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\begin{document}

\title{COV\selectlanguage{polish}İ\selectlanguage{english}D-19 AND HYPERAMYLASEM\selectlanguage{polish}İ\selectlanguage{english}A\selectlanguage{english}}



\author[1]{Ferhat Bacaksız}%
\author[1]{Berat Ebik}%
\author[1]{Nazım Ekin}%
\author[1]{Jehat Kılıc}%
\affil[1]{Diyarbakir Gazi Yasargil Training and Research Hospital}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Object: Our aim is to evaluate the elevation of pancreatic enzymes in
COVID-19 patients and their relationship with severity of COVID-19.
Method: In this study, 1378 patients with COVID-19 infection were
included. Relation of elevated amylase and lipase levels and co-morbid
conditions with the severity of COVID-19 were checked. The effect of
hemodynamic parameters and organ failures on pancreatic enzymes and
their relations with prognosis were statistically analyzed. Results:
There were 678 (\%49,2) female patients and 700 (50,8\%) male patients.
Of all patients, 687 (49,9\%) had mild, 691 (50,1\%) severe COVID-19
infections. Elevated amylase levels were detected in 23\% of patients
(n:316). 19\% (261) of them had a slight (1-3 times) increase in amylase
levels, while 4\% (55) had a more than 3 times increase in amylase than
normal. Only 6\% of patients with elevated amylase leves had the acute
pancreatitis according to Atlanta criteria. According to univariate and
multivariate analyses, elevated amylase levels was found statistically
related with severity of COVID-19 (OR:4,37-p \textless{}0,001). And also
diabetes mellitus (DM) (OR:1,82-p:0,001), kidney failure (OR:5,18-
p\textless{} 0,001), liver damage (OR:6,63 p \textless{} 0,001),
hypotension (OR:6,86-p\textless{} 0,001), sepsis (OR:6,20-p:0.008) were
found to related to death of COVID-19. Conclusions: Elevated pancreatic
enzyme levels in COVID-19 infections is to related to severity of
COVID-19 infection and hemodynamic instability. Similar to other organs,
the pancreas can be affected by severe COVID-19 infection.%
\end{abstract}%



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\selectlanguage{polish}\textbf{COVİD-19 AND HYPERAMYLASEMİA}\selectlanguage{english}

\textbf{ABSTRACT}

\textbf{Object:} Our aim is to evaluate the elevation of pancreatic
enzymes in COVID-19 patients and their relationship with severity of
COVID-19.

\textbf{Method:} In this study, 1378 patients with COVID-19 infection
were included. Relation of elevated amylase and lipase levels and
co-morbid conditions with the severity of COVID-19 were checked. The
effect of hemodynamic parameters and organ failures on pancreatic
enzymes and their relations with prognosis were statistically analyzed.

\textbf{Results:} There were 678 (\%49,2) female patients and 700
(50,8\%) male patients. Of all patients, 687 (49,9\%) had mild, 691
(50,1\%) severe COVID-19 infections. Elevated amylase levels were
detected in 23\% of patients (n:316). 19\% (261) of them had a slight
(1-3 times) increase in amylase levels, while 4\% (55) had a more than 3
times increase in amylase than normal. Only 6\% of patients with
elevated amylase leves had the acute pancreatitis according to Atlanta
criteria. According to univariate and multivariate analyses, elevated
amylase levels was found statistically related with severity of COVID-19
(OR:4,37-p \textless{}0,001). And also diabetes mellitus (DM)
(OR:1,82-p:0,001), kidney failure (OR:5,18- p\textless{} 0,001), liver
damage (OR:6,63 p \textless{} 0,001), hypotension (OR:6,86-p\textless{}
0,001), sepsis (OR:6,20-p:0.008) were found to related to death of
COVID-19.

\textbf{Conclusions:} Elevated pancreatic enzyme levels in COVID-19
infections is to related to severity of COVID-19 infection and
hemodynamic instability. Similar to other organs, the pancreas can be
affected by severe COVID-19 infection.

\textbf{Key Words:} COVID-19, Pancreas, Amylase

\textbf{What's already known about this topic?}

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 amylase enzyme in Covid-19 patients.

\textbf{What does this article add?}

Covid-19 does not directly cause pancreatic damage. Pancreatic enzyme
elevation in patients with Covid-19 develops in the advanced stages of
the disease due to multiorgan dysfunction and shock.

\textbf{INTRODUCTION:}

COVID-19 infection, which was initially thought to affect only the upper
respiratory tracts, can affect almost all systems, not just the
respiratory system. This is due to the angiotensin-converting enzyme 2
(ACE 2) receptors, which coronavirus binds in to enter the cells. These
receptors are also commonly available in the gastrointestinal system
such as liver, pancreatic, colonic cells. \textsuperscript{\textbf{1-2}}

Recent studies have shown that COVID-19 infection can cause damage to
the pancreas due to the high expression of ACE2 receptors from the
pancreatic tissue. \textsuperscript{\textbf{3}} Additionally, it has
been stated in another study that hyperglycemia can occur due to
pancreatic islet cell damage in patients with COVID-19 and severe
patients with COVID-19 should be followed up closely in terms of
pancreatic damage.\textsuperscript{\textbf{4-5}}

In this study, we evaluated the amylase and lipase elevations in
patients with COVID-19. And additionally, we aim to research the
relation between pancreatic enzyme elevations and severity of COVID-19
infection and to identify underlying conditions.

\textbf{MATERIAL AND METHODS}

In this study, 1378 patients with COVID-19 infection between
March-December in 2020 in our hospital were included. Signs such as
fever, blood pressure, laboratory parameters, treatments, and co-morbid
conditions were followed-up during the hospitalization. Next to these
parameters, amylase and lipase levels were checked. Values above 105 U/l
for amylase and 65 IU/L for lipase were considered
high.\textsuperscript{\textbf{6}} Patients with pancreatitis were
diagnosed according to Atlanta criteria. \textsuperscript{\textbf{7}}

Additionally, pancreatic enzyme elevation in COVID-19 infection related
to the severity of disease was investigated. Patients were divided into
two groups mild and severe COVID-19 infection. Patients with fever,
headache, loss of taste and smell, generalized myalgia, and without
tachypnea (Oxygen saturation \textgreater{}\%92) were considered a mild
infection. Patients on invasive or non-invasive respiratory support or
with deteriorated hemodynamic conditions were considered severe COVID-19
infection. \textsuperscript{\textbf{8}}

The causes of pancreatic enzyme elevation were questioned in patients
with mild and severe COVID-19 infection and patients who died and
recovered. The relation between elevated pancreatic enzymes and
metabolic parameters, hemodynamic findings, single and multiple organ
failures was examined. \textsuperscript{\textbf{9-10}}

Mean arterial pressure was used to measure the hypotension. Mean
arterial pressure between 60-110 mmHg as normal, below 60 mmHg as
hypotension, above 110 mmHg was evaluated as
hypertension.\textsuperscript{\textbf{11}}

Liver damage was determined according to the EASL 2019 guidelines.12
(ALT [?] 5 \selectlanguage{ngerman}× ULN (Upper limit of normal) or ALP \selectlanguage{english}[?] 2 ULN (In the absence of
known bone pathology) or ALT \selectlanguage{english}[?] 3 ULN with simultaneous increase of total
bilirubin concentration \selectlanguage{english}[?]2 ULN). \textsuperscript{\textbf{12}} Kidney
injury was determined according to RIFLE
criteria.\textsuperscript{\textbf{13}}

This study was conducted in accordance with the Helsinki Declaration and
permission was obtained from the hospital's ethics committee. (Issue
number 611 dated 16.10.2020)

\textbf{Statistical Analysis}

Kolmogorov-Smirnov, Shapiro-Wilk test, coefficient of variation,
skewness, and kurtosis methods were used to check the normal
distribution of patient data. Mean and Standard deviation values were
specified for continuous variables, while categorical variables were
expressed as a percentage (\%). 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 in which
groups significant results were obtained. Welch ANOVA and Kruskal-Wallis
tests were performed for the non-homogeneous parameters. Pearson and
Spearman correlation analyses were performed for the relationship
between pancreatic enzyme elevation and other parameters. Univariate and
multivariate analyzes were performed to determine the factors associated
with pancreatic enzyme elevation. All tests were bilateral and

a p-value \textless{} 0.05 was considered statistically significant.
Statistical analysis was performed using SPSS26.0 for Windows (SPSS Inc.
Chicago, IL, USA) package program.

\textbf{RESULTS}

A total of 1378 patients, 687 of them mild and 691 of them severe, were
included in the study. 678 of patients (\%49.2) were women; 700 of
patients were male. There were significant difference between mild and
severe COVID-19 patients in terms of laboratory parameters. Kidney
failure, diabetes mellitus, ischemic hepatitis, sepsis were clearly
higher in patients with severe COVID-19. Amylase and lipase levels were
also higher in patients with severe COVID-19. (Table 1)

Amylase elevation at different levels occured in 316 (\%23) of 1378
patients with COVID-19. There were amylase elevations in 261 patients as
much 1-3 times than normal and in 55 (\%4) patients 3 times more than
normal. Pancreatitis was detected in only 6 (\%1.89) of these patients
according to Atlanta criteria. Amylase and lipase elevation was found to
related to severity of COVID-19 infection in the rest of all patients.
And also diabetes mellitus, kidney failure, hypotension, ischemic
hepatitis was found to related to mortality from COVID-19 infection.
There were no relation between lymphopenia and elevated amylase levels.
(Table-2) Those older than 65 years were more likely to have (1,89
times) elevated increased enzyme levels during the examination of causes
of amylase and lipase elevation in COVID infection.

In addition, the rate of elevated amylase levels was 2.04 times higher
in men than in women. In particular, hypotension (OR:6,63), sepsis
(OR:6,20), ischemia related liver damage (OR:6,63) and renal failure
(OR:5,18) were found to be significantly associated with pancreatic
enzyme levels. (Table-3) There was a weak correlation between amylase
level, age and gender in patients with Covid-19. Likewise, the presence
of DM showed a weak but statistically significant correlation with the
amylase level. The strongest correlation with the level of amylase was
found to be related to the severity of Covid-19. Especially the presence
of liver damage, renal failure, hypotension and MODS in these patients
were correlated with amylase level. (Figure-1)

\textbf{DISCUSSION}

We have been detected that 23\% of patients with COVID-19 infection had
pancreatic enzyme elevations. And there was a relationship between
pancreatic enzyme elevation and severity of COVID-19 infection,
hemodynamic instability and MODS.

Although 10,9\% of patients with mild COVID-19 infection had elevated
amylase, This rate was 34,9\% in patients with severe COVID-19
infection. It has been detected that causes of pancreatic enzyme
elevation were hypotension and ischemia in severe infection. Elevated
amylase levels were 10,3\% and 44,2\% in patients with normal mean
arterial pressure and with low arterial pressure (\textless{}60 mmHg)
respectively. Out of 316 patients with a high level of amylase, 36.7\%
of patients recovered and 63.3\% of patients died. 53\% of patients with
ischemic hepatitis had concurrently amylase and lipase elevations. And
also next to liver and intestinal damage, pancreatic damage might occur
in shock with the decreased blood flow to the gastrointestinal system.

In a study over the relation between COVID-19 infection and pancreas, it
has been reported that pancreatic damage was found 1-2\% and 17\% in
patients with mild and severe infection consecutively. Additionally, it
has been reported that pancreatic damage can be exacerbated with
systemic inflammation. Amylase and lipase elevation, suggesting
pancreatic damage, has been reported between 8.5\%-17,3\% in patients
with COVID-19. Moreover, it has been stated that there were higher
enzyme levels in severe
patients.\textsuperscript{\textbf{14-15-16-17}}Paralel to these studies,
hemorrhagic and necrotic changes with focal pancreatitis were detected
in one of the autopsy studies 5/11 (45,5\%) and in the other study 2/8
(25\%).

These changes without clinical signs have been attributed to ischemia
and end-organ damage.\textsuperscript{\textbf{18-19}} Therefore, it is
quite difficult to use the elevated lipase and amylase developing in
COVID-19 infection as a prognostic indicator. Since enzyme elevation
occurs in the intensive care period where the disease is severe and
requires mechanical ventilation. At this stage, most patients have
single or multiple organ failure and receive vasopressor support.
Therefore, the high amylase level is a result of the severity of
COVID-19 infection.

As a result, although ACE-2 receptors are expressed highly in pancreatic
tissue, pancreatic enzyme elevations occurring in COVID-19 infection
might be result of severity of disease and hemodynamic instability.
Otherwise, there would have been many pancreatitis caused by ACE-2
receptors. Despite over a hundred million cases, pancreatitis remained
only at the level of case reports.\textsuperscript{\textbf{20-21}}

\textbf{Conflict of interest}

Regarding this study, the authors and/or their family members do not
have scientific and medical committee membership or relationship with
their members, consultancy, expertise, working status in any company,
shareholding or similar situations that may have a potential conflict of
interest.

\textbf{Financial Resource}

During this study any support from any pharmaceutical company with a
direct connection to the subject of the research or any company that
supplies medical tools, equipments and materials, or any commercial
company was not received. During the evaluation process of study, any
material or intangible support that may adversely affect the decision to
be made about study was not received.

\textbf{Author Contributions}

\textbf{Idea/Concept:} FB; \textbf{Design:}
NE,\textbf{Supervision/Consultancy:} BE, \textbf{Data collection and
processing:} JK, \textbf{Analysis and Interpretation:}
NE,\textbf{Literature Review:} JK, \textbf{Manuscript Writing:}
FB-BE,\textbf{Critical Review:} FB, \textbf{Materials:} JK

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