Acute pancreatitis biomarkers: to many or too few?
by Dr Allison B. Chambliss
The diagnosis of acute pancreatitis has long relied on elevations in serum amylase or lipase. Recent test utilization efforts have called f or the discontinuation of amylase in acute pancreatitis, favouring the higher specificity and longer elevation of lipase. However, neither biomarker correlates with disease severity, and early recognition of severe cases remains a diagnostic challenge.
Introduction to acute pancreatitis
Acute pancreatitis (AP) represents one of the most common gastrointestinal-related causes for hospital admissions. AP refers to an inflammatory condition of the pancreas commonly associated with a severe, rapid onset of abdominal pain. Patients may also experience other non-specific symptoms, including fever, tachycardia, nausea and vomiting. AP may be classified as mild, moderate or severe based on the degree of organ failure and systemic complications, a system referred to as the revised Atlanta classification (Table 1) [1].
The most frequent cause of AP is gallstones, which are hardened deposits of bile. Gallstones may account for 40–70% or more of AP cases, depending on the geographic region [2]. Gallstone pancreatitis typically resolves upon spontaneous or endoscopic removal of the stone. Once recovered, gallstone pancreatitis patients typically undergo cholecystectomy, the surgical removal of the gallbladder, to prevent recurrent AP episodes. Alcohol abuse is typically ranked as the second most frequent cause of AP (25–35% of cases), followed by a variety of other rarer causes such as metabolic abnormalities, drugs and toxins, and trauma.
Treatment for most patients involves supportive care, including fluid resuscitation, pain control and monitoring. Although patients with mild disease may recover within a few days without complications, the most severe cases may involve systemic inflammatory response syndrome with the failure of multiple organs, including acute respiratory failure, shock, and/or renal failure. Rapid diagnosis of AP and assessment of risk for disease severity, both of which rely on laboratory testing, are critical to guide patient management. Recurrent episodes of AP may progress to chronic pancreatitis.
Increases in disease prevalence
The annual incidence of AP is estimated at 20–40 per 100¦000 worldwide [3]. Interestingly, the incidence has increased over the past few decades, particularly in Western countries [4]. One study found an increase of 13.2% in AP-related hospital admissions in 2009–2012 compared to 2002–2005 across the USA [5]. Although these epidemiological trends are not entirely understood, several reasons for the overall increasing incidence of AP have been proposed. One hypothesis is the global epidemic of obesity, which may promote gallstone formation. Increases in alcohol consumption could also play a role in some countries. Other experts suggest that the wider availability and increased frequency of laboratory testing may be major factors. This latter concept is in alignment with the fact that although cases in AP have risen, the mortality rate of the disease has, in fact, declined [5]. Nevertheless, mortality remains high in the severe case category.
Biomarkers for AP
Serum amylase and lipase are well-established as the primary biomarkers for the diagnosis of AP. Both amylase and lipase are digestive enzymes; amylase hydrolyses complex carbohydrates to simple sugars, and lipase catalyses the hydrolysis of triglycerides. Although lipase is synthesized predominantly by the pancreas, amylase is produced both by the pancreas (P-type) and the salivary glands (S-type) and is found in several other organs and tissues. Both enzymes are released into the circulation at the onset of AP, and elevations of both are typically observed within 3-6|h [6, 7]. Multiple clinical societies and guidelines recommend a serum amylase or lipase test result greater than three times the upper reference limit as a diagnostic criterion for AP, in addition to characteristic symptoms and imaging findings [2, 8]. Both biomarkers are widely measured by automated enzymatic methods and are thus commonly found in routine hospital laboratories, permitting rapid diagnoses. Notably, most routine assays do not distinguish between P-type and S-type amylase. This distinction requires the analysis of amylase isoenzymes, which is typically limited to reference laboratories.
Questioning the value of amylase
Serum amylase and lipase are well-established as the primary biomarkers for the diagnosis of AP. Both amylase and lipase are digestive enzymes; amylase hydrolyses complex carbohydrates to simple sugars, and lipase catalyses the hydrolysis of triglycerides. Although lipase is synthesized predominantly by the pancreas, amylase is produced both by the pancreas (P-type) and the salivary glands (S-type) and is found in several other organs and tissues. Both enzymes are released into the circulation at the onset of AP, and elevations of both are typically observed within 3-6|h [6, 7]. Multiple clinical societies and guidelines recommend a serum amylase or lipase test result greater than three times the upper reference limit as a diagnostic criterion for AP, in addition to characteristic symptoms and imaging findings [2, 8]. Both biomarkers are widely measured by automated enzymatic methods and are thus commonly found in routine hospital laboratories, permitting rapid diagnoses. Notably, most routine assays do not distinguish between P-type and S-type amylase. This distinction requires the analysis of amylase isoenzymes, which is typically limited to reference laboratories.
Questioning the value of amylase
In contrast to amylase, lipase is reabsorbed by the tubules of the kidney and is not excreted into the urine. Thus, lipase tends to remain elevated for longer than amylase, which may allow for a longer diagnostic window for AP. This advantage, in addition to lipase’s higher specificity for the pancreas, has led some organizations to recommend lipase over amylase for the diagnosis of AP. The American Board of Internal Medicine Foundation’s Choosing Wisely® campaign, in collaboration with the American Society for Clinical Pathology, has recommended: “Do not test for amylase in cases of suspected acute pancreatitis. Instead, test for lipase” [9].
Despite these recommendations, many hospital laboratories still maintain assays for amylase. We performed a retrospective audit at our institution to determine the ordering patterns of amylase relative to lipase in cases of AP. We found that in a cohort of 438 consecutive patients admitted with AP, lipase was ordered for all patients, while amylase was only ordered for 12% of patients [10]. We observed that most of the amylase orders stemmed from patients with gallstone pancreatitis who were referred for laparoscopic cholecystectomy procedures and who were under the care of the surgical team. We speculated that amylase may have been co-ordered with lipase in this subgroup of patients to check for biomarker normalization. Laparoscopic cholecystectomy is ideally to be performed as early as possible when gallstone AP resolves, and normalization of amylase or lipase may be used to document that resolution. Because amylase is believed to fall more rapidly than lipase after AP, trending amylase over time could possibly allow for a quicker documentation of biomarker normalization. However, our study also showed that there was no significant difference in amylase versus lipase in the time for the biomarker to fall below three times the upper reference limit. These observations led us to further question the added value of amylase relative to lipase alone in the diagnosis and management of AP.
Lipase does have limitations that may preclude it from being the AP biomarker of choice in some cases. Lipase may be elevated in non-pancreatic conditions such as renal insufficiency and cholecystitis (Table 2). Both amylase and lipase may rarely be non-specifically elevated due to complexes with immunoglobulins, termed macroamylasemia and macrolipasemia. Further, amylase may be useful in the workup of other pancreatic diseases and, unlike lipase, can be measured in the urine. Quantitation of amylase in body fluids, such as pancreatic fluid and peritoneal fluid, can aid in the evaluation of pancreatic cysts and pancreatic ascites [11]. For these reasons, many laboratories choose to maintain amylase assays.
An unmet need for biomarkers for AP severity
Although AP may be easily diagnosed with elevations in amylase or lipase, there is an unmet need for biomarkers or algorithms that can specifically identify severe forms of AP early in the disease course. Twenty to thirty percent of AP patients may develop a moderate or severe form of the disease involving single or multiple organ dysfunction or failure and requiring intensive care. Identifying the severe cases early such that treatment may be tailored to minimize complications remains one of the major challenges of AP. Risk factors such as old age and obesity often correlate with disease severity. However, neither amylase nor lipase levels correlate with disease severity, and no other laboratory tests are consistently accurate to predict severity in patients with AP.
In 2019, the World Society of Emergency Surgery (WSES) published guidelines for the management of severe AP [12]. These guidelines indicate that C-reactive protein (CRP), an acute phase reactant synthesized by the liver and a non-specific indicator of inflammation, may have a role as a prognostic factor for severe AP. However, CRP may not reach peak levels for 48 to 72|h, limiting it as an early severity indicator. Specifically, WSES recommended that a CRP result greater than or equal to 150|mg/L on the third day after AP onset could be used as a prognostic factor for severe disease. Elevated or rising blood urea nitrogen, hematocrit, lactate dehydrogenase, and procalcitonin have also demonstrated predictive value for pancreatic necrosis infections.
Other biomarkers have been investigated to distinguish mild from non-mild forms of AP. Interleukin-6 has shown good discriminatory capability in combination with CRP [13]. Resistin is a more recently discovered peptide hormone that was first described as a contributor to insulin resistance (hence the name). Resistin is secreted by adipocytes and may play a role in obesity, hypertriglyceridemia, and inflammatory cytokine reactions. A prospective observational study found that resistin levels were better than CRP for predicting severe AP on the third day and for predicting the development of necrosis [14]. However, more studies are needed before resistin can be recommended as a prognostic indicator, and clinical resistin testing is not widely available. Thus, there still remains a need for prognostic severity biomarkers that rise early (prior to 48|h) in the course of AP.
The authors
Allison B. Chambliss PhD, DABCC
Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
E-mail: abchambl@usc.edu
