Authors: Ferhat Bacaksız, 1 Berat Ebik, 1 Nazım Ekin, 1 and Jihat Kılıc 2
Int J Clin Pract. 2021 Aug 6 : e14692.doi: 10.1111/ijcp.14692 [Epub ahead of print] PMCID: PMC8420122PMID: 34331821
Abstract
Object
We aimed to evaluate the elevation of amylase and lipase enzymes in coronavirus disease 2019 (COVID‐19) patients and their relationship with the severity of COVID‐19.
Method
In this study, 1378 patients with COVID‐19 infection were included. Relation of elevated amylase and lipase levels and comorbidities with the severity of COVID‐19 was analysed. The effects of haemodynamic parameters and organ failure on pancreatic enzymes and their relations with prognosis were statistically analysed.
Results
The 1378 patients comprised of 700 (51.8%) men and 678 (%49.2) women. Of all patients, 687 (49.9%) had mild and 691 (50.1%) patients had severe COVID‐19 infection. Amylase elevation at different levels occurred in 316 (%23) out of 1378 patients. In these patients, the amylase levels increased one to three times in 261 and three times in 55 patients. Pancreatitis was detected in only six (%1.89) of these patients according to the Atlanta criteria. According to univariate and multivariate analyses, elevated amylase levels were significantly associated with the severity of COVID‐19 (odds ratio [OR]: 4.37; P < .001). Moreover, diabetes mellitus (DM; OR: 1.82; P = .001), kidney failure (OR: 5.18; P < .001), liver damage (OR: 6.63; P < .001), hypotension (OR: 6.86; P < .001) and sepsis (OR: 6.20; P = .008) were found to be associated with mortality from COVID‐19.
Conclusion
Elevated pancreatic enzyme levels in COVID‐19 infections are related to the severity of COVID‐19 infection and haemodynamic instability. In a similar way to other organs, the pancreas can be affected by severe COVID‐19 infection.
What’s known
- It has been suggested that COVID‐19 can cause pancreatic damage.
- There are a limited number of studies related to the possibility of an increase in the level of pancreatic enzymes in COVID‐19 patients.
What’s new
- COVID‐19 does not directly cause pancreatic damage.
- Pancreatic enzyme elevation in patients with COVID‐19 develops in the advanced stages of the disease caused by multiple organ dysfunction and shock.
1. INTRODUCTION
Coronavirus disease 2019 (COVID‐19) infection was initially considered to attack only the upper respiratory tract, but was later found to potentially affect almost all systems. This is caused by the angiotensin‐converting enzyme 2 (ACE2) receptors that coronavirus binds to in order to enter the cells. These receptors are also commonly available in the gastrointestinal system such as in hepatic, pancreatic and colonic cells.1, 2
Recent studies have shown that COVID‐19 infection can cause damage to the pancreas caused by the high expression of ACE2 receptors from the pancreatic tissue.3 Additionally, it has also been reported that hyperglycaemia can occur because of pancreatic islet cell damage in patients with COVID‐19 and that severe patients with COVID‐19 should be followed up closely in terms of pancreatic damage.4, 5
In this study, we evaluated the amylase and lipase elevations in patients with COVID‐19 in order to investigate the relationship between pancreatic enzyme elevations and the severity of COVID‐19 infection and to identify the underlying conditions.Go to:
2. PATIENTS AND METHODS
The study included 1378 patients with COVID‐19 infection who presented to our hospital between March and December 2020. Clinical characteristics including temperature, blood pressure, laboratory parameters, treatments and comorbidities were monitored throughout hospitalisation. In addition to other laboratory parameters, amylase and lipase levels were also studied in order to determine the ratio of patients with elevated pancreatic enzymes. Values above 105 U/L for amylase and 65 IU/L for lipase were considered high.6 Patients with pancreatitis were identified according to the Atlanta criteria.7
Additionally, pancreatic enzyme elevation in COVID‐19 infection was investigated with regard to the severity of disease. Patients were divided into two groups based on the severity of their COVID‐19 symptoms: mild (n = 687) and severe (n = 691). Patients with fever, headache, loss of taste and smell and generalised myalgia without tachypnoea (oxygen saturation >92%) were considered to have a mild infection, whereas patients on invasive or non‐invasive respiratory support or with deteriorated haemodynamic conditions were considered to have severe COVID‐19 infection.8
The causes of pancreatic enzyme elevation were compared between patients with mild and severe COVID‐19 infection and between surviving and non‐surviving patients. Relation between elevated pancreatic enzymes and metabolic parameters, haemodynamic findings, single and multiple organ failures was also examined.9, 10
Hypotension was evaluated based on mean arterial pressure (MAP). A MAP value of 60‐110 mmHg was accepted as normal, <60 mmHg as hypotensive and >110 mmHg as hypertensive.11
Liver damage was determined according to the 2019 European Association for the Study of the Liver (EASL) guidelines, based on the upper limits of normal (ULN) serum alanine aminotransferase activity (ALT) and serum alkaline phosphatase activity (ALP), as follows: ALT ≥5 × ULN or ALP ≥2 ULN [in the absence of known bone pathology] or ALT ≥3 ULN with simultaneous increase of total bilirubin concentration ≥2 ULN.12 Kidney injury was determined according to the RIFLE (Risk, Injury, Failure, Loss of kidney function and End‐stage kidney disease) criteria.13
The study was conducted in accordance with the Helsinki Declaration and the study protocol was approved by the local ethics committee (No: 611, Date: 16 October 2020).
2.1. Statistical analysis
Data were analysed using SPSS 26.0 for Windows (Armonk, NY: IBM Corp.). Normal distribution of data was assessed using Kolmogorov‐Smirnov, Shapiro‐Wilk test, coefficient of variation, skewness and kurtosis. Continuous variables were expressed as mean and standard deviation (SD), and categorical variables were expressed as percentages (%). Student t test and Mann‐Whitney U‐test were used in paired groups to compare pancreatic enzymes and disorders of other organs between patients with severe and mild COVID‐19 infection. ANOVA test was used for parameters homogeneously distributed in triple groups. Bonferroni correction was used to determine the significant results in groups. Welch’s ANOVA and Kruskal‐Wallis tests were performed for non‐homogeneous parameters. Pearson and Spearman correlation coefficients were used to analyse the relationship between pancreatic enzyme elevation and other parameters. Univariate and multivariate analyses were performed to determine the factors associated with pancreatic enzyme elevation. All tests were bilateral and a P‐value of <.05 was considered significant.Go to:
3. RESULTS
The 1378 patients comprised of 700 (51.8%) men and 678 (%49.2) women. The prevalence of kidney failure, DM, ischaemic hepatitis and sepsis was significantly higher in patients with severe COVID‐19 compared with patients with mild disease. Moreover, amylase and lipase levels were also higher in patients with severe COVID‐19 (Table 1).
TABLE 1
Demographic data and biochemical parameters of patients with mild and severe COVID‐19
| Mild COVID‐19±SD | Severe COVID‐19±SD | P | |
|---|---|---|---|
| N | 687 (49.9%) | 691 (50.1%) | |
| Age | 60.2 (29‐84) | 65 (51‐86) | <.001 |
| Gender F/M | 356/331 | 322/369 | .053 |
| Amylase (U/L) | 82.6 ± 50.4 | 264.7 ± 292.0 | <.001 |
| Lipase (IU/L) | 59.7 ± 51.2 | 79.0 ± 24.2 | .045 |
| ALT (IU/L) | 70.4 ± 60.2 | 82.7 ± 56.4 | <.001 |
| AST (IU/L) | 61.6 ± 40.7 | 180 ± 135.5 | <.001 |
| ALP (IU/L) | 84.1 ± 35.4 | 133.2 ± 107.2 | .295 |
| GGT (IU/L) | 54.2 ± 51.5 | 79.4 ± 58.9 | .099 |
| T.Bil (mg/dL) | 0.67 ± 0.33 | 1.95 ± 1.53 | <.001 |
| LDH (IU/L) | 411.9 ± 210 | 1137 ± 248.7 | <.001 |
| Urea (mg/dL) | 45.7 ± 26.9 | 187.0 ± 92.8 | <.001 |
| Creatinine (mg/dL) | 0.89 ± 0.49 | 3.74 ± 1.96 | <.001 |
| Glucose (mg/dL) | 138 ± 85.0 | 290 ± 135 | <.001 |
| WBC (cell/µL) | 9840 ± 4485 | 18 422 ± 6039 | <.001 |
| Lymphocyte (cell/µL) | 1993 ± 665 | 1655 ± 946 | <.001 |
| CRP (mg/L) | 107.8 ± 67.2 | 217.9 ± 69.1 | <.001 |
| Procalcitonin (ng/mL) | 1.04 ± 4.65 | 8.03 ± 19.7 | <.001 |
Abbreviations: ALP, alkaline phosphatase, GGT, gamma glutamyl transpeptidase WBC, white blood cell, CRP, C reactive protein; ALT, alanine transaminase; AST, aspartate transaminase; LDH, lactate dehydrogenase; SD, standard deviation.
Amylase elevation at different levels occurred in 316 (%23) out of 1378 patients. In these patients, the amylase levels increased one to three times in 261 and three times in 55 patients. Pancreatitis was detected in only six (%1.89) of these patients according to the Atlanta criteria. Amylase and lipase elevation was found to be related to the severity of COVID‐19 infection in the remaining patients. The development of DM, kidney failure, hypotension and ischaemic hepatitis was found to be related to mortality from COVID‐19 infection. However, there was no relationship between lymphopenia and elevated amylase levels (Table 2). On the other hand, patients older than 65 years were more likely to have (1.89 times) elevated increased enzyme levels.
TABLE 2
Relationship between amylase level in COVID‐19 patients and gender, comorbid status, severity and consequence of COVID‐19, haemodynamic status, other organ failures and laboratory parameters
| Feature | Amylase (normal) | Amylase (1‐3 times) | Amylase (more than 3 times) | P‐values |
|---|---|---|---|---|
| N/% | 1062 (77.0%) | 261 (19.0%) | 55 (4.0%) | |
| Gender | ||||
| Female (678%‐49.2%) | 565 (83.3%) | 100 (14.8%) | 13 (1.9%) | <.001 |
| Male (700%‐50.8%) | 497 (71.0%) | 161 (23.0%) | 42 (6.0%) | |
| COVID‐19 severity | ||||
| Mild COVID‐19 (687%‐49.9%) | 612 (89.1%) | 71 (10.3%) | 4 (0.6%) | <.001 |
| Severe COVID‐19 (691%‐50.1%) | 450 (65.1%) | 190 (27.5%) | 51 (7.4%) | |
| COVID‐19 | ||||
| Healing (909%‐66.0%) | 793 (87.2%) | 109 (12.0%) | 7 (0.8%) | <.001 |
| Death (469%‐34.0%) | 269 (57.4%) | 152 (32.4%) | 48 (10.2%) | |
| Diabetes | ||||
| Absent (866%‐62.8%) | 703 (81.2%) | 143 (16.5%) | 20 (2.3%) | <.001 |
| Available (512%‐32.6%) | 359 (70.1%) | 118 (23.0%) | 35 (6.9%) | |
| Kidney failure | ||||
| Absent (934%‐67.8%) | 808 (86.5%) | 114 (12.2%) | 12 (1.3%) | <.001 |
| AKI (316%‐22.9%) | 186 (58.8%) | 101 (32.0%) | 29 (9.2%) | |
| CRF (128%‐9.3%) | 68 (53.1%) | 46 (36.0%) | 14 (10.9%) | |
| Blood pressure | ||||
| Normal (810%‐58.8%) | 727 (89.7%) | 76 (9.4%) | 7 (0.9%) | <.001 |
| Hypotension (466%‐33.8%) | 260 (55.8%) | 161 (34.5%) | 45 (9.7%) | |
| Hypertension (102%‐7.4%) | 75 (73.6%) | 24 (23.5%) | 3 (2.9%) | |
| ALT | ||||
| Normal (562%‐40.8%) | 488 (86.8%) | 65 (11.6%) | 9 (1.6%) | <.001 |
| 1‐3 times (488%‐35.4%) | 389 (79.7%) | 86 (17.6%) | 13 (2.7%) | |
| 3‐5 times (135%‐9.8%) | 89 (65.9%) | 37 (27.4%) | 9 (6.7%) | |
| 5‐10 times (65%‐4.7%) | 36 (55.4%) | 20 (30.8%) | 9 (13.8%) | |
| >10 times (61%‐4.4%) | 32 (52.5%) | 26 (42.6%) | 3 (4.9%) | |
| >1000 (IU/L) (67%‐4.9%) | 28 (41.8%) | 27 (40.3%) | 12 (17.9%) | |
| AST | ||||
| Normal (468%‐34.0%) | 428 (91.4%) | 36 (7.7%) | 4 (0.9%) | <.001 |
| 1‐3 times (564%‐40.9%) | 454 (80.5%) | 98 (17.4%) | 12 (2.1%) | |
| 3‐5 times (121%‐8.8%) | 76 (62.8%) | 38 (31.4%) | 7 (5.8%) | |
| 5‐10 times (71%‐5.1%) | 35 (49.3%) | 27 (38.0%) | 9 (12.7%) | |
| More than 10 times (45%‐3.3%) | 22 (48.9%) | 16 (35.6%) | 7 (15.5%) | |
| >1000 (IU/L) (109%‐7.9%) | 47 (43.1%) | 46 (42.2%) | 16 (14.7%) | |
| ALP | ||||
| Normal (966%‐70.1%) | 737 (76.3%) | 191 (19.8%) | 38 (3.9%) | .092 |
| 1‐2 times (234%‐17.0%) | 176 (75.2%) | 45 (19.2%) | 13 (5.6%) | |
| More than 2 times(178%‐12.9%) | 149 (83.7%) | 25 (14.0%) | 4 (2.3%) | |
| GGT | ||||
| Normal (909%‐66%) | 722 (79.4%) | 158 (7.4%) | 29 (3.2%) | .072 |
| 1‐2 times (254%‐18.4%) | 173 (68.1%) | 62 (24.4%) | 19 (7.5%) | |
| More than 2 times (215%‐15.6%) | 167 (77.7%) | 41 (19.1%) | 7 (3.2%) | |
| Total Bilirubin | ||||
| Normal (1059%‐76.9%) | 860 (81.2%) | 171 (16.2%) | 28 (2.6%) | <.001 |
| 1‐2 times (257%‐18.6%) | 172 (66.9%) | 68 (26.4%) | 17 (6.7%) | |
| More than 2 times (62%‐4.5%) | 30 (48.4%) | 22 (35.5%) | 10 (16.1%) | |
| LDH | ||||
| Normal (<225 IU/L) (161%‐11.7%) | 157 (97.5%) | 4 (2.5%) | 0 (0.0%) | <.001 |
| Normal‐1000 (IU/L) (969%‐70.3%) | 788 (81.3%) | 158 (16.3%) | 23 (2.4%) | |
| 1000‐2250 (IU/L) (148%‐10.7%) | 79 (53.4%) | 55 (37.2%) | 14 (9.4%) | |
| >2250 (IU/L)(100%‐7.3%) | 38 (38.0%) | 44 (44.0%) | 18 (18.0%) | |
| Lymphocyte levels | ||||
| Normal (724%‐52.5%) | 581 (80.3%) | 119 (16.4%) | 24 (3.3%) | .120 |
| Mild lymphopenia (489%‐35.5%) | 360 (73.6%) | 111 (22.7%) | 18 (3.7%) | |
| Severe lymphopenia (165%‐12.0%) | 121 (73.3%) | 31 (18.8%) | 13 (7.9%) |
Abbreviations: AKI, Acute kidney injury; ALP, alkaline phosphatase, GGT, gamma glutamyl transpeptidase; ALT, alanine transaminase; AST, aspartate transaminase; CRF, Chronic renal failure; LDH, lactate dehydrogenase.
The prevalence of elevated amylase was 2.04 times higher in men than that in women. Hypotension (odds ratio [OR]: 6.63), sepsis (OR: 6.20), ischaemia‐related liver damage (OR: 6.63) and renal failure (OR: 5.18) were found to be significantly associated with pancreatic enzyme levels (Table 3).
TABLE 3
Analysis of factors affecting enzyme elevation in COVID‐19 patients with elevated amylase and lipase
| Feature | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| OR | 95% Cl | P value | OR | 95% Cl | P value | |
| Age | 1.89 | 1.46‐2.44 | .001 | 1.72 | 1.40‐2.11 | .001 |
| Gender | 2.04 | 1.57‐2.64 | .001 | 1.86 | 1.50‐2.31 | .001 |
| COVID‐19 Severity | 4.37 | 3.28‐5.81 | <.001 | 3.76 | 2.90‐4.88 | <.001 |
| Death from COVID‐19 | 5.08 | 3.89‐6.64 | <.001 | 4.23 | 3.33‐5.36 | <.001 |
| Diabetes | 1.82 | 1.41‐2.35 | .001 | 1.72 | 1.40‐2.11 | .001 |
| Kidney failure | 5.18 | 3.95‐6.79 | <.001 | 3.78 | 3.00‐4.75 | <.001 |
| Liver damage | 6.63 | 4.56‐9.64 | <.001 | 3.09 | 2.43‐3.94 | <.001 |
| Hypotension | 6.86 | 4.50‐10.40 | <.001 | 5.67 | 3.90‐8.22 | <.001 |
| Sepsis | 6.20 | 3.83‐10.05 | .008 | 2.88 | 2.24‐3.70 | .003 |
| Pancreatitis | 21.2 | 2.54‐166.7 | .005 | 8.02 | 4.54‐86.3 | .026 |
A very strong positive correlation was found between amylase and lipase levels in all patients (r: .828, P < .001), which implicates that the increased amylase in COVID‐19 patients is caused by the pancreas. A weak correlation was found between amylase level and age or gender. Likewise, a weak but statistically significant correlation was found between amylase level and DM. A strong correlation was detected between the amylase level and the severity of COVID‐19. Additionally, the presence of liver damage, renal failure, hypotension and multiple organ dysfunction syndrome (MODS) in these patients was moderately correlated with amylase level (Figure 1).FIGURE 1
Correlation between amylase level and risk factors in COVID‐19 patients with hyperamylasaemiaGo to:
4. DISCUSSION
We found that 23% of patients with COVID‐19 infection had pancreatic enzyme elevations, and we also detected a relationship between pancreatic enzyme elevation and the severity of COVID‐19 infection, haemodynamic instability and MODS.
Although 10.9% of patients with mild COVID‐19 infection had elevated amylase levels, this rate was 34.9% in patients with severe COVID‐19 infection. It was also revealed that the causes of pancreatic enzyme elevation were hypotension and ischaemia in patients with severe COVID‐19 infection. Elevated amylase levels were detected in 10.3% and 44.2% of patients with a normal MAP and low MAP (<60 mmHg), respectively. Out of 316 patients with a high amylase level, 36.7% of the patients recovered and 63.3% of them died. Moreover, 53% of patients with ischaemic hepatitis had both amylase and lipase elevations. We consider that after the development of shock in the body, pancreatic damage occurs in addition to hepatic and intestinal injury as a result of the decrease in blood flow to the gastrointestinal system.
A study investigating the relationship between COVID‐19 infection and pancreas reported pancreatic damage in 1%‐2% and 17% of patients with mild and severe infection, respectively. The authors suggested that pancreatic damage can be exacerbated by systemic inflammation.14, 15, 16, 17 Amylase and lipase elevation suggestive of pancreatic damage has been reported in 8.5%‐17.3% of patients with COVID‐19. Moreover, higher enzyme levels have been reported in severe COVID‐19 patients.14, 15, 16, 17 Likewise, in two previous autopsy studies, five of 11 (45.5%) and two of eight (25%) cases were detected with focal pancreatitis with haemorrhagic and necrotic changes in the pancreas. These changes had no clinical manifestations and were attributed to ischaemia and end‐organ damage.18, 19 In the light of our data, we consider that pancreatic damage is the most important cause of amylase and lipase elevations. The exact pathophysiology of pancreatic damage remains unclear, while the most widely accepted hypothesis points to pancreatic ischaemia.20, 21, 22 If septicaemia progresses towards septic shock, not only in COVID‐19 but also in other infections, the resulting hypotension and vasodilation reduce blood flow to organs. To protect blood flow to vital organs such as the brain and heart, blood flow to the celiac, superior and inferior mesenteric arteries are reduced as a part of the protective mechanism. Afterwards, this is followed by renal and iliac arteries. This is the neurohormonal mechanism protecting vital organs. Gastrointestinal system is the target organ of shock and hypotension. As a result, the blood flow to the liver, pancreas and the entire gastrointestinal system is reduced, thereby causing symptoms such as nausea, vomiting, distension, ileus, or diseases such as ischaemic hepatitis.
Pancreas is supplied well by pancreatic arteries that stem from the splenic, gastroduodenal and superior mesenteric arteries. Amylase, lipase, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) are released into the bloodstream caused by the ischaemia resulting from decreased blood flow to the pancreas.23 This damage is mainly caused by haemodynamic deterioration, not by the virus itself. Similarly, in our study, elevated amylase and lipase levels were found to be associated with haemodynamic parameters and hypotension.
Although increased amylase and lipase levels might have clinical importance, it seems highly unlikely to use these parameters as prognostic indicators in clinical practice, mainly because enzyme elevation occurs during the intensive care period when the disease is severe and requires mechanical ventilation. At this stage, most patients have single or multiple organ failure and require vasopressor support.
In conclusion, although ACE2 receptors are expressed highly in pancreatic tissue, pancreatic enzyme elevations occurring in COVID‐19 infection might be associated with the severity of disease and haemodynamic instability. If the opposite was the case, we would have seen too many cases of pancreatitis, mainly because the pancreas has ACE2 receptors. As a matter of fact, despite the huge number of COVID‐19 cases, which has exceeded 100 million, pancreatitis has remained only at the level of case reports.24, 25Go to:
Notes
Bacaksız F, Ebik B, Ekin N, Kılıc J. Pancreatic damage in COVID‐19: Why? How? Int J Clin Pract. 2021;00:e14692. 10.1111/ijcp.14692 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
DATA AVAILABILITY STATEMENT
Data may be made available upon request to the corresponding author.
REFERENCES
1. Vedel AG, Holmgaard F, Rasmussen LS, et al. Perfusion Pressure Cerebral Infarct (PPCI) trial ‐ the importance of mean arterial pressure during cardiopulmonary bypass to prevent cerebral complications after cardiac surgery: study protocol for a randomised controlled trial. Trials. 2016;17:247. [PMC free article] [PubMed] [Google Scholar]
2. Chai X, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019‐nCoV infection. BioRxiv. 2020:4–16. [Google Scholar]
3. Furong L, Xin Long BZ, Wanguang ZXC, Zhanguo Z. ACE2 expression in pancreas may cause pancreatic damage after SARS‐CoV‐2 infection. Clin Gastroenterol Hepatol. 2020;18:2128‐2130.e2. [PMC free article] [PubMed] [Google Scholar]
4. Yang JK, Feng Y, Yuan MY, et al. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabet Med. 2006;23:623‐628. [PubMed] [Google Scholar]
5. Yang JK, Lin SS, Ji XJ, et al. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 2010;47:193‐199. [PMC free article] [PubMed] [Google Scholar]
6. James PC, Christopher C, Schlz TJ, Arvan DA. Combined serum amylase and lipase determinations for diagnosis of suspected. Clin Chem. 1993;39:2495‐2499. [PubMed] [Google Scholar]
7. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis 2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62:102‐111. [PubMed] [Google Scholar]
8. Clinical management of COVID‐19 . WHO interim guidance. COVID‐19: Clinical care. 2020. https://www.who.int/publications/i/item/clinical‐management‐of‐covid‐19. Accessed January 25, 2021.
9. Johnson CD, Abu‐Hilal M. Persistent organ failure during the first week as a marker of fatal outcome in acute pancreatitis. Gut. 2004;53:1340‐1344. [PMC free article] [PubMed] [Google Scholar]
10. Mofidi R, Duff MD, Wigmore SJ, et al. Association between early systemic inflammatory response, severity of multiorgan dysfunction and death in acute pancreatitis. Br J Surg. 2006;93:738‐744. [PubMed] [Google Scholar]
11. Jothimani D, Venugopal R, Abedin MF, Kaliamoorthy I, Rela M. COVID‐19 and liver. J Hepatol. 2020:1231–1240. [PMC free article] [PubMed] [Google Scholar]
12. EASL . EASL clinical practice guidelines: drug‐induced liver injury. J Hepatol. 2019;70:1222‐1611. [PubMed] [Google Scholar]
13. Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute kidney injury: a systematic review. Kidney Int. 2008;73:538‐546. [PubMed] [Google Scholar]
14. Bruno G, Fabrizio C, Santoro CR, Buccoliero GB. Pancreatic injury in the course of coronavirus disease 2019 (COVID‐19): a not‐so‐rare occurrence. J Med Virol. 2021;93:74–75. [PMC free article] [PubMed] [Google Scholar]
15. McNabb‐Baltar J, Jin DX, Grover AS, et al. Lipase elevation in patients with COVID‐19. Am J Gastroenterol. 2020;115:1286‐1288. [PMC free article] [PubMed] [Google Scholar]
16. Wang F, Wang H, Fan J, Zhang Y, Wang H, Zhao Q. Pancreatic injury patterns in patients with coronavirus disease 19 pneumonia. Gastroenterology. 2020;159:367‐370. [PMC free article] [PubMed] [Google Scholar]
17. Barlass U, Wiliams B, Dhana K, et al. Marked elevation of lipase in COVID‐19 disease: a cohort study. Clin Transl Gastroenterol. 2020;11:e00215. [PMC free article] [PubMed] [Google Scholar]
18. Lax SF, Skok K, Zechner P, et al. Pulmonary arterial thrombosis in COVID‐19 with fatal outcome: results from a prospective, single‐center, clinicopathologic case series. Ann Intern Med. 2020;173:350–361. [PMC free article] [PubMed] [Google Scholar]
19. Hanley B, Naresh KN, Roufosse C, et al. Histopathological findings and viral tropism in UK patients with severe fatal COVID‐19: a post‐mortem study. Lancet Microbe. 2020;1:e245‐e253. [PMC free article] [PubMed] [Google Scholar]
20. Raper RF, Sibbald WJ, Hobson J, Rutledge FS. Effect of PGE1 on altered distribution of regional blood flows in hyperdynamic sepsis. Chest. 1991;100:1703‐1711. [PubMed] [Google Scholar]
21. Hiltebrand LB, Krejci V, Banic A, Erni D, Wheatley AM, Sigurdsson GH. Dynamic study of the distribution of microcirculatory blood flow in multiple splanchnic organs in septic shock. Crit Care Med. 2000;28:3233‐3241. [PubMed] [Google Scholar]
22. Anis C, Karim AH, Kamel B, et al. Pancreatic injury in patients with septic shock: a literature review. World J Gastrointest Oncol. 2016;8:526‐531. [PMC free article] [PubMed] [Google Scholar]
23. Leif J, Per‐Ola C. Pancreatic blood flow with special emphasis on blood perfusion of the islets of Langerhans. Compr Physiol. 2019;9:799‐837. [PubMed] [Google Scholar]
24. Rabice SR, Altshuler PC, Bovet C, Sullivan C, Gagnon AJ. COVID‐19 infection presenting as pancreatitis in a pregnant woman: a case report. Case Rep Womens Health. 2020;27:e00228. [PMC free article] [PubMed] [Google Scholar]
25. Cheung S, Delgado Fuentes A, Fetterman AD. Recurrent acute pancreatitis in a patient with COVID‐19 infection. Am J Case Rep. 2020;21:e9270. [PMC free article] [PubMed] [Google Scholar]