Clinical Evaluation of Patients with Elevated Serum Lipase

Introduction

In our clinical practice, we frequently encounter patients with elevated serum lipase levels, a finding often associated with acute pancreatitis (AP). However, it can occur in other conditions, even at levels ≥ 3 × upper limit of normal (ULN). In patients without clinical or imaging suggestive of AP, alternative causes should be explored, including other pancreatic diseases and nonpancreatic hyperlipasemia (NPHL) [1]. From our experience, it is crucial to maintain an open mind and explore all possible diagnoses, especially when typical signs of pancreatitis are absent. In this review, we briefly summarize key data and suggest practical approach to hyperlipasemia.

Hyperlipasemia and Acute Pancreatitis

AP is diagnosed when two of the following criteria are met: (i) characteristic abdominal pain, (ii) serum amylase and/or lipase levels exceeding three times the ULN, or (iii) characteristic abdominal imaging findings [2, 3]. Lipase sensitivity for AP diagnosis at ≥ 3 × ULN ranges from 64 to 100%, with specificity ranging from 87 to 99.4%. Amylase sensitivity ranges from 35 to 93%, and specificity from 87 to 99.1% [4, 5].

When evaluating hyperlipasemia, AP should always be considered in the differential diagnosis, even in the absence of abdominal pain. At least two studies have explored the incidence of AP in cases of painless hyperlipasemia (lipase levels ≥ 3 × ULN) in different settings. A study in the Emergency Department reported a 29% incidence of AP [6], while another in the Intensive Care Unit (ICU) found a 22% incidence after performing appropriate abdominal imaging [7].

Radiological imaging findings, such as peri-pancreatic fat stranding, pancreatic edema, necrosis (both pancreatic and extra-pancreatic), and fluid collections, can confirm AP [1, 3].

Imaging of the abdomen should be performed in patients with hyperlipasemia, particularly those with levels ≥ 3 × ULN. However, advancements in imaging may detect subtle pancreatic injuries in possible subclinical pancreatic lesions, potentially erroneous reclassifying hyperlipasemia in patients currently defined as NPHL.

Hyperlipasemia and Other Pancreatic Diseases

From our experience, hyperlipasemia can be a red flag for more insidious conditions, including pancreatic cancer and pancreatic duct obstruction.

Nonpancreatic Hyperlipasemia (NPHL)

Over the course of our careers, we have encountered a wide range of causes for NPHL, which can include conditions like sepsis (27.7%), cirrhosis (3–25.5%), renal failure (12.7–15.7%), malignancy (13.7%), drugs (4.2–11.8%), colitis (9.8%), gastrointestinal bleeding (1–7.8%), type 2 diabetes (4.7%), neurosurgical pathology (4%), post-endoscopic retrograde cholangiopancreatography (4%), trauma (3.9%), intestinal obstruction (2–3.9%), diabetic ketoacidosis (1.5%), and inflammatory bowel disease (1.2%) [1, 4, 5, 8] Table 1.

Table 1.

Causes of nonpancreatic hyperlipasemia

Intra-abdominal causes • Cholecystitis • Cholangitis • Celiac disease • Inflammatory bowel disease • Cirrhosis • Viral hepatitis • Peptic ulcer • Post-ERCP lipasemia • Gastroenteritis • Bowel ischemia/perforation • Abdominal typhoid • Malignancy • Gastrointestinal hemorrhage • Abdominal aortic aneurysms • Peritonitis

Reduced clearance of serum lipase • Renal impairment • Macrolipase formation

Critical Illness • Sepsis • Intracranial hemorrhage • Traumatic brain injury • Severe burns • Toxic epidermal necrolysis/Stevens-Johnson syndrome

Diabetes (type 1, type 2, and diabetic ketoacidosis)

Drugs/Medications • PD-1 inhibitors (nivolumab, pembrolizumab) • Nonsteroidal anti-inflammatory drugs (NSAIDs) • DPP-4 inhibitors (sitagliptin and saxagliptin) • Chemotherapeutic agents (sorafenib, nilotinib) • Chronic alcohol use • Opioid analgesics

Miscellaneous • Hematologic malignancies • Sarcoidosis • Renal transplant rejection • Viral infections such as Covid-19, HIV, and cytomegalovirus (CMV) infection

The limitations to identify NPHL are caused by the lack of a gold standard in defining AP. These include limitations in imaging and autopsy findings of AP that was not suspected antemortem, such as seen in Covid-19 [9].

Why Is Lipase Elevated in These Conditions?

Through our practice, we have come to appreciate that the elevation of lipase in NPHL is not always well understood but can result from various mechanisms.

Reduced Clearance of Serum Lipase

Reduced clearance of lipase from circulation can result from renal impairment or the formation of macrolipase. Elevated pancreatic enzyme levels are often observed in uremic patients without clinical signs of pancreatitis. A review suggests that the incidence of hyperlipasemia in renal failure ranges from 14 to 80% [10]. This wide range is attributed to the heterogeneity of the original studies and varying degrees of impaired renal clearance.

A study comparing pancreatic enzyme levels among patients with chronic kidney disease (CKD), those on hemodialysis (HD), peritoneal dialysis, and renal transplant recipients revealed higher lipase levels in all patient groups compared to the control population. However, significantly hyperlipasemia (lipase levels ≥ 2 × ULN) waspredominantly observed in HD patients, with a prevalence of 3% in this group [11].

In renal impairment, lipase is typically removed from circulation through glomerular filtration, with most of it being reabsorbed and degraded within the renal tubules. However, diminished glomerular filtration only partially accounts for elevated lipase levels, as lipase concentrations do not consistently correlate with changes in renal function [4, 5]. Macrolipase, characterized by the formation of lipase–immunoglobulin complexes, persists in the serum and can artificially elevate lipase levels due to reduced renal filtration [1, 5, 8].

Intra-abdominal Causes of Lipase Elevation

Lipase may also be elevated due to various intra-abdominal pathologies. The pancreas is highly sensitive to inflammation in adjacent organs, such as the biliary and gastrointestinal tract. Obstructions causing biliary regurgitation into the pancreas can lead to pancreatic inflammation, e.g., small bowel obstruction or pancreatic/biliary ductal obstruction. Additionally, lipase can originate from alternative sources, including the stomach, small bowel, liver, and gallbladder [1, 5]. Elevated lipase levels have also been observed in cases of inflammatory bowel disease, celiac disease, gastrointestinal hemorrhage, abdominal aortic aneurysms, and peritonitis [1, 5, 8].

Critical Illness Resulting in Lipase Elevation

In critical care patients with multi-organ failure, lipase elevation may result from pancreatic hypoperfusion and cellular stress [5, 10]. In neurosurgical patients with severe head injuries associated with raised intracranial pressure, including intracerebral hemorrhage, and traumatic brain injury, exocrine pancreatic enzyme production may be triggered by central pathways. This includes increased vagal tone, altered adrenergic stimulation, and the release of activating hormones like cholecystokinin [5]. In critically injured trauma patients without direct pancreatic injuries and those with Stevens-Johnson syndrome, pancreatic hypoperfusion may cause elevated lipase levels [5, 10].

Drugs

Drugs associated with NPHL include PD-1 inhibitors, nonsteroidal anti-inflammatory drugs, DPP-4 inhibitors, chemotherapeutic agents, and chronic alcohol use [1, 4, 5]. Opioid analgesics used for abdominal pain can independently elevate lipase levels due to the sphincter of Oddi spasm [1].

Covid-19

A recent systematic review and meta-analysis showed the overall prevalence and mortality for increased pancreatic enzymes (> 3 ULN) were 6.1% and 39.2%, respectively. Patients with increased pancreatic enzymes had worse clinical outcomes, including need for ICU admission, mechanical ventilation, and mortality [12].

Miscellaneous

Other NPHL conditions include sarcoidosis, renal transplant rejection, and viral infections such as hepatitis C, HIV, and cytomegalovirus infection [1, 5].

Clinical Outcomes of Patients with NPHL

Da et al. [8] and Feher et al. [4] studied the natural history of NPHL, finding significantly lower serum lipase levels than in AP patients. Both studies noted that laboratory markers indicating the severity of the condition, such as albumin levels and kidney function, were significantly impaired in both NPHL and AP groups [4, 8].

Contrary to Da et al.'s findings, which reported no differences in ICU duration or mortality, Feher et al. observed that patients hospitalized with NPHL required nearly twice the ICU treatment duration and experienced significantly higher in-hospital mortality rates (22.4% vs. 5.1%) compared to those admitted with AP. This underscores NPHL as a serious clinical predictor. Among nearly 400 hospitalized patients with NPHL, the increased incidence was primarily associated with acute kidney injury (AKI) and sepsis. Similar causes of NPHL were also described by Da et al. (Tables 2).

Table 2.

Etiology of hyperlipasemia (Lipase levels > 3 UNL) in hospitalized patients

Etiology	Prevalence
Gastric and bowel disorders
Peptic ulcer	0.5%
Gastrointestinal bleeding	1–7.8%
Bowel necrosis/perforation	1%
Bowel obstruction	2–3.9%
Inflammatory Bowel Disease	1.2%
Hepatobiliary disorders
Cholecystitis	2%
Cholangitis	3.2%
Liver disease	3.5–22.5%
Post-ERCP lipasemia	4%
Cancers	13.7%
Pancreatic cancers	5.5%
Nonpancreatic cancers	6.7%
Hematological malignancies	1.5%
Diabetes
Type 2 diabetes mellitus	4.7%
Diabetic ketoacidosis	1.5%
Neurosurgical pathology	4%
Cardiovascular disease	4.2%
Drugs side effect	4.2–11.8%
Other
Infection without sepsis	7.5%
Infection with sepsis
Sepsis without acute kidney injury (AKI)	7.2%
Sepsis with acute kidney injury (AKI)	20.4%
Acute kidney injury (AKI) without sepsis	12.7–15.7%

Combined data extracted from Feher et al. 2024 [4] (401 patients) and from Da et al. 2016 [6] (51 patients)

How Do We Approach Patients with NPHL?

Based on our collective experience, we’ve developed a systematic approach to evaluating patients with elevated lipase levels:

Medical History

Key considerations include symptom onset and duration, past conditions (e.g., pancreatitis, abdominal surgery, endoscopic procedures), alcohol use, smoking, abdominal trauma, family history, and recent medications.

Laboratory Evaluation

A complete blood count, renal function panel, and liver function tests were included to identify the systemic causes of hyperlipasemia.

NPHL Diagnosis and Abdominal Imaging

It is essential to consider nonpancreatic causes of hyperlipasemia. The primary goal is to rule out AP or other pancreatic diseases by assessing lipase levels (≥ 3 × ULN or < 3 × ULN) and the presence of typical abdominal pain (Figs. 1 and 2).

• Elevated lipase levels ≥ 3 × ULN without abdominal pain: Abdominal imaging is advised, to investigate asymptomatic AP.

• Elevated lipase levels < 3 × ULN with abdominal pain: Abdominal imaging is advised to investigate potential AP or other intra-abdominal causes of NPHL, even if the pain is atypical for pancreatitis.

• Elevated lipase levels < 3 × ULN without abdominal pain: This group presents the greatest diagnostic challenge. The decision to perform abdominal imaging should be guided by clinical judgment.

Fig. 1.

Approach to a patient with elevated serum lipase

Fig. 2.

Visual approach for diagnosis and etiology of NPHL

NPHL in the Context of the Clinical Setting

Acute Setting

Most of the data presented pertain to acute episodes of elevated lipase. Primary causes are often associated with infections, AKI, and critical illnesses, such as sepsis, intracranial hemorrhage, and severe burns. Treatment primarily involves addressing the underlying cause and providing appropriate supportive care.

Chronic Setting

In chronic scenarios, differential diagnoses should include CKD, medications, cirrhosis, and other chronic abdominal conditions such as inflammatory bowel disease and celiac disease (Table 1).

For patients whose history and physical examination suggest that the source of chronically elevated lipase is pancreatic in origin, endoscopic ultrasound can be a valuable tool for diagnosing chronic pancreatitis and reliably ruling out occult pancreatic malignancy.

Take-Home Message

Through our years of clinical experience, we have learned that elevated serum lipase levels can occur in a wide variety of conditions, both pancreatic and nonpancreatic. While lipase is more specific than amylase for pancreatitis, its elevation alone cannot definitively diagnose acute pancreatitis. We recommend that clinicians approach hyperlipasemia with a systematic evaluation, particularly when typical signs of pancreatitis are absent, to avoid unnecessary treatments and interventions. By considering alternative diagnoses, we can help ensure that patients receive the appropriate care without the risks of unnecessary procedures.

Author Contributions

Arjun Chatterjee and Renan Prado—initial draft. Hassan Siddiki and Tyler Stevens—reviewing and final approval of the manuscript.

Data Availability

No datasets were generated or analyzed during the current study.

Declarations

Conflict of interest

The authors disclose no known conflicts of interest.