Classic acute pancreatitis is manifested by sudden onset of severe epigastric pain (90%-100% of patients) that may radiate elsewhere, often to the back. There may be vomiting (30%-96%), fever (60%-95%), abdominal distention (70%-80%), and paralytic ileus (50%-80%). Jaundice occasionally is present (8%-30%). Hypotension or shock develops in 30%-40% of cases. In severe and classic disease, the diagnosis is frequently obvious; unfortunately, various symptoms found in acute pancreatitis regardless of severity may occur in other diseases as well. In disease of mild or moderate degree or in patients with chronic low-grade or intermittent pancreatitis, symptoms may be vague or atypical. The most common diseases that clinically are confused with acute (or sometimes chronic) pancreatitis are perforated peptic ulcer, biliary tract inflammation or stones, intestinal infarction, and intraabdominal hemorrhage. Myocardial infarct may sometimes enter the differential diagnosis since the pain occasionally radiates to the upper abdomen; in addition, the aspartate aminotransferase (AST; formerly serum glutamic oxaloacetate transaminase, SGOT) level may be elevated in more than one half of patients with acute pancreatitis.

Acute pancreatitis is associated with alcohol abuse or biliary tract stones in 60%-90% of cases. About 50% are associated with common duct stones (range, 20%-75%); the percentage associated with alcohol is less well documented and is more variable (probably about 20%-25% in the United States; range in different populations, 5%-49%). Alcohol use is usually heavy and longstanding. A substantial number of patients with acute pancreatitis also have cirrhosis or alcoholic liver disease. Drug hypersensitivity is another factor. Alcohol is thought to be the most common cause of chronic relapsing pancreatitis.

Nonspecific laboratory tests

In acute pancreatitis there is some variation in laboratory findings according to the severity of the disease. Mild or moderate leukocytosis with a neutrophil shift to the left is reported in about 80% of patients, more frequently in the more severe cases. Moderate postprandial hyperglycemia or even mild fasting hyperglycemia may be present in about one third of patients (literature range, 10%-66%). There is hyperbilirubinemia (usually mild) in 10%-20% (literature range, 10%-50%), which could be due to biliary tract stones, liver disease, or edema around the ampulla of Vater. Decreased serum calcium levels may be found in 10%-30% of cases (literature range, 10%-60%). However, since total calcium measurements include both protein-bound and nonprotein-bound (ionized) calcium, since about one half of total calcium is protein-bound, since the protein-bound fraction is predominantly bound to albumin, and since hypoalbuminemia occurs in at least 10% of acute pancreatitis cases, the serum calcium level must be correlated with the serum albumin level. Of course, there could be a coexisting artifactual and actual calcium decrease. When a calcium decrease that is not artifactually caused by hypoalbuminemia occurs, the decrease often appears 3-14 days after onset of symptoms, most frequently on the fourth or fifth day. It is attributed to the liberation of pancreatic lipase into the peritoneal cavity, with resulting digestion of fat and the combination of fatty acids with calcium, which we see grossly as fat necrosis. Again, in very severe disease there may be hemorrhagic phenomena due either to release of proteolytic enzymes such as trypsin into the blood or to release of blood into the abdominal cavity from a hemorrhagic pancreas.

Serum amylase

In acute pancreatitis, the most commonly used laboratory test is measurement of alpha amylase. Alpha amylase actually has several components (isoenzymes), some derived from the pancreas and some from salivary glands. Clearance from serum takes about 2 hours. A significant portion is cleared via the kidney by glomerular filtration and the remainder (some data indicate >50%) by other pathways. Serum levels become abnormal 2-12 hours after onset of acute pancreatitis in many patients and within 24 hours in about 85%-90% of cases (literature range, 17%-100%. Those studies reporting less than 75% sensitivity were in a minority and were mostly published before 1975). In most patients the serum amylase level reaches a peak by 24 hours and returns to normal in 48-72 hours. If there is continuing pancreatic cell destruction, the serum amylase level will remain elevated longer in some patients but will return to reference range in others.

Falsely normal results. In certain situations there may be falsely low or normal serum amylase levels. The administration of glucose causes a decrease in the serum amylase level, so that values obtained during intravenous fluid therapy containing glucose may be unreliable; and one should wait at least 1 hour and preferably 2 after the patient has eaten before measuring the serum amylase value. In massive hemorrhagic pancreatic necrosis there may be no serum amylase elevation at all because no functioning cells are left to produce it. Pancreatic destruction of this degree is uncommon, however. Serum lipemia produces artifactual decrease in serum amylase values using most current methodologies. Since hypertriglyceridemia occurs in about 10%-15% of patients with acute pancreatitis (literature range, 5%-38%) and since many laboratories cannot be depended on to recognize the problem or to report the appearance of the serum, the possibility of lipemia should be considered if serum amylase results do not agree with the clinical impression.

Important causes of elevated serum amylase levels. Following is a list of important causes of elevated serum amylase levels.

1. Primary acute pancreatitis or chronic relapsing pancreatitis: idiopathic; traumatic; and pancreatitis associated with alcohol, drug sensitivity (thiazides, furosemide, oral contraceptives, tetracyclines, valproic acid, metronidazole), viral hepatitis, and hyperparathyroidism.
2. Hyperamylasemia associated with biliary tract disease: cholecystitis, biliary tract lithiasis, tumor, spasm of the sphincter of Oddi produced by morphine and meperidine (Demerol) or following biliary tract cannulation.
3. Hyperamylasemia associated with nonbiliary acute intraabdominal disease: perforated or nonperforated peptic ulcer, peritonitis, intraabdominal hemorrhage, intestinal obstruction or infarct, and recent abdominal surgery.
4. Nonpancreatic or nonalpha amylase: acute salivary gland disease, and macroamylase.
5. Miscellaneous: renal failure, severe cardiac circulatory failure (29% of cases), diabetic ketoacidosis in the recovery phase (41%-80% of cases), pregnancy, cerebral trauma, extensive burns, and cholecystography using radiopaque contrast medium (the contrast medium effect may last up to 72 hours in some cases).

In some instances of biliary tract disease there is probably a retrograde secondary pancreatitis, in other cases there is release of amylase into the circulation when pancreatic duct obstruction takes place, and in still others there is no convincing anatomical explanation. Likewise, in some cases of acute nonbiliary tract intraabdominal disease there is a surface chemical pancreatitis; when intestinal obstruction or infarction occurs, there may be escape of intraluminal enzyme; but in other instances no definite cause is found.

Serum amylase levels are elevated in about 10%-15% of patients following abdominal surgery (literature range, 9%-32%). About one half of the cases have been traced to elevation of salivary amylase levels and about one half to elevation of pancreatic amylase levels.

Several studies have reported that serum amylase levels more than 5 times the upper reference limit are much more likely to be secondary pancreatitis caused by biliary tract disease (cholecystitis or stones in the gallbladder or common bile duct) than by idiopathic or alcoholic acute pancreatitis. However, this is not sufficiently reliable by itself to differentiate primary and secondary pancreatic disease. The serum amylase level is said to be normal in most patients with pancreatic carcinoma, but occasionally some degree of acute pancreatitis may coexist with the tumor.

Patients with poor renal function may have false elevation of serum amylase, pancreatic amylase isoenzyme, lipase, immunoreactive trypsin, and amylase/creatinine clearance ratio. In one study it was reported that a creatinine clearance value of 40 ml/min represented the degree of renal function beyond which false enzyme elevation began to occur. However, regardless of severity of renal failure, some patients had enzyme values that remained within the normal range (60% [ literature range, 40%-81%;] had elevated amylase and 60% had elevated lipase). One study found that the highest false amylase elevation was 5 times normal (4 times normal in chronic renal failure); for lipase, 6 times normal; and for trypsin, 5.5 times normal. Patients with acute renal failure have higher values than those with chronic renal failure.

Sensitivity and specificity of alpha amylase as a test for acute pancreatitis has varied considerably in reports using different manufacturer’s kits and even between investigators using the same kit. As noted previously, the average sensitivity in acute pancreatitis seems to be about 85%-90% (range, 17%-100%), with specificity about 45%-50% (range, 0%-89%). In nonpancreatic diseases with elevated amylase levels, the frequency of elevated values above 3 times the upper reference limit was about 15% (range, 0%-36%).

Urine amylase

Urine amylase determination may also be helpful, especially when the serum amylase level is normal or equivocally elevated. Urine amylase usually rises within 24 hours after serum amylase and as a rule remains abnormal for 7-10 days after the serum concentration returns to normal. Various investigators have used 1-, 2-, and 24-hour collection periods with roughly equal success. The shorter collections must be very accurately timed, whereas the 24-hour specimen may involve problems in complete collection. It is important to have the results reported in units per hour. Frequently the values are reported in units/100 ml, but such values are inaccurate because they are influenced by fluctuating urine volumes. One drawback to both serum and urine amylase determination is their relation to renal function. When renal function is sufficiently diminished to produce serum blood urea nitrogen elevation, amylase excretion also diminishes, leading to mild or moderate elevation in serum amylase levels and a decrease in urine amylase levels.

Amylase/creatinine clearance ratio

Because renal excretion of amylase depends on adequate renal function, amylase urinary excretion correlates with creatinine clearance. In acute pancreatitis, however, there seems to be increased clearance of amylase compared with creatinine. The amylase/creatinine clearance ratio (A/CCR) is based on this observation. Determination of A/CCR involves “simultaneous” collection of one serum and one urine specimen and does not require a timed or complete urine collection. The A/CCR becomes abnormal 1-2 days after elevation of serum amylase levels but is said to remain abnormal about as long as urine amylase. The A/CCR has been the subject of widely discrepant reports. Early investigators found more than 90% sensitivity for acute pancreatitis. Later reports indicated a sensitivity varying from 33%-75%. One great problem in evaluating reports of sensitivity for any biochemical pancreatic function test is the fact that there is no noninvasive perfect way to detect all cases of acute pancreatitis (while at the same time not producing false abnormality due to nonpancreatic disease) against which the various tests may be compared, and even the invasive diagnostic procedures may fail to detect relatively mild disease.

The A/CCR is more specific for pancreatitis than changes in the serum amylase level. Many of the etiologies for hyperamylasemia that do not evoke a secondary pancreatitis are associated with normal A/CCR values. The exact degree of specificity is not yet established; reports have appeared that A/CCR may be elevated in some cases of diabetic ketoacidosis and burns. Behavior in renal failure is variable. In mild azotemia, the A/CCR may be normal, but in more severe azotemia or in uremia sufficient to require dialysis, it may be elevated. In addition, different investigators have adapted different ratio numbers as upper limits of normal, and there have been suggestions that the particular amylase method used can influence results. Some investigators feel that the A/CCR ratio has little value. More data is needed before final conclusions about A/CCR can be made.

Notwithstanding the limitations of the A/CCR previously noted and the ongoing debate in the literature regarding its usefulness, the sensitivity and specificity results for other tests suggest that the A/CCR is probably the most reliable of the readily available tests for acute pancreatitis. However, since there are serious questions about its sensitivity, serum and urine amylase measurements would be helpful if the A/CCR result is within reference limits. Therefore, if the urine amylase specimen is collected as a timed specimen, the result of urine amylase test as well as that of the serum amylase test would be available as a single test result. Urine amylase is especially useful since it remains elevated longer than serum amylase and is not affected by macroamylasemia. Poor renal function can be a disruptive factor in all of these tests.

Macroamylase is a macromolecular complex that contains alpha amylase bound to other molecules. Although macroamylase is thought to be uncommon, two studies detected it in 1.1%-2.7% of patients with elevated serum amylase levels. Macroamylase does not pass the glomerular filter but accumulates in serum; if a serum amylase test is performed, the macroamylase will be included in the amylase measurement and may produce an elevated test result. This could simulate pancreatic disease. Since macroamylase does not reach the urine, the urine amylase level is normal or low. The combination of an elevated serum amylase level and a normal or low urine amylase level produces a low A/CCR, and the elevated serum amylase level plus reduced A/CCR has been used to diagnose macroamylasemia. However, in early acute pancreatitis the serum amylase level may be elevated before the urine amylase level becomes elevated. Also, since occasionally patients with elevated serum amylase levels due to salivary (rather than pancreatic) amylase may have a reduced A/CCR, macroamylase should be confirmed by special techniques such as selective chromatography. Renal failure introduces an additional source of confusion, since both serum amylase and lipase levels are frequently elevated and the A/CCR may not be reliable. Other hints that an elevated serum amylase level might be due to macroamylase would include a normal serum lipase level and failure of the elevated serum amylase level to decrease significantly over several additional days.

Amylase isoenzyme fractionation

Alpha amylase consists of two groups of isoenzymes: pancreatic and salivary. Each group consists of more than one isoenzyme. Separation of serum amylase into its component isoenzymes is possible by selective enzymatic or chemical inhibition or by electrophoresis. In clinical acute pancreatitis, reports indicate that the expected increase in pancreatic-type isoenzymes is observed. In hyperamylasemia without clinical pancreatitis (e.g., occurring during diabetic ketoacidosis or after abdominal surgery), some patients exhibit increased salivary type isoenzymes and others, increased pancreatic type. Pancreatic isoenzyme kits have only recently become commercially available. The majority use an enzyme derived from wheat germ that inhibits salivary isoenzyme. Most evaluations to date found that isoenzyme fractionation was very helpful, especially since the finding of elevated salivary-type isoamylase without the pancreatic type would suggest a nonpancreatic amylase source. Although theoretically the pancreatic-type isoenzyme should be specific for pancreatic origin, a minority of investigators reported relatively frequent elevation of pancreatic-type isoenzyme in several nonpancreatic conditions.

Serum lipase

The serum lipase level is considered more specific for pancreatic damage than the amylase level. Lipase levels rise slightly later than the serum amylase levels, beginning in 3-6 hours, with a peak most often at 24 hours, and tend to remain abnormal longer, in most instances returning to reference range in 7-10 days. Lipase is excreted by filtration through renal glomeruli, after which most is reabsorbed by the renal proximal tubules and catabolized elsewhere. Urine lipase assay is not currently used. Evaluation of serum lipase sensitivity and specificity for acute pancreatitis has shown considerable variation, with sensitivity averaging about 75%-80% (range, 18%-100%) and with specificity averaging about 70% (range, 40%-99%). Some consider lipase very sensitive and specific for acute pancreatic disease, especially methods using a lipase cofactor called colipase. In general, however, the consensus in the literature is that lipase is probably about 10% less sensitive than serum amylase but is about 20%-30% more specific. In those reports that indicated less specificity, lipase elevations were found in some (but not as many) of the same nonpancreatic conditions associated with elevated serum amylase. Renal failure is the nonpancreatic condition most frequently associated with elevated serum lipase levels. About 80% of patients with renal failure are said to have lipase elevation 2-3 times the upper limit of reference range; about 5% have elevation over 5 times the upper limit. Other conditions that sometimes elevate serum lipase levels are acute cholangitis, intestinal infarction, and small intestine obstruction. In most patients with these conditions, lipase elevations are less than 3 times the upper limit. Other associated conditions include mumps, extrahepatic biliary obstruction, acute cholecystitis, peptic ulcer, and pancreatic carcinoma. Some of these conditions, however, could actually be associated with acute pancreatitis. Lipemia produces falsely decreased serum lipase and serum amylase levels.

Serum immunoreactive trypsin

Several investigators in recent years have developed radioimmunoassay (RIA) procedures for se rum trypsin, and at least one manufacturer has a commercial kit available. Trypsin is produced exclusively by the pancreas. In serum a considerable proportion is bound to alpha-1 antitrypsin, and some is also complexed to alpha-2 macroglobulin. Normally the trypsin activity in serum (as measured by current RIA techniques) actually is not trypsin but the trypsin precursor trypsinogen. In acute pancreatic disease there is activation of trypsinogen to form trypsin. Some of the RIA techniques described in the literature measure trypsin bound to alpha-1 antitrypsin as well as trypsinogen, and some do not. None measure trypsin complexed to alpha-2 macroglobulin.

Serum immunoreactive trypsin (SIT) levels are reported to be elevated in 95%-100% of patients with acute pancreatitis or acute exacerbation of chronic pancreatitis. They are also elevated in 80%-100% of patients with renal failure. There are insufficient and conflicting data on SIT behavior in nonpancreatic disorders, with some investigators reporting normal results in patients with cirrhosis and biliary tract disease and others reporting elevation in more than one half of patients with common duct stones and 6%-16% of patients with cirrhosis (the larger incidence being alcoholic cirrhosis). One investigator found elevated values in patients with viral infections such as mumps. In one report 50% of patients with pancreatic carcinoma had elevated values, whereas 19% had subnormal values.

Because only large medical centers or reference laboratories currently offer the test, the time delay necessary for results makes SIT less useful for diagnosing acute pancreatitis.

Other tests. Carboxypeptidase A and phospholipase A have been advocated to diagnose acute pancreatitis. Both have had mixed evaluation reports and at present do not appear to have clear-cut advantages over current tests. The carboxypeptidase A level does remain elevated longer than serum amylase or lipase levels and is a little more specific for pancreatic disease.

Endoscopic retrograde cholangiopancreatography

As the term implies, endoscopic retrograde cholangiopancreatography (ERCP) entails placing a special side-viewing fiberoptic duodenoscope into the duodenum under fluoroscopic control, finding the ampulla of Vater, cannulating the ampulla, and injecting x-ray contrast media into either the common bile duct or the pancreatic duct, or both. In the case of the pancreas, alterations in pancreatic duct x-ray morphology can suggest acute pancreatitis, chronic pancreatitis, pancreatic carcinoma, and pancreatic cyst. Clear separation of all of these entities from each other is not always possible in every patient. Current consensus is that ERCP is the most sensitive and reliable single procedure to detect clinically significant degrees of pancreatic dysfunction and to establish normal function (this does not take into account minimal or minor degrees of pancreatic disease, since the test depends on alteration of duct structure from abnormality in surrounding parenchyma). It is said to be especially useful when pancreatic ductal surgery or drainage procedures are being considered, in patients with possible traumatic injury to the pancreas, in cases where other diagnostic modalities fail to yield a clear-cut diagnosis, and in cases where strong clinical suspicion of pancreatic disease exists but other modalities are normal.

Disadvantages of ERCP are insensitivity to mild or minimal pancreatic disease as noted previously, the invasiveness of the procedure, the need for very experienced endoscopists and radiologists, and the considerable cost involved. About 10%-20% of attempts fail for various technical reasons. Complications of ERCP are uncommon (<2%), with sepsis and self-limited episodes of acute pancreatitis being the most frequent problems. There is a transient increase in serum amylase levels after ERCP in about 40% of patients. If there is barium in the GI tract that could obscure x-ray visualization of the pancreatic duct system, ERCP of the pancreas cannot be performed.

Computerized tomography and ultrasound

Both computerized tomography (CT) and ultrasound can visualize the pancreas, and both have their enthusiasts. Ultrasound is a little better in very thin persons, and CT is better in obese persons. Both can detect abnormality of the pancreas in about 80%-85% of patients. Neither ultrasound nor CT can always delineate the normal pancreas, although failure is less frequent with newer CT models. In general, in the average hospital CT of the pancreas is easier to perform and interpret than ultrasound. However, ultrasound is generally considered the best procedure for the diagnosis of pancreatic pseudocyst. Both CT and ultrasound depend on focal or generalized gland enlargement, so that small tumors or mild generalized disease are likely to be missed.