The pancreas secretes 1500−3000 mL of isosmotic alkaline (pH >8) fluid per day containing about 20 enzymes. The pancreatic secretions provide the enzymes needed to effect the major digestive activity of the gastrointestinal tract and provide an optimal pH for the function of these enzymes.
Regulation of Pancreatic Secretion
The exocrine pancreas is influenced by intimately interacting hormonal and neural systems. Gastric acid is the stimulus for the release of secretin from the duodenum, which stimulates the secretion of water and electrolytes from pancreatic ductal cells. Release of cholecystokinin (CCK) from the duodenum and proximal jejunum is largely triggered by long-chain fatty acids, certain essential amino acids (tryptophan, phenylalanine, valine, methionine), and gastric acid itself. CCK evokes an enzyme-rich secretion from acinar cells in the pancreas. The parasympathetic nervous system (via the vagus nerve) exerts significant control over pancreatic secretion. Secretion evoked by secretin and CCK depends on permissive roles of vagal afferent and efferent pathways. This is particularly true for enzyme secretion, whereas water and bicarbonate secretions are heavily dependent on the hormonal effects of secretin and to a lesser extent CCK. Also, vagal stimulation effects the release of vasoactive intestinal peptide (VIP), a secretin agonist.
Pancreatic exocrine secretion is influenced by inhibitory neuropeptides such as somatostatin, pancreatic polypeptide, peptide YY, neuropeptide Y, enkephalin, pancreastatin, calcitonin gene−related peptides, glucagon, and galanin. Although pancreatic polypeptide and peptide YY may act primarily on nerves outside the pancreas, somatostatin acts at multiple sites. Nitric oxide (NO) is also an important neurotransmitter. The mechanism of action of these various factors has not been fully defined.
Water and Electrolyte Secretion
Bicarbonate is the ion of primary physiologic importance within pancreatic secretion. The ductal cells secrete bicarbonate predominantly derived from plasma (93%) more than from intracellular metabolism (7%). Bicarbonate enters through the sodium bicarbonate cotransporter with depolarization caused by chloride efflux through the cystic fibrosis transmembrane conductance regulator (CFTR). Secretin and VIP, both of which increase intracellular cyclic AMP, act on the ductal cells opening the CFTR in promoting secretion. CCK, acting as a neuromodulator, markedly potentiates the stimulatory effects of secretin. Acetylcholine also plays an important role in ductal cell secretion. Bicarbonate helps neutralize gastric acid and creates the appropriate pH for the activity of pancreatic enzymes and bile salts.
The acinar cell is highly compartmentalized and is concerned with the secretion of pancreatic enzymes. Proteins synthesized by the rough endoplasmic reticulum are processed in the Golgi and then targeted to the appropriate site, whether that be zymogen granules, lysosomes, or other cell compartments. The pancreas secretes amylolytic, lipolytic, and proteolytic enzymes. Amylolytic enzymes such as amylase, hydrolyze starch to oligosaccharides and to the disaccharide maltose. The lipolytic enzymes include lipase, phospholipase A2, and cholesterol esterase. Bile salts inhibit lipase in isolation, but colipase, another constituent of pancreatic secretion, binds to lipase and prevents this inhibition. Bile salts activate phospholipase A and cholesterol esterase. Proteolytic enzymes include endopeptidases (trypsin, chymotrypsin), which act on internal peptide bonds of proteins and polypeptides; exopeptidases (carboxypeptidases, aminopeptidases), which act on the free carboxyl- and amino-terminal ends of peptides, respectively; and elastase. The proteolytic enzymes are secreted as inactive precursors and packaged as zymogens. Ribonucleases (deoxyribonucleases, ribonuclease) are also secreted. Enterokinase, an enzyme found in the duodenal mucosa, cleaves the lysine-isoleucine bond of trypsinogen to form trypsin. Trypsin then activates the other proteolytic zymogens and phospholipase A2 in a cascade phenomenon. All pancreatic enzymes have pH optima in the alkaline range. The nervous system initiates pancreatic enzyme secretion. The neurologic stimulation is cholinergic, involving extrinsic innervation by the vagus nerve and subsequent innervation by intrapancreatic cholinergic nerves. The stimulatory neurotransmitters are acetylcholine and gastrin-releasing peptides. These neurotransmitters activate calcium-dependent second messenger systems, resulting in the release of zymogen granules. VIP is present in intrapancreatic nerves and potentiates the effect of acetylcholine. In contrast to other species, there are no CCK receptors on acinar cells in humans. CCK in physiologic concentrations stimulates pancreatic secretion by stimulating afferent vagal and intrapancreatic nerves.
Autoprotection of the Pancreas
Autodigestion of the pancreas is prevented by the packaging of pancreatic proteases in precursor form and by the synthesis of protease inhibitor [i.e., pancreatic secretory trypsin inhibitor (PSTI) or SPINK1], which can bind and inactivate about 20% of trypsin activity. Mesotrypsin, chymotrypsin c, and enzyme y can also lyse and inactivate trypsin. These protease inhibitors are found in the acinar cell, the pancreatic secretions, and the α1- and α2-globulin fractions of plasma. In addition, low calcium concentration within the cytosol of acinar cells in the normal pancreas promotes the destruction of spontaneously activated trypsin. Loss of any of these protective mechanisms leads to zymogen activation, autodigestion, and acute pancreatitis.
Insulin appears to be needed locally for secretin and CCK to promote exocrine secretion; thus, it acts in a permissive role for these two hormones.
Enteropancreatic Axis and Feedback Inhibition
Pancreatic enzyme secretion is controlled, at least in part, by a negative feedback mechanism induced by the presence of active serine proteases in the duodenum. To illustrate, perfusion of the duodenal lumen with phenylalanine causes a prompt result in increased plasma CCK levels as well as increased secretion of chymotrypsin and other pancreatic enzymes. However, simultaneous perfusion with trypsin blunts both responses. Conversely, perfusion of the duodenal lumen with protease inhibitors actually leads to enzyme hypersecretion. The available evidence supports the concept that the duodenum contains a peptide called CCK-releasing factor (CCK-RF) that is involved in stimulating CCK release. It appears that serine proteases inhibit pancreatic secretion by inactivating a CCK-releasing peptide in the lumen of the small intestine. Thus, the integrative result of both bicarbonate and enzyme secretion depends on a feedback process for both bicarbonate and pancreatic enzymes. Acidification of the duodenum releases secretin, which stimulates vagal and other neural pathways to activate pancreatic duct cells, which secrete bicarbonate. This bicarbonate then neutralizes the duodenal acid, and the feedback loop is completed. Dietary proteins bind proteases, thereby leading to an increase in free CCK-RF. CCK is then released into the blood in physiologic concentrations, acting primarily through the neural pathways (vagal-vagal). This leads to acetylcholine-mediated pancreatic enzyme secretion. Proteases continue to be secreted from the pancreas until the protein within the duodenum is digested. At this point, pancreatic protease secretion is reduced to basic levels, thus completing this step in the feedback process.
Pancreatic inflammatory disease may be classified as (1) acute pancreatitis or (2) chronic pancreatitis. The pathologic spectrum of acute pancreatitis varies from interstitial pancreatitis, which is usually a mild and self-limited disorder, to necrotizing pancreatitis, in which the extent of pancreatic necrosis may correlate with the severity of the attack and its systemic manifestations.
The incidence of pancreatitis varies in different countries and depends on cause [e.g., alcohol, gallstones, metabolic factors, and drugs (Table 313-1)]. The estimated incidence in the United States is increasing and is now estimated to be 70 hospitalizations/100,000 persons annually, thus resulting in >200,000 new cases of acute pancreatitis per year.
Table 313-1 Causes of Acute Pancreatitis |Favorite Table|Download (.pdf)
Table 313-1 Causes of Acute Pancreatitis
|Gallstones (including microlithiasis)|
|Alcohol (acute and chronic alcoholism) Hypertriglyceridemia|
|Endoscopic retrograde cholangiopancreatography (ERCP), especially after biliary manometry|
|Trauma (especially blunt abdominal trauma)|
|Postoperative (abdominal and nonabdominal operations)|
|Drugs (azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline, valproic acid, anti-HIV medications)|
|Sphincter of Oddi dysfunction|
|Vascular causes and vasculitis (ischemic-hypoperfusion states after cardiac surgery)|
|Connective tissue disorders and thrombotic thrombocytopenic|
|Cancer of the pancreas|
|Infections (mumps, coxsackievirus, cytomegalovirus, echovirus, parasites)|
|Autoimmune (e.g., Sjögren's syndrome)|
|Causes to Consider in Patients with Recurrent Bouts of Acute Pancreatitis without an Obvious Etiology|
|Occult disease of the biliary tree or pancreatic ducts, especially microlithiasis, sludge|
|Sphincter of Oddi dysfunction|
Etiology and Pathogenesis
There are many causes of acute pancreatitis (Table 313-1), but the mechanisms by which these conditions trigger pancreatic inflammation have not been fully elucidated. Gallstones continue to be the leading cause of acute pancreatitis in most series (30−60%). The risk of acute pancreatitis in patients with at least one gallstone <5 mm in diameter is fourfold greater than that in patients with larger stones. Alcohol is the second most common cause, responsible for 15−30% of cases in the United States. The incidence of pancreatitis in alcoholics is surprisingly low (5/100,000), indicating that in addition to the amount of alcohol ingested unknown factors affect a person's susceptibility to pancreatic injury. The mechanism of injury is incompletely understood. Acute pancreatitis occurs in 5−20% of patients following endoscopic retrograde cholangiopancreatography (ERCP). Despite extensive research into the medical and endoscopic prevention of post-ERCP pancreatitis, there has been little decline in incidence. Use of prophylactic pancreatic duct stent after retrograde pancreatogram or pancreatic sphincterotomy has shown promise in reducing pancreatitis but requires further prospective evaluation. Risk factors for post-ERCP pancreatitis include minor papilla sphincterotomy, sphincter of Oddi dysfunction, prior history of post-ERCP pancreatitis, age <60 years, >2 contrast injections into the pancreatic duct, and endoscopic trainee involvement. Hypertriglyceridemia is the cause of acute pancreatitis in 1.3−3.8% of cases; serum triglyceride levels are usually >11.3 mmol/L (>1000 mg/dL). Most patients with hypertriglyceridemia, when subsequently examined, show evidence of an underlying derangement in lipid metabolism, probably unrelated to pancreatitis. Such patients are prone to recurrent episodes of pancreatitis. Any factor (e.g., drugs or alcohol) that causes an abrupt increase in serum triglycerides to levels >11 mmol/L (1000 mg/dL) can precipitate a bout of acute pancreatitis. Finally, patients with a deficiency of apolipoprotein CII have an increased incidence of pancreatitis; apolipoprotein CII activates lipoprotein lipase, which is important in clearing chylomicrons from the bloodstream. Patients with diabetes mellitus who have developed ketoacidosis and patients who are on certain medications such as oral contraceptives may also develop high triglyceride levels. Approximately 2−5% of cases of acute pancreatitis are drug related. Drugs cause pancreatitis either by a hypersensitivity reaction or by the generation of a toxic metabolite, although in some cases it is not clear which of these mechanisms is operative (Table 313-1).
Autodigestion is a currently accepted pathogenic theory; according to it, pancreatitis results when proteolytic enzymes (e.g., trypsinogen, chymotrypsinogen, proelastase, and lipolytic enzymes such as phospholipase A2) are activated in the pancreas rather than in the intestinal lumen. A number of factors (e.g., endotoxins, exotoxins, viral infections, ischemia, anoxia, lysosomal calcium, and direct trauma) are believed to facilitate activation of trypsin. Activated proteolytic enzymes, especially trypsin, not only digest pancreatic and peripancreatic tissues but also can activate other enzymes, such as elastase and phospholipase A2. Spontaneous activation of trypsin also can occur.
Activation of Pancreatic Enzymes in the Pathogenesis of Acute Pancreatitis
Several recent studies have suggested that pancreatitis is a disease that evolves in three phases. The initial phase is characterized by intrapancreatic digestive enzyme activation and acinar cell injury. Trypsin activation appears to be mediated by lysosomal hydrolases such as cathepsin B that become colocalized with digestive enzymes in intracellular organelles; it is currently believed that acinar cell injury is the consequence of trypsin activation. The second phase of pancreatitis involves the activation, chemoattraction, and sequestration of leukocytes and macrophages in the pancreas, resulting in an enhanced intrapancreatic inflammatory reaction. Neutrophil depletion induced by prior administration of an antineutrophil serum has been shown to reduce the severity of experimentally induced pancreatitis. There is also evidence to support the concept that neutrophil sequestration can activate trypsinogen. Thus, intrapancreatic acinar cell activation of trypsinogen could be a two-step process (i.e., an early neutrophil-independent and a later neutrophil-dependent phase). The third phase of pancreatitis is due to the effects of activated proteolytic enzymes and cytokines, released by the inflamed pancreas, on distant organs. Activated proteolytic enzymes, especially trypsin, not only digest pancreatic and peripancreatic tissues but also activate other enzymes such as elastase and phospholipase A2. The active enzymes and cytokines then digest cellular membranes and cause proteolysis, edema, interstitial hemorrhage, vascular damage, coagulation necrosis, fat necrosis, and parenchymal cell necrosis. Cellular injury and death result in the liberation of bradykinin peptides, vasoactive substances, and histamine that can produce vasodilation, increased vascular permeability, and edema with profound effects on many organs, most notably the lung. The systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS) as well as multiorgan failure may occur as a result of this cascade of local as well as distant effects.
There appear to be a number of genetic factors that can increase the susceptibility and/or modify the severity of pancreatic injury in acute pancreatitis. Four susceptibility genes have been identified: (1) cationic trypsinogen mutations (PRSS1m, R122Hm, and N291), (2) pancreatic secretory trypsin inhibitor (SPINK1), (3) CFTR, and (4) monocyte chemotactic protein (MCP-1). Experimental and clinical data indicate that MCP-1 may be an important inflammatory mediator in the early pathologic process of acute pancreatitis, a determinant of the severity of the inflammatory response, and a promoter of organ failure.
Approach to the Patient: Abdominal Pain
Abdominal pain is the major symptom of acute pancreatitis. Pain may vary from a mild and tolerable discomfort and more commonly to severe, constant, and incapacitating distress. Characteristically, the pain, which is steady and boring in character, is located in the epigastrium and periumbilical region and often radiates to the back as well as to the chest, flanks, and lower abdomen. The pain is frequently more intense when the patient is supine, and patients may obtain some relief by sitting with the trunk flexed and knees drawn up. Nausea, vomiting, and abdominal distention due to gastric and intestinal hypomotility and chemical peritonitis are also frequent complaints.
Physical examination frequently reveals a distressed and anxious patient. Low-grade fever, tachycardia, and hypotension are fairly common. Shock is not unusual and may result from (1) hypovolemia secondary to exudation of blood and plasma proteins into the retroperitoneal space and a “retroperitoneal burn” due to activated proteolytic enzymes; (2) increased formation and release of kinin peptides, which cause vasodilation and increased vascular permeability; and (3) systemic effects of proteolytic and lipolytic enzymes released into the circulation. Jaundice occurs infrequently; when present, it usually is due to edema of the head of the pancreas with compression of the intrapancreatic portion of the common bile duct. Erythematous skin nodules due to subcutaneous fat necrosis may occur. In 10−20% of patients, there are pulmonary findings, including basilar rales, atelectasis, and pleural effusion, the latter most frequently left sided. Abdominal tenderness and muscle rigidity are present to a variable degree, but, compared with the intense pain, these signs may be unimpressive. Bowel sounds are usually diminished or absent. An enlarged pancreas with walled off necrosis or a pseudocyst may be palpable in the upper abdomen later in the disease course (i.e., four to six weeks). A faint blue discoloration around the umbilicus (Cullen's sign) may occur as the result of hemoperitoneum, and a blue-red-purple or green-brown discoloration of the flanks (Turner's sign) reflects tissue catabolism of hemoglobin. The latter two findings, which are uncommon, indicate the presence of a severe necrotizing pancreatitis.
The diagnosis of acute pancreatitis is usually established by the detection of an increased level of serum amylase and lipase. Values threefold or more above normal virtually clinch the diagnosis if gut perforation, ischemia, and infarction are excluded. However, there appears to be no definite correlation between the severity of pancreatitis and the degree of serum lipase and amylase elevations. After three to seven days, even with continuing evidence of pancreatitis, total serum amylase values tend to return toward normal. However, pancreatic isoamylase and lipase levels may remain elevated for 7 to 14 days. It will be recalled that amylase elevations in serum and urine occur in many conditions other than pancreatitis (see Chap. 312, Table 312-2). Importantly, patients with acidemia (arterial pH ≤7.32) may have spurious elevations in serum amylase. In one study, 12 of 33 patients with acidemia had elevated serum amylase, but only 1 had an elevated lipase value; in 9, salivary-type amylase was the predominant serum isoamylase. This finding explains why patients with diabetic ketoacidosis may have marked elevations in serum amylase without any other evidence of acute pancreatitis. Serum lipase activity increases in parallel with amylase activity. A threefold elevated serum lipase value is usually diagnostic of acute pancreatitis; these tests are especially helpful in patients with nonpancreatic causes of hyperamylasemia (see Chap. 312, Table 312-2).
Table 313-2 Severe Acute Pancreatitis |Favorite Table|Download (.pdf)
Table 313-2 Severe Acute Pancreatitis
|Risk Factors for Severity|
- Age >60 years
- Obesity, BMI >30
- Comorbid disease
|Markers of Severity within 24 Hours|
- SIRS [temperature >38° or <36°C (>100.4° or 96.8°F), Pulse >90, Tachypnea >24, ↑ WBC >12,000]
- Hemoconcentration (Hct >44%)
- (B) Blood urea nitrogen (BUN) >22 mg%
- (I) Impaired mental status
- (S) SIRS: 2/4 present
- (A) Age >60 years
- (P) Pleural effusion
- Organ Failure
- Cardiovascular: systolic BP <90 mmHg, heartrate >130
- Pulmonary: Pao2 <60 mmHg
- Renal serum creatinine >2.0 mg%
|Markers of Severity during Hospitalization|
- Persistent organ failure
- Pancreatic necrosis
- Hospital-acquired infection
Leukocytosis (15,000−20,000 leukocytes per μL) occurs frequently. Patients with more severe disease may show hemoconcentration with hematocrit values >44% and/or azotemia with a blood urea nitrogen (BUN) level >22 mg/dL because of loss of plasma into the retroperitoneal space and peritoneal cavity. Hemoconcentration may be the harbinger of more severe disease (i.e., pancreatic necrosis), while azotemia is a significant risk factor for mortality. Hyperglycemia is common and is due to multiple factors, including decreased insulin release, increased glucagon release, and an increased output of adrenal glucocorticoids and catecholamines. Hypocalcemia occurs in ∼25% of patients, and its pathogenesis is incompletely understood. Although earlier studies suggested that the response of the parathyroid gland to a decrease in serum calcium is impaired, subsequent observations have failed to confirm this phenomenon. Intraperitoneal saponification of calcium by fatty acids in areas of fat necrosis occurs occasionally, with large amounts (up to 6.0 g) dissolved or suspended in ascitic fluid. Such “soap formation” may also be significant in patients with pancreatitis, mild hypocalcemia, and little or no obvious ascites. Hyperbilirubinemia [serum bilirubin >68 μmol/L (>4.0 mg/dL)] occurs in ∼10% of patients. However, jaundice is transient, and serum bilirubin levels return to normal in four to seven days. Serum alkaline phosphatase and aspartate aminotransferase levels are also transiently elevated and they parallel serum bilirubin values and may point to gallbladder-related disease. Markedly elevated serum lactic dehydrogenase levels [>8.5 μmol/L (>500 U/dL)] suggest a poor prognosis. Hypertriglyceridemia occurs in 5−10% of patients, and serum amylase levels in these individuals are often spuriously normal (Chap. 312). Approximately 5−10% of patients have hypoxemia (arterial Po2 ≤ 60 mmHg), which may herald the onset of ARDS. Finally, the electrocardiogram is occasionally abnormal in acute pancreatitis with ST-segment and T-wave abnormalities simulating myocardial ischemia.
A CT scan can confirm the clinical impression of acute pancreatitis even with less than a threefold increase in serum amylase and lipase levels. Importantly, CT can be helpful in indicating the severity of acute pancreatitis and the risk of morbidity and mortality and in evaluating the complications of acute pancreatitis (Table 313-3). However, a CT scan obtained within the first several days of symptom onset may underestimate the extent of tissue injury. What may appear to be intestinal pancreatitis on initial CT scan may evolve to pancreatic necrosis on repeat CT scan three to five days later (Fig. 313-1). Sonography is useful in acute pancreatitis to evaluate the gallbladder if gallstone disease is suspected. Radiologic studies useful in the diagnosis of acute pancreatitis are discussed in Chap. 312, and listed in Table 312-1, and depicted in Figs. 313-1, 313-2, 313-3.
Table 313-3 CT Findings and Grading of Acute Pancreatitis [CT Severity Index (CTSI)] |Favorite Table|Download (.pdf)
Table 313-3 CT Findings and Grading of Acute Pancreatitis [CT Severity Index (CTSI)]
|A||Normal pancreas: normal size, sharply defined, smooth contour, homogeneous enhancement, retroperitoneal peripancreatic fat without enhancement||0|
|B||Focal or diffuse enlargement of the pancreas, contour may show irregularity, enhancement may be inhomogeneous but there is no peripancreatic inflammation||1|
|C||Peripancreatic inflammation with intrinsic pancreatic abnormalities||2|
|D||Intrapancreatic or extrapancreatic fluid collections||3|
|E||Two or more large collections or gas in the pancreas or retroperitoneum||4|
|Necrosis score based on contrast-enhanced CT|
A. Pancreaticopleural fistula: pancreatic duct leak on ERCP. Pancreatic duct leak demonstrated (arrow) at the time of retrograde pancreatogram in a patient with acute exacerbation of alcohol-induced acute or chronic pancreatitis. B. Pancreaticopleural fistula: CT Scan. Contrast-enhanced CT scan (coronal view) with arrows showing fistula tract from pancreatic duct disruption in the pancreatic pleural fistula. C. Pancreaticopleural fistula: Chest x-ray. Large pleural effusion in the left hemithorax from a disrupted pancreatic duct. Analysis of pleural fluid revealed elevated amylase concentration. (Courtesy of Dr. KJ Mortele, Brigham and Women's Hospital; with permission.)
Any severe acute pain in the abdomen or back should suggest the possibility acute pancreatitis. The diagnosis is usually entertained when a patient with a possible predisposition to pancreatitis presents with severe and constant abdominal pain, frequently associated with nausea, emesis, fever, tachycardia, and abnormal findings on abdominal examination. Laboratory studies may reveal leukocytosis, hypocalcemia, and hyperglycemia. The diagnosis of acute pancreatitis requires two of the following: typical abdominal pain, threefold or greater elevation in serum amylase and/or lipase level, and/or confirmatory findings on cross-sectional abdominal imaging. Although not required for diagnosis, markers of severity include hemoconcentration (hematocrit >44%), azotemia (BUN >22 mg/dL), and signs of organ failure (Table 313-2).
The differential diagnosis should include the following disorders: (1) perforated viscus, especially peptic ulcer; (2) acute cholecystitis and biliary colic; (3) acute intestinal obstruction; (4) mesenteric vascular occlusion; (5) renal colic; (6) myocardial infarction; (7) dissecting aortic aneurysm; (8) connective tissue disorders with vasculitis; (9) pneumonia; and (10) diabetic ketoacidosis. A penetrating duodenal ulcer can usually be identified by imaging studies or endoscopy. A perforated duodenal ulcer is readily diagnosed by the presence of free intraperitoneal air on abdominal imaging. It may be difficult to differentiate acute cholecystitis from acute pancreatitis, since an elevated serum amylase may be found in both disorders. Pain of biliary tract origin is more right sided or epigastric than periumbilical and can be more severe; ileus is usually absent. Sonography is helpful in establishing the diagnosis of cholelithiasis and cholecystitis. Intestinal obstruction due to mechanical factors can be differentiated from pancreatitis by the history of crescendo-decrescendo pain, findings on abdominal examination, and CT of the abdomen showing changes characteristic of mechanical obstruction. Acute mesenteric vascular occlusion is usually suspected in elderly debilitated patients with brisk leukocytosis, abdominal distention, and bloody diarrhea, confirmed by CT or MR angiography. Systemic lupus erythematosus and polyarteritis nodosa may be confused with pancreatitis, especially since pancreatitis may develop as a complication of these diseases. Diabetic ketoacidosis is often accompanied by abdominal pain and elevated total serum amylase levels, thus closely mimicking acute pancreatitis. However, the serum lipase level is not elevated in diabetic ketoacidosis.
Course of the Disease and Complications
The initial assessment of severity in acute pancreatitis is critical for the appropriate triage and management of patients. The basis for the classification, severity, and complications of acute pancreatitis was initially established at the International Symposium held in Atlanta in 1992. While the definitions have come under greater scrutiny in recent years, it still serves as the common language for clinical care and research in acute pancreatitis. The criteria for severity in acute pancreatitis was defined as organ failure of at least one organ system (defined as a systolic blood pressure <90 mmHg, Pao2 ≤60 mmHg, creatinine >2.0 mg/dL after rehydration, and gastrointestinal bleeding >500 mL/24 hours) and the presence of a local complication such as necrosis, pseudocyst, and abscess.
Early predictors of severity at 48 hours included ≥3 Ranson's signs and APACHE II score ≥8. Traditional severity indices such as APACHE II and Ranson's criteria have not been clinically useful since they are cumbersome, require collection of a large amount of clinical and laboratory data over time, and do not have acceptable positive and negative predictive value for severe acute pancreatitis. A recent simplified scoring system for the early prediction of mortality was developed from a large cohort of patients with acute pancreatitis. This scoring system, referred to as the Bedside Index of Severity in Acute Pancreatitis (BISAP), incorporates five clinical and laboratory parameters obtained within the first 24 hours of hospitalization: (Table 313-2) (BUN >25, Impaired mental status, SIRS, Age >60 years, Pleural effusion on radiography). Presence of three or more of these factors was associated with substantially increased risk for in-hospital mortality among patients with acute pancreatitis.
Apart from the severity indices, there are additional factors that can be used to assess severity in acute pancreatitis. They are best separated into risk factors for severity and markers of severity within 24 hours of admission and during hospitalization. Risk factors for severe acute pancreatitis on admission include older age (>60 years), obesity (BMI ≥30), and comorbid disease. There is also evidence to support initial episode and alcohol use as additional risk factors for severity. At admission and during the first 24 hours, markers of severity in acute pancreatitis include scoring systems such as BISAP score and APACHE II, SIRS, azotemia, hemoconcentration, and organ failure. During hospitalization, markers of severity include persistent organ failure lasting more than 48 hours and pancreatic necrosis.
The course of acute pancreatitis is defined by two phases. In the first phase, which lasts one to two weeks, severity is defined by clinical parameters rather than morphologic findings. The most important clinical parameter is persistent organ failure (i.e., lasting longer than 48 hours), which is the usual cause of death. Severity in the second phase is defined by both clinical parameters and morphologic criteria. The important clinical parameter of severity, as in the first phase, is persistent organ failure. The morphologic criteria of greatest interest is the development of necrotizing pancreatitis, especially when it prolongs hospitalization and/or it requires active intervention such as operative, endoscopic, or percutaneous therapy or requires supportive measures such as renal dialysis, ventilator support, or need for nasoenteric feeding.
The importance of the recognition of interstitial versus necrotizing acute pancreatitis has lead to the development of a CT severity index (Table 313-3) as another measure of severity that is best evaluated three to five days into hospitalization because it may not be possible to distinguish interstitial from necrotizing pancreatitis on contrast-enhanced CT scan on the day of admission. CT identification of local complications, particularly necrosis, is critical because patients with infected and sterile necrosis are at greatest risk of mortality (Figs. 313-1, 313-2). The median prevalence of organ failure is 54% in necrotizing pancreatitis. The prevalence of organ failure is perhaps slightly higher in infected versus sterile necrosis. With single organ system failure, the mortality is 3−10% but increases to 47% with multisystem organ failure. These data serve to highlight that a patient found to have pancreatic necrosis with multisystem organ failure is the most likely to die.
However, it should be noted that necrotizing pancreatitis is uncommon (10% of all patients with acute pancreatitis), and the far greater proportion of patients presenting in clinical practice have interstitial pancreatitis, which also is associated with organ failure in 10% and death in 3% of cases. This roughly translates to similar absolute mortality figures in the interstitial and necrotizing pancreatitis populations since interstitial disease is far more prevalent.
The majority of patients with mild acute pancreatitis and either no organ failure or only transient organ failure will respond to simple supportive care measures that form the hallmark of treatment in acute pancreatitis: bowel rest, intravenous hydration with crystalloid, and analgesia. Oral intake can be resumed once the patient is essentially pain free in the absence of parenteral analgesia, has no nausea or vomiting, normal bowel sounds, and is hungry. Typically, a clear or full liquid diet has been recommended for the initial meal, but a low-fat solid diet is a reasonable choice following recovery from mild acute pancreatitis. Patients with gallstone pancreatitis are at increased risk of recurrence. Therefore, following recovery from mild pancreatitis, consideration should be given to performing a laparoscopic cholecystectomy during the same admission. An alternative for patients who are not surgical candidates would be to perform an endoscopic biliary sphincterotomy.
Severe Acute Pancreatitis (See Figs. 313-1, 313-2)
Patients with predictive markers of severity on admission such as obesity or hemoconcentration are also managed with supportive measures outlined as above. It is recommended that vigorous fluid resuscitation take place. Measurement of hematocrit and BUN every 12 hours is recommended to ensure adequacy of fluid resuscitation. A decrease in hematocrit and BUN during the first 12 to 24 hours is strong evidence that sufficient fluids are being administered. If the hematocrit remains elevated or increases further (particularly among those whose hematocrit on admission are >44), fluid resuscitation is inadequate.
Patients with persistent organ failure that does not respond to increased fluids (to counteract hypotension and increased serum creatinine) and/or nasal oxygen to overcome hypoxemia as well as those patients with labored respirations that may herald respiratory failure should be transferred to an intensive care unit for aggressive hydration and close monitoring for the possible need of intubation with mechanical ventilation, hemodialysis, and support of blood pressure.
Treatment: Acute Pancreatitis
In most patients (85−90%) with acute pancreatitis, the disease is self-limited and subsides spontaneously, usually within three to seven days after treatment is instituted. Conventional measures include (1) analgesics for pain, (2) IV fluids and colloids to maintain normal intravascular volume, and (3) no oral alimentation.
Once it is clear that a patient will not be able to tolerate oral feeding (a determination that can usually be made within 48−72 hours), enteral nutrition should be considered [rather than total parenteral nutrition (TPN)] since it maintains gut barrier integrity, thereby preventing bacterial translocation, is less expensive, and has fewer complications than TPN. The route through which enteral feeding is administered is under debate. Nasogastric access is easier to establish and may be as safe as nasojejunal enteral nutrition. However, enteral nutrition that bypasses the stomach and duodenum stimulates pancreatic secretions less and this rationale theoretically supports the use of the nasojejunal route. It has not been demonstrated whether either route is superior in altering morbidity and mortality. When patients with necrotizing pancreatitis begin oral intake of food, consideration should also be given to the addition of pancreatic enzyme supplementation and proton pump inhibitor therapy to assist with fat digestion and reduce gastric acid.
There is currently no role for prophylactic antibiotics in either interstitial or necrotizing pancreatitis. Although several early studies suggested a role for prophylactic antibiotics in patients with necrotizing pancreatitis, two recent double-blind, randomized controlled trials failed to demonstrate a reduction in pancreatic infection with use of antibiotic prophylaxis. However, it should also be noted that the overall rate of infected necrosis has been in decline over the past 10−15 years and currently is found in 20% of patients with necrotizing pancreatitis. It is reasonable to start antibiotics in a patient who appears septic while awaiting the results of cultures. If cultures are negative, the antibiotics should be discontinued to minimize the risk of developing fungal superinfection.
Percutaneous aspiration of necrosis with Gram stain and culture should generally not be performed until at least 7−10 days after establishing a diagnosis of necrotizing pancreatitis and only if there are ongoing signs of possible pancreatic infection such as sustained leukocytosis, fever, or organ failure. Once a diagnosis of infected necrosis is established, appropriate antibiotics should be instituted and surgical debridement should be undertaken. There exist minimally invasive alternative therapies such as endoscopic, percutaneous catheter, and retroperitoneal techniques for necrosectomy. However, there are currently no randomized studies supporting the use of one over another modality. For patients with sterile necrosis, medical management is usually maintained indefinitely unless patients develop serious complications such as compartment syndrome, intestinal perforation, pseudoaneurysms not responding to embolization, or inability to resume oral intake after four to six weeks of treatment (Fig. 313-2).
There are several clearly defined roles for ERCP in acute pancreatitis. Urgent ERCP (within 24 hours) is indicated in patients who have severe acute biliary pancreatitis with organ failure and/or cholangitis. Elective ERCP with sphincterotomy can be considered in patients with persistent or incipient biliary obstruction, those deemed to be poor candidates for cholecystectomy, and for those in whom there is strong suspicion for bile duct stones after cholecystectomy. ERCP with stent placement is also indicated for pancreatic ductal disruptions that occur as part of the inflammatory process and result in peripancreatic fluid collections (Fig. 313-3A).
Several drugs have been evaluated by prospective controlled trials and found ineffective in the treatment of acute pancreatitis. The list, by no means complete, includes glucagon, H2 blockers, protease inhibitors such as aprotinin, glucocorticoids, calcitonin, nonsteroidal anti-inflammatory drugs (NSAIDs), and lexipafant, a platelet-activating factor inhibitor. A recent meta-analysis of somatostatin, octreotide, and the antiprotease gabexate mesylate in the therapy of acute pancreatitis suggested (1) a reduced mortality rate but no change in complications with octreotide and (2) no effect on the mortality rate but reduced pancreatic damage with gabexate.
A dynamic contrast-enhanced CT (CECT) scan performed three to five days after hospitalization provides valuable information on the severity and prognosis of acute pancreatitis (Fig. 313-1). In particular, a CECT scan allows estimation of the presence and extent of pancreatic necrosis. Recent studies suggest that the likelihood of prolonged pancreatitis or a serious complication is negligible when the CT severity index is 1 or 2 and low with scores of 3−6. However, patients with scores of 7−10 had a 92% morbidity rate and a 17% mortality rate (Table 313-3). A few retrospective studies have raised concern that the use of IV contrast early in the course of acute pancreatitis might intensify pancreatic necrosis. However, since prospective human studies are not available, it is recommended that a CECT scan be obtained only after vigorous initial fluid resuscitation.
Elevation of serum amylase/lipase or persistent inflammatory changes seen on CT scans should not discourage feeding a hungry asymptomatic patient. In this regard, persistence of inflammatory changes on CT scans or persistent elevations in serum amylase/lipase may not resolve for weeks to months. The patient with unremitting severe necrotizing pancreatitis requires vigorous fluid resuscitation and close attention to complications such as cardiovascular collapse, respiratory insufficiency, and pancreatic infection. A useful indicator of severe/complicated forms of acute pancreatitis is the persistence of the systemic SIRS beyond 48 hours. SIRS was defined in 1992 in a joint conference of the American College of Chest Physicians and Society of Critical Care Medicine as a standardized clinical syndrome to indicate the presence of systemic inflammation irrespective of etiology. Several studies have linked persistent SIRS with an increased risk of organ failure and death in acute pancreatitis. Complications from acute pancreatitis should be managed by a combination of radiologic and surgical means (see below). Although sterile necrosis is most often managed conservatively, surgical pancreatic debridement (necrosectomy) should be considered for definitive management of infected necrosis. Such decisions are influenced by response to antibiotic treatment. Multiple operations may be required. A recent study compared the step-up approach, i.e., percutaneous or endoscopic transgastric drainage with open necrosectomy for necrotizing pancreatitis. One third of the patients successfully treated with the step-up approach did not require major abdominal surgery. Enteral-feeding with a nasojejunal tube has been demonstrated to have fewer infectious complications than with total parenteral nutrition (TPN) and is the preferred method of nutritional support. In addition to nutritional support, enteral feeding helps to maintain integrity of the intestinal tract during severe acute pancreatitis.
Patients with severe gallstone-induced pancreatitis, complicated by cholangitis, may improve dramatically if papillotomy is carried out within the first 36−72 hours of the attack. Studies indicate that only those patients with gallstone pancreatitis who are in the very severe group should be considered for urgent ERCP. Finally, the treatment for patients with hypertriglyceridemia-associated pancreatitis includes (1) weight loss to ideal weight, (2) a lipid-restricted diet, (3) exercise, (4) avoidance of alcohol and of drugs that can elevate serum triglycerides (i.e., estrogens, vitamin A, thiazides, and propranolol), and (5) control of diabetes.
Approximately 25% of patients who have had an attack of acute pancreatitis have a recurrence. The two most common etiologic factors are alcohol and cholelithiasis. In patients with recurrent pancreatitis without an obvious cause the differential diagnosis should encompass occult biliary tract disease including microlithiasis, hypertriglyceridemia, drugs, pancreatic cancer, sphincter of Oddi dysfunction, pancreas divisum, cystic fibrosis, and pancreatic cancer (Table 313-1). In one series of 31 patients diagnosed initially as having idiopathic or recurrent acute pancreatitis, 23 were found to have occult gallstone disease. Thus, approximately two-thirds of patients with recurrent acute pancreatitis without an obvious cause actually have occult gallstone disease due to microlithiasis. Genetic defects as in hereditary pancreatitis can result in recurrent pancreatitis. Other diseases of the biliary tree and pancreatic ducts that can cause acute pancreatitis include choledochocele; ampullary tumors; pancreas divisum; and pancreatic duct stones, stricture, and tumor. Approximately 2−4% of patients with pancreatic carcinoma present with acute pancreatitis.
Infected Pancreatic Necrosis and Pseudocyst
Pancreatic necrosis does not usually become secondarily infected until at least 7−10 days after the onset of acute pancreatitis. Approximately one-half of cases of infected necrosis can be diagnosed between the 7th and 21st day, the remainder after 21 days. The diagnosis of pancreatic infection can be accomplished by CT-guided needle aspiration with Gram stain and culture. The organisms are most frequently gram-negative bacteria of intestinal origin. Clinical clues that should alert the clinician to the possibility of infected necrosis are persistent fever, leukocytosis, and organ failure in a patient with necrotizing pancreatitis. Some reports suggest that patients who have more than 50% pancreatic necrosis are more likely to have infected pancreatic necrosis than those who have lesser amounts of necrosis. Choices of treatment in infected pancreatic necrosis include surgical debridement; endoscopic debridement, if the pancreatic necrosis has been circumscribed into the entity termed walled-off necrosis that affects the posterior wall of the stomach; and, on occasion, radiologic catheter drainage with irrigation in an effort to eliminate at least some infected semisolid material as well as the infected liquid material. Radiologic approach is usually suggested to treat a patient who is too ill to undergo surgical debridement.
In necrotizing pancreatitis, there is invariably an intense inflammatory response involving the fat around the pancreas. This inflammatory process frequently results in peripancreatic necrosis. Eventually, after three to six weeks, there is coalescence of the pancreatic necrosis and peripancreatic fat necrosis into a structure that is encapsulated by fibrous tissue. The name that was originally used to describe this entity was “organized necrosis.” New terminology now refers to it as “walled-off necrosis.”
The walled-off necrosis contains semisolid necrotic tissue together with a considerable amount of dark fluid representing liquefaction of devitalized pancreatic and peripancreatic tissue as well as some blood.
Walled-off necrosis and a pancreatic pseudocyst may look very similar on first inspection of a contrast-enhanced CT scan. Both show a low attenuation nonenhancing round structure enclosed by a capsule containing fibrous tissue that enhances due to small blood vessels within the capsule. On closer inspection, a distinction can be made. In walled-off necrosis, serial images clearly show that a portion of the pancreas as well as variable amounts of peripancreatic tissue are necrotic. In interstitial pancreatitis, the pancreas enhances normally in response to intravenous contrast, thereby confirming that the process is interstitial pancreatitis. The encapsulated structure is readily seen to be adjacent to the pancreas.
Pseudocysts of the pancreas are extrapancreatic collections of pancreatic fluid containing pancreatic enzymes and a small amount of debris. In contrast to true cysts, pseudocysts do not have an epithelial lining. The walls consist of necrotic tissue, granulation tissue, and fibrous tissue.
A pseudocyst should be distinguished from a postnecrotic fluid collection that contains heterogeneous material including residual necrotic debris. Disruption of the pancreatic ductal system is common. However, the subsequent course of this disruption varies widely, ranging from spontaneous healing to continuous leakage of pancreatic juice, which results in tense ascites. Pseudocysts are preceded by pancreatitis in 90% of cases and by trauma in 10%. Approximately 85% are located in the body or tail of the pancreas and 15% in the head. Some patients have two or more pseudocysts. Abdominal pain, with or without radiation to the back, is the usual presenting complaint. A palpable, tender mass may be found in the middle or left upper abdomen.
On imaging studies, 75% of pseudocysts can be seen to displace some portion of the gastrointestinal tract. Sonography, however, is reliable in detecting pseudocysts. Sonography also permits differentiation between an edematous, inflamed pancreas, which can give rise to a palpable mass, and an actual pseudocyst. Furthermore, serial ultrasound studies will indicate whether a pseudocyst has resolved. CT or MRI complements ultrasonography in the diagnosis of pancreatic pseudocyst, especially when the pseudocyst is infected as suggested by the rare finding of gas within the fluid collection.
In earlier studies with sonography, lesions thought to be pseudocysts were seen to resolve in 25−40% of patients. However, it is now recognized that it is important to distinguish between walled-off necrosis and pseudocysts that typically develop later in the course of acute pancreatitis. Pseudocysts that are >5 cm in diameter may persist for >6 weeks. Recent natural history studies have suggested that noninterventional, expectant management is the best course in selected patients with minimal symptoms and no evidence of active alcohol use in whom the pseudocyst appears mature by radiography and does not resemble a cystic neoplasm. A significant number of these pseudocysts resolve spontaneously in >6 weeks after their formation. Also, these studies demonstrate that large pseudocyst size is not an absolute indication for interventional therapy and that many peripancreatic fluid collections detected on CT in cases of acute pancreatitis resolve spontaneously. A pseudocyst that does not resolve spontaneously can occasionally lead to serious complications, such as (1) pain caused by expansion of the lesion and pressure on other viscera, (2) rupture, (3) hemorrhage, and (4) abscess. Rupture of a pancreatic pseudocyst is a particularly serious complication. In this case, shock almost always supervenes, and mortality rates range from 14% if the rupture is not associated with hemorrhage to >60% if hemorrhage has occurred. Rupture and hemorrhage are the prime causes of death from pancreatic pseudocyst. A triad of findings—an increase in the size of the mass, a localized bruit over the mass, and a sudden decrease in hemoglobin level and hematocrit without obvious external blood loss—should alert one to the possibility of hemorrhage from a pseudocyst. Thus, in patients who are stable and free of complications and in whom serial ultrasound studies show that the pseudocyst is shrinking, conservative therapy is indicated. Conversely, if the pseudocyst is expanding and is complicated by severe pain, hemorrhage, or abscess, the patient should be operated on. Chronic pseudocysts can be treated safely and drainage can be accomplished by endoscopic, radiologic, or surgical means.
Pseudoaneurysms develop in up to 10% of patients with acute pancreatitis at sites reflecting the distribution of pseudocysts and fluid collections (Fig. 313-2D). The splenic artery is most frequently involved, followed by the inferior and superior pancreatic duodenal arteries. This diagnosis should be suspected in patients with pancreatitis who develop upper gastrointestinal bleeding without an obvious cause or in whom thin-cut CT scanning reveals a contrast-enhanced lesion within or adjacent to a suspected pseudocyst. CT angiography can identify the lesion, which can then be treated with angiographic embolization.
The local and systemic complications of acute pancreatitis are summarized in Table 313-4. Systemic complications include pulmonary, cardiovascular, hematologic, renal, metabolic, and central nervous system (CNS) abnormalities. Purtscher's retinopathy, a relatively unusual complication, is manifested by a sudden and severe loss of vision in a patient with acute pancreatitis. It is characterized by a peculiar funduscopic appearance with cotton-wool spots and hemorrhages confined to an area limited by the optic disc and macula; it is believed to be due to occlusion of the posterior retinal artery with aggregated granulocytes.
Table 313-4 Complications of Acute Pancreatitis |Favorite Table|Download (.pdf)
Table 313-4 Complications of Acute Pancreatitis
- Walled-off necrosis
Pancreatic fluid collections
- Pancreatic abscess
- Pancreatic pseudocyst
- Obstruction of gastrointestinal tract (stomach, duodenum, colon)
- Disruption of main pancreatic duct
- Leaking pseudocyst
Involvement of contiguous organs by necrotizing pancreatitis
- Massive intraperitoneal hemorrhage
- Thrombosis of blood vessels (splenic vein, portal vein)
- Bowel infarction
- Pleural effusion
- Mediastinal abscess
- Acute respiratory distress syndrome
- Sudden death
- Nonspecific ST-T changes in electrocardiogram simulating myocardial infarction
- Disseminated intravascular coagulation
- Peptic ulcer disease
- Erosive gastritis
- Hemorrhagic pancreatic necrosis with erosion into major blood vessels
- Portal vein thrombosis, variceal hemorrhage
- Renal artery and/or renal vein thrombosis
- Acute tubular necrosis
- Sudden blindness (Purtscher's retinopathy)
Central nervous system
- Subcutaneous tissues (erythematous nodules)
- Miscellaneous (mediastinum, pleura, nervous system)
Pancreatitis in Patients with AIDS
The incidence of acute pancreatitis is increased in patients with AIDS for two reasons: (1) the high incidence of infections involving the pancreas such as infections with cytomegalovirus, Cryptosporidium, and the Mycobacterium avium complex; and (2) the frequent use by patients with AIDS of medications such as didanosine, pentamidine, trimethoprim-sulfamethoxazole, and protease inhibitors (Chap. 189).
Pancreatic Ascites and Pancreatic Pleural Effusions
Pancreatic ascites or pancreatic pleural effusion are initially identified based on CT or MRI imaging and are usually due to disruption of the main pancreatic duct, often by an internal fistula between the duct and the peritoneal cavity or a leaking pseudocyst (Fig. 313-3A). This diagnosis is suggested in a patient with a history of acute pancreatitis in whom the ascites or pleural fluid has both increased levels of albumin [>30 g/L (>3 g/dL)] and a markedly elevated level of amylase. An ERCP or magnetic resonance cholangio pancreatography (MRCP) confirms the clinical suspicion and radiologic findings and often demonstrates passage of contrast material from a disrupted major pancreatic duct or a pseudocyst into the peritoneal cavity. The differential diagnosis of pancreatic ascites should include intraperitoneal carcinomatosis, tuberculous peritonitis, constrictive pericarditis, and Budd-Chiari syndrome.
Treatment: Pancreatic Ascites and Pancreatic Pleural Effusions
If the pancreatic duct disruption is posterior, an internal fistula may develop between the pancreatic duct and the pleural space, producing a pleural effusion (pancreaticopleural fistula) that is usually left-sided and often massive (Fig. 313-3). If the pancreatic duct disruption is anterior, amylase- and lipase-rich peritoneal fluid accumulate (pancreatic ascites). A leaking, disrupted pancreatic duct is best treated by ERCP and “bridging” stent placement and infrequently requires thoracentesis or chest tube drainage.
Treatment may also require enteral or parenteral alimentation to improve nutrition. If ascites or pleural fluid persists after two to three weeks of medical management, and the disruption is unable to be stented, the patient should be considered for surgical intervention after retrograde pancreatography to define the anatomy of the disrupted duct.
Chronic pancreatitis is a disease process characterized by irreversible damage to the pancreas as distinct from the reversible changes noted in acute pancreatitis. The condition is best defined by the presence of histologic abnormalities, including chronic inflammation, fibrosis, and progressive destruction of both exocrine and eventually endocrine tissue. A number of etiologies may result in chronic pancreatitis, and may result in the cardinal complications of chronic pancreatitis such as abdominal pain, steatorrhea, weight loss, and diabetes mellitus (Table 313-5).
Table 313-5 Chronic Pancreatitis and Pancreatic Exocrine Insufficiency: TIGAR-O Classification System |Favorite Table|Download (.pdf)
Table 313-5 Chronic Pancreatitis and Pancreatic Exocrine Insufficiency: TIGAR-O Classification System
- Tobacco smoking
- Chronic renal failure
- Medications—phenacetin abuse
- Toxins—organotin compounds (e.g., DBTC)
- Early onset
- Late onset
- Hereditary pancreatitis
- Cationic trypsinogen
- CFTR mutations
- SPINK1 mutations
- Isolated autoimmune chronic pancreatitis
- Autoimmune chronic pancreatitis associated with Sjögren's syndrome
- Inflammatory bowel disease
- Primary biliary cirrhosis
Recurrent and Severe Acute Pancreatitis
- Postnecrotic (severe acute pancreatitis)
- Recurrent acute pancreatitis
- Vascular diseases/ischemia
- Pancreas divisum
- Sphincter of Oddi disorders (controversial)
- Duct obstruction (e.g., tumor)
- Preampullary duodenal wall cysts
- Posttraumatic pancreatic duct scars
The events that initiate the inflammatory process in the pancreas are incompletely understood. Current experimental and clinical observations have shown that alcohol has a direct toxic effect on the pancreas. While patients with alcohol-induced pancreatitis generally consume large amounts of alcohol, some consume as little as ≤50 g/d. Prolonged consumption of socially acceptable amounts of alcohol is compatible with the development of chronic pancreatitis. Findings of extensive pancreatic fibrosis in patients who died during their first attack of clinical acute alcohol-induced pancreatitis support the concept that such patients already had chronic pancreatitis.
There is a strong association of smoking and chronic pancreatitis. Cigarette smoke leads to an increased susceptibility to pancreatic self-digestion and predisposes to dysregulation of duct cell CFTR function. It has become increasingly apparent that smoking is an independent, dose-dependent risk factor for chronic pancreatitis and recurrent acute pancreatitis. Smoking is clearly associated with progression of disease in late-onset idiopathic chronic pancreatitis and with increased disease severity in alcohol-induced chronic pancreatitis.
Recent characterization of pancreatic stellate cells (PSC) has added insight to the underlying cellular responses behind development of chronic pancreatitis. Specifically, PSCs are believed to play a role in maintaining normal pancreatic architecture that can shift toward fibrogenesis in the case of chronic pancreatitis. The sentinel acute pancreatitis event (SAPE) hypothesis uniformly describes the events in the pathogenesis of chronic pancreatitis. It is believed that alcohol or additional stimuli lead to matrix metalloproteinase−mediated destruction of normal collagen in pancreatic parenchyma, which later allows for pancreatic remodeling. Proinflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin 1 (IL-1), and interleukin 6 (IL-6) as well as oxidant complexes are able to induce PSC activity with subsequent new collagen synthesis. In addition to being stimulated by cytokines, oxidants, or growth factors, PSCs also possess transforming growth factor β (TGF-β)−mediated self-activating autocrine pathways that may explain disease progression in chronic pancreatitis even after removal of noxious stimuli.
Among adults in the United States, alcoholism is the most common cause of clinically apparent chronic pancreatitis, while cystic fibrosis is the most frequent cause in children. In up to 25% of adults in the United States with chronic pancreatitis, the cause is not known. That is, they are labeled as idiopathic chronic pancreatitis. Recent investigations have indicated that up to 15% of patients with idiopathic pancreatitis may have pancreatitis due to genetic defects (Table 313-5).
Whitcomb and associates studied several large families with hereditary chronic pancreatitis and were able to identify a genetic defect that affects the gene encoding for trypsinogen. Several additional defects of this gene have also been described. The defect prevents the destruction of trypsinogen and allows it to be resistant to the effect of trypsin inhibitor, become spontaneously activated, and to remain activated. It is hypothesized that this continual activation of digestive enzymes within the gland leads to acute injury and, finally, chronic pancreatitis. This group of investigators has also reported that another form of hereditary chronic pancreatitis tends to present later in life, has a female predominance, and frequently leads to chronic pancreatitis.
Several other groups of investigators have documented mutations of CFTR. This gene functions as a cyclic AMP−regulated chloride channel. In patients with cystic fibrosis, the high concentration of macromolecules can block the pancreatic ducts. It must be appreciated, however, that there is a great deal of heterogeneity in relationship to the CFTR gene defect. More than 1000 putative mutations of the CFTR gene have been identified. Attempts to elucidate the relationship between the genotype and pancreatic manifestations have been hampered by the number of mutations. The ability to detect CFTR mutations has led to the recognition that the clinical spectrum of the disease is broader than previously thought. Two recent studies have clarified the association between mutations of the CFTR gene and another monosymptomatic form of cystic fibrosis (i.e., chronic pancreatitis). It is estimated that in patients with idiopathic pancreatitis, the frequency of a single CFTR mutation is 11 times the expected frequency and the frequency of two mutant alleles is 80 times the expected frequency. In these studies, the patients were adults when the diagnosis of pancreatitis was made; none had any clinical evidence of pulmonary disease, and sweat test results were not diagnostic of cystic fibrosis. The prevalence of such mutations is unclear, and further studies are certainly needed. In addition, the therapeutic and prognostic implication of these findings with respect to managing pancreatitis remains to be determined. Long-term follow-up of affected patients is needed. CFTR mutations are common in the general population. It is unclear whether the CFTR mutation alone can lead to pancreatitis as an autosomal recessive disease. A recent study evaluated 39 patients with idiopathic chronic pancreatitis to assess the risk associated with these mutations. Patients with two CFTR mutations (compound heterozygotes) demonstrated CFTR function at a level between that seen in typical cystic fibrosis and cystic fibrosis carriers and had a fortyfold increased risk of pancreatitis. The presence of an N34S SPINK1 mutation increased the risk twentyfold. A combination of two CFTR mutations and an N34S SPINK1 mutation increased the risk of pancreatitis 900-fold. Table 313-5 lists recognized causes of chronic pancreatitis and pancreatic exocrine insufficiency.
Autoimmune Pancreatitis (Table 313-6)
Table 313-6 Clinical Features of Autoimmune Pancreatitis (AIP) |Favorite Table|Download (.pdf)
Table 313-6 Clinical Features of Autoimmune Pancreatitis (AIP)
- Mild symptoms usually abdominal pain, but without frequent attacks of pancreatitis, which are unusual
- Presentation with obstructive jaundice
- Diffuse swelling and enlargement of the pancreas, especially the head, the latter mimicking carcinoma of the pancreas
- Diffuse irregular narrowing of the pancreatic duct in ERCP
- Increased levels of serum gamma globulins especially IgG4
- Presence of other autoantibodies (ANA), rheumatoid factor (RF)
- Can occur with other autoimmune diseases: Sjögren's syndrome, primary sclerosing cholangitis, ulcerative colitis, rheumatoid arthritis
- Extra pancreatic bile duct changes such as stricture of the common bile duct and intrahepatic ducts
- Absence of pancreatic calcifications or cysts
- Pancreatic biopsies reveal extensive fibrosis and lymphoplasmacytic infiltration
- Glucocorticoids are effective in alleviating symptoms, decreasing size of the pancreas, and reversing histopathologic changes
- Two-thirds of patients present with either obstructive jaundice or a “mass” in the head of the pancreas mimicking carcinoma
Autoimmune pancreatitis (AIP) is an uncommon disorder of presumed autoimmune causation with characteristic laboratory, histologic, and morphologic findings. AIP has been described as a primary pancreatic disorder; however, it is also associated with other disorders of presumed autoimmune etiology, including primary sclerosing cholangitis, primary biliary sclerosis, rheumatoid arthritis, Sjögren's syndrome, ulcerative colitis, mediastinal adenopathy, autoimmune thyroiditis, tubulointerstitial nephritis, and retroperitoneal fibrosis. Mild symptoms, usually abdominal pain, are present but attacks of acute pancreatitis are unusual. Furthermore, AIP is not a common cause of idiopathic recurrent pancreatitis. In the United States, 50−75% of patients with AIP present with obstructive jaundice.
Weight loss and new onset of diabetes may also occur. An obstructive pattern on liver tests is common (i.e., disproportionately elevated serum alkaline phosphatase and minimally elevated serum aminotransferases). Elevated serum levels of immunoglobulin G4 (IgG4) provide a marker for the disease, particularly in Western populations. Serum IgG4 normally accounts for only 5−6% of the total IgG4 in healthy patients but is elevated at least twofold higher than 135 mg/dL in those with AIP. CT scans reveal abnormalities in the majority of patients and include diffuse enlargement, focal enlargement, and a distinct enlargement at the head of the pancreas. ERCP or MRCP reveals strictures in the bile duct in more than one-third of patients with AIP; these may be common bile duct strictures, intrahepatic bile duct strictures, or proximal bile duct strictures, with accompanying narrowing of the pancreatic bile duct. This has been termed autoimmune cholangitis. Characteristic histologic findings include extensive lymphoplasmacytic infiltrates with dense fibrosis around pancreatic ducts, as well as a lymphoplasmacytic infiltration, resulting in an obliterative phlebitis.
The Mayo Clinic criteria indicate that AIP can be diagnosed with at least one of three abnormalities: (1) diagnostic histology; (2) characteristic findings on CT and pancreatography combined with elevated IgG4 levels; and (3) response to glucocorticoid therapy, with improvement in pancreatic and extrapancreatic manifestations.
Glucocorticoids have shown efficacy in alleviating symptoms, decreasing the size of the pancreas, and reversing histopathologic features in patients with AIP. Patients may respond dramatically to glucocorticoid therapy within a two- to four-week period. Prednisone is usually administered at an initial dose of 40 mg/d for four weeks followed by a taper of the daily dosage by 5 mg/week based on monitoring of clinical parameters. Relief of symptoms, serial changes in abdominal imaging of the pancreas and bile ducts, decreased serum γ-globulin and IgG4 levels, and improvements in liver tests are parameters to follow. A poor response to glucocorticoids over a two- to four-week period should raise suspicion of pancreatic cancer or other forms of chronic pancreatitis. In most reports, 50−70% of patients responded to glucocorticoids, but about 25% required a second course of treatment while a smaller number required maintenance treatment with prednisone at a dosage of 5−10 mg/d. Patients with bile duct strictures are less likely to have a sustained response to glucocorticoids and may require immunosuppressive therapy with azathioprine or 6-mercaptopurine.
Clinical Features of Chronic Pancreatitis
Patients with chronic pancreatitis seek medical attention predominantly because of two symptoms: abdominal pain or maldigestion and weight loss. The abdominal pain may be quite variable in location, severity, and frequency. The pain can be constant or intermittent with frequent pain-free intervals. Eating may exacerbate the pain, leading to a fear of eating with consequent weight loss. The spectrum of abdominal pain ranges from mild to quite severe, with narcotic dependence as a frequent consequence. Maldigestion is manifested as chronic diarrhea, steatorrhea, weight loss, and fatigue. Patients with chronic abdominal pain may or may not progress to maldigestion, and ∼20% of patients will present with symptoms of maldigestion without a history of abdominal pain. Patients with chronic pancreatitis have significant morbidity and mortality and utilize appreciable amounts of societal resources. Despite the steatorrhea, clinically apparent deficiencies of fat-soluble vitamins are surprisingly uncommon. Physical findings in these patients are usually unimpressive so that there is a disparity between the severity of abdominal pain and the physical signs that usually consist of some mild tenderness.
In contrast to acute pancreatitis, the serum amylase and lipase levels are usually not strikingly elevated in chronic pancreatitis. Elevation of serum bilirubin and alkaline phosphatase may indicate cholestasis secondary to common bile duct stricture caused by chronic inflammation. Many patients have impaired glucose tolerance with elevated fasting blood glucose levels. The diagnostic test with the best sensitivity and specificity is the hormone stimulation test utilizing secretin. It becomes abnormal when ≥60% of the pancreatic exocrine function has been lost. This usually correlates well with the onset of chronic abdominal pain. In earlier studies, approximately 40% of patients with chronic pancreatitis had cobalamin (vitamin B12) malabsorption. This can be corrected by the administration of oral pancreatic enzymes. The fecal elastase-1 and small bowel biopsy are useful in the evaluation of patients with suspected pancreatic steatorrhea. The fecal elastase level will be abnormal and small bowel histology will be normal in such patients. A decrease of fecal elastase level to <100 g per gram of stool strongly suggests severe pancreatic exocrine insufficiency.
Utilizing radiographic techniques (Fig. 313-4), it can be shown that diffuse calcifications noted on plain film of the abdomen usually indicate significant damage to the pancreas. While alcohol is by far the most common cause of pancreatic calcification such calcification may also be noted in hereditary pancreatitis, posttraumatic pancreatitis, hypercalcemic pancreatitis, islet cell tumors, idiopathicchronic pancreatitis, and tropical pancreatitis. Abdominal ultrasonography, CT scanning, and MRCP greatly aid in the diagnosis of pancreatic disease (Fig. 313-4). In addition to excluding a pseudocyst and pancreatic cancer, CT may show calcification, dilated ducts, or an atrophic pancreas. MRCP provides a direct view of the pancreatic duct and is now the diagnostic procedure of choice. The role of endoscopic ultrasonography (EUS) in diagnosing early chronic pancreatitis is still being defined. A total of nine endosonographic features have been described in chronic pancreatitis. The presence of five or more features is considered diagnostic of chronic pancreatitis. EUS complements pancreatic function tests, and a combination of a hormone-stimulation function test and EUS is a modality to evaluate the pancreatic duct morphology, parenchymal architecture, and secretory function for the presence or extent of chronic pancreatitis (Chap. 312). Whether EUS alone can detect early, noncalcific chronic pancreatitis with the same degree of accuracy as the hormone-stimulation test is controversial. Data comparing these modalities head-to-head have indicated that EUS is not a sensitive enough test for detecting early chronic pancreatitis (Chap. 312) and may show positive features in patients who have dyspepsia or even in normal controls. However, recent data suggest that EUS can be combined with endoscopic pancreatic function testing (EUS-ePFT) during a single endoscopy to screen for chronic pancreatitis in patients with chronic abdominal pain.
A. Chronic pancreatitis and pancreatic calculi: CT scan. In this contrast-enhanced CT scan of the abdomen, there is evidence of an atrophic pancreas with multiple calcifications and stones in the parenchyma and dilated pancreatic duct (arrow). B. In this contrast-enhanced CT scan of the abdomen, there is evidence of an atrophic pancreas with multiple calcifications (arrows). Note the markedly dilated pancreatic duct seen in this section through the body and tail (open arrows). C. Chronic pancreatitis on MRCP: dilated duct with filling defects. Gadolinium-enhanced MRI/MRCP reveals a dilated pancreatic duct (arrow) in chronic pancreatitis with multiple filling defects suggestive of pancreatic duct calculi. (A, C, courtesy of Dr. KJ Mortele, Brigham and Women's Hospital; with permission.)
Complications of Chronic Pancreatitis
The complications of chronic pancreatitis are protean and are listed in Table 313-7. Although most patients have impaired glucose tolerance, diabetic ketoacidosis and coma are uncommon. Likewise, end-organ damage (retinopathy, neuropathy, nephropathy) is also uncommon. A nondiabetic retinopathy may be due to either vitamin A and/or zinc deficiency. Gastrointestinal bleeding may occur from peptic ulceration, gastritis, a pseudocyst eroding into the duodenum, or ruptured varices secondary to splenic vein thrombosis due to chronic inflammation of the tail of the pancreas. Jaundice, cholestasis, and biliary cirrhosis may occur from the chronic inflammatory reaction around the intrapancreatic portion of the common bile duct. Twenty years after the diagnosis of calcific chronic pancreatitis, the cumulative risk of pancreatic carcinoma is 4%. Patients with hereditary pancreatitis are at a tenfold higher risk for pancreatic cancer.
Table 313-7 Complications of Chronic Pancreatitis |Favorite Table|Download (.pdf)
Table 313-7 Complications of Chronic Pancreatitis
Impaired glucose tolerance
Effusions with high amylase content
Cholangitis and/or biliary cirrhosis
Subcutaneous fat necrosis
Treatment: Chronic Pancreatitis
The treatment of steatorrhea with pancreatic enzymes is straightforward even though complete correction of steatorrhea is unusual. Enzyme therapy usually brings diarrhea under control and restores absorption of fat to an acceptable level and effects weight gain. Thus, pancreatic enzymes have been the cornerstone of pancreatic therapy. In treating steatorrhea, it is important to use a potent pancreatic formulation that will deliver sufficient lipase into the duodenum to correct maldigestion and decrease steatorrhea (Table 313-8). In an attempt to standardize the enzyme activity, potency and bioavailability, the Food and Drug Administration (FDA) required that all pancreas enzyme drugs in the United States obtain a New Drug Application (NDA) by April 2008. Table 313-8 lists frequently utilized formulations but availability will be based on compliance with the FDA mandate. Recent data suggests that dosages up to 80,000−100,000 units of lipase per meal may be necessary to normalize nutritional parameters in malnourished chronic pancreatitis patients.
Table 313-8 Frequently Utilized Pancreatic Enzyme Preparations |Favorite Table|Download (.pdf)
Table 313-8 Frequently Utilized Pancreatic Enzyme Preparations
|Enzyme Preparations||Manufacturer, Location||Lipase*||Protease*||Amylase*|
|Enteric Coated (EC)|
[EC microspheres in capsules]
|Axcan Pharma, Birmingham, AL|
[delayed-release capsules containing EC spheres]
|Solvay Pharmaceuticals, Marietta, GA|
[EC microtablets in capsule]
|Ortho-McNeil Pharmaceuticals, Riritan, NJ|
|Pancrease MT 4||4,000||12,000||12,000|
|Pancrease MT 10||10,000||30,000||30,000|
|Pancrease MT 16||16,000||48,000||48,000|
|Pancrease MT 20||20,000||44,000||56,000|
[EC microspheres (buffered) in delayed-release capsule]
|Digestive Care, Inc., Bethlehem, PA|
(pancrelipase, USP) Tablets, Powder
|Axcan Scandipharm, Birmingham, AL|
|Viokase Powder: Lactose, sodium chloride, each 0.7 g (1/4 teaspoonful)||16,800||70,000||70,000|
|UCB Inc., Rochester, NY|
The management of pain in patients with chronic pancreatitis is problematic.
Recent meta-analyses have shown no consistent benefit of enzyme therapy at reducing pain in chronic pancreatitis. In some patients with idiopathic chronic pancreatitis, conventional nonenteric coated enzyme preparations containing high concentrations of serine proteases may relieve mild abdominal pain or discomfort. The pain relief experienced by these patients actually may be due to improvements in the dyspepsia from maldigestion. Table 313-8 lists the frequently utilized pancreatic enzyme preparations in the United States.
Oxidative stress has also been implicated in the pathophysiology of the pain of chronic pancreatitis. A recent randomized prospective study from India showed antioxidant therapy to be beneficial at reducing pain in mild chronic pancreatitis. Gastroparesis is also quite common in patients with chronic pancreatitis. It is important to recognize this because treatment with enzymes may fail simply because gastroparesis is preventing the appropriate delivery of enzymes into the upper intestine where the enzymes can then act via a feedback inhibition process. In patients with painful chronic pancreatitis, it is important to evaluate gastric emptying and, if gastric emptying is impaired, to effect proper emptying with prokinetic agents. In this setting, enzyme therapy is more apt to be successful.
Endoscopic treatment of chronic pancreatitis pain may involve sphincterotomy, stenting, stone extraction, and drainage of a pancreatic pseudocyst. Therapy directed to the pancreatic duct would seem to be most appropriate in the setting of a dominant stricture, if a ductal stone has led to obstruction. The use of endoscopic stenting for patients with chronic pain, but without a dominant stricture, has not been subjected to any controlled trials. It is now appreciated that significant complications can occur from stenting (i.e., bleeding, cholangitis, stent migration, and stent clogging). All of these may lead to pancreatitis. Importantly, damage to the pancreatic duct and the pancreatic parenchyma can occur following stenting. In patients with large-duct disease usually from alcohol-induced chronic pancreatitis, ductal decompression has been the therapy of choice. Among such patients, 80% seem to obtain immediate relief; however, at the end of three years, one-half the patients have recurrence of pain. Two randomized prospective trials comparing endoscopic to surgical therapy for chronic pancreatitis demonstrated that surgical therapy was superior to endoscopy at decreasing pain and improving quality of life in selected patients with dilated ducts and abdominal pain. This would suggest that chronic pancreatitis patients with dilated ducts and pain should be considered for surgical intervention. The role of preoperative stenting prior to surgery as a predictor of response has yet to be proven.
A Whipple procedure as well as total pancreatectomy and autologous islet cell transplantation have been used in selected patients with chronic pancreatitis and abdominal pain refractory to conventional therapy. The patients who have benefited the most from total pancreatectomy have chronic pancreatitis without prior pancreatic surgery or evidence of islet cell insufficiency. The role of this procedure remains to be fully defined but may be an option in lieu of ductal decompression surgery or pancreatic resection in patients with intractable, painful small-duct disease, particularly as the standard surgical procedures tend to decrease islet cell yield. Celiac plexus block has not been demonstrated to provide long-lasting pain relief.
Hereditary pancreatitis is a rare disease that is similar to chronic pancreatitis except for an early age of onset and evidence of hereditary factors (involving an autosomal dominant gene with incomplete penetrance). A genomewide search using genetic linkage analysis identified the hereditary pancreatitis gene on chromosome 7. Mutations in ion codons 29 (exon 2) and 122 (exon 3) of the cationic trypsinogen gene cause autosomal dominant forms of hereditary pancreatitis. The codon 122 mutations lead to a substitution of the corresponding arginine with another amino acid, usually histidine. This substitution, when it occurs, eliminates a fail-safe trypsin self-destruction site necessary to eliminate trypsin that is prematurely activated within the acinar cell. These patients have recurring attacks of severe abdominal pain that may last from a few days to a few weeks. The serum amylase and lipase levels may be elevated during acute attacks but are usually normal. Patients frequently develop pancreatic calcification, diabetes mellitus, and steatorrhea; in addition, they have an increased incidence of pancreatic carcinoma, with the cumulative incidence being as high as 40% by age 70 years. A recent natural history study of hereditary pancreatitis in more than 200 patients from France reported that abdominal pain started in childhood at age 10 years, steatorrhea developed at age 29 years, diabetes at age 38 years, and pancreatic carcinoma at age 55 years. Such patients often require surgical ductal decompression for pain relief. Abdominal complaints in relatives of patients with hereditary pancreatitis should raise the question of pancreatic disease.
Pancreatic Secretory Trypsin Inhibitor (PSTI) Gene Mutations
PSTI, or SPINK1, is a 56-amino-acid peptide that specifically inhibits trypsin by physically blocking its active site. SPINK1 acts as the first line of defense against prematurely activated trypsinogen in the acinar cell. Recently, it has been shown that the frequency of SPINK1 mutations in patients with idiopathicchronic pancreatitis is markedly increased, suggesting that these mutations may be associated with pancreatitis.
Pancreatic Endocrine Tumors
Pancreatic endocrine tumors are discussed in Chap. 350.