Etiology and Epidemiology

In 2001 in California, the rate of hospital admission with an initial attack of acute pancreatitis was 44 per 100,000 per year, an increase of more than 32% over the decade of the study. Overall rates of hospitalization in the Unites States over the last 20 years has increased from 40 per 100,000 to 80 per 100,000 and included both sexes and all age groups.²⁰ The increasing incidence of acute pancreatitis is believed to be related to increases in alcohol consumption and gallstone disease in some societies. Acute pancreatitis is slightly more common in men than in women, with a male-to-female ratio of 1 : 1.2 to 1 : 1.5. Predisposing factors related to race have not been identified, but both hospitalization rates and emergency department visits for patients diagnosed with acute pancreatitis are higher for blacks than for whites. Pancreatitis can occur in any age group, but cases in the very young (<3 years) are likely to be related to a systemic disease such as hemolytic uremic syndrome or cystic fibrosis. On the other hand, alcohol-related acute pancreatitis has a peak incidence between 45 and 55 years of age, with a gradual decline thereafter. Gallstone pancreatitis can occur in any age group, but its frequency increases with age. Biliary pancreatitis is more common in women, and alcohol-related acute pancreatitis is more common in men.

Understanding the etiology of a particular case of pancreatitis is important; evaluation and treatment depend to some extent on the predisposing disease process.^6,17 Gallstones are the leading cause of acute pancreatitis in developed countries and account for 45% of all cases. A biliary etiology should be suspected in female patients older than age 40 with a serum alanine aminotransferase level greater than three times the upper reference limit. Gallstone pancreatitis is the commonest form of pancreatitis in older patients. Since the frequency of gallstones increases with age, gallstones should be suspected in elderly patients.

Alcohol abuse typically accounts for about 35% of cases of acute pancreatitis; however, it is unclear whether acute alcoholic pancreatitis ever arises in the absence of chronic injury to the gland.²¹ Infrequent, but not rare, causes of pancreatitis include drug reactions (usually idiosyncratic), pancreatic and ampullary tumors, hypertriglyceridemia, hypercalcemia (almost always secondary to hyperparathyroidism), hypothermia, congenital abnormalities of the biliary or pancreatic duct (e.g., choledochal cyst), trauma (including acute pancreatitis after endoscopic retrograde cholangiopancreatography), and infectious or parasitic organisms. Rare causes include bites of certain spiders, scorpions, and the Gila monster lizard. Unidentified causes are termed idiopathic. The roles of sphincter of Oddi dysfunction, pancreas divisum, and bile crystals or sludge in the development of acute pancreatitis are less clear.²⁰

Pathogenesis and Genetic Susceptibility

Regardless of the actual underlying cause, pancreatitis is an inflammatory process that can initiate SIRS.⁶ In spite of much investigation into the molecular pathogenesis of acute pancreatitis, the exact intracellular mechanisms initiating and accelerating pancreatitis are not completely understood. Three phenotypic responses occur in the acinar cell in the early phases of acute pancreatitis^22,23: changes in secretions, intracellular activation of proteases, and generation of inflammatory mediators. Shortly after an appropriate stimulus, secretions are released from the apical cells into the pancreatic duct. This process entails exocytotic fusion of zymogen granules with the apical plasma membrane; the granules do not fuse with the basolateral membrane. However during acute pancreatitis, there is (1) markedly decreased apical secretion from the acinar cell, (2) disruption of the paracellular barrier in the pancreatic duct with leakage of contents into the paracellular space, and (3) redirection of secretion from zymogen granules from the apical pole to the basolateral regions of the acinar cell. Inappropriate activation of the proteolytic enzyme, trypsin, is thought to be the initial step in the development of acute pancreatitis. Trypsinogen activation is promotion by cationic trypsinogen mutations (PRSS1+), active trypsin, high calcium ion concentration, and low pH. Calcium levels are regulated in part by calcium-sensing receptors (CASR) and dysregulated by ethanol.^22,23 Degradation of active trypsin is blocked by high calcium ion concentration. If trypsin in active within the pancreas, inflammation results and this up-regulates serine protease inhibitor Kazak 1 (SPINK1), which further blocks activation of trypsinogen.²² Trypsin also activates cells via the trypsin receptor, also known as protease-activated receptor 2 (PAR-2) (Figure 104-1).²² Pancreatic acinar and duct cells abundantly express PAR-2. Trypsin activity in the pancreas is controlled mainly by the pancreatic secretory trypsin inhibitor (PSTI), also called serine protease inhibitor Kazal type 1 (SPINK1).²² PSTI is synthesized in pancreas acinar cells and acts as a potent natural inhibitor of trypsin. Normally when trypsinogen is cleaved to release trypsin in the pancreas, PSTI immediately binds to the enzyme to prevent further activation of additional pancreatic enzymes. PSTI also blocks further activation of pancreatic cells via the trypsin receptor, PAR-2.

Figure 104-1 Activation pathways of proenzymes and protease-activated receptor (PAR)-2 by trypsin. When trypsin is activated, it is capable of activating many digestive proenzymes. Trypsin also activates inflammatory cells via PAR-2. Trypsin activity in the pancreas is mainly controlled by pancreatic secretory trypsin inhibitor (PSTI). When trypsinogen is activated into trypsin in the pancreas, PSTI immediately binds to trypsin to prevent further activation of pancreatic enzymes.

Several additional protective systems prevent pancreatic autodigestion by trypsin, and the genetic expression of these systems may contribute to the risk of developing acute pancreatitis or modulate the severity of the disease when it occurs. Trypsin-activated trypsinlike enzymes such as mesotrypsin degrade trypsinogen. Bicarbonate-rich pancreatic secretions are affected by abnormal expression of the cystic fibrosis transmembrane conductance receptor. A mutation in SPINK1, N34S, has been reported in people with familial pancreatitis,²⁴ in children with idiopathic chronic pancreatitis,^25,26 and in 2% of the control population.²⁶ Because these mutations in SPINK1 are much more common than pancreatitis, this mutation probably is a disease modifier rather than a causative factor underlying the development of acute pancreatitis.

Genetic linkage and candidate gene studies have identified six pancreas-targeting factors that are associated with changes in susceptibility to acute and/or chronic pancreatitis, including cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2), serine protease inhibitor Kazal 1 (SPINK1), cy regulator (CFTR), chymotrypsinogen C (CTRC) and calcium-sensing receptor (CASR).²²

Diagnosis

The diagnosis of acute pancreatitis is relatively straightforward when acute upper abdominal pain and tenderness, nausea, vomiting, and hyperamylasemia or hyperlipasemia are present.²⁷ These clinical and biochemical signs are nonspecific, however, and can be present in many other acute intraabdominal conditions such as acute perforation of a hollow organ or mesenteric infarction. Many cases of acute pancreatitis still are diagnosed at autopsy. The diagnosis of acute pancreatitis can be particularly difficult in postoperative patients. Acute pancreatitis also can be hard to diagnose in patients receiving drugs for sedation and patients who are hypothermic or unable to complain of abdominal pain. The Cullen sign and the Grey Turner sign (periumbilical and flank bruising, respectively) are rare and can be present with any disease associated with retroperitoneal hemorrhage. Although hyperamylasemia is common in patients with acute pancreatitis, normal circulating amylase levels are present in 10% to 20% of all cases of acute pancreatitis. Normal serum amylase concentrations are seen predominantly in acute pancreatitis secondary to hyperlipidemia, acute exacerbations of chronic pancreatitis, and late in the course of acute pancreatitis.²⁸ Advantages of serum amylase determination include its technical simplicity, wide availability, and sensitivity.²⁹ This diagnostic test is plagued by low specificity, however. Serum lipase concentration increases within 4 to 8 hours of the onset of acute pancreatitis, peaks at 24 hours, and returns to normal after 8 to 14 days.²⁹ The major advantage of serum lipase determination as a diagnostic test is its excellent sensitivity in acute alcoholic pancreatitis. Measurement of serum lipase activity also is valuable when patients present to an emergency department days after the onset of the disease, because serum lipase levels remain elevated longer than amylase levels.²⁹ Although serum lipase formerly was believed to be a specific marker for acute pancreatitis, increased circulating levels of serum lipase can occur in many other diseases. Simultaneous estimation of amylase and lipase levels does not improve accuracy.²⁹ Other pancreatic enzymes such as P-isoamylase, macroamylases, immunoreactive trypsinogen, and elastase generally are not considered useful for making the diagnosis of acute pancreatitis.

Serum triglyceride levels should be determined when an etiology of pancreatitis is uncertain and lipemic serum is suspected. Hydrolysis of triglycerides by pancreatic lipase and formation of free fatty acids that induce inflammatory changes are postulated to account for the pathophysiology of this form of pancreatitis. While it has never been proven, circulating triglyceride levels above 1000 mg/dL (11.3 mm/L) are believed to trigger pancreatitis.

Severity and Scoring

Prediction of the severity of the disease at the time of admission can be difficult, and patients can appear clinically well at admission but clinically deteriorate within 48 hours. Several different prognostic scoring systems with clinical, laboratory, and radiologic criteria have been proposed, yet none of the proposed scoring systems have a high sensitivity, specificity, positive predictive value, or negative likelihood ratio, and frequent clinical assessment is essential for identifying patients with severe disease.³⁰ Ranson’s criteria (Table 104-1),³¹ the Imrie³² (Glasgow) score, the Acute Physiologic and Chronic Health Evaluation (APACHE) II and III scores,³³ the simplified acute physiology score, and Balthazar’s computed tomography (CT) index (Table 104-2)^34–36 are the most popular scoring systems and often are used to determine the need for admission to an ICU. Ranson’s criteria are based on 11 prognostic signs present at presentation and 48 hours later.³¹ A meta-analysis of studies using the Ranson criteria reported the following with regard to predicting severe acute pancreatitis (SAP): sensitivity, 74%: specificity, 77%; positive predictive value, 49%; and negative predictive value, 91%.³⁰ The Glasgow (Imrie) severity score system collects data on 9 variables at admission but is not complete until 48 hours after admission. Many institutions routinely utilize the APACHE scoring system for all patients admitted to the ICU.³³ Patients with SAP and an APACHE II score above 8 have severe disease and are likely to develop organ failure. Key statistical parameters related to APACHE II score of above 7 and the prediction of SAP are as follows: sensitivity, 65%; specificity, 76%; positive predictive value, 43%; and negative predictive value, 89%. Balthazar’s CT index^34–36 uses both fluid collections and amount of pancreatic necrosis to predict outcome. A recent international group of experts concluded that an additional group of patients should be identified: those with moderately severe acute pancreatitis (MSAP).³⁷ This is a large group of patients who meet the Atlanta classification of severe disease but do not develop organ failure. Patients in the MSAP group often develop local complications and often have long hospitalizations with significant morbidity but without mortality. In a strategy to identify those patients who will not need ICU care, Lankish et al. proposed and validated a “harmless acute pancreatitis score (HAPS).” Using this scoring system, 98% of 204 patients were correctly identified as having non-severe disease within 30 minutes of presentation.³⁸ These simple measures included rebound or guarding on clinical examination, hematocrit greater than 43% in men and greater than 39.6 in women, and serum creatinine concentration above 2 mg/dL. Imamura and colleagues have recently proposed a simplified grading of early CT scans based on the presence or loss of enhancement of the renal rim fat. This simple assessment compared favorably with all the commonly used scoring systems.³⁹

TABLE 104-1 Ranson’s Criteria for Patients with Non–Gallstone-Associated Pancreatitis

Modified from Blamey SL, Imrie CW, O’Neill J, Gilmour WH, Carter DC. Prognostic factors in acute pancreatitis. Gut 1984;25:1340-6.

Many investigators have studied and proposed a variety of serum biomarkers as predictors of the severity and prognosis of acute pancreatitis.^40–42 High circulating levels of C-reactive protein (CRP) (cutoff 150 mg/L) are associated with pancreatic necrosis, but there is a 48-hour latency before CRP increases, limiting its utility as an early predictor. This marker has a sensitivity and specificity of 80%. Although not ideal predictors of severity, serum concentrations of procalcitonin and interleukins (IL) 6 and 8 have some predictive value.^40–42 Certain urinary markers also have some predictive value. While not used extensively clinically at the current time, procalcitonin appears to offer the greatest promise. Serum procalcitonin levels higher than 3.8 ng/mL accurately predict later organ dysfunction (sensitivity, 79%; specificity, 93%).⁴²

The scoring systems mentioned help quantify the degree of illness, but it is essential that clinicians identify patients with impending or actual organ failure. Patients with signs of SIRS are especially at risk for further organ dysfunction.⁴⁵ In a review of 259 patients with acute pancreatitis, mortality was significantly higher in patients who developed or had persistent SIRS at 48 hours (25.4%) than in patients who had transient SIRS (8%) or no SIRS in the first 48 hours (0.7%).³⁷

An update of the Atlanta Classification system for severity of acute pancreatitis is expected soon; the system developed at the initial consensus meeting in 1992 has allowed comparisons among clinical trials and different treatment strategies.³⁶ It defined SAP by its association with organ failure, local complications such as necrosis, abscess, or pseudocyst, or both. By consensus, the Atlanta Classification also defined SAP based upon the presence of ≥3 of Ranson’s criteria or an APACHE II score ≥ 8. Most often, SAP is a clinical expression of the development of pancreatic necrosis. Less commonly, patients with interstitial (edematous) pancreatitis can present with SAP. In addition to the previously proposed scoring systems, there is another very simple scoring system termed the Panc 3 Score.⁴⁶ Three findings—hematocrit over 44 mg/dL, body mass index above 30 kg/m², and a pleural effusion on chest x-ray—were the most sensitive predictors of overall severity. In the validation set of data, when all three of these findings were present and the pretest probability of pancreatitis was between 12% and 25%, the posttest likelihood of severe disease was 99%.⁴³

Serum concentrations of CRP, neutrophil elastase, pancreatitis-associated peptide, IL-6, IL-8, IL-1, IL-10, and soluble tumor necrosis factor (TNF) receptors might be useful for the early prediction of severity of disease in acute pancreatitis.⁴⁰ Circulating CRP concentration is an independent predictor of outcome in acute pancreatitis, but it is not predictive of severity at presentation.⁴⁴ Laboratory tests also can be used for severity stratification; serum IL-6 concentration greater than 2.7 pg/mL within 48 hours from disease onset and a serum CRP level above 150 mg/L at 48 hours after pain onset can both be used. A recent meta-analysis of the role of procalcitonin in the identification of patients with SAP suggested that the test has a sensitivity of 0.72 for the diagnosis, a specificity of 0.86, and an area under the curve of 0.87, but the studies showed a fair amount of heterogeneity.⁴² Trypsinogen-2 can be measured via a simple serum immunofluorometric assay or urine dipstick assay, using a threshold of 50 µg/L.⁴¹

Imaging

Computed Tomography

Contrast-enhanced CT is considered the gold standard for diagnosing pancreatic necrosis and peripancreatic collections and for grading acute pancreatitis (see Table 104-2).^34–36 Necrosis is detected by CT as focal or diffuse areas of diminished pancreatic parenchymal contrast enhancement (<50 Hounsfield units). The accuracy of this test is greater than 90%. CT findings of acute pancreatitis include diffuse or segmental enlargement of the pancreas (interstitial edema), irregularity of the contour of the pancreas with obliteration of the peripancreatic fat planes, heterogeneous appearance with areas of decreased density within the pancreas, and variable ill-defined fluid collections (Figures 104-2 and 104-3).^34–36 The Balthazar index ranges from 0 to 10 and is obtained by adding the points attributed to the extent of the inflammatory process to the volume of pancreatic necrosis. Although CT findings correlate with clinical course and severity of patients with acute pancreatitis,³⁶ it is not necessary to obtain this study in patients with mild pancreatitis. In a recent Dutch observational study of 166 patients admitted with acute pancreatitis, early CT (within 4 days of admission) was performed in 47% of all patients. However, only 18 of the 166 patients had severe disease, and 11 eventually developed pancreatic necrosis. No changes in clinical management resulted from obtaining early CT scans. These data suggest that the use of early CT, especially in patients with mild disease, should be discouraged.⁴⁹ CT can be helpful when the diagnosis is in doubt or when complications of pancreatitis may be developing. In general, contrast-enhanced CT scans should not be performed during the first 72 hours of the disease, because necrosis may not be fully established until after 96 hours, and there have been isolated reports of intravenous (IV) contrast material causing derangements of the pancreatic microcirculation.⁴⁹ Contrast administration also can trigger or exacerbate renal insufficiency.

Figure 104-2 Computed tomography scan of a patient with severe necrotizing pancreatitis and Balthazar grade E scan; more than 50% necrosis of the gland was seen on previous scans of the gland, giving the patient a Balthazar index of 10. The patient developed pancreatic infection more than 4 weeks into his hospital course.

Figure 104-3 Computed tomography scan of a patient with severe acute pancreatitis, a large fluid collection, and significant (>50%) necrosis. Pancreatic infection occurred on hospital day 17.

Management