Continuing Education Activity

Hyperamylasemia refers to elevated serum amylase levels. It is most commonly observed and evaluated in patients with acute pancreatitis to confirm the diagnosis. However, hyperamylasemia may also be associated with a wide range of diagnoses. This activity reviews the evaluation and management of hyperamylasemia and highlights the role of an interprofessional care team in appropriately diagnosing patients with this condition and treating the causes.

Objectives:

• Assess the etiology of hyperamylasemia.

• Evaluate the management of hyperamylasemia.

• Identify the prognostic value of hyperamylasemia.

• Communicate interprofessional team strategies for improving care coordination when caring for patients with hyperamylasemia.

Introduction

Hyperamylasemia refers to an elevated serum amylase level beyond the upper limit of normal (the normal range is typically 30 U/L to 110 U/L). Amylase is 1 of the digestive enzymes that is designed to act intracellularly. Its function is to break down starch into smaller carbohydrate units, yielding monosaccharides in the end. The process is completed using hydrolysis of the glycoside bonds, causing the release of maltose and oligosaccharides. Serum amylase is mainly released from the pancreas (40%-45%) and salivary glands (55%-60%). It is an enzyme produced in 2 isoforms, P-type amylase and S-type amylase. P-type amylase is secreted from the pancreas, while S-type amylase is secreted from the salivary glands. Amidase clearance occurs through the kidney (25%) and the reticuloendothelial system (75%).[1][2] Serum amylase is not the most appropriate test for diagnosing pancreatitis as it lacks specificity. Although it is increased in around 75% of cases of pancreatitis, serum amylase may be within the normal range, even in the case of massive pancreatic necrosis.[3]

Etiology

Hyperamylasemia can be from pancreatic sources, salivary glands, or other etiologies. Pancreatic causes of hyperamylasemia include: 

• Acute pancreatitis usually presents with severe epigastric abdominal pain and elevations of serum amylase beyond 3 times the upper limit of normal. Elevated serum amylase levels usually return to baseline in 3 to 7 days. In the first instance of acute pancreatitis, if hyperamylasemia persists for longer than usual, it may be associated with the recurrence of the disease.[4]
• Trauma, such as blunt trauma, surgery, or recent endoscopic retrograde cholangiopancreatography (ERCP) of the pancreatic duct, leads to the release of amylase enzyme from within the pancreatic cells. Risk factors include difficult cannulation, age below 60 years, history of diabetes, a stent in the biliary duct, and nasobiliary drainage.[5][6]
• Chronic pancreatitis
• Pancreatic pseudocysts
• Pancreatic ascites
• Pancreatic trauma[7]
• Choledocholithiasis

 Salivary gland-related causes include:[8][9][10]

• Trauma to the salivary gland
• Radiation to the neck area involving the parotid gland
• Salivary gland obstruction with calculi

Decreased metabolic clearance of amylase can also lead to hyperamylasemia and can be due to:

• Renal failure
• Liver failure (ie, hepatitis or cirrhosis)

 Other known etiologies of hyperamylasemia include: 

• Macroamylasemia
• Intestinal disease (eg, inflammatory disease of the small intestine, mesenteric ischemia, intestinal obstruction, peritonitis)
• Female reproductive tract disease (eg, ruptured ectopic pregnancy, fallopian or ovarian cysts, salpingitis)
• Malignancy (eg, lung, ovary, pancreas, pheochromocytoma, thymoma, multiple myeloma, breast)
• Acidosis (ketoacidosis and nonketotic acidosis)[3]
• Balloon-assisted enteroscopy[11][12][13]

Epidemiology

Amylase levels are routinely evaluated in patients suspected of acute pancreatitis. However, while it is sensitive, it is not specific.[14] In a study involving 1000 emergency department patients presenting with abdominal pain, 39% of individuals received a test for amylase, but only 3.9% of individuals were diagnosed with pancreatitis.[15] Furthermore, in patients with nonpancreatic abdominal pain, 11% to 13% of patients have elevated pancreatic enzymes.[16] Hyperamylasemia is common following cardiac surgery and occurs in 30% to 60% of patients.[17]

Appropriate reference ranges should be applied to assess serum amylase levels as they differ based on age and different ethnic and racial groups. A study found that 32% of Asian Americans and 50% of Native Americans had higher total amylase levels above the upper limit of normal compared to the White population.[18] Another study found that the total serum amylase was higher in the elderly for both men and women, potentially resulting from an age-related decrease in renal clearance.[19]

Pathophysiology

Hyperamylasemia is due to impaired metabolic clearance or pathology involving the organs containing amylase enzyme. In acute pancreatitis, inflammation of pancreatic cells leads to the secretion of amylase into the bloodstream. Pathologies that involve trauma of the organs, such as blunt trauma to the pancreas or parotid gland or even ERCP to the pancreatic duct, can lead to the release of stored amylase. Given amylase is cleared by the kidney and the reticuloendothelial system, renal failure and liver disease (ie, hepatitis or cirrhosis) are associated with hyperamylasemia. Chronic alcohol abuse can also lead to hyperamylasemia and is thought to be related to liver damage.[20]

History and Physical

As a result of the various etiologies responsible for hyperamylasemia, a detailed history aids in identifying the underlying disease. Acute pancreatitis should be suspected in patients with serum amylase levels beyond 3 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 a history of sialolithiasis. Patients can present with longstanding symptoms of parotitis if there is an underlying infection with pathogens, such as mycobacterium.[8] Occasionally, toxicity with certain substances can cause hyperamylasemia. For instance, organophosphate intoxication may lead to parotitis, which results in increased serum amylase levels.[9] Inquire if the patient has had any recent ERCP, trauma, or surgery history. In a pediatric patient, assess if the patient is up-to-date with vaccination to rule out mumps infection. Evaluate if the patient has a prior history of alcohol abuse, inflammatory bowel disease, renal failure, liver disease, or a family history of pancreatitis.

Evaluation

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 3 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.[14] If abdominal pain is associated with an elevated serum amylase but less than 3 times the upper limit of normal, additional imaging with computed tomography (CT scan) with contrast can be made. Additional laboratory workups 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 elucidate pancreatic pathologies and may reveal pancreatic pseudocysts or ascites.[21]

Amylase levels can also be obtained after an ERCP due to its value in predicting postprocedure pancreatitis.[22] An amylase level done within a few hours post-ERCP is valuable in predicting postprocedure pancreatitis. A study observed that a 6-hour level more than 5 times normal had an 86% predictive accuracy.[23][22] In patients with isolated amylase elevation without 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, resulting in isolated hyperamylasemia. Macroamylasemia is diagnosed using the amylase-to-creatinine clearance ratio (ACCR). ACCR is reduced to a ratio of less than 1 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)][24]

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. A lipase-to-amylase ratio is not a reliable indicator of alcoholic pancreatitis. However, if it is more than 2, it could suggest alcoholic pancreatitis.[25] In the cases of pancreatoduodenectomy, a postoperative serum amylase level of less than 130 IU/l on day 0 allows early and reliable categorization of patients at the least risk for the development of postoperative pancreatic fistula. This could be an indicator to identify patients appropriate for early removal of surgical drains.[26]

Treatment / Management

Treatment of hyperamylasemia 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 (ie, normal saline or lactated Ringer solution), pain control, and nutrition. Fluid resuscitation is typically provided at a rate of 5 ml/kg/hr to 10 ml/kg/hour for all patients. In patients with severe volume loss, rapid repletion should be given with up to 20 ml/kg of fluid over 30 minutes, followed by 3 ml/kg/hour for 8 to 12 hours. 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 ml/kg/hour to 1 ml/kg/hour. 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.[27]

Post-ERCP hyperamylasemia is 1 of the most common complications that can lead to substantial morbidity.[28][29] A study showed that using guidewire for cannulation significantly reduced the incidence of post-ERCP hyperamylasemia. However, there was no considerable effect on the development of pancreatitis.[30] In patients with parotid disease as the cause of hyperamylasemia, appropriate management should be started to treat the underlying parotid illness. With treatment, the inflammation of the parotid gland reduces, and serum amylase levels return to baseline.

Differential Diagnosis

Differential diagnosis hyperamylasemia varies as per the pancreatic, salivary gland, and miscellaneous etiologies:

 Pancreatic

• Acute/chronic pancreatitis
• Complications of acute pancreatitis, such as 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

Prognosis

Prolonged hyperamylasemia for over a week after an initial episode of acute pancreatitis may be associated with future recurrence.[4] However, amylase level does not play a role in determining the severity or the etiology of acute pancreatitis.[31] There is no benefit of trending amylase levels once the diagnosis of acute pancreatitis has been made.[16] Patients with a prolonged elevation of amylase levels would have more risk of developing pancreatic complications, such as necrosis, pseudocyst, or abscess.[14][32]

Complications

Prolonged hyperamylasemia is associated with complications of acute pancreatitis, specifically the presence of pancreatic pseudocysts, necrosis, or abscess.[33] Prolonged hyperamylasemia has also been shown to be independently associated with alcohol use.[4] 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.[34] However, a prospective follow-up study was unable to confirm the finding.[35]

Deterrence and Patient Education

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 is an important data point for diagnosing 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 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.

Enhancing Healthcare Team Outcomes

Management of hyperamylasemia involves an interprofessional team potentially consisting of a gastroenterologist, emergency physician, internist, or family medicine physician. Amylase levels 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.[36] Prolonged hyperamylasemia beyond 1 week after an initial episode of acute pancreatitis may be associated with complications of pseudocysts or necrosis and may involve surgical consultation.[37] Overall, serum amylase is a data point requiring correlation to clinical presentation.