43. Dellinger EP, Tellado JM, Soto NE, et al. Early antibiotic treatment for severe acute necrotizing

pancreatitis: a randomized, double-blind, placebo-controlled study. Ann Surg 2007;245:674–683.

44. de Vries AC, Besselink MG, Buskens E, et al. Randomized controlled trials of antibiotic prophylaxis

in severe acute pancreatitis: relationship between methodological quality and outcome.

Pancreatology 2007;7:531–538.

45. Bai Y, Gao J, Zou DW, et al. Prophylactic antibiotics cannot reduce infected pancreatic necrosis and

mortality in acute necrotizing pancreatitis: evidence from a meta-analysis of randomized controlled

trials. Am J Gastroenterol 2008;103:104–110.

46. Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute

pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008;371:651–659.

47. Bradley EL, Clements JL Jr., Gonzalez AC. The natural history of pancreatic pseudocysts: a unified

concept of management. Am J Surg 1979;137:135–141.

48. Vitas GJ, Sarr MG. Selected management of pancreatic pseudocysts: operative versus expectant

management. Surgery 1992;111:123–130.

49. Yeo CJ, Bastidas JA, Lynch-Nyhan A, et al. The natural history of pancreatic pseudocysts

documented by computed tomography. Surg Gynecol Obstet 1990;170:411–417.

50. Cannon JW, Callery MP, Vollmer CM Jr. Diagnosis and management of pancreatic pseudocysts:

what is the evidence? J Am Coll Surg 2009;209:385–393.

51. Nealon WH, Bhutani M, Riall TS, et al. A unifying concept: pancreatic ductal anatomy both predicts

and determines the major complications resulting from pancreatitis. J Am Coll Surg 2009;208:790–

799.

52. Varadarajulu S, Bang JY, Sutton BS, et al. Equal efficacy of endoscopic and surgical

cystogastrostomy for pancreatic pseudocyst drainage in a randomized trial. Gastroenterology

2013;145:583–590.

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Chapter 54

Chronic Pancreatitis

Katherine A. Morgan and David B. Adams

Key Points

1 Chronic pancreatitis is heterogeneous in etiology with an increasingly recognized role of smoking

and genetic factors.

2 The most common indication for intervention in chronic pancreatitis is severe, debilitating

abdominal pain.

3 Medical and endoscopic therapies are frontline management of chronic pancreatitis, but are often

unsuccessful.

4 Surgical intervention is aimed at achieving durable pain relief with least perioperative and long term

morbidity.

5 Cutting edge therapies for chronic pancreatitis include total pancreatectomy with islet

autotransplantation and minimally invasive techniques (laparoscopic and robotic).

INTRODUCTION

Chronic pancreatitis (CP) is an inflammatory disorder of the pancreas marked by fibrotic replacement of

the pancreatic parenchyma. The clinical hallmark of disease is severe, debilitating, and recalcitrant

abdominal pain, often associated with nutritional failure. CP typically results in progressive endocrine

failure (type 3c diabetes mellitus)1 and exocrine failure (malabsorption) in afflicted patients.

Management of this challenging disorder is problematic due the complexities of disease pathogenesis,

the clinical management of pain, and attendant impairments in patient quality of life.

EPIDEMIOLOGY

CP is a significant public health concern. Its prevalence and annual incidence are estimated at 0.2% to

0.6% and 7 to 10/100,000 respectively in the United States and Europe.2 The economic impact is

notable, with estimated annual healthcare expenditures for pancreatitis in the United States in 2004

were $3.7 billion.3

ETIOLOGY

The etiology of CP is heterogeneous and multifactorial. The M-ANNHEIM classification can be utilized

to describe the (M) multiple risk factors for the development of pancreatitis including (A) alcohol

consumption, (N) nicotine use, (N) nutrition, (H) hereditary factors, (E) efferent ductal obstruction, (I)

immunologic factors, and (M) metabolic factors.4

Historically, alcohol use has been the most commonly implicated etiologic factor in CP in the Western

world, classically comprising 60% to 90% of cases in observational studies in the 1970s to the 1990s.5–7

More recent data from multiinstitutional prospective data, however, have demonstrated a lesser

contributory role from alcohol, with association in approximately 45% of cases.8 Dose and duration of

alcohol consumption have been demonstrated to be contributory to CP development, although several

more recent studies suggest that alcohol alone is not sufficient to cause CP. Byproducts from ethanol

metabolism injure acinar cells and can activate pancreatic stellate cells (PSCs) to form extracellular

matrix. Recent investigation suggests an association between pancreatitis and a locus on the X

chromosome. A risk factor for alcoholic pancreatitis on the X chromosome may partially explain the

higher incidence of alcoholic pancreatitis in men than in women, a difference that cannot be explained

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solely by alcohol consumption rate differences in men and women. In women, the high-risk allele acts

as a recessive genetic disorder with consequent risk diminishment.9

1 Smoking has been determined as a significant risk factor in the development of CP. In the 1990s, a

relationship between tobacco consumption and pancreatic calcifications was noted.10 In addition, the

synergistic effects of smoking and alcohol have been described.11 More recently, a large multicenter

epidemiologic study has shown that smoking is an independent risk factor for CP in a dose-dependent

fashion.8,12 In addition, tobacco use has been shown to be a strong risk factor for the progression of

acute pancreatitis to CP, suggesting a role for smoking in pancreatic fibrogenesis.13

Genetic causes of CP have been increasingly recognized over the past couple of decades. In 1952,

Comfort and Steinberg14 described hereditary pancreatitis (HP) and in 1996, Whitcomb and colleagues

delineated a mutation in the cationic trypsinogen gene PRSS1, which results in the inappropriate

activation of trypsin and is responsible for HP.15 HP is an autosomal dominant disorder with 80%

penetrance, marked by recurrent acute pancreatitis beginning in early childhood, progression to CP in

many, and a greatly (50×) increased risk of pancreatic cancer beginning in the fifth decade. Since,

several other mutations in the PRSS1 gene have been identified. In addition, multiple other genetic foci

have been implicated as contributing agents in CP as well, primarily related to the inappropriate

activation of trypsin. Pancreas secretory trypsin inhibitor (serine protease inhibitor, kazal type 1, and

SPINK1),16 cystic fibrosis transmembrane conductance regulator gene (CFTR), chymotrypsinogen C

(CTRC),17 calcium-sensing receptor gene (CASR),18 and gamma-glutamyltransferase 1 gene (GGT1)19

have all been elucidated as conferring a susceptibility to CP development. Conversely the anionic

trypsinogen gene PRSS2 may confer a protective advantage against the development of pancreatitis.

Clearly, the etiology of pancreatitis is variable, complex, and incompletely understood.

Figure 54-1. Three-hit hypothesis for pathophysiology of chronic pancreatitis. NGF, nerve growth factor. Adapted from Whitcomb

DC. Genetic risk factors for pancreatic disorders. Gastroenterology 2013;144:1292–1302.

PATHOPHYSIOLOGY

The pathophysiology of CP is not well elucidated. A theory known as the “three-hit hypothesis” holds

that (1) a stochastic event occurs resulting in (2) inappropriate trypsin activation causing acute

pancreatitis. The patient then has (3) an unfavorable immunologic response to the inflammation

resulting in fibrosis and CP (Fig. 54-1).20 Environmental factors (e.g., alcohol and tobacco) are

implicated as the inciting events to this cascade, with potential key modulating factors including

genetics and the histologic milieu.

Insights into pathophysiology of pancreatitis have occurred through advances in cellular basic science.

PSCs are causative in pancreatic fibrogenesis. PSCs are residents of the healthy pancreas that become

activated by inflammatory cytokines during pancreatitis to become myofibroblast-like cells, producing

extracellular matrix in the interstitial space.21 In addition, several matrix metalloproteinases are

implicated in altering extracellular matrix remodeling and collagen degradation, enhancing fibrogenesis

and irreversibly altering the organ architecture to a diseased, fibrotic pancreas.22

The pathophysiology of the CP pain syndrome is not well delineated and is likely multifactorial.

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Classically, pancreatic ductal obstruction due to fibrosis and resulting in elevated intraductal pressures

has been implicated as a primary cause for pain. Additionally, pancreatic capsular and parenchymal

fibrosis resulting in intracapsular hypertension and ischemia, create a “pancreatic compartment

syndrome,” and has been theorized to result in pain. More recent theories have focused on

peripancreatic neuropathy. On a histologic level, peripancreatic neuronal hypertrophy as well as

infiltration of periaxonal tissue with inflammatory cells is evident.23,24 Increased presence of the “pain

neurotransmitters” is identified including calcitonin gene-related peptide and substance P, stimulated by

nerve growth factor.25 These changes in the peripancreatic neuronal milieu may result in peripheral and

central neural sensitization and undoubtedly contribute to the CP pain syndrome. The pancreas has a

uniquely villainous role in abdominal pain syndromes. No other visceral organ can match it in terms of

pain severity. Neural remodeling precipitated by pancreas-synthesized tachykinins may lead to

centralization of pain that is precipitated by extra pancreatic stimuli. The “phantom pancreatitis” pain

that occurs after total pancreatectomy (TP) is related to centralization of pain pathways and is a

reminder of the vast intersecting neuronal web of the pancreas and the foregut.

CLINICAL PRESENTATION

2 The primary presentation of CP is severe, intractable epigastric abdominal pain that radiates into the

back. The classic pain is daily and constant with periods of exacerbation. Patients typically describe

pancreatitis pain as if someone is slowing twisting a knife into the epigastrium and interscapular region.

Patients often have associated gut dysfunction, with nausea, emesis, and difficulty tolerating a diet

consistently, particularly during pain episodes. Pain and nausea are frequently precipitated by ingestion

of a fatty meal or less commonly a high protein meal. Patients may develop endocrine failure

(pancreatogenic diabetes, type 3c) and exocrine pancreatic insufficiency (EPI) over time. Less often,

patients may present with an acute complication of CP such as biliary or duodenal obstruction, a

pancreatic pseudocyst, pancreatic ascites, mesenteric venous thrombosis, or mesenteric arterial

pseudoaneurysm (Table 54-1).

On physical examination, patients may generally appear malnourished and underweight. Abdominal

tenderness in the epigastrum may be elicited. Significant laboratory values to be examined include

chemistries to evaluate for dehydration and acidosis. A hepatic panel may reveal elevated alkaline

phosphatase or direct bilirubin, indicating biliary obstruction, or hypoalbuminemia from chronic

malnutrition. Serum amylase and lipase may be elevated or may be normal during pain exacerbations in

advanced disease.

Table 54-1 Complications of Chronic Pancreatitis

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