Hyperamylasemia

Amylase is a digestive enzyme that normally acts extracellularly to cleave starch into smaller carbohydrate groups and, finally, into monosaccharides, by hydrolysis of the internal alpha-1,4-glycoside bonds, which results in the production of maltose and oligosaccharides.

Among healthy individuals, the pancreas and the salivary glands account for almost all the serum amylase, 40%-45% from the pancreas and 55%-60% from the salivary glands.

Serum amylase is increased in at least 75% of pancreatitis cases; however, serum amylase can be normal, even in the face of massive pancreatic necrosis. The major limitation of using serum amylase measurement in diagnosing pancreatitis is the lack of specificity. ^[1]

Origins of serum amylase

A variety of organs and body secretions contain amylase activity. The pancreas and salivary glands contain amylase concentrations that are several orders of magnitude greater than other organs. Electrophoresis shows that serum amylase is of two main types, as follows: (1) P-type amylase from the pancreas, and (2) S-type amylase from the salivary glands.

The other locations of amylase include fallopian tubes and cyst fluid, testes, lungs, thyroid, tonsils, breast milk, sweat, tears, and some malignant neoplasms. They contribute little to the serum amylase level. Fallopian tube secretions, tears, breast milk, and sweat have amylases with a similar electrophoretic mobility of salivary isoamylase. However, the salivary glands account for almost all of the S-type isoamylase.

Metabolic clearance of serum amylase

The exact pathways of serum amylase metabolism are still not fully understood. Humans who have had a nephrectomy or have renal insufficiency have average serum amylase levels that are 50% higher than healthy individuals. Therefore, the kidneys can be assumed to play a major role in amylase metabolism. However, the kidney is not the sole organ responsible for amylase clearance in humans. The extrarenal mechanisms of amylase clearance have not been clearly defined.

Because high serum amylase levels are also observed in hepatic necrosis and cirrhosis, the liver is thought to play a role in amylase metabolism.

Factors influencing serum amylase

Many conditions have been reported to cause hyperamylasemia. Although hyperamylasemia is commonly assumed to be due to the release of amylase into the serum by the diseased organ, the precise relationship between hyperamylasemia and an affecting condition is not entirely clear. Hyperamylasemia is most commonly the result of (1) pancreatitis or parotitis, (2) decreased metabolic clearance of amylase, or (3) amylase released from an involved organ.

Pancreatic diseases

Acute or chronic pancreatitis is associated with increases in the P-type isoamylase. In acute pancreatitis, serum amylase is usually elevated 3-fold and then returns to normal by 3-7 days. Prolonged hyperamylasemia in patients experiencing a first attack of acute pancreatitis is associated with recurrence of acute pancreatitis. ^[2] Patients with pancreatitis associated with hypertriglyceridemia or those with considerable acinar cell injury due to previous episodes of pancreatitis or chronic pancreatitis may not exhibit hyperamylasemia.

Other reasons for hyperamylasemia that are associated with pancreatitis are pseudocysts, pancreatic ascites, pancreatic trauma, ^[3] and choledocholithiasis. Pancreatic trauma can be a result of blunt trauma, abdominal or retroperitoneal surgery, or endoscopic retrograde cholangiopancreatography (ERCP). ^[4] Trauma related to ERCP is thought to result from the regurgitation of amylase into the blood, which may occur in 75% of ERCPs, but most have no evidence of pancreatic injury. A 3- to 4-times increase in serum amylase levels 4 hours after ERCP predicts the occurrence of complicating postprocedure pancreatitis. In patients presenting with biliary-type abdominal pain, a 3-fold increase in serum amylase levels that returns to normal within 48-72 hours suggests stone passage through the common bile duct.

Risk factors for developing post-ERCP hyperamylasemia appear to include difficult cannulation and pancreatography, and age younger than 60 years, as well as a previous history of diabetes, biliary duct stent placement, and nasobiliary drainage. ^{[5, 6]}

Salivary diseases

Parotitis is associated with increases in the S-type isoamylase. Parotitis is usually caused by trauma or surgery of the salivary gland, radiation to the neck area involving the parotid gland followed subsequently by duct obstruction, or calculi of the salivary duct. ^{[7, 8, 9]}

Another cause of damage to the salivary gland is from chronic alcoholism. Salivary amylase levels are three times higher than normal in 10% of patients with alcoholism; this may be related to chronic liver disease.

Decreased metabolic clearance

Renal failure results in increased S-type and P-type isoamylases.

Liver disease from hepatitis or cirrhosis also results in increased S-type and P-type isoamylases.

Macroamylasemia

Macroamylasemia is a benign condition in which the amylase molecule binds with a large complex molecule (eg, immunoglobulin, polysaccharide), thereby decreasing renal clearance and prolonging its half-life. About 2%-5% of patients with hyperamylasemia have macroamylasemia.

Intestinal disease

Gut diseases, including mucosal inflammatory disease of the small intestine, mesenteric infarction, intestinal obstruction, appendicitis, and peritonitis, usually result in increased P-type isoamylase because of increased absorption of amylase from the intestinal lumen. Gut perforation is associated with leakage of intestinal contents into the peritoneum causing inflammation and absorption of amylase across the inflamed peritoneum. This can result in hyperamylasemia.

Female reproductive tract disease

Ruptured ectopic pregnancy, fallopian or ovarian cysts, and salpingitis can result in increased S-type isoamylase.

Miscellaneous causes

Ectopic amylase production by lung, ovary, pancreas, and colon malignancies; pheochromocytoma; thymoma; multiple myeloma (increased salivary amylase); and breast cancer (increased pancreatic amylase) are miscellaneous causes of hyperamylasemia.

Acidosis, which can be due to (1) ketoacidosis that results in increased S-type and P-type isoamylases or (2) nonketotic acidosis that results in increased S-type isoamylase, can cause hyperamylasemia.

Amylase increases may occur postoperatively, resulting in increased S-type and P-type isoamylases; however, an increase in salivary amylase is more common. This may occur after extracorporeal circulation or nonabdominal surgery (eg, 30% of patients undergoing cardiac surgery have elevated S-type isoamylase).

Rare cases of hyperamylasemia have been reported in association with systemic lupus erythematosus (SLE), as well as with ciprofloxacin treatment. Other causes of hyperamylasemia include pneumonia (increased salivary amylase), cerebral trauma, burns, abdominal aortic aneurysms (increased pancreatic amylase), drugs (increased salivary and/or pancreatic amylase), anorexia nervosa and bulimia (increased salivary amylase), nonpathologic (increased salivary and/or pancreatic amylase), and organophosphate poisoning. Postprocedure balloon-assisted enteroscopy has also been associated with elevated amylase levels; measure pancreatic amylase levels rather than total amylase levels following these procedures. ^{[10, 11, 12, 13]}

Elevated pancreatic enzymes can be found in critically injured trauma patients even in the absence of true pancreatitis. ^[3] Reviewing data from 2,711 critically injured trauma patients who had not suffered pancreatic injury, Malinoski and colleagues found that 481 (18%) of these patients had elevated amylase levels (defined in the study as more than twice the upper limit of normal amylase levels).

The investigators also found that, in comparison with patients without elevated serum amylase, a greater proportion of patients with elevated serum levels presented in shock (16% vs 8%), required massive transfusion (19% vs 9%), or developed organ failure (34% vs 16%). ^[3] Their mortality rate was higher as well (23% vs 13%). Similarly, patients with elevated serum lipase also were more likely to need massive transfusion or to suffer from organ failure.

The investigators could not determine whether the higher pancreatic enzyme levels reported in the study resulted from ischemia of the pancreas or from the translocation of intraluminal enteric pancreatic enzymes.

The most widely used application of serum amylase measurements is to support a diagnosis of acute pancreatitis. In acute pancreatitis, the serum amylase is increased at least 3-fold in approximately 75% of cases on the initial day of symptoms; then, it usually returns to normal by 3-7 days. The specificity of the test increases with higher levels of the enzyme.

Serum amylase measurements are not very sensitive or specific for pancreatic injury because they may be normal in patients with preexisting acinar injury or chronic pancreatitis and because many other causes of hyperamylasemia are described (see Etiology). ^[1] One should remember that a patient with asymptomatic chronic hyperamylasemia almost never has pancreatic disease as the cause of the amylase elevation. ^[14]  Serum isoamylase measurements to determine S-type isoamylase, P-type isoamylase, or macroamylasemia are the best tests to use when the etiology of hyperamylasemia is obscure.

An amylase level obtained within a few hours after an endoscopic retrograde cholangiopancreatogram has value in predicting postprocedure pancreatitis. In one study, a 6-hour level of greater than 5 times normal had a predictive accuracy of 86%. ^[15]

In patients undergoing pancreatoduodenectomy, a postoperative day 0 serum amylase level of less than 130 IU/l is reported to allow for the early and accurate categorization of patients at the least risk for clinically significant postoperative pancreatic fistula. This may help identify patients suitable for an early removal of drains placed at the time of surgery. ^[16]

Measuring the salivary amylase level could be useful for stress assessment and is a marker for sympathetic activity. ^[17] It has been used in assessing stress levels of space crew members and populations working in a stressful and isolated environment. ^[18]

The amylase-to-creatinine clearance ratio (ACR) can help differentiate acute pancreatitis from other conditions. ^[19] This ratio is calculated using the following equation:

• ACR = (amylase [urine] X creatinine [serum])/(amylase [serum] X creatinine [urine]) X 100

An ACR of greater than 5% suggests acute pancreatitis. However, the ACR is also known to be increased in diabetic ketoacidosis and renal disease and after surgery. An ACR of less than 1% suggests macroamylasemia. Because findings of urinary amylase are relatively nonspecific, calculations for urinary amylase excretion have almost no clinical value. Generally, the ACR measurement has been abandoned, except to confirm a diagnosis of macroamylasemia, which is characterized by a low ACR.

A lipase-to-amylase ratio of greater than 2 may suggest alcoholic pancreatitis, but it is not a reliable predictor of alcoholic pancreatitis. ^[20]

In pancreatitis with associated hypertriglyceridemia, serum amylase levels may be erroneously normal. This is attributed to an inhibitor associated with triglyceride elevations that interferes with the assay for the enzyme. Diluting the serum can reduce the activity of the inhibitor such that a recalculation of serum amylase can uncover the true serum amylase levels.