As a result of the various etiologies responsible for hyperamylasemia, a detailed history will aide in the identification of the underlying disease.

Acute pancreatitis should be suspected in patients with serum amylase levels beyond three times the upper limit of normal who present with acute epigastric pain and abdominal tenderness on physical examination.

Parotid duct obstruction should be suspected if patients present with hyperamylasemia in the setting of parotid gland tenderness and history of sialolithiasis.

Inquire if the patient has had any recent history of endoscopic retrograde cholangiopancreatography (ERCP), trauma, or surgery. In a pediatric patient, assess if the patient is up-to-date with vaccination to rule mumps infection.

Evaluate if the patient has a prior history of alcohol abuse, inflammatory bowel disease, renal failure, liver disease, or family history of pancreatitis.

Serum amylase is primarily used to support the diagnosis of acute pancreatitis despite its low specificity. If the patient has severe epigastric pain that can be reproduced on palpation during a physical examination and has a serum amylase elevated to three times the upper limit of normal or higher, a diagnosis of acute pancreatitis can be made without further imaging. Serum lipase can also be collected, though the co-ordering of both tests has not been shown to increase diagnostic sensitivity and specificity.[4]

If abdominal pain is associated with an elevated serum amylase but less than three times the upper limit of normal, additional imaging with computed tomography (CT scan) with contrast can be made. Additional laboratory workup such as complete blood count, basic metabolic panel, alanine aminotransferase (ALT), calcium, albumin, aspartate aminotransferase (AST), and direct and total bilirubin can also be obtained to guide the diagnosis. Magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatogram (MRCP) can also be used to elucidate pancreatic pathologies and may reveal pancreatic pseudocysts or ascites.[11]

Amylase levels can also be obtained after an endoscopic retrograde cholangiopancreatogram (ERCP) due to its value in predicting postprocedure pancreatitis.[12]

In patients with isolated amylase elevation without the presence of any other symptoms, the diagnosis of macroamylasemia should be considered. Macroamylasemia occurs in settings of inflammatory states, including celiac disease, rheumatoid arthritis, and monoclonal gammopathy. In the inflammatory state, amylase is bound to macromolecules such as immunoglobins and polysaccharides to form large complexes. These complexes are too large to be excreted by the kidney and results in isolated hyperamylasemia. Macroamylasemia is diagnosed using the amylase-to-creatinine clearance ratio (ACCR). ACCR is reduced to a ratio of less than one in macroamylasemia due to poor filtration of the large macroamylase complexes. The formula is as follows:

ACCR = [Amylase (urine) x creatinine (serum) x 100]/[amylase (serum) x Creatinine (urine)][13]

For patients with isolated hyperamylasemia negative for macroamylasemia or abdominal pain with no other specific signs or symptoms to suggest alternative diagnoses, no further evaluation is needed.

Treatment of hyperamylasemia will be directed at the suspected underlying etiology. Asymptomatic isolated hyperamylasemia without suspicion of any underlying etiology is benign and does not warrant treatment.

In acute pancreatitis, treatment is directed toward fluid resuscitation with an isotonic crystalloid solution (i.e., normal saline or lactated Ringer’s solution), pain control, and nutrition. Fluid resuscitation is typically provided at a rate of 5 cc/kg/hr to 10 cc/kg/hr for all patients. In patients with severe volume loss, rapid repletion should be given with up to 20 cc/kg of fluid over 30 minutes, followed by 3 cc/kg/hr for 8 to 12 hrs. Reassess fluid requirements every 6 hours over the next 24 to 48 hours based on clinical assessment of volume status, creatinine, and blood urea nitrogen (BUN) values. The target heart rate should be less than 120 beats/minute with mean arterial pressure between 65 mmHg to 85 mmHg, and urine output of at least 0.5 cc/kg/hr to 1 cc/kg/hr. Pain control should be managed with analgesics and in severe cases of pain. For most mild cases of acute pancreatitis, patients can be managed with intravenous (IV) fluids and resume a low-fat solid diet within 24 hours as tolerated if pain and nausea/vomiting symptoms are improving.[14]

Differential diagnosis can be sorted by pancreatic, salivary gland, and miscellaneous etiologies:

 Pancreatic

• Acute/chronic pancreatitis
• Complications of acute pancreatitis including abscess, pseudocyst, ascites
• Trauma (ERCP, blunt trauma, recent surgery)
• Malignancy (pancreatic carcinoma)

 Salivary gland

• Duct obstruction/calculi
• Chronic alcohol abuse
• Trauma (blunt trauma, recent surgery)
• Mumps
• Sjogren syndrome
• Anorexia/bulimia

Miscellaneous:

• Macroamylasemia
• Malignancy (ovary, renal cell, breast, thymoma, multiple myeloma, pheochromocytoma, colon)
• Inflammatory bowel disease
• Renal failure
• Liver disease (hepatitis, cirrhosis, hepatocellular carcinoma)
• Ketotic and non-ketotic acidosis

Prolonged hyperamylasemia for over a week after an initial episode of acute pancreatitis may be associated with future recurrence.[15] However, amylase level does not play a role in determining the severity or the etiology of acute pancreatitis.[16] There is no benefit of trending amylase levels once the diagnosis of acute pancreatitis has been made.[6]

Prolonged hyperamylasemia has been shown to be associated with complications of acute pancreatitis, specifically the presence of pancreatic pseudocysts, necrosis, or abscess.[17] Prolonged hyperamylasemia has also been shown to be independently associated with alcohol use.[15] Serum lipase to amylase ratio may be used to determine the etiology of acute pancreatitis, with a higher ratio positively correlating with the specificity of alcohol as the etiology.[18] However, a prospective follow-up study was unable to confirm the finding.[19]

Patients should be educated about the relevance of testing for serum amylase to rule out certain diagnoses. In its most common use, healthcare providers should explain that serum amylase will be an important data point to guide the diagnosis of acute pancreatitis. They should be educated that there is no clinical value to trending amylase levels as it does not determine the severity of acute pancreatitis. Patients can be educated that imaging studies may also be conducted in conjunction with lab work to rule out high suspicion of acute pancreatitis. Hyperamylasemia, without suspicion of any other underlying pathology, does not need further workup or intervention.

Management of hyperamylasemia involves an interprofessional team potentially consisting of a gastroenterologist, emergency physician, internist, or family medicine physician. Amylase levels will most commonly be assessed in the acute care setting when ruling out the diagnosis of acute pancreatitis. Gastroenterologists may evaluate serum amylase levels post-ERCP to assess for post-procedural pancreatitis.[20] Prolonged hyperamylasemia beyond one week after an initial episode of acute pancreatitis may be associated with complications of pseudocysts or necrosis and may involve surgical consultation.[21] Overall, serum amylase is a data point requiring correlation to clinical presentation. [Level 3]