Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Exocrine Pancreas


Anatomy

The average pancreas weighs between 75 g and 125 g and measures 10 cm to 20 cm. It lies in the retroperitoneum just anterior to the first lumbar vertebra and is anatomically divided into five sections, the head, uncinate, neck, body, and tail. The head lies to the right of midline within the C loop of the duodenum, immediately anterior to the vena cava at the confluence of the renal veins. The uncinate process extends from the head of the pancreas behind the superior mesenteric vein (SMV) and terminates adjacent to the superior mesenteric artery (SMA). The neck is the short segment of pancreas that immediately overlies the SMV. The body and tail of the pancreas then extend across the midline, anterior to Gerota fascia and slightly cephalad, terminating within the splenic hilum. The transition point between body and tail is nebulous. ( Fig. 56.1 ).

Fig. 56.1, Anatomy.

Arterial Blood Supply

The pancreas is supplied by a complex arterial network arising from the celiac trunk and SMA. The head and uncinate process are supplied by the pancreaticoduodenal arteries (superior and inferior). The superior pancreaticoduodenal artery arises from the gastroduodenal artery and divides into anterior and posterior branches as it runs inferiorly within the pancreaticoduodenal groove. The inferior pancreaticoduodenal artery arises from SMA and also divides into anterior and posterior branches as it runs superiorly within pancreaticoduodenal groove. Terminal branches of superior and inferior pancreaticoduodenal arteries join each other to form the arcade, which supplies the head and uncinate process of the pancreas and the duodenum. The neck, body, and tail receive arterial supply from the splenic arterial system. Several small branches originate from the length of the splenic artery, including the dorsal pancreatic artery and greater pancreatic artery. The dorsal pancreatic courses posterior to the body of the gland to become the inferior pancreatic artery (also known as the transverse pancreatic artery). The inferior pancreatic artery then runs along the inferior border of the pancreas, terminating at its tail.

Venous Drainage

The venous drainage mimics the arterial supply, with blood flow from the head of the pancreas draining into the anterior and posterior pancreaticoduodenal veins. The posterior superior pancreaticoduodenal vein enters the SMV laterally at the superior border of the neck of the pancreas. The anterior superior pancreaticoduodenal vein enters the right gastroepiploic vein just before its confluence with the SMV at the inferior border of the pancreas. The anterior and posterior inferior pancreaticoduodenal veins enter the SMV along the inferior border of the uncinate process. The remaining body and tail are drained through the splenic venous system.

Lymphatic Drainage

Understanding the lymphatic drainage of the pancreas is paramount to performing an appropriate oncologic resection. The pancreas can be thought of as having four quadrants of primary drainage. The tissue in the left side of the gland drains to lymph nodes in the splenic hilum or gastrosplenic omentum via lymphatics along the superior and inferior border of the pancreas. Small lymph nodes are present along this drainage pathway. Tissue in the right side of the gland drains superiorly to gastroduodenal lymph nodes and inferiorly to infrapancreatic lymph nodes. Again, small lymph nodes are present along these lymphatic channels. These four pathways form a “ring” around the border of the pancreas. A secondary drainage pathway occurs via retropancreatic lymph nodes located anterior to the aorta between the celiac and SMAs. These lymph nodes can receive drainage either directly from the pancreatic tissue (first order lymph nodes) or from the “ring” (second order). A schematic of this drainage is shown in Fig. 56.2 .

Fig. 56.2, Lymphatic drainage of the pancreas.

Embryology

The exocrine pancreas begins development during the fourth week of gestation. Pluripotent pancreatic epithelial stem cells give rise to exocrine and endocrine cell lines as well as the intricate pancreatic ductal network. Initially, dorsal and ventral buds appear from the primitive duodenal endoderm ( Fig. 56.3A ). The dorsal bud typically appears first and ultimately develops into the superior head, neck, body, and tail of the mature pancreas. The ventral bud develops as part of the hepatic diverticulum and maintains communication with the biliary tree throughout development. The ventral bud will become the inferior part of the head and uncinate process of the gland. Between the fourth and eighth weeks of gestation, the ventral bud rotates posteriorly in a clockwise fashion to fuse with the dorsal bud ( Fig. 56.3B ). At approximately eight weeks of gestation, the dorsal and ventral buds are fused ( Fig. 56.3C ).

Fig. 56.3, Embryologic development of the pancreas.

The initiation of pancreas bud formation and differentiation of the ventral bud from the hepatic-biliary fates is dependent on the expression of pancreatic duodenal homeobox 1 (PDX1) protein and pancreas-specific transcription factor 1 (PTF1). In the absence of PDX1 expression in mice, pancreatic agenesis occurs, indicating its importance in the early phases of organogenesis. PTF1 expression is first detectable shortly after PDX1 in cells of the early endoderm, which will become the dorsal and ventral pancreas. By lineage analysis, 95% of acinar cells express PTF1. In PTF1 null mice, acini do not form. The notch signaling pathway is also critical to duct and acinar differentiation. In the absence of notch signaling, embryonic cells commit to endocrine lineage, suggesting that notch signaling is vital to exocrine differentiation. In addition to PDX1, PTF1, and notch signaling, complex interactions between mesenchymal growth factors such as transforming growth factor-β (TGF-β) and other signaling pathways, including hedgehog and Wnt, seem to play critical roles in pancreas development. The precise interactions that lead to normal organogenesis continue to be defined. Table 56.1 summarizes the factors and pathways that affect pancreas development.

Table 56.1
Molecular factors and pathways associated with pancreatic organogenesis.
Gene Relevance
PDX1 Critical role in exocrine differentiation; knockout mice develop primitive pancreatic buds but agenesis of the organ
PTF1 Coexpression with PDX1 determines progenitor cells to pancreatic fate
Notch signaling pathway Suppresses endocrine differentiation, promoting exocrine development via induction of Hes1 transcription factor. Prolonged notch expression prevents acinar formation via RBP-Jκ binding of Ptf1a
Hedgehog Inhibition of hedgehog in PDX1 -positive cells leads to initiation of endoderm differentiation into pancreas lineage
Wnt Complex Wnt signaling is important in all aspects of pancreas development; lack of Wnt signaling results in varying levels of pancreatic agenesis
Neurogenin 3 Repressed by notch signaling, drives endocrine lineage differentiation.
Arx and Pax-4 Arx expression favors α/PP cell differentiation, while Pax-4 expression favors β vs δ cell differentiation depending on length of exposure.
Arx , Aristaless related homeobox; Pax-4 , paired box gene 4; PDX1 , insulin promoter factor 1; PTF1, pancreas-specific transcription factor 1.

Pancreas Divisum

During normal organogenesis, the primitive ducts of both the dorsal and ventral anlage contribute to the mature ductal system of the pancreas. These ducts fuse together such that the proximal aspect of the dorsal anlage duct forms the duct of Santorini, while the distal aspect combines with the duct of the ventral bud to form the duct of Wirsung. The duct of Wirsung is generally the major exocrine drainage pathway of the pancreas, joins the common bile duct at the ampulla of Vater, and enters the duodenum through the major papilla. The duct of Santorini may drain through a minor papilla that is more proximal in the duodenum. Failure of the dorsal and ventral ducts to fuse during embryogenesis leads to pancreas divisum, a condition identified by a ventral pancreatic duct and common bile duct that enter the duodenum through a major papilla, whereas a dorsal pancreatic duct enters through a minor papilla that is slightly proximal ( Fig. 56.4 ). Because most pancreatic exocrine secretions exit through the dorsal duct, pancreas divisum can lead to a condition of partial obstruction caused by a small minor papilla, leading to chronic backpressure in the duct. This relative outflow obstruction has been implicated in the development of relapsing acute or chronic pancreatitis. Although 10% of the population is affected by pancreas divisum, only rarely do affected individuals develop pancreatitis.

Fig. 56.4, MRCP showing pancreas divisum, with the dorsal pancreatic duct draining through the minor papilla and the ventral pancreatic duct joining the biliary tree draining through the major papilla. MRCP , Magnetic resonance cholangiopancreatography.

Annular Pancreas

Annular pancreas results from aberrant migration of the ventral pancreas bud, which leads to circumferential or near-circumferential pancreas tissue surrounding the second portion of the duodenum. This abnormality may be associated with other congenital defects, including Down syndrome, malrotation, intestinal atresia, and cardiac malformations. If symptoms of obstruction occur, surgical bypass through duodenojejunostomy is performed instead of dividing the pancreatic tissue, as this annular pancreas has a pancreatic duct and its division will likely lead to pancreatic fistula formation.

Ectopic Pancreas

Ectopic pancreas may arise anywhere along the primitive foregut but is most common in the stomach, duodenum, and Meckel’s diverticulum. Clinically, ectopic nodules may result in bowel obstruction caused by intussusception, bleeding, or ulceration. They can sometimes be found incidentally as firm yellow nodules that arise from the submucosa. Although there have been rare case reports of adenocarcinoma arising in ectopic pancreas tissue, resection is not necessary unless symptoms occur.

Physiology

The human pancreas is a complex gland with endocrine and exocrine functions. It is mainly composed of acinar cells (85% of the gland) and islet cells (2%) embedded in a complex extracellular matrix, which composes 10% of the gland. The remaining 3% to 4% of the gland is composed of the epithelial duct system and blood vessels.

Major Components of Pancreatic Juice

The main function of the exocrine pancreas is to provide most of the enzymes needed for alimentary digestion. Acinar cells synthesize many enzymes that digest food proteins, such as trypsin, chymotrypsin, carboxypeptidase, and elastase. Under physiologic conditions, acinar cells synthesize these proteases as inactive proenzymes that are stored as intracellular zymogen granules. With stimulation of the pancreas, these proenzymes are secreted into the pancreatic duct and eventually the duodenal lumen. The duodenal mucosa expresses enterokinase on its brush boarder, which catalyzes the enzymatic activation of trypsin from trypsinogen. Trypsin also plays an important role in protein digestion by propagating pancreatic enzyme activation through autoactivation of trypsinogen and other proenzymes, such as chymotrypsinogen, procarboxypeptidase, and proelastase. Fig. 56.5 summarizes the mechanisms of pancreatic exocrine secretion.

Fig. 56.5, Physiology of the secretion of pancreatic enzymes. The presence of peptides and fatty acids from food triggers the release of cholecystokinin (CCK) . CCK induces the release of pancreatic enzymes into the duodenal lumen. Conversely, S cells located in the duodenum release secretin in response to the acidification of the duodenum. Secretin induces the secretion of HCO 3 − from pancreatic cells into the duodenum.

In addition to protease production, acinar cells also produce pancreatic amylase and lipase, also known as glycerol ester hydrolase, as active enzymes. With the exception of cellulose, pancreatic amylase hydrolyzes major polysaccharides into small oligosaccharides, which can be further digested by the oligosaccharidases present in the duodenal and jejunal epithelium. Pancreatic lipase hydrolyzes ingested fats into free fatty acids and 2-monoglycerides. In addition to pancreatic lipase, acinar cells produce other enzymes that digest fat, but they are secreted as proenzymes, like the proteases previously mentioned. These include colipase, cholesterol ester hydrolase, and phospholipase A2. The main function of colipase is to stabilize the activity of pancreatic lipase in the presence of bile salts. Pancreatic acinar cells also secrete deoxyribonuclease and ribonuclease, enzymes required for the hydrolysis of DNA and RNA, respectively.

Pancreatic enzymes are inactive inside acinar cells because they are synthesized and stored as inactive enzymes. In addition to this autoprotective mechanism, acinar cells synthesize pancreatic secretory trypsin inhibitor, which also protects acinar cells from autodigestion because it counteracts premature activation of trypsinogen inside acinar cells. Pancreatic secretory trypsin inhibitor is encoded by serine protease inhibitor Kazal type 1 (SPINK1) gene. SPINK1 gene mutations are associated with the development of chronic pancreatitis, especially in childhood.

The primary function of pancreatic duct cells is to provide the water and electrolytes required to dilute and to deliver the enzymes synthesized by acinar cells. Although the concentrations of sodium and potassium are similar to their respective concentrations in plasma, the concentrations of bicarbonate and chloride vary significantly according to the secretion phase.

The mechanism responsible for the secretion of bicarbonate was first described in 1988 on the basis of in vitro studies. According to this model, extracellular CO 2 diffuses across the basolateral membrane of ductal cells. Once CO 2 is inside pancreatic duct cells, it is hydrated by intracellular carbonic anhydrase; as a result of this reaction, HCO 3 − and H + are generated. The apical membrane of pancreatic duct cells contains an anion exchanger that secretes intracellular HCO 3 − into the lumen of the cell and favors the exchange of luminal Cl − inside the ductal epithelium. Studies have shown that this exchanger interacts with the cystic fibrosis transmembrane conductance regulator (CFTR); mutations in the CFTR gene have been linked to chronic pancreatitis. This may correlate with the inability of patients with cystic fibrosis to secrete water and bicarbonate. Although the nature of this exchanger has not been completely elucidated, it is possible that this anion exchanger is an SLC26 family member. This family contains different anion exchangers that transport monovalent and divalent anions, such as Cl − and HCO 3 − . Some of these exchangers are known to interact with CFTR. Thus, HCO 3 − level in the pancreatic juice varies inversely to the Cl - level. Secretin hormone is the major stimulator of the HCO 3 − secretion. Cholecystokinin (CCK) weakly stimulates HCO 3 − secretion and also synergizes with the effect of secretin.

In addition to HCO 3 − CO 2 hydration also generates H + ions, which are secreted by Na + and H + exchangers present in the basolateral membrane of ductal cells. These exchangers belong to the SLC9 gene family. The main function of these exchangers is to maintain the intracellular pH within a physiologic range. In addition, the basolateral membrane of duct cells contains multiple Na + ,K + -ATPases that provide the primary force that drives HCO 3 − secretion; the Na + ,K + -ATPase maintains the Na + gradient used to extrude H + as well. Finally, K + channels present in the basolateral membrane of acinar cells maintain the membrane potential to allow recirculation of K + ions brought by the Na + ,K + pump inside the cell. Fig. 56.6 illustrates HCO 3 − secretion inside pancreatic duct cells. The level of Na + and K + in pancreatic juice remains relatively constant without much variation with the secretory rate.

Fig. 56.6, Cellular mechanism proposed for HCO 3 − secretion by pancreatic duct epithelium.

Once the HCO 3 − secreted by pancreatic duct cells reaches the duodenal lumen, it neutralizes the hydrochloric acid secreted by gastric parietal cells. Pancreatic enzymes are inactivated at a low pH; therefore, pancreatic bicarbonate provides an optimal pH for pancreatic enzyme function. The optimal pH for the function of chymotrypsin and trypsin is 8.0 to 9.0; for amylase, the optimal pH is 7.0; and for lipase, it is 7.0 to 9.0.

Phases and Regulation of Pancreatic Secretion

Pancreatic exocrine secretion occurs during the interdigestive state and after the ingestion of food, which is also known as the digestive state. The same phases of secretion that have been identified in the stomach during the digestive state have also been described in pancreatic secretion. The first phase is the cephalic phase, in which the pancreas is stimulated by the vagus nerve in response to the sight, smell, or taste of food. This phase is generally mediated by the release of acetylcholine at the terminal endings of postganglionic fibers. The main effect of acetylcholine is to induce acinar cell secretion of enzymes. This phase accounts for 20% to 25% of the daily secretion of pancreatic juice.

The second phase of pancreatic secretion is known as the gastric phase. It is mediated by vagovagal reflexes triggered by gastric distention after the ingestion of food. These reflexes induce acinar cell secretion. It accounts for 10% of the pancreatic juice produced daily.

The most important phase of pancreatic secretion is the intestinal phase, which accounts for 65% to 70% of the total secretion of pancreatic juice. It is mediated by secretin and CCK. Acidification of the duodenal lumen induces the release of secretin by S cells. Secretin was the first polypeptide hormone identified more than 100 years ago. It is the most important mediator of the secretion of water, bicarbonate, and other electrolytes into the duodenum. Secretin receptors are located in the basolateral membrane of all pancreatic duct cells but cannot be identified in other pancreatic components, such as islet cells, blood vessels, or extracellular matrix. Secretin receptors are members of the G protein–coupled receptor superfamily. The most important effect of secretin stimulation is an increase of intracellular cyclic adenosine monophosphate, which activates the HCO 3 − -Cl − anion exchanger in the apical membrane of pancreatic duct cells. It also increases the activity of the enzyme carbonic anhydrase, the excretion of H + outside the duct cell, and the activity of the CFTR.

The presence of lipid, protein, and carbohydrates inside the duodenum induces the secretion of CCK-releasing factor and monitor peptide. Both peptides induce release of CCK by I cells present in the duodenal mucosa. Whereas secretin is the main mediator of the secretion of water and bicarbonate in the intestinal phase, CCK is the main mediator of the secretion of pancreatic enzymes. CCK exerts a number of effects:

  • 1.

    CCK travels through the bloodstream and induces the release of pancreatic enzymes by acinar cells.

  • 2.

    CCK induces local duodenal vagovagal reflexes that cause the release of acetylcholine, vasoactive intestinal peptide, and gastrin-releasing peptide, which promotes the release of pancreatic enzymes.

  • 3.

    CCK induces the relaxation of the sphincter of Oddi. Also, CCK potentiates the effects of secretin, and vice versa.

Acute Pancreatitis

The incidence of acute pancreatitis (AP) has increased during the past 20 years. AP is responsible for more than 300,000 hospital admissions annually in the United States. Most patients develop a mild and self-limited course; however, 10% to 20% of patients have a rapidly progressive inflammatory response associated with prolonged length of hospital stay and significant morbidity and mortality. Patients with mild pancreatitis have a mortality rate of less than 1%, but in severe pancreatitis, this increases up to 10% to 50%. The highest mortality rates in this group of patients are those who present with multiple organ dysfunction syndrome. Mortality in pancreatitis has a bimodal distribution. In the first two weeks (early phase), it is a result of multiple organ dysfunction caused by the intense inflammatory cascade triggered by pancreatic inflammation. Mortality after two weeks (late phase) is often caused by septic complications.

Pathophysiology

The exact mechanism whereby predisposing factors such as ethanol and gallstones produce pancreatitis is not completely known. Most researchers believe that AP is the final result of abnormal pancreatic enzyme activation inside acinar cells. Immunolocalization studies have shown that after 15 minutes of pancreatic injury, both zymogen granules and lysosomes colocalize inside the acinar cells. The fact that zymogen and lysosome colocalization occurs before amylase level elevation, pancreatic edema, and other markers of pancreatitis are evident suggests that colocalization is an early step in the pathophysiologic process and not a consequence of pancreatitis. Studies also suggest that lysosomal enzyme cathepsin B activates trypsin in these colocalization organelles. In vitro and in vivo studies have elucidated an intricate model of acinar cell death induced by premature activation of trypsin. In this model, once cathepsin B in lysosomes and trypsinogen in zymogen granules are brought in contact by colocalization induced by pancreatitis-inciting stimuli, activated trypsin then induces leak of colocalized organelles, releasing cathepsin B into the cytosol. It is the cytosolic cathepsin B that then induces apoptosis or necrosis, leading to acinar cell death. Thus, acinar cell death and to a degree the inflammatory response seen in AP can be prevented if acinar cells are pretreated with cathepsin B inhibitors. In vivo studies have also shown that cathepsin B knockout mice have a significant decrease in the severity of pancreatitis.

Intraacinar pancreatic enzyme activation induces autodigestion of normal pancreatic parenchyma. In response to this initial insult, acinar cells release proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-1, IL-2, and IL-6, and antiinflammatory mediators, such as IL-10 and IL-1 receptor antagonist. These mediators do not initiate pancreatic injury but propagate the response locally and systemically. As a result, TNF-α, IL-1 and IL-6, neutrophils, and macrophages are recruited into the pancreatic parenchyma and cause the release of more TNF-α, IL-1 and IL-6, reactive oxygen metabolites, prostaglandins, platelet-activating factor, and leukotrienes. The local inflammatory response further aggravates the pancreatitis because it increases the permeability and damages the microcirculation of the pancreas. In severe cases, the inflammatory response causes local hemorrhage and pancreatic necrosis. In addition, some of the inflammatory mediators released by neutrophils aggravate the pancreatic injury because they cause pancreatic enzyme activation.

The inflammatory cascade is self-limited in approximately 80% to 90% of patients. However, in the remaining patients, a vicious circle of recurring pancreatic injury and local and systemic inflammatory reaction persists. In a small number of patients, there is a massive release of inflammatory mediators to the systemic circulation. Active neutrophils mediate acute lung injury and induce the adult respiratory distress syndrome frequently seen in patients with severe pancreatitis. The mortality seen in the early phase of pancreatitis is the result of this persistent inflammatory response. A summary of the inflammatory cascade seen in AP is shown in Fig. 56.7 .

Fig. 56.7, Pathophysiology of severe acute pancreatitis. The local injury induces the release of tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1). Both cytokines produce further pancreatic injury and amplify the inflammatory response by inducing the release of other inflammatory mediators, which cause distant organ injury. This abnormal inflammatory response is responsible for the mortality seen during the early phase of acute pancreatitis. ERCP, Endoscopic retrograde cholangiopancreatography; PAF, XXX.

Risk Factors

Gallstones and ethanol abuse account for 70% to 80% of AP cases. In pediatric patients, abdominal blunt trauma and systemic diseases are the two most common conditions that lead to pancreatitis. Autoimmune and drug-induced pancreatitis should be a differential diagnosis in patients with rheumatologic conditions such as systemic lupus erythematosus and Sjögren syndrome.

Biliary or Gallstone Pancreatitis

Gallstone pancreatitis is the most common cause of AP in the West. It accounts for 40% of U.S. cases. The overall incidence of AP in patients with symptomatic gallstone disease is 3% to 8%. It is seen more frequently in women between 50 and 70 years of age. The exact mechanism that triggers pancreatic injury has not been completely understood, but two theories have been proposed. In the obstructive theory, pancreatic injury is the result of excessive pressure inside the pancreatic duct. This increased intraductal pressure is the result of continuous secretion of pancreatic juice in the presence of pancreatic duct obstruction. Animal studies suggest that high intraductal pressure initiates pancreatitis through a mechanism dependent on calcineurin signaling. The second, or reflux, theory proposes that stones become impacted in the ampulla of Vater and form a common channel that allows bile salt reflux into the pancreas. Animal models have shown that bile salts cause direct acinar cell necrosis because they increase the concentration of calcium in the cytoplasm; however, this has never been proven in humans.

Alcohol-Induced Injury

Excessive ethanol consumption is the second most common cause of AP worldwide. It accounts for 35% of cases and is more prevalent in young men (30–45 years of age) than in women. However, only 5% to 10% of patients who drink alcohol develop AP. Factors that contribute to ethanol-induced pancreatitis include heavy ethanol abuse (>100 g/day for at least 5 years), smoking, and genetic predisposition. Compared with nonsmokers, the relative risk of alcohol-induced pancreatitis in smokers is 4.9.

Alcohol has a number of deleterious effects in the pancreas and its mechanism of injury is likely multifaceted. It has been shown to: 1) trigger proinflammatory pathways via upregulation of nuclear factor κB (NF-κB), TNF-α, and IL-1, 2) cause inappropriate basolateral exocytosis of pancreatic zymogens, 3) increased autophagy possibly due to dysregulation of cathepsin L and B, 4) increased oxidative stress leading to mitochondrial dysfunction, 5) activation of pancreatic stellate cells (PSCs) leading to increased secretion of matrix metalloproteases, 6) impaired pancreatic cell repair due to dysregulation in developmental factors PDX1, PTF1a, and Notch, and 7) a shift in cell death caused by apoptosis to necrosis by decreasing caspase 3/8 activity and loss of adenosine triphosphate (ATP) production via mitochondrial depolarization.

Anatomic Obstruction

Abnormal flow of pancreatic juice into the duodenum can result in pancreatic injury. AP has been described in patients with pancreatic tumors, parasites, and congenital defects.

Pancreas divisum is an anatomic variation present in 10% of the population. Its association with AP is controversial. Patients with this variation have a 5% to 10% lifetime risk for development of AP caused by relative outflow obstruction through the minor papilla. Endoscopic retrograde cholangiopancreatography (ERCP) with minor papillotomy and stenting may be beneficial for such patients.

Infrequent anatomic obstructions that have been associated with AP include Ascaris lumbricoides infection and annular pancreas. Although pancreatic cancer is not uncommon, patients with pancreatic cancer usually do not develop AP.

Endoscopic Retrograde Cholangiopancreatography–Induced Pancreatitis

AP is the most common complication after ERCP, occurring in up to 5% of patients. However, the incidence of this complication after ERCP could be as high as 15% in high-risk patients. PostERCP pancreatitis is more common in female patients, young individuals, and in patients with prior history of ERCP induced pancreatitis. AP occurs more frequently in patients who have undergone therapeutic procedures compared with diagnostic procedures. It is also more common in patients who have had multiple attempts of cannulation, sphincter of Oddi dysfunction, and abnormal visualization of the secondary pancreatic ducts after injection of contrast material. The clinical course is mild in 90% to 95% of patients. ERCP-induced pancreatitis is one of the rare opportunities where primary prevention of development of AP may be possible. First, ERCP should only be performed when absolutely necessary. With improvement in other diagnostic modalities including magnetic resonance cholangiopancreatography (MRCP), the use of diagnostic ERCP with its associated complications including ERCP-induced pancreatitis has decreased. Among pharmacologic agents to prevent ERCP-induced pancreatitis, use of indomethacin has gained the most traction. Technique related and interventional strategies, which have been shown to reduce the risk of postERCP pancreatitis, include use of pancreatic stents and using minimal pressure while performing ERCP.

Drug-Induced Pancreatitis

Up to 2% of AP cases are caused by medications. The most common agents include sulfonamides, metronidazole, erythromycin, tetracyclines, didanosine, thiazides, furosemide, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), azathioprine, 6-mercaptopurine, 5-aminosalicylic acid, sulfasalazine, valproic acid, and human immunodeficiency virus antiretroviral agents.

Metabolic Factors

Hypertriglyceridemia and hypercalcemia can also lead to pancreatic damage. Direct pancreatic injury can be induced by triglyceride metabolites. It is more common in patients with type I, II, or V hyperlipidemia. It should be suspected in patients with a triglyceride level higher than 1000 mg/dL. A triglyceride level higher than 2000 mg/dL confirms the diagnosis. Hypertriglyceridemia secondary to hypothyroidism, diabetes mellitus, and alcohol does not typically induce AP.

Hypercalcemia is postulated to induce pancreatic injury through the activation of trypsinogen to trypsin and intraductal precipitation of calcium, leading to ductal obstruction and subsequent attacks of pancreatitis. Approximately 1.5% to 13% of patients with primary hyperparathyroidism develop AP.

Miscellaneous Conditions

Blunt and penetrating abdominal trauma can be associated with AP in 0.2% and 1% of cases, respectively. Prolonged intraoperative hypotension and excessive pancreatic manipulation during abdominal surgery can also result in AP. Pancreatic ischemia in association with acute pancreatic inflammation can develop after splenic artery embolization. Other rare causes include scorpion venom stings and perforated duodenal ulcers.

Clinical Manifestations

The cardinal symptom of AP is epigastric or periumbilical pain that radiates to the back. Up to 90% of patients have nausea or vomiting that typically does not relieve the pain. The nature of the pain is constant; therefore, if the pain disappears or decreases, another diagnosis should be considered.

Dehydration, poor skin turgor, tachycardia, hypotension, and dry mucous membranes are commonly seen in patients with AP. Severely dehydrated and older patients may also develop mental status changes.

The physical examination findings of the abdomen vary according to the severity of the disease. With mild pancreatitis, the physical examination findings of the abdomen may be normal or reveal only mild epigastric tenderness. Significant abdominal distention associated with generalized rebound and abdominal rigidity is present in severe pancreatitis. The nature of the pain described by the patient may not correlate with the physical examination findings or the degree of pancreatic inflammation.

Rare findings include flank and periumbilical ecchymosis (Grey Turner and Cullen signs, respectively). Both are indicative of retroperitoneal bleeding associated with severe pancreatitis. Patients with concomitant choledocholithiasis or significant edema in the head of the pancreas that compresses the intrapancreatic portion of the common bile duct can present with jaundice. Dullness to percussion and decreased breathing sounds in the left or, less commonly, in the right hemithorax suggest pleural effusion secondary to AP.

Diagnosis

The diagnosis of AP requires two of the following three features to be present according to international consensus: 1) abdominal pain consistent with AP (acute onset of a persistent, severe, epigastric pain often radiating to the back), 2) a threefold or higher elevation of serum amylase or lipase levels above the upper laboratory limit of normal, or 3) characteristics findings of pancreatitis by imaging. The serum half-life of amylase (10 hours) is shorter than that of lipase (6.9–13.7 hours) and therefore normalizes faster (3–5 vs. 8–14 days, respectively). In patients who do not present to the emergency department within the first 24 to 48 hours after the onset of symptoms, determination of lipase levels is a more sensitive indicator to establish the diagnosis. Lipase is also a more specific marker of AP because serum amylase levels can be elevated in a number of conditions, such as peptic ulcer disease, mesenteric ischemia, salpingitis, and macroamylasemia.

Patients with AP are typically hyperglycemic; they can also have leukocytosis and abnormal elevation of liver enzyme levels. The elevation of alanine aminotransferase levels in the serum in the context of AP confirmed by high pancreatic enzyme levels has a positive predictive value of 95% in the diagnosis of acute biliary pancreatitis.

Imaging Studies

Imaging studies are not required for diagnosis, but may be helpful in determining need for intervention in severe AP or elucidating an elusive etiology. Although simple abdominal radiographs are not useful for diagnosis of pancreatitis, they can help rule out other conditions, such as perforated ulcer disease. Nonspecific findings in patients with AP include air-fluid levels suggestive of ileus, cutoff colon sign as a result of colonic spasm at the splenic flexure and widening of the duodenal C loop caused by severe pancreatic head edema.

The usefulness of ultrasound for diagnosis of pancreatitis is limited by intraabdominal fat and increased intestinal gas as a result of the ileus. Nevertheless, this test should always be ordered in patients with AP because of its high sensitivity (95%) in diagnosing gallstones. Combined elevations of liver transaminase and pancreatic enzyme levels and the presence of gallstones on ultrasound have an even higher sensitivity (97%) and specificity (100%) for diagnosing acute biliary pancreatitis.

Contrast-enhanced computed tomography (CT) is currently the best modality for evaluation of the pancreas, especially if the study is performed with a multidetector CT scanner. Indications for CT include diagnostic uncertainty, confirmation of severity based on clinical predictors, failure to respond to conservative treatment, or clinical deterioration. The most valuable contrast phase in which to evaluate the pancreatic parenchyma is the portal venous phase (65–70 seconds after injection of contrast material), which allows evaluation of the viability of the pancreatic parenchyma, amount of peripancreatic inflammation, and presence of intraabdominal free air or fluid collections. Noncontrast CT scanning may also be of value in the setting of renal failure by identifying fluid collections or extraluminal air.

Abdominal magnetic resonance imaging (MRI) is also useful to evaluate the extent of necrosis, inflammation, and presence of free fluid. However, its cost and availability and the fact that patients requiring imaging are critically ill and need to be in intensive care units limit its applicability in the acute phase. Although MRCP is not indicated in the acute setting of AP, it has an important role in the evaluation of patients with unexplained or recurrent pancreatitis because it allows noninvasive complete visualization of the biliary and pancreatic duct anatomy. For difficult to view pancreatic ducts, intravenous (IV) administration of secretin can be injected prior to imaging to stimulate pancreatic juice secretion, thereby causing a transient distention of the pancreatic duct. Any pain associated with the timing of secretin stimulation should be noted as it may help in confirming an uncertain etiology of epigastric pain. For example, secretin stimulated MRCP is useful in patients with AP and no evidence of a predisposing condition to rule out pancreas divisum, intraductal papillary mucinous neoplasm (IPMN), or a small tumor in the pancreatic duct.

In the setting of gallstone pancreatitis, endoscopic ultrasound (EUS) may play an important role in the evaluation of persistent choledocholithiasis. Several studies have shown that routine ERCP for suspected gallstone pancreatitis reveals no evidence of persistent obstruction in most cases and may actually worsen symptoms because of manipulation of the gland. EUS has been proven to be sensitive for identifying choledocholithiasis; it allows examination of the biliary tree and pancreas with no risk of worsening of the pancreatitis. In patients in whom persistent choledocholithiasis is confirmed by EUS, ERCP can be used selectively as a therapeutic measure.

Assessment of Severity of Disease

The earliest scoring system designed to evaluate the severity of AP was introduced by Ranson and colleagues in 1974. It predicts the severity of the disease on the basis of 11 parameters obtained at the time of admission or 48 hours later. The mortality rate of AP directly correlates with the number of parameters that are positive. Severe pancreatitis is diagnosed if three or more of the Ranson criteria are fulfilled. The main disadvantage is that it does not predict the severity of disease at the time of the admission because six parameters are assessed only after 48 hours of admission. The Ranson score has a low positive predictive value (50%) and high negative predictive value (90%). Therefore, it is mainly used to rule out severe pancreatitis or to predict the risk of mortality. The original scoring symptom designed to predict the severity of the disease and its modification for acute biliary pancreatitis are shown in Boxes 56.1 and 56.2 .

Box 56.1
Ranson Prognostic Criteria for Nongallstone Pancreatitis

  • At presentation

    • Age >55 years

    • Blood glucose level >200 mg/dL

    • White blood cell count >16,000 cells/mm 3

    • Lactate dehydrogenase level >350 IU/L

    • Aspartate aminotransferase level >250 IU/L

  • After 48 hours of admission

    • Hematocrit ∗

      ∗ Compared with admission value.

      : decrease >10%

    • Serum calcium level <8 mg/dL

    • Base deficit >4 mEq/L

    • Blood urea nitrogen level: increase >5 mg/dL

    • Fluid requirement >6 L

    • Pa o 2 <60 mm Hg

  • Ranson score ≥3 defines severe pancreatitis.

Box 56.2
Ranson prognostic criteria for gallstone pancreatitis.

  • At presentation

    • Age >70 years

    • Blood glucose level >220 mg/dL

    • White blood cell count >18,000 cells/mm 3

    • Lactate dehydrogenase level >400 IU/L

    • Aspartate aminotransferase level >250 IU/L

  • After 48 hours of admission

    • Hematocrit ∗

      ∗ Compared with admission value.

      : decrease >10%

    • Serum calcium level <8 mg/dL

    • Base deficit >5 mEq/L

    • Blood urea nitrogen level: increase >2 mg/dL

    • Fluid requirement >4 L

    • Pa o 2 : Not available

  • Ranson score ≥3 defines severe pancreatitis.

AP severity can also be addressed by the Acute Physiology and Chronic Health Evaluation (APACHE II) score. Based on the patient’s age, previous health status, and 12 routine physiologic measurements, APACHE II provides a general measure of the severity of disease. An APACHE II score of eight or higher defines severe pancreatitis. The main advantage is that it can be used on admission and repeated at any time. However, it is complex, not specific for AP, and based on the patient’s age, which easily upgrades the AP severity score. APACHE II has a positive predictive value of 43% and a negative predictive value of 89%.

Using imaging characteristics, Balthazar and associates have established the CT severity index. This index correlates CT findings with the patient’s outcome. The CT severity index is shown in Table 56.2 .

Table 56.2
Computed Tomography Severity Index (CTSI) for acute pancreatitis.
Feature Points
Pancreatic Inflammation

  • Normal pancreas

0

  • Focal or diffuse pancreatic enlargement

1

  • Intrinsic pancreatic alterations with peripancreatic fat inflammatory changes

2

  • Single fluid collection or phlegmon

3

  • Two or more fluid collections or gas, in or adjacent to the pancreas

4
Pancreatic Necrosis

  • None

0

  • ≤30%

2

  • 30%–50%

4

  • >50%

6
CTSI 0–3, mortality 3%, morbidity 8%; CTSI 4–6, mortality 6%, morbidity 35%; CTSI 7–10, mortality 17%, morbidity 92%.

While many prognostic indices have been developed to predict severity of disease, most are hindered by complexity, need for imaging, or inability to be calculated at admission. This has led to multiple professional societies recommending the use of the systemic inflammatory response syndrome (SIRS) scoring system ( Box 56.3 ) as a fast, inexpensive, and reliable replacement. , Having a persistent SIRS throughout hospital admission, having a transient SIRS, or never meeting SIRS criteria has been associated with mortality rates of 25%, 8%, and 0%, respectively.

Box 56.3
Definition of systemic inflammatory response syndrome (SIRS).
From Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63–78.

Two or more of the following conditions must be met:

  • Temperature >38.3°C or <36.0°C

  • Heart rate of >90 beats/minute

  • Respiratory rate of >20 breaths/minute or PaCO 2 of <32 mm Hg

  • WBC count of >12,000 cells/mL, <4000 cells/mL, or >10% immature (band) forms

In 1992, the International Symposium on Acute Pancreatitis defined severe pancreatitis as the presence of local pancreatic complications (necrosis, abscess, or pseudocyst) or any evidence of organ failure. Severe pancreatitis is diagnosed if there is any evidence of organ failure or a local pancreatic complication ( Box 56.4 ). In 2012, the International Symposium on Acute Pancreatitis updated their three-tiered grading schema of pancreatitis severity. Mild pancreatitis has no organ dysfunction or local/systemic complications, moderate pancreatitis can have organ failure lasting less than 48 hours and/or local/systemic complications, while severe pancreatitis is characterized by organ failure lasting beyond 48 hours. With increasing severity comes increased rates of morbidity and mortality.

Box 56.4
Atlanta criteria for acute pancreatitis.

Organ Failure, as Defined by

  • Shock (systolic blood pressure <90 mm Hg)

  • Pulmonary insufficiency (Pa o 2 <60 mm Hg)

  • Renal failure (creatinine level >2 mg/dL after fluid resuscitation)

  • Gastrointestinal bleeding (>500 mL/24 hour)

Systemic Complications

  • Disseminated intravascular coagulation (platelet count ≤100,000)

  • Fibrinogen <1 g/L

  • Fibrin split products >80 μg/dL

  • Metabolic disturbance (calcium level ≤7.5 mg/dL)

Local Complications

  • Necrosis

  • Abscess

  • Pseudocyst

  • Severe pancreatitis is defined by the presence of any evidence of organ failure or a local complication.

C-reactive protein (CRP) is an inflammatory marker that peaks 48 to 72 hours after the onset of pancreatitis and correlates with the severity of the disease. A CRP level of 150 mg/mL or higher defines severe pancreatitis. The major limitation is that it cannot be used on admission; the sensitivity of the assay decreases if CRP levels are measured within 48 hours after the onset of symptoms. In addition to CRP, a number of studies have shown other biochemical markers (e.g., serum levels of procalcitonin, IL-6, IL-1, elastase) that correlate with the severity of the disease. However, their main limitation is their cost, and they are not widely available.

Treatment

Regardless of the cause or the severity of the disease, the cornerstones of treating AP are aggressive fluid resuscitation with isotonic crystalloid solution, pain control, and early nutrition. The rate of fluid administration should be individualized and adjusted on the basis of age, comorbidities, vital signs, mental status, skin turgor, and urine output. Patients who do not respond to initial fluid resuscitation or have significant renal, cardiac, or respiratory comorbidities often require invasive monitoring with central venous access and a Foley catheter. While the nature of fluid which should be used for initial resuscitation is still being debated, some evidence suggest that Ringer’s lactate may be the best fluid for initial resuscitation.

In addition to fluid resuscitation, patients with AP require continuous pulse oximetry because one of the most common systemic complications of AP is hypoxemia caused by the acute lung injury associated with this disease. Patients should receive supplementary oxygen to maintain arterial saturation above 95%.

It is also essential to provide effective analgesia. Narcotics are usually preferred, especially morphine. One of the physiologic effects described after systemic administration of morphine is an increase in tone in the sphincter of Oddi; however, there is no evidence that narcotics exert a negative impact on the outcome of patients with AP.

Nutritional support is vital in the treatment of AP. Oral feeding may be impossible because of persistent ileus, pain, or intubation. In addition, 20% of patients with severe AP develop recurrent pain shortly after the oral route has been restarted. The main options to provide this nutritional support are enteral feeding and total parenteral nutrition (TPN). Although there is no difference in the mortality rate between both types of nutrition, enteral nutrition is associated with fewer infectious complications and reduces the need for pancreatic surgery. Although TPN provides most nutritional requirements, it is associated with mucosal atrophy, decreased intestinal blood flow, increased risk of bacterial overgrowth in the small bowel, antegrade colonization with colonic bacteria, and increased bacterial translocation. In addition, patients with TPN have more central line infections and metabolic complications (e.g., hyperglycemia, electrolyte imbalance). Whenever possible, enteral nutrition should be used rather than TPN and TPN should be used only if there is intolerance to enteral feeding. Nasojejunal feeding tube placement is currently favored, but there is some low-level evidence suggesting that nasogastric feeding can safely be considered as an alternative if significant gastric outlet obstruction is not present.

Given the significant increase in mortality associated with septic complications in severe pancreatitis, a number of physicians advocated the use of prophylactic antibiotics in the 1970s. Recent meta-analyses and systematic reviews that have evaluated multiple randomized controlled trials have proved that prophylactic antibiotics do not decrease the frequency of surgical intervention, infected necrosis, or mortality in patients with severe pancreatitis. In addition, they are associated with gram-positive cocci infection, such as by Staphylococcus aureus , and Candida infection, which is seen in 5% to 15% of patients. Current recommendations are to only administer antibiotics if a preexisting infection is present on presentation or radiographic imaging suggests infected peripancreatic fluid collections (e.g., air within collection or rim enhancement).

Special Considerations

Endoscopic retrograde cholangiopancreatography

Early ERCP, with or without sphincterotomy, was initially advocated to reduce the severity of pancreatitis because the obstructive theory of AP states that pancreatic injury is the result of pancreatic duct obstruction. However, multiple randomized trials have evaluated the use and efficacy of early ERCP in the management of acute biliary pancreatitis. The results of these trials do not support the use of ERCP in the management of acute biliary pancreatitis regardless of the severity. Routine use of ERCP is not indicated for patients with mild pancreatitis because the bile duct obstruction is usually transient and resolves within 48 hours after the onset of symptoms. Based on a meta-analysis of these clinical trials as well as two major society guidelines based on these clinical trials, ERCP is only indicated for patients who develop cholangitis and those with persistent bile duct obstruction demonstrated by other imaging modalities, such as EUS. Finally, in older patients with poor performance status or severe comorbidities that preclude surgery, ERCP with sphincterotomy is a safe alternative to prevent recurrent biliary pancreatitis.

Laparoscopic cholecystectomy

In the absence of definitive treatment, 30% of patients with acute biliary pancreatitis will have recurrent disease. With the exception of older patients and those with poor performance status, laparoscopic cholecystectomy is indicated for all patients with mild acute biliary pancreatitis. Studies have shown that early laparoscopic cholecystectomy, defined as laparoscopic cholecystectomy during the initial admission to the hospital, is a safe procedure that decreases recurrence of the disease. Choledocholithiasis can be excluded by intraoperative cholangiography, EUS, or MRCP. For patients with severe pancreatitis, early surgery may increase the morbidity and length of stay. Current recommendations suggest conservative treatment for at least 6 weeks before laparoscopic cholecystectomy is attempted in this setting. This approach has significantly decreased morbidity.

Complications

Sterile and Infected Peripancreatic Fluid Collections

Discussion regarding appropriate management of pancreatic and peripancreatic fluid collections requires an understanding of the current classification of these entities as defined in Table 56.3 . Fluid collections are divided into acute (present for less than four weeks) and chronic (lasting past four weeks) and either being simple or complex in nature. Acute peripancreatic fluids collections are simple in nature and after four weeks are referred to as a pseudocyst. Fluid collections associated with necrotizing pancreatitis are referred to as an acute necrotic collection (ANC) before four weeks and as walled off necrosis after that period. The presence of acute peripancreatic fluids collection during an episode of AP has been described in 30% to 57% of patients. In contrast to pseudocysts and cystic neoplasias of the pancreas, fluid collections are not surrounded or encased by epithelium or fibrotic capsule. Treatment is supportive because most fluid collections will be spontaneously reabsorbed by the peritoneum. All of these fluid collections may become infected. The usual signs and symptoms of infection (e.g., fever, elevated white blood cell count, and abdominal pain) may also be present without an infection in AP due to a robust SIRS response in many of these patients, making diagnosis of infection difficult. Evidence of gas within a fluid collection on imaging is highly suggestive. Acute decompensation or failure to improve after 10 to 14 days may suggest infection and consideration should be given to CT-guided fluid sampling. Drainage (percutaneous or endoscopic) and IV administration of antibiotics should be instituted if infection is present. Antibiotics known to penetrate pancreatic necrosis include carbapenems, quinolones, metronidazole, and high-dose cephalosporins.

Table 56.3
Revised definitions of morphological features of acute pancreatitis.
Adapted from: Banks,P, Bollen, T, Dervenis C. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by internationa1. Banks PA, Bollen TL, Dervenis C, et al: Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut . 2013;62:102–111.
Time from Onset Subtype of Pancreatitis Fluid Collection Nomenclature Computed Tomography Findings
4 Weeks
Interstitial edematous ∗ Acute peripancreatic fluid collection

  • Homogeneous collection with fluid density

  • Confined by normal peripancreatic fascial planes

  • No definable wall encapsulating the collection

  • Adjacent to pancreas (no intrapancreatic extension)

Necrotizing † Acute necrotic collection

  • Heterogeneous and nonliquid density of varying degrees in different locations (some appear homogeneous early in their course)

  • No definable wall encapsulating the collection

  • Location—intrapancreatic and/or extrapancreatic

>4 Weeks
Interstitial edematous ∗ Pseudocyst

  • Well circumscribed, usually round or oval

  • Homogeneous fluid density

  • No nonliquid component

  • Well-defined wall; that is, completely encapsulated

Necrotizing † Walled-off necrosis

  • Heterogeneous with liquid and nonliquid density with varying degrees of loculations (some may appear homogeneous)

  • Well-defined wall; that is, completely encapsulated

  • Location—intrapancreatic and/or extrapancreatic

∗ Acute inflammation of the pancreatic parenchyma and peripancreatic tissues but without recognizable tissue necrosis.

† Inflammation associated with pancreatic parenchymal necrosis and/or peripancreatic necrosis.

Pancreatic Necrosis and Infected Necrosis

Necrosis is the presence of nonviable pancreatic parenchyma or peripancreatic fat and can manifest as a focal area or diffuse involvement of the gland. Contrast-enhanced CT is the most reliable technique to diagnose ANC and are typically seen as areas of low attenuation (<40–50 HU) after the IV injection of contrast material. Normal parenchyma usually has a density of 100 to 150 HU. Up to 20% of patients with AP develop ANCs. It is important to identify and to provide proper treatment of these complications because most patients who develop multiorgan failure have necrotizing pancreatitis; pancreatic necrosis has been documented in up to 80% of the autopsies of patients who died after an episode of AP.

The main complication of ANC is infection. The risk is directly related to the amount of necrosis; in patients with pancreatic necrosis involving less than 30% of the gland, the risk of infection is 22%. The risk is 37% for patients with pancreatic necrosis that involves 30% to 50% of the gland and up to 46% if more than 70% of the gland is affected. This complication is associated with bacterial translocation usually involving enteric flora, such as gram-negative rods (e.g., Escherichia coli, Klebsiella, and Pseudomonas spp.) and Enterococcus spp.

Infected necrotic collection should be suspected in patients with prolonged fever, elevated white blood cell count, or progressive clinical deterioration. It should also be suspected if the patient develops sepsis, SIRS, and/or organ failure later in the course of the disease (>7 days after the onset of the AP). Evidence of air within the pancreatic necrosis seen on a CT scan confirms the diagnosis but is a rare finding. If infected necrosis is suspected, fine-needle aspiration (FNA) may be performed if the diagnosis is equivocal; from the aspirate, a positive Gram stain or culture establishes the diagnosis. Although positive cultures are confirmatory, a review has demonstrated that despite negative preoperative cultures, 42% of patients with so-called persistent unwellness will have infected necrosis. Fig. 56.8 illustrates the pathophysiologic process of pancreatic necrosis infection.

Fig. 56.8, Pathophysiology of pancreatic necrosis infection. The acute inflammatory injury that occurs during the first 48 to 72 hours causes mucosal ischemia and reperfusion injury. Both effects favor bacterial overgrowth because they alter local immunity. Mucosal ischemia also produces an increase in the permeability of intestinal cells, which is initiated 72 hours after the acute episode but typically peaks one week later. These transient episodes of bacteremia are associated with pancreatic necrosis infection. Less frequently, distant sources of infection, such as pneumonia and vascular or urinary tract infection associated with central lines and catheters, are associated with bacteremia and pancreatic necrosis. Finally, local contamination after surgery or interventional procedures such as endoscopic retrograde cholangiopancreatography is responsible for necrosis infection.

With decades of experience with treatment of pancreatic necrosis, few general concepts have emerged. First, all sterile necrotic collections do not need to be intervened upon. Indications for intervening in sterile necrotizing pancreatitis include: persistent pain, failure to improve clinically with conservative management, and/or symptomatic biliary or enteric obstruction. Intervention for these indications should be delayed as much as possible to allow development of walled off necrosis. Second, clinical suspicion of or documented infected necrotic collection with clinical deterioration is a clear indication for intervention. Even in this situation, the intervention should be delayed as much as possible to allow the collection to become walled off.

Once infection has been demonstrated, IV antibiotics should be given. Because of their penetration into the pancreas and spectrum coverage, carbapenems are the first option of treatment. Alternative therapy includes quinolones, metronidazole, third-generation cephalosporins, and piperacillin. Historically, the definitive treatment of infected pancreatic necrosis is surgical debridement with necrosectomy, closed continuous irrigation, or open packaging ( Fig. 56.9 ). The overall mortality rate after open necrosectomy has been as high as 25% to 30% because of the severe nature of the disease as well as the high complication rate of an open debridement. Outcomes are time dependent; patients who undergo surgery in the first 14 days have a mortality rate of 75%, and those who undergo surgery between 15 and 29 days and after 30 days have mortality rates of 45% and 8%, respectively. As a result of the elevated morbidity and mortality rates with open debridement, percutaneous, endoscopic, and laparoscopic techniques have been employed as alternatives.

Fig. 56.9, Infected pancreatic necrosis. This 45-year-old man had severe ethanol-induced pancreatitis. Four weeks after the initial episode, the patient developed fever (39.5°C [103°F]), hypotension, and leukocytosis (19,000 cells/mm 3 ). The computed tomography (CT) scan documented pancreatic necrosis involving 35% of the gland. After fine-needle aspiration (FNA), Gram staining documented the presence of gram-negative rods. The exploratory laparotomy indicated pancreatic necrosis involving mainly the body of the gland (arrow). The patient was treated with necrosectomy, closed drainage, and intravenous meropenem. Final culture documented the presence of Escherichia coli . The patient was discharged home 56 days after the initial episode.

In 2010, the Dutch Pancreatitis Study Group performed a randomized trial evaluating open necrosectomy versus a “step-up approach” consisting of percutaneous drainage followed by minimally invasive video-assisted retroperitoneal debridement for necrotizing and infected necrotizing pancreatitis. The results showed that long-term end-point complications (e.g., exocrine and endocrine insufficiency) and mortality rates were better in the “step-up approach” group compared with the open necrosectomy group. A companion study to this was published in 2018 wherein endoscopic management was compared to the “step-up approach”. While the endoscopic approach was nonsuperior to the minimally invasive surgical approach regarding mortality and most secondary endpoints, it was associated with fewer pancreatic fistulae, reduced cumulative hospital length of stay, and lower cost.

Currently, an endoscopic drainage with a large-bore stent and possible endoscopic debridement with or without percutaneous drainage can avoid an operation in most patients. If the endoscopic and/or percutaneous management fails, a minimally invasive operation will usually be more straightforward and the results improved. Regardless of which route is taken, physiologic and nutritional support of the patient will have a large impact on outcome.

Pancreatic Pseudocysts

Pancreatic pseudocysts occur in 5% to 15% of patients who have peripancreatic fluid collections after AP. By definition, the capsule of a pseudocyst is composed of collagen and granulation tissue, and it is not lined by epithelium. The fibrotic reaction typically requires at least four to eight weeks to develop. Fig. 56.10 shows CT scans of a large pseudocyst arising in the tail of the pancreas.

Fig. 56.10, Computed tomography (CT) scans showing a large pseudocyst arising in the tail of the pancreas.

Up to 50% of patients with pancreatic pseudocysts will develop symptoms. Persistent pain, early satiety, nausea, weight loss, and elevated pancreatic enzyme levels in plasma suggest this diagnosis. The diagnosis is corroborated by CT or MRI. EUS with FNA is indicated for patients in whom the diagnosis of pancreatic pseudocyst is not clear. Characteristic features of pancreatic pseudocysts include high amylase levels associated with the absence of mucin and low carcinoembryonic antigen (CEA) levels.

Observation is indicated for asymptomatic patients because spontaneous regression has been documented in up to 70% of cases; this is particularly true for patients with pseudocysts smaller than 4 cm in diameter, located in the tail, and no evidence of pancreatic duct obstruction or communication with the main pancreatic duct. Invasive therapies are indicated for symptomatic patients or when the differentiation between a cystic neoplasm and pseudocyst is not possible. Because most patients are treated with decompressive procedures and not with resection, it is imperative to have a pathologic diagnosis. Surgical drainage had been the traditional approach for pancreatic pseudocysts. However, modern evidence suggests that transgastric and transduodenal endoscopic drainage are safe and effective approaches for patients with pancreatic pseudocysts in close contact (defined as <1 cm) with the stomach and duodenum, respectively. In addition, transpapillary drainage can be attempted in pancreatic pseudocysts communicating with the main pancreatic duct. For patients in whom a pancreatic duct stricture is associated with a pancreatic pseudocyst, endoscopic dilation and stent placement are indicated.

Surgical drainage is generally reserved for patients with pancreatic pseudocysts that cannot be treated with endoscopic techniques for anatomic reasons and for patients who fail to respond to endoscopic treatment. Definitive treatment depends on the location of the cyst. Pancreatic pseudocysts closely attached to the stomach should be treated with a cystogastrostomy. In this procedure, an anterior gastrostomy is performed (see ). Once the pseudocyst is located, it is drained through the posterior wall of the stomach using a linear stapler. The defect in the anterior wall of the stomach is closed in two layers. Pancreatic pseudocysts located in the head of the pancreas that are in close contact with the duodenum are treated with a cystoduodenostomy. Finally, some pseudocysts are not in contact with the stomach or duodenum. The surgical treatment for these patients is a Roux-en-Y cystojejunostomy. Surgical cyst enterostomy is successful in achieving immediate cyst drainage in more than 90% of cases. After initial resolution, pseudocyst formation may recur in up to 12% of cases during long-term follow-up, depending on the location of the cyst and underlying cause of the disease.

Laparoscopic cyst gastrostomy

Complications of pancreatic pseudocysts include bleeding and pancreaticopleural fistula secondary to vascular and pleural erosion, respectively; bile duct and duodenal obstruction; rupture into the abdominal cavity; and infection. Percutaneous drainage is indicated only for septic patients secondary to pseudocyst infection because it has a high incidence of external fistula.

Pancreatic Ascites and Pancreaticopleural Fistulas

Although very rare, complete disruption of the pancreatic duct can lead to significant accumulation of fluid. This condition should be suspected in patients who have an episode of AP, develop significant abdominal distention, and have free intraabdominal fluid. Diagnostic paracentesis typically demonstrates elevated amylase and lipase levels. Treatment consists of abdominal drainage combined with endoscopic placement of a pancreatic stent across the disruption. Failure of this therapy requires surgical treatment; it consists of distal resection and closure of the proximal stump.

Posterior pancreatic duct disruption into the pleural space has been described rarely. Symptoms that suggest this condition include dyspnea, abdominal pain, cough, and chest pain. The diagnosis is confirmed with chest radiography, thoracentesis, and CT scan. Fig. 56.11 demonstrates a large, left-sided pleural effusion caused by a pancreatic-pleural fistula. Amylase levels above 50,000 IU in the pleural fluid confirm the diagnosis. It is more common after alcoholic pancreatitis and in 70% of patients is associated with pancreatic pseudocysts. Iatrogenic pancreaticopleural fistulas may also be seen after placement of percutaneous drainage catheters that traverse the diaphragm. Initial treatment requires chest drainage, parenteral nutritional support, and administration of octreotide. Up to 60% of patients respond to this therapy. Persistent drainage should also be treated with endoscopic sphincterotomy and stent placement. Patients who do not respond to these measures require surgical treatment, similar to that described for pancreatic ascites.

Fig. 56.11, Massive left-sided pleural effusion secondary to a pancreaticopleural fistula.

Vascular Complications

AP is rarely associated with arterial vascular complications. The most common vessel affected is the splenic artery, but the SMA, cystic artery, and gastroduodenal artery (GDA) have also been found to be affected. It has been proposed that pancreatic elastase damages the vessels, leading to pseudoaneurysm formation. Spontaneous rupture results in massive bleeding. Clinical manifestations include sudden onset of abdominal pain, tachycardia, and hypotension. If possible, arterial embolization should be attempted to control the bleeding. Refractory cases require ligation of the vessel affected. The mortality ranges from 28% to 56%.

Pancreatic inflammation can also produce vascular thrombosis; the vessel usually affected is the splenic vein, but in severe cases, it can extend into the portal venous system. Imaging demonstrates splenomegaly, gastric varices, and splenic vein occlusion. Thrombolytics have been described in the acute early phase; however, most patients can be managed with conservative treatment. Anticoagulation for splanchnic vein thrombosis related to pancreatitis has not been shown to improve recanalization rates compared to expectant management. Recurrent episodes of upper gastrointestinal bleeding caused by venous hypertension should be treated with splenectomy.

Pancreatocutaneous Fistula

The frequency of pancreatic fistulas is low. Only 0.4% of patients have this complication after an acute episode. However, the incidence of this complication increases in patients with other complications after AP: 4.5% in patients with pancreatic pseudocysts (4.5%) and 40% in patients with infected necrosis after surgical debridement. Treatment is conservative for most patients.

Chronic Pancreatitis

In contrast to AP, the histologic hallmark of chronic pancreatitis is the persistent inflammation and irreversible fibrosis associated with atrophy of the pancreatic parenchyma. These histologic features are associated with chronic pain and endocrine and exocrine insufficiency that significantly decrease the quality of life of these patients. Chronic pancreatitis affects between 3 and 10/100,000 persons.

Risk Factors

The specific cause and frequency of each condition vary among countries, hospital populations, and referral practices. In general, heavy alcohol consumption is the most common cause of chronic pancreatitis (70%–80% of cases), especially in urban hospitals. Conditions such as chronic duct obstruction, trauma, pancreas divisum, cystic dystrophy of the duodenal wall, hyperparathyroidism, hypertriglyceridemia, autoimmune pancreatitis, tropical pancreatitis, and hereditary pancreatitis are rare and account for less than 10% of all cases. However, hereditary, chronic, and autoimmune pancreatitis are more common in referral centers. In up to 20% of patients, a clear cause cannot be documented and cases are considered to be idiopathic.

Alcohol Abuse

Prolonged alcohol abuse is the most important risk factor associated with chronic pancreatitis. The fact that only 3% to 7% of heavy drinkers develop chronic pancreatitis suggests that alcohol is only a cofactor and that other factors are required for development of this complication. Alcohol exerts multiple noxious effects in the pancreas: it increases the total protein concentration in the pancreatic juice, it promotes the synthesis and secretion of lithostathine by acinar cells, and it increases glycoprotein 2 secretion in pancreatic juice. These factors lead to protein precipitation and subsequent formation of protein plugs and eventually stones inside the pancreatic duct. As a result of the obstruction, acinar cells are no longer able to secrete pancreatic enzymes and are predisposed to autodigestion. In addition, several products of alcohol metabolism, such as fatty acid ethyl esters and reactive oxygen species, cause fragility of intraacinar organelles, such as zymogen granules and lysosomes, which leads to abnormal pancreatic enzyme activation inside acinar cells. Acetaldehyde, another alcohol metabolite, causes direct acinar injury. Chronic alcohol consumption is associated with enhanced NF-κB activity, decreased perfusion in the microcirculation of the pancreas, and increased intracellular calcium levels.

The identification of PSCs in the late 1990s is one of the most important discoveries in the pathophysiology of chronic pancreatitis. PSCs are specialized quiescent fibroblasts found at the base of acinar cells. Once stimulated, PSCs differentiate into activated myofibroblasts, which synthesize proteins that form the extracellular matrix. Examples of these proteins include collagen I and III, fibronectin, laminin, and matrix metalloproteinases. PSCs have responses similar to hepatic stellate cells; chronic necrosis and inflammation (necroinflammation) induce the release of inflammatory mediators, such as platelet-derived growth factor, TGF-β, TNF-α, IL-1, and IL-6, which are known to activate PSCs. Consequently, the synthesis of collagen and other components of pancreatic fibrosis is increased. It has been postulated that the chronic necroinflammation induced by ethanol activates PSCs and induces pancreatic fibrosis. Interestingly, it has also been shown that alcohol and some of its metabolites (e.g., acetaldehyde) cause activation of PSCs.

Although they have been evaluated only in preclinical studies, novel therapies that target the activation of PSCs are being investigated. It has been reported that antioxidants, angiotensin-converting enzyme inhibitors, peroxisome proliferator-activated receptor gamma ligands, and vitamin A inhibit the activity of PSCs.

Smoking

Epidemiologic studies have shown that smoking increases the risk of alcohol-induced chronic pancreatitis. Active smokers develop chronic pancreatitis at a younger age compared with nonsmokers. In addition, the risk of pancreatic calcifications and diabetes mellitus is increased in patients who smoke compared with nonsmokers.

Gene Mutations

Under physiologic conditions, pancreatic enzyme activation is strictly controlled. Mutations in proteins that regulate this activation increase the risk of chronic pancreatitis. Mutations in the cationic trypsinogen gene, also known as protease serine 1 (PRSS1) gene, are common in hereditary chronic pancreatitis. PRSS1 is located on chromosome 7 and regulates trypsinogen production; mutations in this gene are associated with intraacinar trypsinogen activation. PRSS1 mutations have been documented in hereditary pancreatitis but are uncommon in other forms of chronic pancreatitis.

SPINK-1 is a peptide secreted by acinar cells that regulates the premature activation of trypsinogen. Because SPINK1 mutations are present in 1% to 2% of healthy patients but the prevalence of chronic pancreatitis is much lower, it has been hypothesized that SPINK1 mutations are not enough to trigger pancreatic inflammation. However, they lower the threshold for its development and influence the severity of the disease. SPINK1 mutations are more prevalent in alcoholic, hereditary, and idiopathic pancreatitis.

The secretion of bicarbonate and chloride in respiratory and pancreatic secretions is regulated by the CFTR gene. CFTR mutations affect the normal secretion of bicarbonate, decrease pancreatic juice volume, and augment the concentration of pancreatic enzymes inside the pancreatic duct. Homozygous CFTR mutations result in cystic fibrosis; heterozygous mild mutations predispose to pancreatic exocrine insufficiency and chronic pancreatitis. The prevalence of CFTR gene mutations is higher in patients with alcoholic, idiopathic, and hereditary pancreatitis compared with the general population. Similarly, mutation in human chymotrypsin C gene has been found to be associated with development of chronic pancreatitis. It seems that chymotrypsin C protects against pancreatitis by degrading trypsinogen and thereby curtailing harmful intrapancreatic trypsinogen activation.

While our understanding of pathogenesis of chronic pancreatitis has evolved in a largely trypsin centric fashion, animal studies in trypsin knockout mice suggest that even in the absence of trypsin, chronic noxious stimuli can induce chronic pancreatitis. These results suggest that alternative pathways independent of trypsin may exist that can lead to chronic injury in pancreatitis, and elucidation of these pathways may lead to development of novel therapeutics.

Types of Chronic Pancreatitis

Autoimmune Pancreatitis

Autoimmune pancreatitis is a chronic inflammatory disorder that involves the pancreas. At least two different histologic variants have been defined: 1) Type 1, which is the pancreatic manifestation of an immunoglobulin G4-related disease; and 2) Type 2, a pancreatic specific disorder, not associated with immunoglobulin G4. Type 1 is the most common; it is characterized by dense, periductal lymphoplasmacytic infiltrates, storiform fibrosis, and obliterative venulitis. Plasmatic cells typically stain positive for immunoglobulin G4. In type 2, the pancreas is infiltrated by neutrophils, lymphocytes, and plasma cells that destroy and obliterate the epithelium in the pancreatic duct. Autoimmune pancreatitis is more common in men than in women. Up to 80% of patients are older than 50 years. Patients with autoimmune pancreatitis can develop acute symptoms such as jaundice or AP, closely mimicking patients with pancreatic adenocarcinoma. However, most patients with chronic pancreatitis develop chronic abdominal discomfort associated with abnormal elevation of amylase and lipase levels.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Related Posts