is given a 30-

minute intravenous infusion of 0.5 g/kg of arginine, which stimulates secretion of islet cell hormones.

Blood samples are taken every 10 minutes and radioimmunoassays are performed for the hormone in

1351

question. This test is most useful for glucagon-secreting tumors and is not commonly used. Elevations of

plasma glucagon levels to over 400 pg/mL are diagnostic for glucagonoma.

Tolbutamide is a sulfonylurea that stimulates insulin secretion and secretion of other pancreatic

endocrine hormones. After fasting overnight, blood samples are drawn and a patient is given 1 g of

tolbutamide intravenously. Blood glucose is monitored for 1 hour and blood samples are drawn to

determine levels of the hormone of interest. Sustained hypoglycemia with hypersecretion of insulin is

diagnostic of insulinoma. Somatostatin levels more than twice as high as the normal values of the

particular assay used are considered diagnostic of somatostatinoma.

PANCREATIC ANATOMY

The pancreas lies in the retroperitoneum at the level of the second lumbar vertebrae. It lies obliquely

and transversely from its most caudal point at the duodenal C-loop on the right to its most cranial point

in the splenic hilum on the left. The pancreas is composed of four anatomic parts: the head (including

the uncinate process), the neck, the body, and the tail (Fig. 52-7).

Figure 52-7. Normal pancreatic anatomy. The pancreatic head lies within the C-loop of the duodenum. The main pancreatic duct

and common bile duct run through the head of the pancreas and drain into the duodenum at the ampulla of Vater. The superior

mesenteric artery and vein lie posterior to the pancreatic neck.

Relationship to Adjacent Structures

The pancreatic head is further subdivided into the head and uncinate process. The head and uncinate

process lie within the C-loop of the duodenum and include all the pancreatic parenchyma to the right of

the superior mesenteric vessels. The pancreatic head is attached to the medial aspect of the descending

and third portion of the duodenum and the two organs share a blood supply. The uncinate process

projects from the inferior portion of the pancreatic head medially to the left, then posterior to the

superior mesenteric vessels. The inferior vena cava, right renal artery and vein, and left renal vein lie

posterior to the uncinate process and pancreatic head. The bile duct runs through the posterior and

superior aspect of the pancreatic head, joining the pancreatic duct and draining into the duodenum

medially at the ampulla of Vater (Fig. 52-7).

The pancreatic neck is the portion of pancreatic tissue that overlies the superior mesenteric artery and

vein anteriorly. The anterior surface of the pancreatic neck lies directly posterior to the pylorus of the

stomach. The body of the pancreas continues left from the pancreatic neck. The anterior surface of the

pancreatic neck, body, and tail are covered with peritoneum and forms the floor of the omental bursa

within the lesser sac. The stomach overlies the pancreatic body/lesser sac anteriorly. The posterior

surface of the pancreatic body is not peritonealized and directly contacts the aorta, left adrenal gland,

left kidney, and left renal artery and vein. The body of the pancreas is the portion overlying the second

lumbar vertebrae. The tail of the pancreas begins anterior to the left kidney and extends superolaterally

1352

to the hilum of the spleen. The splenic artery and vein run along the posterior surface of the pancreas.

The tail of the pancreas is in close proximity to the spleen and splenic flexure of the colon.

Pancreatic Ductal Anatomy

The main pancreatic duct, or duct of Wirsung, begins in the pancreatic tail. It most commonly runs

within the posterior aspect of the pancreatic parenchyma, midway between the superior and inferior

border of the gland. In the head of the pancreas, the pancreatic duct turns inferiorly at the genu of the

pancreatic duct and joins the common bile duct, draining into the second portion of the duodenum at

the ampulla of Vater. A common channel may exist between the common bile duct and main pancreatic

duct and it varies in length across the population. At the level of the ampulla of Vater, the pancreatic

duct is anterior and inferior to the common bile duct. At the ampulla of Vater, the sphincter of Oddi

prevents reflux of duodenal contents into the bile duct and pancreatic duct. This sphincter of Oddi is

controlled by a variety of neural and hormonal factors that regulate relaxation and constriction.

A normal main pancreatic duct is 2 to 4 mm in diameter and has a ductal pressure of approximately

15 to 30 mm Hg. This is higher than the pressure in the common bile duct (7 to 17 mm Hg) and serves

to prevent reflux of bile into the pancreatic ductal system. There are over 20 side branches of the main

pancreatic duct throughout the pancreas providing drainage of acinar units. The accessory pancreatic

duct, or duct of Santorini, is more variable than the main pancreatic duct. It typically drains the

uncinate process and inferior portion of the pancreatic head into the duodenum at the minor papilla,

proximal to the ampulla of Vater.

Arterial Blood Supply

The pancreatic blood supply arises from the celiac axis and superior mesenteric artery. The celiac axis

arises from the abdominal aorta and most commonly gives rise to the splenic artery, the left gastric

artery, and the common hepatic artery (Fig. 52-8A). The splenic artery courses along the posterior

surface of the pancreatic body and tail and gives rise to more than 10 branches which supply the

pancreatic body and tail. The first branch of the splenic artery is the dorsal pancreatic artery; it arises

close to the origin of the splenic artery and supplies blood to the proximal body. Further distally, the

great pancreatic artery supplies the midportion of the body and the caudal pancreatic artery supplies the

pancreatic tail.

The head of the pancreas is supplied by both the celiac and superior mesenteric artery (SMA). The

gastroduodenal artery is the first branch off the common hepatic artery. Distal to the first portion of the

duodenum, the gastroduodenal artery becomes the superior pancreaticoduodenal artery and divides into

anterior and posterior branches. The SMA gives rise to the inferior pancreaticoduodenal artery, which

also divides into anterior and posterior branches. The inferior and superior pancreaticoduodenal arcades

form an extensive collateral network with the superior pancreaticoduodenal arcades, supplying both the

duodenum and head of the pancreas. Anteriorly these arcades lie in the groove between the pancreas

and duodenum. Posteriorly, they cross the common bile duct. The arterial blood supply of ampulla of

Vater is from three pedicles off the superior and inferior pancreaticoduodenal arteries. The posterior

pedicle, located at 11 o’clock, arises from the superior pancreaticoduodenal artery. The ventral

commissural pedicle, located at 1 o’clock, arises from both arcades. Finally, the inferior pedicle at 6

o’clock arises from the anterior branch of the inferior pancreaticoduodenal artery. Near the head of the

pancreas, branches arising from the splenic artery form collaterals with the inferior pancreaticoduodenal

arcades.

1353

 

Serum amylase, lipase, and trypsinogen are not elevated in the physiologic state. As amylase is found

in organs other than the pancreas (salivary glands, liver, small intestine, kidneys, and fallopian tubes),

serum amylase levels may be elevated in both pancreatic and nonpancreatic diseases (Table 52-4). When

pancreatic disease is suspected, the measurement of serum amylase and lipase levels serve as a useful

screening test. Assays for the isoenzymes of amylase can be performed, but are unreliable in

determining whether the source of amylase is pancreatic or nonpancreatic and are not widely used. It

has been shown that serum lipase is a more accurate biomarker of acute pancreatitis than serum

amylase, with 19% of patients with acute pancreatitis having normal serum amylase levels, but only 3%

having normal serum lipase levels.27 Unlike amylase and lipase, serum trypsinogen is made only by the

pancreas and may serve as a better marker for acute pancreatitis. Trypsinogen can also be measured in

the urine and serves as a specific screening test for acute pancreatitis.28,29 All three markers are cleared

by the kidneys so in the setting of acute renal failure, all may be falsely elevated. These levels do not

measure actual endocrine function, but are commonly used to diagnose acute pancreatitis and monitor

its resolution.

In the case of acute pancreatitis, serum amylase and lipase levels are usually elevated and peak within

24 hours of the onset of symptoms. They return to normal within 2 to 4 days if the inflammation

resolves. In cases of severe necrotizing pancreatitis, pancreatic ductal obstruction, and pseudocyst

formation, amylase and lipase levels can remain elevated for much longer periods of time. In this case,

elevated levels often reflect amylase-rich fluid within peripancreatic collections and not ongoing acute

inflammation.

While amylase and lipase levels are elevated in over 85% of patients with acute pancreatitis, their

elevation is far less common in chronic pancreatitis, where the exocrine function of the pancreas may be

impaired. Amylase levels may be normal in patients with acute pancreatitis if there is a delay in their

diagnosis or if their pancreatitis is related to hypertriglyceridemia, which can falsely decrease the serum

amylase levels.24

Endocrine Function

The primary function of the endocrine pancreas is regulation of carbohydrate metabolism, primarily

through regulation of insulin and glucagon secretion through a variety of feedback and regulatory

mechanisms. Insulin promotes glucose transport into cells, inhibits glycogenolysis and fatty acid

breakdown, and stimulates protein synthesis. Glucagon is the major counter-regulatory hormone to

insulin. Glucagon secretion leads to elevated blood glucose levels through stimulation of glycogenolysis

and gluconeogenesis.

Insulin Synthesis, Secretion, and Action

Insulin is a 56-amino-acid polypeptide with a molecular weight of 6 kD. It consists of two polypeptide

chains (A and B) joined by two disulfide bridges. Insulin is synthesized by the B cells within the islets of

Langerhans. Insulin is an anabolic hormone, promoting glucose transport into all cells except B cells,

hepatocytes, and central nervous system cells. It also inhibits glycogenolysis and fatty acid breakdown

but stimulates protein synthesis.

Table 52-4 Pancreatic and Nonpancreatic Causes of Hyperamylasemia

1348

Figure 52-6. Synthesis of insulin. Proinsulin is synthesized by the endoplasmic reticulum and packaged within the secretory

granules of the B cell. There it is cleaved into insulin and C peptide. Equimolar amounts of insulin and C peptide are secreted into

the bloodstream.

The amino acid sequence varies among species, but the location of the disulfide bridges are highly

conserved and are critical for its biologic activity. When pancreatic B cells are stimulated, proinsulin

(precursor peptide to insulin) is synthesized in the endoplasmic reticulum and transported to the Golgi.

In the Golgi, the proinsulin is packaged into granules where it is cleaved into insulin and the residual

connecting peptide, C peptide (Fig. 52-6). The granules are then released directly into the bloodstream.

Defects in the synthesis and cleavage of insulin can lead to rare forms of diabetes mellitus such as

Wakayama syndrome and proinsulin syndrome.30

The secretion of insulin is tightly regulated by nutrient, neural, and hormonal factors. In response to

glucose, the predominant nutrient regulator, insulin is secreted in two phases. The first phase is a short

burst of stored insulin that lasts 4 to 6 minutes. This is followed by a sustained secretion of insulin,

which requires active synthesis of the hormone within the islet cell. The B cell is sensitive to even small

changes in glucose concentration and is maximally stimulated at concentrations of 400 to 500 mg/dL.

Insulin is released in an oscillatory or pulsatile pattern controlled by an internal pacemaker which is

present even in isolated islet cells.31 Insulin has a short half-life of 7 to 10 minutes after secretion. Forty

percent to 70% of insulin secreted into the portal venous system is metabolized by hepatocytes on the

first pass through the liver. Excess insulin is then slowly metabolized by the liver, kidneys, and skeletal

muscles. Insulin is not taken up by brain cells or red blood cells.

Insulin binds to a 300-kD glycoprotein cell surface receptor. Stimulation of the insulin receptor is

dependent upon insulin concentration. Insulin resistance, present in type II diabetes, can be the result of

decreased numbers of receptors or a decreased affinity for insulin. Glucose is actively transported across

1349

cell membranes throughout the body by glucose transporters. There are several classes of glucose

transporters with varying affinities for glucose. The GLUT-2 transporter located on B cells has a low

affinity for glucose. This results in low rates of transport at physiologic concentrations of glucose but an

increased rate of transport at higher concentrations, with subsequent higher insulin secretion rates.32

The loss of B-cell GLUT-2 transporter can contribute to the development of diabetes mellitus.33

Through the enteroinsular axis, the release of enteric hormones in response to glucose potentiates

insulin secretion. As such, orally administered glucose has a greater effect on insulin secretion than an

equivalent amount of glucose administered intravenously. Gastric inhibitory polypeptide (GIP) is an

important regulator of insulin secretion.34 Additional gut peptides and hormones that stimulate insulin

secretion include glucagon, glucagon-like peptide-1, and CCK, while somatostatin, amylin, and

pancreastatin inhibit insulin secretion. Nutrients including certain amino acids (arginine, lysine, and

leucine) and free fatty acids also regulate insulin secretion. Sulfonylurea compounds, which act

independently of glucose concentration, also stimulate insulin secretion and are used in the treatment of

type II diabetes, where the primary defect is peripheral insulin resistance and not insulin production or

decreased islet-cell mass.

Parasympathetic and sympathetic innervation also influences B-cell activity. Both cholinergic and bsympathetic fibers stimulate insulin secretion, whereas s-sympathetic fibers are inhibitory. A loss of

pancreatic innervation in the setting of pancreatic transplantation can therefore result in changes in the

pattern and quality of insulin secretion. There is a significant secretory reserve of insulin within the

pancreas. Destruction or removal of 80% of the pancreatic islet cell mass is necessary before endocrine

dysfunction becomes clinically apparent in the form of type I (insulin-dependent) diabetes.35

Glucagon Synthesis, Secretion, and Action

Glucagon, secreted by the islet A, is a single-chain, 29-amino-acid polypeptide with a molecular weight

of 3.5 kD. Glucagon is the major catabolic hormone, elevating blood glucose levels through stimulation

of glycogenolysis and gluconeogenesis in the liver. Like epinephrine, cortisol, and growth hormone,

glucagon is considered a stress hormone because it increases metabolic fuel in the form of glucose

during stress. Secretion of pancreatic glucagon is tightly controlled by neural, hormonal, and nutrient

factors. Like insulin, glucose is the primary regulator, but the two hormones respond to glucose in

reciprocal fashion. Glucose has a strong suppressive effect on glucagon secretion. The two hormones are

counter-regulatory and function together to tightly control blood glucose levels. Excess glucagon can

lead to hyperglycemia, whereas insufficient glucagon can lead to profound hypoglycemia. For this

reason, the diabetes resulting from total pancreatectomy is very brittle and difficult to control due to

the lack of endogenous glucagon to balance exogenously administered insulin.

Glucagon secretion is also stimulated by the amino acids arginine and alanine. Through paracrine

effects within the islets, both insulin and somatostatin have a suppressive effect on glucagon secretion.

The neural regulation of glucagon parallels that of insulin, with cholinergic fibers being strongly

stimulatory, b-sympathetic fibers being weakly stimulatory, and a-sympathetic fibers being inhibitory.

Dysfunctional A-cell secretion of glucagon may play a role in the elevation of blood sugar in diabetes.

Somatostatin Synthesis, Secretion, and Action

9 Somatostatin is a 14-amino-acid polypeptide weighing 1.6 kD. The role of endogenous somatostatin is

unclear; it has not been proven to directly influence the secretion of other peptide hormones from islet

cells. However, exogenous administration of somatostatin has been shown to inhibit the release of

insulin, glucagon, growth hormone, and pancreatic polypeptide. Exogenous somatostatin administration

has also been shown to inhibit gastric, pancreatic, and biliary secretion.

Both short- and long-acting synthetic peptides that mimic somatostatin pharmacologically have been

developed. Somatostatin analogues are more potent inhibitors of growth hormone, glucagon, and

insulin secretion than the natural hormone. They have been used to treat both exocrine and endocrine

disorders of the pancreas. For example, in hormone-producing islet cell tumors which express

somatostatin receptors, octreotide can effectively suppress the hormonal symptoms associated with the

disease process and slow the progression of tumors.36 There has been significant debate about the role

of prophylactic somatostatin analogs in the prevention of pancreatic fistula formation after pancreatic

surgery. A 2007 meta-analysis has shown that prophylactic octreotide reduces pancreatic fistula

formation following elective pancreatic surgery37 and a more recent randomized, controlled trial

demonstrated that pasireotide given before surgery and for 7 days after surgery reduced the incidence

of clinically significant postoperative fistulas, leaks, and abscesses.38 A recent meta-analysis of pooled

1350

 

the islet in an area of discontinuity in the non-B cells surrounding the periphery. The afferent arteriole

then breaks into a capillary bed within the islet. Blood exits the islet through an efferent collecting

venule. The hormones from the islet cells are secreted directly into this rich capillary network within

the islet.

7 The most critical role of the pancreatic islet cells is the secretion of insulin and glucagon to

maintain glucose homeostasis. Pancreatic endocrine secretion also regulates pancreatic exocrine

secretion. Insulin stimulates pancreatic exocrine secretion, amino acid transport, and synthesis of

protein and enzymes, whereas glucagon acts in a counter-regulatory fashion, inhibiting the same

processes. The role of somatostatin is controversial. Somatostatin may have a direct inhibitory effect on

pancreatic acinar cells, which possess somatostatin receptors. It may also act through an inhibitory

effect on islet B cells.

PANCREATIC PHYSIOLOGY

Exocrine Function

The pancreas secretes 1.5 to 3 L of a pancreatic fluid daily. The enzymes and zymogens play a major

role in the digestive activity of the gastrointestinal tract. Pancreatic fluid is alkaline (pH 7.6 to 9.0) and

carries over 20 proteolytic enzymes and zymogens to the duodenum. The enzymes are released into the

duodenum in their inactive state; the fluid serves to neutralize gastric acid and provides an optimal

milieu for the function of these enzymes.

Pancreatic secretion is regulated via an intimate interaction of both hormonal and neural pathways

that integrate the function of the pancreas, biliary tract, and small intestine. Vagal (parasympathetic)

afferent and efferent pathways strongly affect pancreatic secretion. The secretion of enzyme-rich fluid is

largely dependent on the vagal stimulation, whereas fluid and electrolyte secretion are more dependent

on the direct hormonal effects of the secretin and cholecystokinin (CCK). Parasympathetic stimulation

also causes the release of VIP, which also serves to stimulate secretin secretion.18

Table 52-1 Pancreatic Endocrine Cell Types

Many neuropeptides also influence pancreatic secretion in an inhibitory fashion. These include

somatostatin, pancreatic polypeptide, peptide YY, calcitonin gene–related peptides, neuropeptide Y,

pancreastatin, enkephalin, glucagon, and galanin. While these neuropeptides are known to play a role in

regulation of pancreatic secretion, the mechanisms of action and the intricate interplay between the

neuropeptides is not fully understood.18

Bicarbonate Secretion

Bicarbonate is the most physiologically important ion secreted by the pancreas. Bicarbonate is formed

from carbonic acid by the enzyme carbonic anhydrase. The secretion of water and electrolytes

originates in the centroacinar and intercalated duct cells (Fig. 52-4). These cells secrete 20 mmol of

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bicarbonate per liter in the basal state and up to 150 mmol/L in the maximally stimulated state.18 The

bicarbonate secreted from the ductal cells is primarily derived from the plasma. Chloride efflux through

the cystic fibrosis transmembrane conductance regulator (CFTR) leads to depolarization and bicarbonate

entry through the sodium bicarbonate cotransporter.18 As a result, chloride secretion varies inversely

with bicarbonate secretion; the sum of these two anions balances the sodium and potassium cations and

remaining constant and equal to that of the plasma.

Both secretin and VIP stimulate bicarbonate secretion by increasing intracellular cyclic AMP, which

acts on the CFTR.18 Gastric acid is the primary stimulus for release of secretin. Secretin is released from

the duodenal mucosa in response to a duodenal lumen pH of less than 3.0 due to gastric acid.

The duodenum and jejunum release CCK in response to the presence of long-chain fatty acids, some

essential amino acids (methionine, valine, phenylalanine, and tryptophan), and gastric acid. CCK is

weak direct stimulator of bicarbonate secretion, but it acts as a neuromodulator and potentiates the

stimulatory effects of secretin. Gastrin and acetylcholine are also weak stimulators of bicarbonate

secretion.19 Bicarbonate secretion is inhibited by atropine (vagal stimulation) and can be reduced by

50% after truncal vagotomy.20 Islet cell peptides including somatostatin, pancreatic polypeptide,

glucagon, galanin, and pancreastatin are thought to inhibit exocrine secretion.

Enzyme Secretion

Pancreatic enzymes originate in the acinar cells, which are highly compartmentalized. Proteins are

synthesized in the rough endoplasmic reticulum, processed in the Golgi apparatus, and then targeted to

the appropriate cell compartment (zymogen granules, lysosomes, etc.). The acinar cells secrete enzymes

that fall into three major enzyme groups: amylolytic enzymes, lipolytic enzymes, and proteolytic

enzymes. Amylolytic enzymes such as amylase hydrolyze starch to oligosaccharides and the disaccharide

maltose. Lipolytic enzymes such as lipase, phospholipase A, and cholesterol esterase function work in

conjunction with bile salts to digest fats and cholesterol. Proteolytic enzymes include endopeptidases

(trypsin and chymotrypsin) and exopeptidases (carboxypeptidase). Endopeptidases act on the internal

peptide bonds of proteins and polypeptides and exopeptidases act on the free carboxy- and aminoterminal ends of proteins. Proteolytic enzymes are secreted as inactive precursors. Enterokinase cleaves

the lysine–isoleucine bond in trypsinogen to create the active enzyme trypsin. Trypsin then activates the

other proteolytic enzyme precursors.18

The different pancreatic enzymes are not secreted in fixed ratios. They change in response to dietary

alterations and stimuli such as gastric acid, hormones, and neuropeptides. When enzyme secretion is

absent or impaired, malabsorption or incomplete digestion occurs, leading to fat and protein loss

through the gastrointestinal tract. This is seen in patients with acute and chronic pancreatitis (who have

destruction of the exocrine pancreas) and in patients who have undergone surgical resection of all or

part of the pancreas. These patients often present with weight loss and steatorrhea secondary to

malabsorption of nutrients. These signs and symptoms can be corrected by oral replacement of

pancreatic enzymes with meals.

The nervous system initiates pancreatic enzyme secretion. This involves extrinsic innervation by the

vagus nerve and subsequent innervation by the intrapancreatic cholinergic fibers. The

neurotransmitters, acetylcholine and gastrin-releasing peptide activate calcium-dependent release of

zymogen granules.18 In addition, CCK is a predominant regulator of enzyme secretion, doing so through

activation of specific membrane-bound receptors and calcium-dependent second messenger pathways.

Secretin and VIP weakly stimulate acinar cell secretion directly, but also potentiate the effect of CCK on

acinar cells (Fig. 52-5). Insulin is required locally and serves in a permissive role for secretin and CCK

to promote exocrine secretion.18

Through the secretion of the three classes of enzymes, the pancreas regulates complete digestion of

carbohydrates, fats, and proteins. Autodigestion of the pancreas by these proteolytic enzymes is

prevented by packaging of proteases in an inactive precursor form and by the synthesis of protease

inhibitors including pancreatic secretory trypsin inhibitor (PSTI), serine protease inhibitor, kazal type 1

(SPINK1), and protease serine 1 (PRSS1). These enzymes are found in the acinar cell and loss of these

protective mechanisms can lead to activation, autodigestion, and acute pancreatitis. Mutations in the

SPINK1 and PRSS1 genes are known to cause one of the aggressive familial forms of chronic

pancreatitis, leading to recurrent episodes of pancreatitis, with associated exocrine and endocrine

insufficiency.21,22

1345

Figure 52-5. Schematic diagram of the acinar cell, demonstrating receptors for exocrine secretagogues and their intracellular bases

of action. Six distinct classes of receptors are known, with principal ligands shown. CCK, cholecystokinin; VIP, vasoactive intestinal

peptide; CRGP, calcitonin gene–related peptide; DAG, diacylglycerol.

Table 52-2 Characteristic Results of Secretin Testing: Volume, Bicarbonate

Concentration, and Enzyme Secretion Changes in Pancreatic Disease

Processes

Tests of Pancreatic Exocrine Function

8 Several tests are useful in the assessment of pancreatic exocrine function. Such tests are useful in both

diagnosing and determining the etiology of exocrine insufficiency (chronic pancreatitis, malnutrition,

cancer, and Zollinger–Ellison syndrome) (Table 52-2). Steatorrhea from pancreatic exocrine dysfunction

is the result of lipase deficiency and is usually not present until lipase secretion is reduced by 90%. The

secretin test, the dimethadione test (DMO) and the Lundh test require duodenal intubation. The classic

test of pancreatic exocrine function is the secretin test.23 A patient fasts overnight. A double-lumen tube

is then placed in the duodenum. Basal collections are performed for 20 minutes and analyzed for total

volume, bicarbonate output, and enzyme secretion. An intravenous bolus of 2 units of secretin per

kilogram is given and four collections every 20 minutes are analyzed for volume, bicarbonate levels,

and enzyme levels.

Normal values for the standard secretin stimulation test are 2.0 mL of pancreatic fluid per kilogram

per hour, bicarbonate concentration of 80 mmol/L, bicarbonate output of >10 mmol/L in 1 hour, and

1346

amylase secretion of 6 to 18 International Units/kg. The maximal bicarbonate concentration provides

the greatest discrimination between normal subjects and patients with chronic pancreatitis.24 The results

of the secretin stimulation test for different pancreatic disease processes is shown in Table 52-2.

The pancreas metabolizes the anticonvulsant drug trimethadione to its metabolite, DMO. After

placing a double-lumen tube in the duodenum, patients are given 0.45 g of trimethadione three times

daily for 3 days. Secretin is given through the double-lumen tube to maximally stimulate pancreatic

secretion. To measure pancreatic exocrine function, the duodenal output of DMO is analyzed.25

The Lundh test directly measures pancreatic enzyme secretion in response to a meal of carbohydrate,

fat, and protein. A patient fasts overnight, then has a double-lumen duodenal tube placed. After basal

duodenal fluid collection, patients are given a meal consisting of 18 g of corn oil, 15 g of casein, and 40

g of glucose in 300 mL of water. Duodenal fluid is collected every 30 minutes for 2 hours and analyzed

for trypsin, amylase, and lipase. This test relies on endogenous secretin and CCK secretion and may be

abnormal in diseases involving the intestinal mucosa.

N-benzoyl-1-tyrosyl paraaminobenzoic acid (BT-PABA) is cleaved by chymotrypsin to form

paraaminobenzoic acid (PABA), which is then excreted in the urine. The PABA test is performed by

administering 1 g of BT-PABA in 300 mL of water orally. Urine is then collected for 6 hours. Patients

with chronic pancreatitis excrete less than 60% of the ingested dose of PT-PABA.

Suspected pancreatic exocrine dysfunction can also be confirmed giving patients a test meal and

measuring serum levels of the islet cell hormone pancreatic polypeptide (PP). Basal and meal-stimulated

levels of serum PP are reduced in severe chronic pancreatitis and after extensive pancreatic resection.

After an overnight fast, a test meal of 20% protein, 40% fat, and 40% carbohydrate is ingested. The

normal basal range of PP is 100 to 250 pg/mL. In severe chronic pancreatitis, the basal levels are often

less than 50 pg/mL. The normal response to a meal is a rise in PP levels to 700 to 1,000 pg/mL for 2 to

3 hours after the meal. In severe disease, this response is decreased to less than 250 pg/mL. PP release

depends on intact pancreatic innervation and can also be decreased after truncal vagotomy, antrectomy,

or in the setting of diabetic autonomic neuropathy.

The triolein breath test is a noninvasive test of pancreatic exocrine insufficiency or malabsorption, but

does not differentiate between the two.26 25 g of 14C-labeled corn oil (triglycerides) are given to the

patient orally. The metabolite, 14C-carbon dioxide, can be measured in the breath 4 hours after

administration. Patients with disorders of fat digestion or malabsorption exhale less than 3% of the dose

per hour. The test can be repeated after pancreatic enzyme replacement. Patients with pancreatic

insufficiency will achieve a normal rate of excretion of 14C-carbon dioxide, whereas patients with

enteric disorders (malabsorption) show no improvement.

Many tests can help differentiate between steatorrhea caused by pancreatic exocrine insufficiency

versus malabsorption (Table 52-3). The secretin test, the PABA test, and PP will be normal in intestinal

malabsorption and abnormal in pancreatic insufficiency. The fecal fat test measures intraluminal

digestion products. Fecal fat content is measured over a 24-hour time period. If the fecal fat is elevated

to more than 20 g this indicates pancreatic insufficiency, whereas steatorrhea in the presence of low

levels of fecal fat (<20 g) indicates intestinal dysfunction. A reduction of fecal fat can be used to

demonstrate adequate replacement of pancreatic enzymes in patients with exocrine insufficiency.

However, this test is time consuming and disliked by patients and pancreatic enzyme replacement is

often titrated based on symptom relief if the clinical situation leads to a high index of suspicion for

pancreatic exocrine insufficiency (i.e., long-standing chronic pancreatitis) or once the diagnosis of

pancreatic insufficiency is made.

Table 52-3 Differential Diagnosis of Intestinal and Pancreatic Steatorrhea

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Figure 52-1. A–D: Schematic drawings of the successive stages in the development of the pancreas from the fifth through the

eighth weeks. E–G: Diagrammatic transverse sections through the duodenum and the developing pancreas. Growth and rotations

(arrows) of the duodenum bring the ventral pancreatic bud toward the dorsal bud and they subsequently fuse. The bile duct

initially attaches to the ventral aspect of the duodenum and is carried around to the dorsal aspect as the duodenum rotates. The

main pancreatic duct is formed by the union of the distal part of the dorsal pancreatic duct and the entire ventral pancreatic duct.

The endocrine function of the pancreas begins during gestation, whereas the exocrine function does

not begin until after birth. The first glucagon-producing cells are seen in 3-week-old embryos and the

first islets appear at approximately 10 weeks. During this early developmental period, predominantly

glucagon-positive islet cells initially appear in the tail of the pancreas. Early glucagon-positive

endocrine cells convert to nonepithelial cells and lose connection with the lumen and tight junctions.

Subsequently, there is a major amplification of endocrine cell numbers, particularly B cells, which

produce insulin.

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Figure 52-2. Anatomic configuration of the intrapancreatic ductal system. A: The classic anatomy is present in 60% of cases, where

the accessory duct drains into the minor papilla and the main duct drains into the ampulla of Vater. B: The accessory pancreatic

duct is blind and does not drain into the duodenum in 30% of cases. C: A lack of communication between the two ducts, which

occurs in 10% of cases, is referred to as pancreas divisum. When this occurs the main pancreatic duct drains into the duodenum

through the minor papilla. D: Pancreaticogram obtained on ERCP through cannulation of the minor papilla in a patient with

pancreas divisum; the main duct drains into the minor papilla. E: MRCP on the same patient. The main pancreatic duct drains into

the minor papilla and the common bile duct drains into the ampulla of Vater.

Surgical Significance of Congenital Pancreatic Abnormalities

4 Abnormalities in the rotation and fusion of the pancreas during embryonic development can result in

specific congenital anomalies that have surgical significance. In approximately 60% of people, rotation

1340

and fusion occur normally resulting in the classic anatomy seen in Figure 52-2A. The dorsal and ventral

ducts fuse to form the main pancreatic duct which drains the majority of the pancreas into the ampulla

of Vater. The lesser duct, formed from the proximal duct of the dorsal bud, drains into the duodenum at

the minor papilla.

In approximately 30% of cases, the ventral and dorsal ducts fuse and drain normally into the

duodenum at the ampulla of Vater. However, there is atrophy of the accessory or minor duct with a

blind end and drainage into the duodenum (Fig. 52-2B). As this blind duct still communicates with the

main pancreatic duct, this is of little to no clinical significance and most often found only at autopsy.

In 5% to 14% of cases, the fusion of the ventral and dorsal pancreatic ducts is incomplete (Fig. 52-2C–

E).1–3 As a result of the incomplete fusion, the majority of the pancreas is drained into the duodenum

through the minor papilla. This is called pancreas divisum. Only the small remnant duct of the ventral

bud drains the uncinate process into the duodenum via the ampulla of Vater. Whether or not pancreas

divisum causes pancreatitis and abdominal pain is unclear.1,4,5 It is often asymptomatic. However,

mucosal stenosis at the minor papilla may lead to cystic dilatation of the dorsal duct resulting in

pancreatitis and pain.1,6–8 Pancreatitis or abdominal pain due to pancreas divisum is a diagnosis of

exclusion, and other etiologies for the pancreatitis should be thoroughly investigated. If no other causes

of pancreatitis are identified in the setting of abdominal pain, elevated amylase levels, and pancreas

divisum, the anomaly is considered causative and an endoscopic or operative papillotomy of the minor

papilla and accessory duct is indicated. Recurrent acute pancreatitis or chronic pancreatitis with chronic

pain attributed to pancreas divisum is most often seen in young females.

Annular pancreas is a rare congenital anomaly of the pancreas first recognized in 1818. Early autopsy

and surgical series estimate the incidence to be approximately 3 in 20,000.9,10 However, with better

imaging modalities such as computed tomography (CT), magnetic resonance cholangiopancreatography

(MRCP), and endoscopy, the incidence is thought to be closer to 1 in 1,000.11–13 Annular pancreas is

thought to result from abnormal fusion of the ventral pancreatic bud to the duodenum, leading to

improper rotation of the ventral bud around the duodenum.14 This failure of rotation leads to a thin

band of normal pancreatic parenchyma completely surrounding the second portion of the duodenum

(Fig. 52-3A–C). This band is in continuity with the head of the pancreas and causes variable degrees of

duodenal compression and stenosis. This abnormal ring of pancreatic tissue may contain a pancreatic

duct. Therefore, the surgeon must be aware of this anomaly; if annular pancreas is incidentally

encountered during an operation, it should not be divided. Division of the abnormal ring can result in

pancreatic fistula or obstruction of pancreatic ductal drainage.

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Figure 52-3. Annular pancreas. A: CT scan of a patient with annular pancreas. There is a ring of pancreatic tissue surrounding the

duodenum, with a narrowed duodenal lumen. B: EGD image in the same patient. Note narrowing of the duodenal lumen with no

mucosal lesion consistent with external compression by the annular pancreas. C: Intraoperative photo of an annular pancreas. Note

the dilated duodenum after the pylorus, the ring of pancreatic tissue surrounding the duodenum just distal to the dilation, and the

decompressed distal duodenum.

Annular pancreas can present at varying time points from in utero to adulthood.13 When diagnosed in

utero, the most common presentation is polyhydramnios due to duodenal obstruction. Newborns present

most commonly with duodenal obstruction shortly after birth, as evidenced by low birth weight and

feeding intolerance. In people who present in utero or in childhood, it is more commonly associated

with other congenital anomalies including Down syndrome, cardiac anomalies, and other intestinal

anomalies. Duodenal bypass (duodenoduodenostomy or gastrojejunostomy) is the treatment of choice in

children.

Fifty percent of cases of annular pancreas occur in adults. Adults are less likely to present significant

obstruction and less likely to require surgical intervention. If they do present with obstruction,

treatment is similar to that in children. In adults, annular pancreas is more commonly associated with

pancreas divisum and pancreatic neoplasia than in children.13 Heterotopic pancreas is pancreatic tissue

outside the bounds of the normal pancreas without anatomic or vascular connections to the pancreas

itself. Heterotopic pancreas occurs in 0.5% to 14% of autopsy series. The heterotopic pancreatic tissue is

functional and can occur in a variety of sites including the stomach, duodenum, ileum, umbilicus, colon,

appendix, gallbladder, and even within a Meckel diverticulum. This tissue is usually submucosal and

uniformly contains acini and ducts. Up to one-third contains islet cells. Heterotopic pancreas is usually

an incidental finding, but can present with ulceration, obstruction, or intussusception, in which case

treatment is directed at the presenting symptoms and may require resection. In incidental and

asymptomatic cases, no treatment is required. The heterotopic pancreas is susceptible to the same

diseases as normal pancreas and can even undergo malignant transformation.15,16

EXOCRINE AND ENDOCRINE STRUCTURE

The exocrine structures of the pancreas account for 80% to 90% of the pancreatic mass while the

endocrine structure accounts for approximately 2% of the pancreatic mass. The remainder of the

pancreas comprises extracellular matrix, blood vessels, and major ductal structures.

Exocrine Structure

The exocrine structure of the pancreas is composed of two main components: the acinar cells and the

ductal network. The acinar cells produce and secrete the enzymes and zymogens responsible for

digestion. The acinar cells are pyramidal cells with an apex that faces the pancreatic ductal network.

Approximately 20 to 40 acinar cells cluster together to form the functional unit called an acinus (Fig.

52-4A,B). Zymogen granules within the acinar cells contain the digestive enzymes for secretion into the

ductal system. Located more centrally within the acinus, the centroacinar cell secretes alkaline fluid (pH

8.0) into the pancreatic ductal system. The acinus drains initially into small intercalated ducts, which

join to form interlobular ducts that also secrete fluid and electrolytes (Fig. 52-4A). These interlobular

ducts form secondary ducts that drain into the main pancreatic ductal system and eventually the

duodenum at the ampulla of Vater.

1342

Figure 52-4. Histologic anatomy of the acinus. A: Low-magnification view of a portion of the pancreas. B: High-magnification

view of a single acinus. The acinar cells, containing zymogen granules, are pyramidal cells with an apex that faces the pancreatic

ductal network. Twenty to 40 acinar cells that cluster together to form the functional unit called an acinus. The centroacinar cell,

also present within the acinus, functions to secrete fluid and electrolytes of the correct pH into the pancreatic ductal system. The

acinus drains into small intercalated ducts, which join to form interlobular ducts that also secrete fluid and electrolytes. These

interlobular ducts form secondary ducts that drain into the main pancreatic duct.

Endocrine Structure

5 The pancreatic islet cells are of neural crest origin and part of the family of amine precursor uptake

and decarboxylation (APUD) cells. Each pancreatic islet is approximately 40 to 900 mm and contains an

average of 3,000 cells. The islets are composed of four cell types. These cell types are differentially

distributed both throughout the pancreas and within the islets. Table 52-1 describes the cell types, their

hormonal products, and their location within the islet and the pancreas.

B (or beta) cells are located centrally within the islets. They constitute approximately 70% of the islet

cell mass. The main secretory product of B cells is insulin, but they also excrete amylin and

cholecystokinin. A (or alpha) cells and F cells are located peripherally within the islets and constitute

10% and 15% of the islet cell mass, respectively. Glucagon is secreted by A cells, which is the major

counter-regulatory hormone to insulin in glucose homeostasis. F cells secrete pancreatic polypeptide. D

cells are evenly distributed throughout the islet and constitute 5% of the islet cell mass.17 They can be

further divided into D cells which secrete somatostatin and D2 cells which secrete vasoactive intestinal

peptide (VIP). E (or epsilon cells) and C cells comprise <1% of the islet mass and secrete substance P

and serotonin. They are of minimal clinical significance.

6 The distribution of endocrine cell types is not uniform throughout the pancreas. B and D cells are

concentrated in the tail of the pancreas, whereas A cells (as well as C and E cells) are evenly distributed

and F cells are concentrated in the pancreatic head and uncinate process. As such, resection of the

pancreatic body and tail removes more of the insulin-producing cells and is more likely to cause

endocrine insufficiency (diabetes). This distribution also has clinical relevance with regard to the

location of endocrine neoplasms when they occur.

The islet cells have a rich blood supply supporting their endocrine role. The afferent arteriole enters

1343

 

81. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced

gastrointestinal stromal tumors. N Engl J Med 2002;347(7):472–480.

82. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of

localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled

trial. Lancet 2009;373(9669):1097–1104.

83. Mullady DK, Tan BR. A multidisciplinary approach to the diagnosis and treatment of

gastrointestinal stromal tumor. J Clin Gastroenterol 2013; 47(7):578–585.

84. Coco C, Rizzo G, Manno A, et al. Surgical treatment of small bowel neoplasms. Eur Rev Med

Pharmacol Sci 2010;14(4):327–333.

85. Retsas S, Christofyllakis C. Melanoma involving the gastrointestinal tract. Anticancer Res

2001;21(2b):1503–1507.

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SECTION G: PANCREAS

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Chapter 52

Pancreas Anatomy and Physiology

Taylor S. Riall

Key Points

1 The pancreas is both an endocrine and exocrine organ.

2 The primary function of the exocrine pancreas is to synthesize and secrete enzymes necessary for

digestion.

3 The primary function of the endocrine pancreas is regulation of body energy, primarily through

control of carbohydrate metabolism. Pancreatic endocrine hormones also play a critical role in the

complex regulation of pancreatic secretion and digestion.

4 Congenital anomalies of the pancreas largely result from failure of rotation or fusion of the ventral

and dorsal pancreatic buds.

5 The pancreatic islets of Langerhans are composed of four major cell types – alpha (A), beta (B), delta

(D), and pancreatic polypeptide (PP or F) cells which primarily secrete glucagon, insulin,

somatostatin, and PP, respectively.

6 The different types of islet cells are not evenly distributed throughout the pancreas leading to a

differential distribution of functional neuroendocrine tumors. In addition, resection of different parts

of the pancreas has differing endocrine effects.

7 Pancreatic endocrine secretion also regulates pancreatic exocrine secretion. Insulin stimulates

pancreatic exocrine secretion, amino acid transport, and synthesis of protein and enzymes, whereas

glucagon acts in a counter-regulatory fashion, inhibiting the same processes.

8 Tests of pancreatic exocrine function include the secretin test, 24-hour fecal fat determination,

dimethadione (DMO) test, the Lundh test meal, the triolein breath test, and the paraaminobenzoic

acid (PABA) test. These tests help differentiate steatorrhea due to pancreatic insufficiency from other

digestive disorders.

9 Exogenous administration of somatostatin inhibits the release of insulin, glucagon, growth hormone,

and pancreatic polypeptide.

10 Knowledge of the relationship of the pancreas to surrounding structures including the stomach,

duodenum, distal bile duct, hepatic arterial blood supply, splenic artery and vein, celiac axis,

superior mesenteric artery and vein, portal vein, spleen, adrenal glands, colon and kidneys is critical

in preventing injury to these structures during pancreatic surgery.

11 Resectability in pancreatic cancer in the absence of metastatic disease depends on the extent of

involvement of the tumor with the major vascular structures including the superior mesenteric

artery, superior mesenteric vein (SMV), portal vein, and celiac axis.

INTRODUCTION

1 The pancreas is a digestive organ with both exocrine and endocrine function. The exocrine pancreas

constitutes 80% of the pancreatic mass and comprises acinar and ductal cells.

2 Acinar cells synthesize and secrete over 20 enzymes into the complex pancreatic ductal network,

which then delivers them to the duodenum. The pancreatic secretions are alkaline and provide the

optimal environment for the enzymes to carry out their digestive function in the small intestine.

3 The pancreatic endocrine cells are organized in discrete groups throughout the pancreas, called

islets of Langerhans. The islets directly secrete hormones including insulin, glucagon, and somatostatin,

directly into the blood stream in endo crine fashion. The primary function of the endocrine pancreas is

regulation of body energy, primarily through control of carbohydrate metabolism. Pancreatic endocrine

hormones also play a critical role in the complex regulation of pancreatic secretion and digestion.

1337

The pancreas lies transversely in the retroperitoneum at the level of the second lumbar vertebrae.

Understanding of the embryology of the pancreas is critical for recognizing rare congenital anomalies,

understanding their significance, and treating them appropriately. In addition, when performing

pancreatic and other upper abdominal operations, it is critical to understand the close relationship of the

pancreas to adjacent organs (duodenum, stomach, spleen, transverse colon, bile duct, and left adrenal

gland) and major vessels (celiac axis, superior mesenteric artery, superior mesenteric vein (SMV),

splenic artery and vein, portal vein, inferior mesenteric vein, and vena cava). Knowledge of the normal

pancreatic exocrine and endocrine physiology provides insight into the pathologic processes and

subsequent treatments that can affect the normal function of the pancreas.

EMBRYOLOGY

Normal Pancreatic Embryology

The pancreas begins developing during the fifth week of gestation. Pancreatic development begins at

the junction of the foregut and midgut as two endodermal pancreatic buds, the dorsal bud and the

ventral bud. The dorsal and ventral buds comprise endoderm covered in splanchnic mesoderm. Both the

acinar and islet cells differentiate from the endodermal cells found in the embryonic buds while the

splanchnic mesoderm eventually develops into the dorsal and ventral mesentery.

The dorsal bud forms first and is larger. It ultimately forms much of the head, body, and tail of the

pancreas. As the duodenum grows and rotates, the ventral bud rotates clockwise (Fig. 52-1) and fuses

with the dorsal bud forming the uncinate process and inferior head of the pancreas. In the majority of

cases, the duct in the ventral bud fuses with the duct in the dorsal bud to become the main pancreatic

duct (duct of Wirsung), which drains the majority of the pancreas into the duodenum through the major

papilla, or ampulla of Vater. The proximal duct of the dorsal bud forms the lesser or minor pancreatic

duct (duct of Santorini) which drains into the duodenum through the minor papilla proximal to the

ampulla of Vater.

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