Pancreatic Enzyme Testing for Acute Pancreatitis - CAM 198HB
Description
Pancreatitis is an inflammation of pancreatic tissue and can be either acute or chronic. Pancreatic enzymes, including amylase, lipase, and trypsinogen can be used to monitor the relative health of the pancreatic tissue. Damage to the pancreatic tissue, including pancreatitis, can result in elevated pancreatic enzyme concentrations whereas depressed enzyme levels are associated with exocrine pancreatic insufficiency (P. A. Banks et al., 2013; Stevens & Conwell, 2024).
Regulatory Status
Amylase
The FDA has approved multiple tests for human serum total amylase as well as for pancreatic amylase. FDA Device database accessed on 5/30/2018 yielded 141 records for amylase test.
Lipase
The FDA has approved multiple tests for human serum lipase. FDA Device database accessed on May 30, 2018, yielded 51 records for lipase test.
Trypsinogen/Trypsin/TAP
Trypsin immunostaining, trypsinogen-2 dipstick, and TAP serum tests are considered laboratory developed tests (LDT); developed, validated and performed by individual laboratories.
LDTs are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88).
As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.
CRP
The FDA has approved multiple tests for human CRP, including assays for conventional CRP, high sensitivity CRP (hsCRP), and cardiac CRP (cCRP). On Sept. 22, 2005, the FDA issued guidelines concerning the assessment of CRP (FDA, 2005).
Procalcitonin
On April 18, 2017, the FDA approved the Diazyme Procalcitonin PCT Assay, Diazyme Procalcitonin Calibrator Set, and Diazyme Procalcitonin Control Set as substantially equivalent and has received FDA 510K clearance for marketing.
IL-6/IL-8
IL-6 and IL-8 are ELISA-based tests and are considered laboratory developed tests (LDT); developed, validated and performed by individual laboratories. IL-6 and IL-8 can also be components of a cytokine panel test, which is also an LDT.
LDTs are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88).
As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.
Policy
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.
- For individuals presenting with signs and symptoms of acute pancreatitis (see Note 1), measurement of either serum lipase (preferred) or amylase concentration is considered MEDICALLY NECESSARY.
- Measurement of serum lipase and/or amylase concentration is considered NOT MEDICALLY NECESSARY in any of the following situations:
- For individuals with an established diagnosis of acute or chronic pancreatitis.
- More than once per visit.
- For asymptomatic individuals during a general exam without abnormal findings.
- For the diagnosis, assessment, prognosis, and/or determination of severity of acute pancreatitis, measurement of serum or urine trypsin/trypsinogen/TAP (trypsinogen activation peptide) is considered NOT MEDICALLY NECESSARY.
The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of an individual’s illness.
- For the diagnosis, assessment, prognosis, and/or determination of severity of acute pancreatitis, measurement of the following biomarkers is considered NOT MEDICALLY NECESSARY:
- C-Reactive Protein (CRP)
- Interleukin-6 (IL-6)
- Interleukin-8 (IL-8)
- Procalcitonin
- For individuals presenting with signs and symptoms of acute pancreatitis (see Note 1), measurement of urinary amylase concentration for the initial diagnosis of acute pancreatitis is considered NOT MEDICALLY NECESSARY.
- For all other situations or conditions not described above, measurement of serum lipase and/or amylase is considered NOT MEDICALLY NECESSARY.
NOTES:
Note 1: Signs and symptoms of acute pancreatitis (Gapp et al., 2023; NIDDK, 2017):
- Mild to severe epigastric pain that begins slowly or suddenly (may spread to the back in some patients)
- Nausea
- Vomiting
- Tender to palpitation of epigastrium
- Abdominal distention
- Hypoactive bowel sounds
- Fever
- Rapid pulse
- Tachypnea
- Hypoxemia
- Hypotension
- Anorexia
- Diarrhea
- Cullen sign
- Grey Turner sign
Table of Terminology
| Term |
Definition |
| AACC |
American Association for Clinical Chemistry |
| ABIM |
American Board of Internal Medicine |
| ACCR |
Amylase-to-creatinine clearance ratio |
| ACG |
American College of Gastroenterology |
| AED |
Academy For Eating Disorders |
| AGA |
American Gastroenterological Association |
| AP |
Acute pancreatitis |
| APA |
American Pancreatic Association |
| APA |
American Psychiatric Association |
| APACHE-II |
Acute Physiology and Chronic Health Evaluation |
| ASCP |
American Society for Clinical Pathology |
| AUCs |
Area under the curve |
| BISAP |
Bedside index for severity in acute pancreatitis |
| BUN |
Blood urea nitrogen |
| CADTH |
Canadian Agency for Drugs and Technologies in Health |
| cCRP |
Cardiac C-reactive protein |
| CECT |
Contrast-enhanced computed tomography |
| CLIA ’88 |
Clinical Laboratory Improvement Amendments of 1988 |
| CMS |
Centers for Medicare & Medicaid Services |
| CP |
Chronic pancreatitis |
| CPEC |
Clinical Practice and Economics Committee |
| CRP |
C-reactive protein |
| CT |
Computed axial tomography |
| CTSI |
Computed axial tomography severity index |
| ED |
Eating disorder |
| ELISA |
Enzyme-linked immunoassay |
| EPI |
Exocrine pancreatic insufficiency |
| ERCP |
Endoscopic retrograde cholangiopancreatography |
| EUS |
Endoscopic ultrasonography |
| FDA |
Food and Drug Administration |
| GRADE |
Grading of recommendations assessment, development, and evaluation |
| HIV |
Human immunodeficiency virus |
| HMGB1 |
High Mobility Group Box 1 |
| hsCRP |
High sensitivity C-reactive protein |
| HSROC |
Hierarchical summary receiver operating characteristics curve |
| IAP |
International Association of Pancreatology |
| IL-6 |
Interleukin-6 |
| IL-8 |
Interleukin-8 |
| LCDs |
Local Coverage Determinations |
| LDH |
Lactate dehydrogenase |
| LDTs |
Laboratory-developed tests |
| MODS |
Multiorgan dysfunction syndrome |
| MRCP |
Magnetic resonance cholangiopancreatography |
| MRI |
Magnetic resonance imaging |
| NASPGHAN |
North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas Committee |
| NCDs |
National Coverage Determinations |
| PBMCs |
Peripheral blood mononuclear cells |
| PCT |
Procalcitonin |
| PICU |
Pediatric intensive care unit |
| POC |
Point of care |
| RIA |
Radioimmunoassay |
| SIRS |
Systemic inflammatory response syndrome |
| s-isoform |
Salivary glands |
| SPINK1 |
Serine protease inhibitor Kazal type 1 |
| TAP |
Trypsinogen activation peptide |
| ULN |
Upper limit of normal |
| URL |
Upper limit of reference interval |
| UTDT |
Urine trypsinogen dipstick test |
Rationale
Acute Pancreatitis
Acute pancreatitis (AP) is inflammation of the pancreatic tissue that can range considerably in clinical manifestations. In approximately 80% of individuals, AP clears up completely or shows significant improvement within one to two weeks. However, it can sometimes lead to serious complications and as such, is often treated in a hospital (informedhealth.org, 2021). Due to the lack of consensus in diagnosing, characterizing, and treating AP, an international group of researchers and practitioners convened in Atlanta in 1992 to write a clinically based classification system for AP, which is now commonly referred to as the Atlanta convention or Atlanta classification system (Bradley, 1993). The Atlanta classification system was then revised in 2012 (Banks et al., 2013). For the diagnosis of AP, two of the three following criteria must be present: “(1) abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back); (2) serum lipase activity (or amylase activity) at least three times greater than the upper limit of normal; and (3) characteristic findings of acute pancreatitis on contrast-enhanced computed tomography (CECT) and less commonly magnetic resonance imaging (Toouli et al.) or transabdominal ultrasonography” (italics emphasized by the manuscript’s authors) (Banks et al., 2013). This two-of-three criterion is recommended for diagnostic use by several professional societies (Banks & Freeman, 2006; IAP/APA Working Group, 2013; Tenner et al., 2013). AP can be characterized by two temporal phases, early or late, with degrees of severity ranging from mild (with no organ failure) to moderate (organ failure less than 48 hours) to severe (where persistent organ failure has occurred for more than 48 hours). The two subclasses of AP are edematous AP and necrotizing AP. Edematous AP is due to inflammatory edema with relative homogeneity whereas necrotizing AP displays necrosis of pancreatic and/or peripancreatic tissues (Banks et al., 2013). The figure below from Bollen et al. (2015) outlines the revised Atlanta classification system of AP:
Chronic Pancreatitis
Chronic pancreatitis (ASCP) is also an inflammation of the pancreatic tissue. The two hallmarks of CP are severe abdominal pain and pancreatic insufficiency (Freedman & Forsmark, 2024). Alcohol-induced chronic pancreatitis (or alcohol pancreatitis) accounts for approximately 40-70% of all cases of CP (Klochkov et al., 2023)
The endocrine system is comprised of several glands which secrete hormones directly into the bloodstream to regulate many different bodily functions. On the other hand, the exocrine system is comprised of glands which secrete products through ducts, rather than directly into the bloodstream. CP affects both the endocrine and exocrine functions of the pancreas. Fibrogenesis occurs within the pancreatic tissue due to activation of pancreatic stellate cells by toxins (for example, those from chronic alcohol consumption) or cytokines from necroinflammation. Measuring the serum levels of amylase, lipase, and/or trypsinogen is not helpful in diagnosing CP since not every CP patient experiences acute episodes, the relative serum concentrations may be either decreased or unaffected, and the sensitivities of the tests are not enough to distinguish reduced enzyme levels (Witt et al., 2007). The best method to diagnose CP is to histologically analyze a pancreatic biopsy, but this invasive procedure is not always the most practical so “contrast-enhanced computed tomography is the best imaging modality for diagnosis. Computed tomography may be inconclusive in early stages of the disease, so other modalities such as magnetic resonance imaging, magnetic resonance cholangiopancreatography, or endoscopic ultrasonography with or without biopsy may be used” (Barry, 2018). Previously, ERCP was commonly used to diagnose CP, but the procedure can cause post-ERCP pancreatitis. Genetic factors are also implicated in CP, especially those related to trypsin activity, the serine protease inhibitor SPINK1, and cystic fibrosis (Borowitz et al., 1995; Patel, 2017; Witt et al., 2007).
Amylase
Amylase is an enzyme produced predominantly in the salivary glands (s-isoform) and the pancreas (p-isoform or p-isoamylase) and is responsible for the digestion of polysaccharides, cleaving at the internal 1→4 alpha linkage. Up to 60% of the total serum amylase can be of the s-isoform. The concentration of total serum amylase as well as the pancreatic isoenzyme increase following pancreatic injury or inflammation (Basnayake & Ratnam, 2015; Vege, 2024a). Even though the serum concentration of the pancreatic diagnostic enzymes, including amylase, lipase, elastase, and immunoreactive trypsin all increase within 24 hours of onset of symptomology, amylase is the first pancreatic enzyme to return to normal levels so the timing of testing is of considerable importance for diagnostic value (Basnayake & Ratnam, 2015; Ventrucci et al., 1987; Yadav et al., 2002). The half-life of amylase is 12 hours since it is excreted by the kidneys, so its clinical value decreases considerably after initial onset of AP. The etiology of the condition can also affect the relative serum amylase concentration. In up to 50% of AP instances due to hypertriglyceridemia (high blood levels of triglycerides), the serum amylase concentration falls into the normal range, and normal concentrations of amylase has been reported in cases of alcohol-induced AP (Basnayake & Ratnam, 2015; Quinlan, 2014); in fact, one study shows that 58% of the cases of normoamylasemic AP was associated with alcohol use (Clavien et al., 1989). Elevated serum amylase concentrations also can occur in conditions other than AP, including hyperamylasemia (excess amylase in the blood) due to drug exposure (Ceylan et al., 2016; Liu et al., 2016), bulimia nervosa (Wolfe et al., 2011), leptospirosis (Herrmann-Storck et al., 2010), and macroamylasemia (Vege, 2024a). Serum amylase levels are often significantly elevated in individuals with bulimia nervosa due to recurrent binge eating episodes (Wolfe et al., 2011).
Macroamylasemia is a condition where the amylase concentration increases due to the formation of macroamylases, complexes of amylase with immunoglobulins and/or polysaccharides. Macroamylasemia is associated with other disease pathologies, “including celiac disease, HIV infection, lymphoma, ulcerative colitis, rheumatoid arthritis, and monoclonal gammopathy”. Suspected macroamylasemia in instances of isolated amylase elevation can be confirmed by measuring the amylase-to-creatinine clearance ratio (ACCR) since macroamylase complexes are too large to be adequately filtered. Normal values range from three to four percent with values of less than one percent supporting the diagnosis of macroamylasemia. ACCR itself is not a good indicator of AP since low ACCR is also exhibited in diabetic ketoacidosis and severe burns (Vege, 2024a). Hyperamylasemia is also seen in other extrapancreatic conditions, such as appendicitis, salivary disease, gynecologic disease, extra-pancreatic tumors, and gastrointestinal disease (Terui et al., 2013; Vege, 2024a). Gullo’s Syndrome (or benign pancreatic hyperenzymemia) is a rare condition that also exhibits high serum concentrations of pancreatic enzymes without showing other signs of pancreatitis (Kumar et al., 2016). No correlation has been found between the concentration of serum amylase and the severity or prognosis of AP (Lippi et al., 2012).
Urinary amylase and peritoneal amylase concentrations can also be measured. Rompianesi et al. (2017) reviewed the use of urinary amylase and trypsinogen as compared to serum amylase and serum lipase testing. The authors note that “with regard to urinary amylase, there is no clear-cut level beyond which someone with abdominal pain is considered to have acute pancreatitis”. Three studies regarding urinary amylase were reviewed — each with 134 – 218 participants — and used the hierarchical summary receiver operating characteristics curve (HSROC) analysis to compare the accuracy of the studies. Results showed that “the models did not converge” and the authors concluded that “we were therefore unable to formally compare the diagnostic performance of the different tests” (Rompianesi et al., 2017).
Another study investigated the use of peritoneal amylase concentrations for diagnostic measures and discovered that patients with intra-abdominal peritonitis had a mean peritoneal amylase concentration of 816 U/L (142 – 1,746 U/L range), patients with pancreatitis had a mean concentration of 550 U/L (100 – 1,140 U/L range), and patients with other “typical infectious peritonitis” had a mean concentration of 11.1 U/L (0 – 90 U/L range). Conclusions state “that peritoneal fluid amylase levels were helpful in the differential diagnosis of peritonitis in these patients” and that levels > 100 U/L “differentiated those patients with other intra-abdominal causes of peritonitis from those with typical infectious peritonitis” (Burkart et al., 1991). The authors do not state if intraperitoneal amylase is specifically useful in diagnosing AP.
Liu et al. (2021) conducted a retrospective cohort study to evaluate whether serum amylase and lipase could serve as a biomarker to predict pancreatic injury in 79 critically ill children who died of different causes. Through autopsy investigation, the subjects were divided into pancreatic injury group and non-pancreatic injury group. Forty-one patients (51.9%) exhibited pathological changes of pancreatic injury. Levels of lactate, erythrocyte sedimentation rate, alanine transaminase, aspartate transaminase, and troponin-I in the pancreatic injury group were significantly higher than that in the noninjury group. "Multivariable logistic regression analysis showed that serum amylase, serum lipase, and septic shock were significantly associated with the occurrence rate of pancreatic injury". Therefore, the authors conclude that "serum amylase and lipase could serve as independent biomarkers to predict pancreatic injury in critically ill children” (Liu et al., 2021).
In a prospective case control study, Judal et al. (2022) investigated urinary amylase levels for diagnosis of acute pancreatitis. One major challenge with measurement of serum amylase is its short half-life which returns to normal levels within a short period of time. This study enrolled 100 patients (50 healthy and 50 with acute pancreatitis) who were measured for serum amylase, serum lipase, and urinary amylase. There was a statistically significant increase in the serum amylase, lipase, and urinary amylase mean values of patients with AP. "Serum amylase had the highest sensitivity (100%) and serum lipase had the highest specificity (96.53%). The sensitivity and specificity of urinary amylase was found to be 97.25% and 91.47% respectively" (Judal et al., 2022). The authors conclude that urinary amylase is a convenient and sensitive test for diagnosis.
Ryholt et al. (2024) conducted a retrospective study with data collected throughout 2020 to “assess the utilization of appropriate laboratory testing related to the diagnosis of acute pancreatitis.” The authors were particularly interested in the overuse of amylase testing or amylase and lipase testing together when lipase testing alone would have been sufficient for AP diagnosis. Overall, 2,567 (9.3%) of all amylase and lipase tests were determined to be unnecessary, an estimated $128,350 in total cost savings if eliminated. Of the unnecessary tests, 1,881 (73.2%) were amylase tests and 686 (26.7%) were lipases tests. The authors also note that “an analysis of test-ordering behavior by providers revealed that 81.5% of all unnecessary tests were ordered by MDs.” The authors conclude that the “study demonstrated that amylase and lipase tests have been overutilized in the diagnosis of acute pancreatitis” (Ryholt et al., 2024).
Lipase (Pancreatic Lipase or Pancreatic Triacylglycerol Lipase)
Pancreatic lipase or triacylglycerol lipase (herein referred to as “lipase”) is an enzyme responsible for hydrolyzing triglycerides to aid in the digestion of fats. Like amylase, lipase concentration increases shortly after pancreatic injury (within three to six hours). However, contrary to amylase, serum lipase concentrations remain elevated for one to two weeks after initial onset of AP since lipase can be reabsorbed by the kidney tubules (Lippi et al., 2012). Moreover, the pancreatic lipase concentration is 100-fold higher than the concentration of other forms of lipases found in other tissues such as the duodenum and stomach (Basnayake & Ratnam, 2015). Both the sensitivity and the specificity of lipase in laboratory testing of AP are higher than that of amylase (Yadav et al., 2002). A study by Coffey et al. (2013) found “an odds ratio of 7.1 (95% confidence interval 2.5-20.5; P<0.001) for developing severe AP” in patients ages 18 or younger when the serum lipase concentration is at least 7-fold higher than upper limit of normal. However, in general, elevated serum lipase concentration is not used to determine the severity or prognosis of AP (Ismail & Bhayana, 2017). Hyperlipasemia can also occur in other conditions such as Gullo’s Syndrome (Kumar et al., 2016). The use of lipase to determine etiology of AP is of debate. A study by Levy et al. (2005) reports that lipase alone cannot be used to determine biliary cause of AP whereas other studies have indicated that a ratio of lipase-to-amylase concentrations ranging from 2:1 to more than 5:1 can be indicative of alcohol-induced AP (Gumaste et al., 1991; Ismail & Bhayana, 2017; Pacheco & Oliveira, 2007; Tenner & Steinberg, 1992).
The review by Ismail and Bhayana (2017) included a summary table (Table 1 below) comparing various studies concerning the use of amylase and lipase for diagnosis of AP as well as a table (Table 2 below) comparing the cost implication of the elimination of double-testing for AP.
Table 1: Summary of numerous studies comparing lipase against amylase (URL – Upper Limit of Reference interval, AP – Acute Pancreatitis).
| Design and reference |
Participant (patients with abdominal pain/AP) |
Threshold |
Results |
Conclusion |
|
| Serum lipase |
Serum amylase |
||||
| Prospective study [56] |
384/60 |
Two times URL |
Diagnostic accuracy and efficiency are > 95% for both |
No difference between amylase and lipase in diagnosing AP |
|
| Prospective study [57] |
306/48 |
Serum lipase > 208 U/L Serum amylase > 110 U/L |
92% sensitivity 87% specificity 94% Diagnostic accuracy |
93% sensitivity 87% specificity 91% Diagnostic accuracy |
Both tests are associated with AP, but serum lipase is better than amylase |
| Prospective study [58] |
328/51 |
Serum lipase: > 208 U/L (Day 1) > 216 U/L (Day 3) Serum amylase: > 176 U/L > 126 U/L (Day 3) |
Day 1: 64 % Sensitivity 97% Specificity Day 3: 55% Sensitivity 84% Specificity |
Day 1: 45 % Sensitivity 97% Specificity Day 3: 35% Sensitivity 92% Specificity |
Serum lipase is better at diagnosing early and late AP |
| Retrospective study [63] |
17,531/320 *49 had elevated lipase only |
Serum lipase > 208 U/L Serum amylase > 114 U/L |
90.3% Sensitivity 93.6% Specificity |
78.7% Sensitivity 92.6% Specificity |
Serum lipase is more accurate marker for AP |
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