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.