Introduction

Amylase is a digestive enzyme predominantly secreted by the pancreas and salivary glands and found in other tissues in very small levels[1]. Amylase was first described in the early 1800s and is considered one of the first enzymes in history to be scientifically investigated. It was initially termed as diastaste but was later renamed amylase in the early 20th century[2].

Amylases' main function is to hydrolyze the glycosidic bonds in starch molecules, converting complex carbohydrates to simple sugars. There are three main classes of amylase enzymes; Alpha-, beta- and gamma-amylase, and each act on different parts of the carbohydrate molecule. Alpha-amylase can be found in humans, animals, plants, and microbes. Beta-amylase is found in microbes and plants. Gamma-amylase is found in animals and plants. This article will focus on alpha-amylase and its applications[3].

In 1908, a study by Wohlgemuth identified the presence of amylase in urine, and this subsequently led to the use of amylase as a diagnostic laboratory test. Amylase is a commonly ordered test along with lipase, especially in the setting of suspected acute pancreatitis[2].

Etiology and Epidemiology

Although elevated amylase or hyperamylasemia is primarily seen in salivary and pancreatic disease, it may also be seen in different diseases, including gastrointestinal diseases, malignancy, and gynecological diseases (see table below). Reduced amylase levels can be seen in preeclampsia, cystic fibrosis, and liver disease[4][5][6][1][7][8][9][10][11].

Elevated amylase can be seen in a variety of conditions, including pancreatic disease, salivary disease, decreased metabolic clearance, intestinal disease, and macroamylasemia (discussed below). A chronic increase in amylase may also be seen in a rare condition called Benign Pancreatic Hyperenzymemia or Gullo's syndrome. Patients are typically healthy with no pancreatic disease. The etiology of the condition is unknown[3][12].Twenty-six (12.5%) of 208 patients with acute abdominal pain unrelated to the pancreas had elevated serum amylase on admission[13]. Abnormally elevated amylase levels are seen in 35% of patients with liver disease[14]. 16-25% of diabetic ketoacidosis cases present with elevated levels of amylase [15][11]. In a group of 74 patients with surgically resectable lung cancer, 13 showed hyperamylasemia[16].

Pathophysiology

The main function of amylase is to catalyze the hydrolysis of starch into sugars. Several isoforms of amylase have been discovered, but the most abundant that exist are pancreatic amylase (P-amylase) and salivary amylase (S-amylase)P-amylase is specifically found in the pancreas and is synthesized by acinar cells then secreted into the gastrointestinal tract. S-amylase is primarily produced in salivary glands but can also be produced in ovaries, fallopian tubes, gastrointestinal tract, lungs, striated muscle, and malignant neoplasms[17][18]. Serum amylase is tightly regulated in the body. There is a balance between the rate of production and the rate of clearance. Elevated amylase may be due to an increase in pancreatic or extrapancreatic production of a decreased rate of clearance[19].

Amylase has a molecular weight of about 50 to 55 kDa, an optimum physiological pH of 6.7 to 7.0, and requires calcium and chloride ions for optimal enzyme activity.  The small size allows it to be easily filtered through the glomeruli[3]. Amylase is cleared via the kidneys and reticuloendothelial system[1].

Diagnostic Tests

For many years, amylase has been primarily used for diagnosing acute pancreatitis. Amylase can be measured with a blood test or urine test. The urine test may be performed by a clean catch or 24-hour urine collection. The normal range of serum amylase differs from laboratory to laboratory[3]. It is clinically important to differentiate pancreatic amylase from other amylase isoforms. An elevated amylase with normal lipase may be suggestive of a problem outside the pancreas[20].

Interfering Factors

Medications, including aspirin, morphine, antiretrovirals, and estrogen-containing medication, can affect serum levels of amylase. Macroamylasemia, as referred to above, is another well-recognized cause of elevated serum amylase. In this condition, the enzyme forms a complex with proteins such as immunoglobulins and polysaccharides[21]. Due to the large size of the macromolecular complex, renal clearance is reduced, causing persistently elevated amylase levels[22][7]. Macroamylasemia can occur in healthy individuals or diseases including autoimmune disease, diabetes, and cancer such as thyroid cancer[23][24].

Urinary amylase is typically normal macroamylasemia and can help exclude the condition.  This condition occurs in 1 percent of healthy individuals and 2.5 percent of individuals with hyperamylasemia. Macroamylasemia should be considered in an asymptomatic patient with elevated serum amylase. There is no required treatment for the condition[21]. Past studies have shown that macroamylasemia was primarily reported in patients with impaired humoral immunity, such as celiac disease, HIV infection, ulcerative colitis, rheumatoid arthritis, and multiple myeloma[25].

Results, Reporting, Critical Findings

Currently, there is no internationally established reference range for amylase levels. The reference range can be as wide as 20-300 U/L. However, elevated amylase levels of more than three times the upper limit of normal strongly support the diagnosis of acute pancreatitis. Less than this is often associated with other conditions[26]. Abnormally low levels of amylase are not common but can be observed in cystic fibrosis, chronic pancreatitis, diabetes mellitus, obesity, and smoking[8][27]. Clinicians should be aware of such causes to help to interpret low amylase activity in patients[8].

Clinical Significance

Amylase is primarily used in diagnosing pancreatic diseases. Amylase is a commonly measured enzyme due to the availability of inexpensive, easily automated methods[18]. Although amylase is a sensitive indicator of acute pancreatitis, it is not specific as it can be elevated in several conditions unrelated to the pancreas. Pancreatitis can be defined by two out of the three following criteria: abdominal pain, serum amylase and/or lipase levels more than three times the upper limit of normal, and abdominal imaging supporting characteristic findings of pancreatitis[28]. Therefore, its clinical significance has been questioned. In cases of elevated levels of amylase with little support for pancreatitis, alternative causes of hyperamylasaemia should be considered[20]. Amylase is not useful in predicting the severity of an acute pancreatic episode or monitoring the condition[29]. 

Amylase inhibitors such as acarbose have been used in the treatment of type 2 diabetes and have been shown to reduce hemoglobin A1C and peak postprandial glucose[30]. Acarbose has also been shown to improve the remission of dumping syndrome in bariatric patients[31]. The drug also has also been shown to improve the risk of cardiovascular disease by slowing down the thickening of carotid arteries[32]. Elevated amylase can be seen in a wide variety of conditions. It is important for clinicians to have a clear, stepwise approach when hyperamylasemia is found. This will help avoid unnecessary hospitalization and delayed or inappropriate treatment[22][7].

Enhancing Healthcare Team Outcomes

Health care workers must communicate effectively when laboratory results point towards a non-pancreatic cause. It is also important to know the different conditions that may affect amylase levels[18]. Lipase is typically preferred instead of amylase due to higher specificity. Lipase typically stays elevated for up to two weeks, while amylase concentrations remain elevated for up to five days. Therefore, amylase is not as clinically useful as lipase if there is a delay between symptom onset and the time the patient seeks medical attention[26][29]. The 2013 American College of Gastroenterology mentions co-ordering lipase and amylase is neither cost-effective nor treatment advantageous. It also states that ordering amylase alone is unreliable and does not increase diagnostic efficiency compared to lipase[33]. If there is access to lipase testing, adding amylase increases the cost to the patient and has little value in supporting the diagnosis of pancreatitis[34][26].