Serum Lipase Elevations in COVID-19 Patients Reflect Critical Illness and not Acute Pancreatitis
Authors: Mitchell L. Ramsey, B. Joseph Elmunzer, Somashekar G. Krishna
Journal: Clinical Gastroenterology and Hepatology (2021)

We read with interest the article "ACE2 Expression in Pancreas May Cause Pancreatic Damage After SARS-CoV-2 Infection" by Liu et al.1Liu F. et al.Clin Gastroenterol Hepatol. 2020; 18: 2128-2130Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar The authors noted abnormalities of serum amylase and lipase values among nearly 20% of hospitalized patients with COVID-19 and concluded that these enzyme abnormalities represent pancreatic injury and might even lead to chronic pancreatitis. However, many conditions may cause elevations in serum lipase, and these should not be attributed to pancreatic injury in the absence of acute pancreatitis (AP).2Hameed A.M. et al.HPB (Oxford). 2015; 17: 99-112Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar We sought to establish the prevalence of abnormal serum lipase values and the prevalence of AP among a large cohort of patients hospitalized with COVID-19. Consecutive patients hospitalized with COVID-19 at 36 North American medical centers during the earliest phase of the pandemic were identified and their charts were reviewed for clinical characteristics and outcomes, as previously described.3Elmunzer B.J. et al.Clin Gastroenterol Hepatol. 2021; 19: 1355-1365Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar AP was diagnosed according to the Revised Atlanta Criteria (2012), requiring 2 out of 3 of the following: characteristic abdominal pain, imaging abnormalities, or serum pancreas enzyme level greater than 3 times the upper limit of normal (ULN). For the outcome of elevated lipase, an extensive (n = 112 variables) univariable analysis was performed that included patient characteristics, comorbidities, medications, COVID-19 severity parameters and treatment regimens, and gastrointestinal symptoms (Table 1). Subsequently, a multivariable logistic regression model was fit for elevated lipase using stepwise selection among all variables with a significant difference between subjects with and without an elevated lipase at a level of P = .2.Table 1Univariable Associations with Elevated LipaseNormal lipase (n = 300)Elevated lipase (n = 100)P valueaChi-square test unless otherwise noted.Patient characteristicsAge, y60.2715.4859.4314.90.637bStudent t test.Body mass index at presentation, kg/m230.297.7631.678.55.171bStudent t test.,cVariable log transformed for analysis.Male sex19063.336767.00.508Race.774dFisher exact test. American Indian or Alaska Native20.6711.00 Asian299.6788.00 Black or African American9732.334040.00 Native Hawaiian or other Pacific Islander11137.003232.00 White41.3311.00 Multiple5719.001818.00 Unknown Hispanic ethnicity4918.221819.35.807Cigarette smoking status.112 Current smoker124.2699.57 Ex-smoker8329.433031.91 Nonsmoker18766.315558.51Vaping status.043dFisher exact test. Current vaping10.5434.55 Does not vape18398.926293.94 Prior vaping10.5411.52Alcoholism.189 Current197.141112.94 No23387.596880.00 Prior145.2667.06Cannabis use.530dFisher exact test. Current user93.8822.82 No21693.106591.55 Prior user73.0245.63Illicit drug use1.000dFisher exact test. Current user51.9811.20 No23793.687893.98 Prior user114.3544.82ComorbiditiesHypertension19063.336464.00.905Coronary artery disease/prior or current myocardial infarction4615.331717.00.692Congestive heart failure3210.671212.00.712Pulmonary hypertension10.3322.00.156dFisher exact test.Chronic pulmonary obstructive disease3110.3399.00.700Asthma3712.331111.00.722Obstructive sleep apnea3712.331010.00.530Interstitial lung disease/pulmonary fibrosis41.3300.00.576dFisher exact test.Peripheral vascular disease175.6755.00.800Prior or current cerebrovascular accident or transient ischemic attack258.3377.00.670Dementia103.3311.00.305dFisher exact test.Collagen vascular/rheumatologic disease186.0077.00.721Chronic liver disease134.3366.00.587dFisher exact test.Cirrhosis51.6722.001.000dFisher exact test.MELD score before COVID-19 illness14.008.8920.000.00Diabetes mellitus, uncomplicated9331.003030.00.851dFisher exact test.Diabetes mellitus with end-organ damage289.3399.00.921Moderate to severe kidney disease (creatinine >3 mg/dL before admission, end-stage renal disease, dialysis)3511.671414.00.538Active/current malignancy, excluding nonmelanoma skin cancer134.3355.00.783dFisher exact test.Prior malignancy268.6788.00.836Human immunodeficiency virus/AIDS51.6700.00.338dFisher exact test.Solid organ transplant recipient144.6700.00.026dFisher exact test.Bone marrow transplant recipient41.3311.001.000dFisher exact test.Irritable bowel syndrome51.6711.001.000dFisher exact test.Chronic diarrhea20.6722.00.261dFisher exact test.Chronic constipation82.6711.00.461dFisher exact test.Celiac disease00.0000.00n/aPrior biliary disease, including cholelithiasis, cholecystitis, choledocholithiasis, or cholangitis72.3311.00.685dFisher exact test.Prior pancreatitis41.3322.00.643dFisher exact test.Etiology.400dFisher exact test. Acute pancreatitis3100.0150.00 Recurrent acute pancreatitis00.00150.00 Chronic pancreatitis00.0000.00 Inflammatory bowel disease20.6711.001.000dFisher exact test. Other, not fitting into an above category14347.674949.00.817Medications (within 1 mo of admission or current)Angiotensin-converting enzyme inhibitor use5217.871313.68.344Angiotensin receptor blocker use4615.751212.50.438Nonsteroidal anti-inflammatory drug use8639.092936.25.655Antibiotic use8530.142729.03.839Proton pump inhibitor use8229.181718.68.049H2 blocker use3913.8888.70.194COVID-19 parametersHighest level of care.002Inpatient ward15551.673434.00ICU14548.336666.00Duration of symptoms before first seeking medical attention, d5.104.265.114.47.924bStudent t test.,cVariable log transformed for analysis.Duration of symptoms before hospitalization, d6.684.856.294.90.709bStudent t test.,cVariable log transformed for analysis.Duration of hospitalization, d14.8413.6019.8615.73.082bStudent t test.,cVariable log transformed for analysis.If admitted to ICU, duration of ICU stay, d14.2312.2919.2113.06.004bStudent t test.,cVariable log transformed for analysis.Required mechanical ventilation11237.336161.00< .001Required extracorporeal membrane oxygenation62.0044.00.276dFisher exact test.Required vasopressor support9732.335353.00< .001Final discharge disposition.038 Deceased5719.002828.00 Discharged to rehabilitation or nursing facility4816.002121.00 Recovered (or almost recovered)18963.004747.00 Still hospitalized at end of study62.0044.00COVID-19-specific treatmentsRemdesivir165.3399.00.190Hydroxychloroquine16856.006666.00.079Chloroquine20.6700.001.000dFisher exact test.Azithromycin17859.336464.00.408Glucocorticoids4113.671515.00.739Interferon-α00.0000.00n/aIntravenous immunoglobulin00.0011.00.250dFisher exact test.Lopinavir/ritonavir72.3333.00.716dFisher exact test.Oseltamivir165.3355.00.897Tocilizumab206.671616.00.005Convalescent plasma41.3388.00.002dFisher exact test.Anakinra00.0011.00.250dFisher exact test.Ribavirin10.3300.001.000dFisher exact test.Sarilumab31.0022.00.603dFisher exact test.Other4715.671919.00.437None5919.671313.00.133Gastrointestinal symptoms or signsAnorexia8428.002222.00.239Nausea12240.673535.00.315Vomiting7926.332424.00.644Abdominal pain (including cramps)7324.332929.00.354Type Diffuse227.3366.00.651 Periumbilical20.6711.001.000dFisher exact test. Epigastric103.3388.00.089dFisher exact test. Right upper quadrant124.0022.00.532dFisher exact test. Left upper quadrant62.0022.001.000dFisher exact test. Right lower quadrant51.6711.001.000dFisher exact test. Left lower quadrant93.0022.00.738dFisher exact test. Not specified196.331010.00.221Diarrhea11337.674242.00.441Bloody diarrhea10.3300.001.000dFisher exact test.Hematemesis20.6733.00.102dFisher exact test.Melena41.3333.00.373dFisher exact test.Hematochezia (including bright red blood per rectum)51.6755.00.130dFisher exact test.Dysphagia62.0022.001.000dFisher exact test.Odynophagia10.3300.001.000dFisher exact test.Constipation217.0033.00.145Hiccups10.3311.00.438dFisher exact test.Jaundice00.0011.00.250dFisher exact test.Other113.6733.001.000dFisher exact test.None6822.673030.00.140Timing of gastrointestinal symptoms (if any) relative to respiratory/systemic symptoms (if any).813 Cannot tell from medical records review2410.3457.14 GI symptoms came on concurrently with other symptoms7733.192637.14 GI symptoms followed other symptoms8737.502535.71 GI symptoms preceded other symptoms4218.101420.00 GI symptoms were the only manifestation20.8600.00Duration of gastrointestinal symptoms.824 Cannot tell from medical records review3615.521217.14 GI symptoms were present for a short portion (<25% of the duration) of the entire COVID-19 illness9239.662434.29 GI symptoms were present for a significant portion (25%–75% of the duration) of the entire COVID-19 illness6929.742130.00 GI symptoms were present for the entire/almost entire COVID-19 illness3515.091318.57Did gastrointestinal symptoms remain after resolution of other COVID-19 symptoms?1.000dFisher exact test. No13289.804391.49 Yes1510.2048.51 If yes, how long?, d9.679.07——n/aProminence of gastrointestinal symptoms.156 Cannot tell from medical records review125.1711.43 GI symptoms were equally prominent to other symptoms related to COVID-194820.691622.86 GI symptoms were less prominent than other symptoms related to COVID-1915365.954260.00 GI symptoms were less prominent than other symptoms related to COVID-19198.191115.71Gastrointestinal diagnoses established shortly before, during, or shortly after COVID-19 illnessEsophagitis/esophageal ulcers41.3311.001.000dFisher exact test.Gastritis31.0033.00.168dFisher exact test.Peptic ulcer disease00.0000.00n/aNew enteritis00.0022.00.062dFisher exact test.New colitis20.6733.00.102dFisher exact test.Biliary disease, including cholelithiasis, cholecystitis, choledocholithiasis, or cholangitis31.0066.00.009dFisher exact test.Hepatitis103.3344.00.756dFisher exact test.Pancreatitis00.0066.00< .001dFisher exact test.Other268.671111.00.486dFisher exact test.None25886.007575.00.011GI, gastrointestinal; ICU, intensive care unit; MELD, Model for End-Stage Liver Disease; n/a, not available.a Chi-square test unless otherwise noted.b Student t test.c Variable log transformed for analysis.d Fisher exact test. Open table in a new tab GI, gastrointestinal; ICU, intensive care unit; MELD, Model for End-Stage Liver Disease; n/a, not available. Among 1992 subjects with polymerase chain reaction–confirmed COVID-19, serum lipase values were measured on the day of admission in 316 (15.9%). Although 58 subjects had an elevated value, only 9 (2.8%) were 3 times the ULN. Only 2 patients had both lipase >3 times the ULN and abdominal pain. Neither subject underwent cross-sectional imaging during the hospitalization, but an abdominal ultrasound in both cases demonstrated cholecystitis providing an alternative and more likely cause for AP than COVID-19. Serum lipase values were recorded during hospitalization in 400 (20.1%) subjects. Although in 100 subjects the levels were elevated, only 26 patients (6.5%) had a value greater than 3 times the ULN. Among these, 6 subjects met 2 of 3 Revised Atlanta Criteria and did not have an obvious alternative explanation for AP other than COVID-19 infection. Within our cohort of patients hospitalized with COVID-19, there was no association between preexisting diabetes and elevated lipase values during hospitalization (P = .81). Furthermore, patients with diabetes with increased lipase values experienced similar mortality rates to patients with diabetes with normal lipase values (38.5% vs 24.0%; P = .08). There was no significant association between elevated lipase value and the use of angiotensin-converting enzyme inhibitors (13.7% vs 17.9%; P = .344) or angiotensin receptor blockers (12.5% vs 15.8%; P = .44) before admission (Table 1). Multivariable analysis demonstrated that elevated lipase values were associated with mechanical ventilation (n = 173; odds ratio, 2.55; 95% confidence interval, 1.6–4.08) and biliary disease (n = 9; odds ratio, 5.49; 95% confidence interval, 1.3–23.15). Our findings demonstrate that AP occurs rarely in hospitalized subjects with COVID-19, despite the presence of angiotensin converting enzyme-2 receptors in both exocrine and endocrine cells. Mild elevations in pancreas enzymes were seen in approximately 20% of patients hospitalized with COVID-19; these were associated with severity of illness and did not indicate AP. Since the start of the COVID-19 pandemic, there have been several reports on the development of AP among subjects with COVID-19 and its relation to AP severity.4Pandanaboyana S. et al.Gut. 2021; 70: 1061-1069Crossref PubMed Scopus (58) Google Scholar However, a systematic review determined that the work-up to accurately determine the cause of pancreatitis was suboptimal.5Juhász M.F. et al.World J Gastroenterol. 2020; 40: 6270-6278Crossref Scopus (16) Google Scholar Subsequent studies have posited that impaired circulation in the pancreas might explain the elevated serum lipase values among critically ill patients with COVID-19.6Rasch S. et al.Pancreatology. 2021; 1: 306-311Crossref Scopus (17) Google Scholar Among critically ill patients with acute respiratory distress syndrome before the pandemic, elevations in lipase were common, but were not specific to the pancreas.7Cohen J. et al.Pancreatology. 2017; 2: 176-181Crossref Scopus (13) Google Scholar Data from our cohort also suggest that elevated lipase values are associated with critical illness, rather than being directly related to pancreatic injury qualifying as AP. In conclusion, elevations of pancreatic enzymes are relatively common (20%) in COVID-19 hospitalized patients, but rarely signify a clinical diagnosis of AP (1.5%). When AP is diagnosed, further investigation into the cause is warranted. As in other examples of critical illness, elevated serum lipase in COVID-19 patients likely reflects the overall disease severity. The authors acknowledge Darwin L. Conwell, Luis F. Lara, Georgios I. Papachristou, and Alice Hinton for their contributions to this project. The authors acknowledge the remaining members of the North American Alliance for the Study of Digestive Manifestations of COVID-19 for their contributions to the creation of the dataset used in this publication. SARS-CoV-2-Induced Pancreatitis is a Rare but Real EntityClinical Gastroenterology and HepatologyVol. 19Issue 10PreviewWe read with great interest the letter by Ramsey et al1 in which they present original data on hyperlipasemia in 1992 patients with coronavirus disease 2019 (COVID-19) from 36 medical centers. Of 400 patients with hyperlipasemia, they found only 2 patients who presented with pancreatitis of which both had a biliary etiology. They found an additional 6 that were diagnosed with pancreatitis during the hospital stay and were attributed to COVID-19. They conclude that most COVID-19 patients with hyperlipasemia are likely from critical illness and not pancreatitis; and that the cause of pancreatitis needs investigation when present. Full-Text PDF