Acute Pancreatitis
Michael L. Steer
Definition, Classification, and Pathology
Pancreatitis, an inflammatory disease of the pancreas, can be classified as acute or chronic on the basis of clinical, morphologic, or functional criteria. The classification of any particular patient’s disease depends on the criteria being used. Clinically, acute pancreatitis is defined as a process that is of rapid onset and usually associated with pain and alterations in exocrine function. With successful treatment, complete resolution can be expected. Chronic pancreatitis, on the contrary, is usually associated with repeated episodes of pain or diminished exocrine function, or both, that recur even after successful treatment of an attack. The morphologic or functional classification of pancreatitis, which has been the subject of several international symposia [1,2,3,4], also distinguishes between an acute and a chronic form of the disease, but that distinction is based on the reversibility of morphologic or functional changes, or both, in the pancreas. According to this scheme, acute pancreatitis is defined as an inflammatory process that occurs in a gland that was morphologically and functionally normal before the attack and can return to that state after resolution of the attack. In contrast, chronic pancreatitis is defined as an inflammatory disease involving a pancreas that was morphologically or functionally abnormal, or both, before the onset of symptoms or that will remain abnormal even after the attack has resolved. For the most part, the term acute pancreatitis is used in this chapter in its clinical rather than its morphologic or functional context. For reasons of completeness, however, the pathologic, etiologic, and therapeutic issues that are of particular relevance to morphologically or functionally defined chronic pancreatitis also are discussed.
The pathologic changes associated with acute pancreatitis vary to a great extent with the severity of an attack [5]. Mild acute pancreatitis is associated with interstitial edema, a mild infiltration of inflammatory cells, and evidence of intrapancreatic or peripancreatic fat necrosis, or both. In contrast, severe attacks of acute pancreatitis usually are associated with acinar cell necrosis that may be either focal or diffusely distributed throughout the gland. In addition, thrombosis of intrapancreatic vessels, vascular disruption with intraparenchymal hemorrhage, and abscess formation may be noted. Because chronic pancreatitis involves inflammation in a previously diseased gland, areas of scarring with fibrosis along with atrophy of acinar tissue can be seen even in tissue taken during the early stages of an attack. Varying degrees of acute inflammation are usually observed to be superimposed on these more chronic changes.
Etiology
Pancreatitis is associated with a number of other disease states or conditions that collectively are referred to as the etiologies of pancreatitis [6,7,8]. In developed countries, 70% to 80% of patients with pancreatitis have the disorder in association with either ethanol abuse or biliary tract stone disease. Another 10% to 20% of patients have no identifiable cause for pancreatitis and are considered to have idiopathic pancreatitis. In the remaining 5% to 10% of patients, pancreatitis develops in association with one of the various etiologies listed in Table 99.1. In the less well-developed countries, particularly those in Africa and Asia, disease develops as a result of malnutrition or ingestion of potentially toxic agents, or both, in a significant fraction of patients with acute pancreatitis [9,10,11,12]. Their pancreatitis has been termed nutritional or tropical pancreatitis. This entity is particularly common in the Indian subcontinent, but its cause is unknown [12].
Biliary Tract Stone Disease
Biliary tract stones are the most frequent cause of morphologic and functionally defined acute pancreatitis and, along with ethanol abuse, account for 60% to 80% of patients with clinically acute pancreatitis in developed countries. The frequency of either biliary tract stones or ethanol abuse among any group of patients being evaluated with acute pancreatitis depends on the socioeconomic composition of that group; that is, in affluent suburban groups, biliary tract stones account for more attacks, whereas ethanol abuse is more commonly found to be associated with pancreatitis when inner-city and poorer patients are studied [6]. Biliary tract stone disease is a frequent cause of acute pancreatitis among American Indians of the desert Southwest, who are prone to development of stones, and among many Asian groups, who have a high incidence of stone formation as a consequence of chronic bactibilia.
Table 99.1 Miscellaneous Etiologies of Acute Pancreatitis | |
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Reports by Acosta and Ledesma [13] and Acosta et al. [14] indicated that the onset of pancreatitis associated with biliary tract stones is related to the passage of those stones through the terminal biliopancreatic duct and into the duodenum. The mechanism by which stone passage triggers this so-called gallstone pancreatitis has been the subject of considerable speculation and experimental investigation. Three theories have been proposed. The first was the “common channel” theory proposed by Opie [15] in 1901 after he noted gallstones impacted in the ampulla of Vater when patients dying of gallstone pancreatitis underwent autopsy examination. He suggested that such stones might create a common biliopancreatic channel proximal to the stone-induced obstruction and that, as a consequence, bile could reflux into the pancreatic ductal system. He reasoned that bile reflux would be injurious to the pancreas and trigger pancreatitis. Subsequent investigations by many groups, however, have challenged the validity of this theory pointing out that pancreatic duct pressure normally exceeds biliary duct pressure, and therefore pancreatic juice reflux into the biliary tract rather than bile reflux into the pancreas would be expected if an obstruction were to create a common channel [16]. Furthermore, many patients develop pancreatitis but lack a common channel that could permit reflux [17], and bile perfused into the pancreatic duct at normal pressure does not induce pancreatitis [18].
The second theory proposed to explain gallstone-induced pancreatitis suggested that the stone passing through the sphincter of Oddi could render that sphincter incompetent and, as a result, permit reflux of duodenal juice containing activated digestive enzymes into the pancreas [19]. This “duodenal reflux” would seem an unlikely explanation for the development of pancreatitis because it is now clear that neither endoscopic nor surgical procedures that make the sphincter of Oddi incompetent lead to subsequent attacks of acute pancreatitis.
The third theory suggests that either the stone or edema and inflammation resulting from stone passage cause pancreatic duct obstruction and that pancreatic duct obstruction is the event that triggers acute pancreatitis. Studies using a model of acute necrotizing biliary pancreatitis induced in opossums support this theory [20], but in virtually all other species (dog, cat, mouse, rat, rabbit, etc.), pancreatic duct obstruction leads to atrophy of the pancreas with little or no evidence of pancreatitis. This observation has cast considerable doubt on the duct obstruction theory.
Most students of acute pancreatitis favor the “common channel-bile reflux theory” but, clearly, uncertainty regarding mechanisms responsible for gallstone-induced pancreatitis persists. It is generally believed that acute pancreatitis results from an autodigestive injury to the pancreas by enzymes that it normally synthesizes and secretes. Normally, those digestive enzymes are synthesized, intracellularly transported, and secreted from acinar cells as inactive zymogens. Activation normally occurs within the duodenum where the brush border enzyme enterokinase activates trypsinogen and trypsin activates the other zymogens. During pancreatitis, however, zymogen activation appears to occur inside acinar cells, perhaps as a result of pathological changes in cytoplasmic calcium levels and co-localization of digestive zymogens with lysosomal hydrolases such as cathepsin B, and, subsequently, zymogen activation leads to the acinar cell injury/death which is the hallmark of severe pancreatitis [21,22,23,24,25].
Recent studies in our laboratory have revealed that the bile acid receptor Gpbar1 is expressed at the apical (luminal) pole of pancreatic acinar cells and that activation of Gpbar1 in acinar cells can cause pathological rises in cytoplasmic calcium levels, zymogen activation, and cell injury. These very recent findings
[24] suggest that indeed, biliary pancreatitis may be triggered by bile reflux into the pancreatic duct through a common biliopancreatic duct and that bile acids contained within that bile may trigger pancreatitis via events that are set in motion following activation of Gpbar1.
[24] suggest that indeed, biliary pancreatitis may be triggered by bile reflux into the pancreatic duct through a common biliopancreatic duct and that bile acids contained within that bile may trigger pancreatitis via events that are set in motion following activation of Gpbar1.
Ethanol Abuse
In most patients with ethanol-associated pancreatitis, their first clinical attack of pancreatitis develops after many years of ethanol abuse. The incidence of pancreatitis is related to the logarithm of alcohol consumption, but there is no threshold below which alcohol ingestion is not associated with an increased incidence of pancreatitis. The mean consumption of ethanol among patients with ethanol-associated pancreatitis is 150 to 175 g per day. The mean duration of consumption before the first attack is 18 ± 11 years for men and 11 ± 8 years for women [26]. Ethanol-associated pancreatitis, like ethanol abuse itself, is more common among men than among women. Epidemiologic studies suggested that ethanol-associated pancreatitis is most common among those ingesting a high-protein diet with either high or low fat content [26]. The mechanism by which chronic ethanol abuse leads to chronic pancreatic injury is not clear, although some studies suggest that injury may result from secretion of a juice that is high in proteolytic enzyme content, low in proteolytic enzyme inhibitors, and contains lysosomal hydrolases capable of activating trypsin either within acinar cells or in the pancreatic ductal space [26,27,28].
In some patients with ethanol-induced pancreatitis, the disease develops after only one or several exposures to ethanol. This observation, along with the finding that a substantial number of patients dying of ethanol-associated disease do not have pancreatic fibrosis at autopsy [29], suggested that ethanol might be a cause of morphologic and/or functional and clinical acute pancreatitis.
The mechanism by which ethanol might cause acute injury to the pancreas is not clear. Some suggested possibilities include a direct toxic drug-like effect on acinar cells or, alternatively, induction of ductal hypertension as a result of stimulating exocrine secretion and sphincteric contraction [30,31]. Recent reports have suggested that direct cellular injury may be mediated by ethanol metabolites [30,31,32,33,34,35], and that circulating levels of bacterial endotoxin, perhaps released by the intestinal effects of ethanol, may be important contributing events [34]. It is possible that the chronic pancreatitis associated with prolonged ethanol abuse represents the cumulative effect of repeated subclinical attacks of acute pancreatitis. Thus, mild episodes associated with minimal necrosis may progress to fibrosis (i.e., the necrosis–fibrosis concept) [36]. It is also possible that chronic exposure to ethanol interferes with the resolution of inflammation and fibrosis, which normally follow episodes of injury, and that, in this way, ethanol favors the persistence of pancreatic fibrosis/inflammation even after relatively mild episodes of injury [37].
Drugs
Exposure to certain drugs represents perhaps the third most common cause of acute pancreatitis [38,39,40,41] (Table 99.2). The relationship between drug exposure and the development of pancreatitis can be categorized as definite, probable, or equivocal on the strength of the data that indicate that the drug actually causes pancreatitis. The former category includes those drugs whose use is associated with an increased incidence of pancreatitis and that, on specific rechallenge, have been found to induce the disease. On the contrary, drugs in the equivocal category include those that are anecdotally associated with the disease but never demonstrated in prospective studies to be capable of inducing pancreatitis. Historically, diuretic agents such as the thiazides, ethacrynic acid, and furosemide were considered the most likely drugs to cause pancreatitis. More recently, however, drug-related pancreatitis has been reported to be the most common among individuals with acquired immunodeficiency syndrome or acquired immunodeficiency syndrome–related complex receiving dideoxyinosine [42], pentamidine, or related compounds and among transplant patients receiving immunosuppressant agents such as azathioprine. Although previously considered to cause pancreatitis, histamine-2 (H2)–blockers and steroids are not currently believed to be capable of causing acute pancreatitis.
Table 99.2 Drugs Associated with Acute Pancreatitis | ||||||||||||||||||||||||||||||||||
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Pancreatic Duct Obstruction
Obstruction of the pancreatic duct is considered by most investigators to be the mechanism by which biliary tract stones trigger acute pancreatitis. Other events or processes that cause pancreatic duct obstruction also can result in pancreatitis. Thus, pancreatitis may be caused by duodenal, ampullary, biliary duct, or pancreatic tumors that obstruct the duct or by inflammatory lesions (e.g., peptic ulcer, duodenal Crohn’s disease, periampullary diverticulitis) that interfere with pancreatic duct drainage [6]. Pancreatic cysts and pseudocysts and periampullary diverticula filled with food and debris can interfere with duct drainage and as a consequence precipitate pancreatitis. Ductal strictures, frequently the result of traumatic duct injury or previous pancreatitis, can be a cause for obstructive pancreatitis. Finally, certain parasites, such as Ascaris and Clonorchis, can trigger pancreatitis by physically obstructing the pancreatic duct [6,43]. An association between pancreas divisum and pancreatitis has been claimed, presumably reflecting relative obstruction to pancreatic juice flow at the lesser papilla [44], but this is quite controversial [45,46].
Other Miscellaneous Causes of Acute Pancreatitis
Many of the remaining miscellaneous causes of pancreatitis are listed in Table 99.1. Traumatic pancreatitis usually follows blunt abdominal trauma, during which the body of the
pancreas is compressed against the vertebral column. As a result, the gland is “cracked,” and the duct is either partially or completely transected [47]. Lesser degrees of blunt trauma may be associated with pancreatic contusion, whereas penetrating injury can affect any portion of the pancreas. Traumatic injury to the pancreas also can be associated with surgical procedures performed on or near the pancreas [48,49,50]. Postoperative pancreatitis is also frequently associated with procedures performed on or near the sphincter of Oddi (duct exploration, sphincteroplasty, distal gastrectomy), procedures associated with hypoperfusion or atheroembolism of the pancreatic circulation (cardiopulmonary bypass, cardiac transplantation, renal transplantation, translumbar aortography) [51,52], or procedures involving pancreatic duct injection (endoscopic retrograde cholangiopancreatography [ERCP]) [53].
pancreas is compressed against the vertebral column. As a result, the gland is “cracked,” and the duct is either partially or completely transected [47]. Lesser degrees of blunt trauma may be associated with pancreatic contusion, whereas penetrating injury can affect any portion of the pancreas. Traumatic injury to the pancreas also can be associated with surgical procedures performed on or near the pancreas [48,49,50]. Postoperative pancreatitis is also frequently associated with procedures performed on or near the sphincter of Oddi (duct exploration, sphincteroplasty, distal gastrectomy), procedures associated with hypoperfusion or atheroembolism of the pancreatic circulation (cardiopulmonary bypass, cardiac transplantation, renal transplantation, translumbar aortography) [51,52], or procedures involving pancreatic duct injection (endoscopic retrograde cholangiopancreatography [ERCP]) [53].
Chronic pancreatitis can also be a familial disease transmitted by a mutation on chromosome 7 that is transmitted as an autosomal dominant with incomplete penetrance [54]. Reports indicate that the mutation results in synthesis of a cationic trypsinogen that is resistant to autoinactivation after activation has occurred [55]. Patients with classic cystic fibrosis mutations can present with pancreatitis even in the absence of pulmonary disease. Studies indicate that a substantial number of patients with so-called idiopathic pancreatitis may have nonclassic cystic fibrosis mutations or polymorphisms [56].
Pancreatitis can also develop on an autoimmune basis in association with other autoimmune processes such as primary sclerosing cholangitis, Sjogren’s syndrome, and primary biliary cirrhosis. A number of recent reports, particularly from Japan, have drawn attention to a form of autoimmune pancreatitis characterized by extensive lymphoplasmacytic infiltration into the pancreas and sclerosis of the pancreatic and bile ducts. Patients with this form of pancreatitis frequently present with both bile and pancreatic duct obstruction and a mass in the head of the pancreas. They can easily be thought to have neoplastic disease of the pancreas but, if placed on steroid treatment, the changes of autoimmune pancreatitis rapidly resolve. Many, but not all, of these patients have elevated circulating levels of IgG4 and this may permit their identification [57].
Idiopathic Pancreatitis
Approximately 5% to 10% of patients with acute pancreatitis have the disease in the absence of biliary tract stones, ethanol abuse, or any other identifiable etiology. Reports suggest that many of these patients have biliary sludge, that their attacks can be prevented by cholecystectomy, and that they actually have biliary rather than idiopathic pancreatitis [58,59]. Approximately 40% of individuals with chronic pancreatitis neither abuse ethanol nor have malnutrition. As a result, they are considered to have idiopathic chronic pancreatitis [60]. Studies in Europe and the United States suggest that these individuals can be divided into a juvenile group, with an onset of disease at a median age of 18, and a senile group, whose disease begins at a mean age of 60. Disease in the former group is characterized by pain, whereas that in the senile group is most often painless and associated with calcifications, diabetes mellitus, or both [61].
Clinical Presentation
Symptoms
The symptoms of acute pancreatitis include abdominal pain, nausea, and vomiting [6,7,43,62,63] (Table 99.3). The pain typically is localized to the epigastrium but frequently involves one or both upper quadrants. On occasion, it may be felt in the lower abdomen, one or both shoulders, or the lower chest. The pain is usually described as being of rapid onset, slowly increasing to a maximal severity, and then remaining constant. It usually lacks the waxing and waning character of intestinal or ureteral colic, but it may be diminished by assuming an upright position, leaning forward, or lying on the side with the knees drawn upward. The pain may have a pleuritic component and may be associated with rapid but shallow respirations. Frequently, the pain is described as being a boring or knifelike sensation that passes straight through to the midcentral back from the epigastrium.
Table 99.3 Signs and Symptoms of Acute Pancreatitis | ||||||||||||||||||||
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Nausea and vomiting commonly are noted in patients with acute pancreatitis. The vomiting typically persists even after the stomach has been emptied and may result in gastroesophageal tears with bleeding (i.e., Mallory–Weiss syndrome). The vomiting and retching may be relieved by passage of a nasogastric tube, but neither the vomiting nor gastric decompression results in reduction of the abdominal pain.
Physical Examination
Patients with acute pancreatitis typically appear anxious and ill. They may be diaphoretic and hyperthermic. Tachycardia, tachypnea, and hypotension are common. Patients often roll or move around in search of a more comfortable position. In this respect, they are quite unlike those with peritonitis caused by a perforated viscus, which remain motionless because movement exacerbates their pain. Most patients with acute pancreatitis have a clear sensorium, but some have mild or even severe alterations in their mental status as a result of drug or ethanol exposure, hypoxemia, hypotension, or release of circulating toxic agents from the inflamed pancreas. Jaundice is common, even in patients with nonbiliary pancreatitis, among whom the hyperbilirubinemia may reflect nonobstructive cholestasis.
The abdominal examination of patients with acute pancreatitis usually reveals abdominal tenderness and voluntary and involuntary guarding. These findings may be limited to the epigastrium or diffusely present throughout the abdomen. A mass, located in the epigastrium or left upper quadrant of the abdomen, or both, may be felt. Direct, percussion, and rebound tenderness usually can be elicited. Abdominal distention also can be seen. Hypovolemia and dehydration are commonly present and can be detected by the presence of hypotension, tachycardia, collapsed neck veins, dry skin, dry mucous membranes, and decreased subcutaneous elasticity. Bowel sounds are often diminished or absent. Flank ecchymoses (Grey Turner’s sign) or other evidence of retroperitoneal bleeding (Cullen’s sign) may be noted. Examination of the chest may reveal evidence of pleural effusion that may be on either or
both sides but is most commonly present on the left. Because of pleuritic and abdominal pain, deep breathing is difficult, and atelectasis, particularly at the bases, is common. Examination of the skin may reveal areas of tender subcutaneous induration and erythema that resemble erythema nodosum. These lesions are believed to result from fat digestion by circulating pancreatic lipases.
both sides but is most commonly present on the left. Because of pleuritic and abdominal pain, deep breathing is difficult, and atelectasis, particularly at the bases, is common. Examination of the skin may reveal areas of tender subcutaneous induration and erythema that resemble erythema nodosum. These lesions are believed to result from fat digestion by circulating pancreatic lipases.
Laboratory Tests and Radiologic Examinations
Routine Blood Tests
Acute pancreatitis is associated with significant losses of intravascular fluid. A substantial amount of fluid is lost as a result of the anorexia, nausea, and vomiting that accompanies the disease. In addition to these fluid losses, large volumes of fluid can be sequestered in the retroperitoneum as a result of the pancreatic inflammatory process. In addition, a systemic “capillary leak” process may result in additional fluid sequestration. Taken together, these losses of fluid from the intravascular compartment can cause the hematocrit, hemoglobin, blood urea nitrogen, and serum creatinine to rise. Hypoalbuminemia is common, but the serum electrolytes may remain normal unless vomiting has been significant. Because of the pancreatic inflammatory process, the white blood cell count usually is elevated and the differential may show a shift to the left. Hyperglycemia, which commonly is noted, may result from the combined effects of elevated circulating catecholamines, decreased insulin release, and hyperglucagonemia [64,65]. A mild rise in serum bilirubin from nonobstructive cholestasis frequently is seen even in nonbiliary acute pancreatitis. When the disease is induced by the passage of gallstones, the hyperbilirubinemia is even more marked, and superimposed cholangitis with bacteremia and positive blood cultures can occur [66]. Markedly elevated circulating triglyceride levels always are seen in individuals whose pancreatitis is caused by hyperlipoproteinemia [67], but hypertriglyceridemia with lactescent serum also can be seen in alcohol-induced acute pancreatitis [68].
Hypocalcemia is relatively common among individuals with acute pancreatitis [69]. For the most part, the hypocalcemia is caused by hypoalbuminemia, and as a result, the ionized calcium level is actually normal. In some patients, however, hypocalcemia can develop that is out of proportion to the degree of hypoalbuminemia and that reflects a true decrease in circulating ionized calcium levels. Tetany and carpopedal spasm and other complications of their hypocalcemia may develop in some patients. Marked hypocalcemia has been considered to be a sign of a poor prognosis. In patients with severe pancreatitis, disseminated intravascular coagulation may develop [70], and as a result, they may have thrombocytopenia, elevated levels of fibrin degradation products, decreased fibrinogen levels, and prolongations of the partial thromboplastin and prothrombin times.
Amylase
The serum amylase concentration is usually, but not always, elevated during an attack of pancreatitis [7]. The magnitude of that rise does not depend on the severity of pancreatitis, and some reports indicate that as many as 10% of patients with normal or near-normal serum amylase levels may have lethal pancreatitis [71]. To a great extent, this may reflect the fact that amylase elevations during pancreatitis typically are transient, with an increase to 2 to 12 hours after the onset of an attack and a decline in serum amylase values to near-normal levels 3 to 6 days after the attack has begun. Thus, patients presenting long after the onset of an attack may have normal or only slightly increased serum amylase levels.
Table 99.4 Causes of Hyperamylasemia | |
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Serum amylase activity also may be increased in a number of diseases other than pancreatitis [7,63,72]. Amylase may be synthesized at extrapancreatic sites (e.g., salivary glands, fallopian tube, lung) or produced by nonpancreatic tumors (e.g., lung, prostate, ovary), and release of the nonpancreatic amylase into the circulation may result in hyperamylasemia (Table 99.4). Patients with these nonpancreatic extra-abdominal causes for hyperamylasemia rarely are confused with those who have pancreatitis, because the clinical features of pancreatitis usually are absent in the former group. On the contrary, some patients with disorders that might be clinically confused with acute pancreatitis also may have hyperamylasemia. This is particularly true for patients with acute cholecystitis, perforated gastric or duodenal ulcers, small bowel obstruction, intestinal ischemia, and intestinal infarction. It may also be true for some patients passing common bile duct stones into the duodenum who do not have pancreatitis.
The overall sensitivity and specificity of amylase determination in the diagnosis of pancreatitis depends on the value chosen as the cutoff level [73] and the presence or absence of clinical features of pancreatitis. Patients with hyperamylasemia but not pancreatitis usually have mild elevations of the circulating amylase level (approximately 200 IU per L) or lack clinical features of pancreatitis, or both, whereas those with pancreatitis usually manifest profound hyperamylasemia (> 1,000 IU per L) in association with clinical features of the disease.
Approximately 0.5% of individuals have a condition referred to as macroamylasemia in which amylase is bound to an abnormal circulating protein and, as a result, the amylase is not cleared by the kidney [63,74,75]. Some of these individuals may develop abdominal pain and may be incorrectly suspected of having pancreatitis. In this setting, measurement of urinary amylase activity may be particularly helpful because, in macroamylasemia, urinary amylase levels usually are very low. Renal clearance of amylase also may be reduced as a result of renal failure, and this reduced clearance can lead to mild hyperamylasemia. On the contrary, enhanced renal clearance of amylase can occur in pancreatitis, and this phenomenon can
result in an increase in the clearance ratio for amylase compared with creatinine [75,76]. However, measurement of the so-called amylase to creatinine clearance ratio has not been helpful in the diagnosis of pancreatitis. Alterations of this ratio appear to represent a nonspecific response to an acute illness. Thus, the clearance ratio may be elevated in many patients who lack pancreatitis but may be normal in many who have pancreatitis [74,75,76,77,78,79,80].
result in an increase in the clearance ratio for amylase compared with creatinine [75,76]. However, measurement of the so-called amylase to creatinine clearance ratio has not been helpful in the diagnosis of pancreatitis. Alterations of this ratio appear to represent a nonspecific response to an acute illness. Thus, the clearance ratio may be elevated in many patients who lack pancreatitis but may be normal in many who have pancreatitis [74,75,76,77,78,79,80].
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