Journal of Forensic and Legal Medicine 37 (2016) 28e32

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Journal of Forensic and Legal Medicine

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j fl m

Original communication

Evaluation of procalcitonin postmortem levels in some models

of death: An experimental study
Afaf M. Attia, Hend M. Abo El-Atta*, Mohamed El-sherbiny, Eman E. El-Shahat
Faculty of Medicine, Mansoura University, Egypt

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 9 April 2015
Received in revised form
20 August 2015
Accepted 27 August 2015
Available online 6 September 2015

Post-mortem determination of biochemical parameters, especially for obscure cases, has been recognized useful in diagnosis of the underlying causes of death. Procalcitonin (PCT) is known to rise in a
response to any proinammatory stimulus. The present study aims to estimate postmortem PCT levels in
serum and kidney, liver, brain; and whether it is similar in different causes of death models (trauma,
drowning and freezing) models or not. The study was performed on 60 male rabbits. Rabbits were
divided into four different death induced models (15 rabbit each): trauma, infection, drowning and
freezing models. At the end of the study, all rabbits were sacriced; blood samples, kidneys, livers and
brains were collected. PCT was measured using ELISA assay. Results showed highly signicant increase in
PCT levels in all tested samples in different models of death. The infection induced model showed the
highest levels in all tested samples compared to other groups mainly in liver; followed by trauma model
and drowning model which were increased mainly in brain's samples. The least model which showed
increased PCT levels was the freezing model mainly in liver samples. Post Hoc multiple comparisons test
showed signicant differences between groups in most of liver, brain and kidney samples, while PCT
serum blood samples were signicant only between trauma and infection groups. It was concluded that
PCT can differentiate between sepsis and non-sepsis related deaths and that organs like liver, kidney and
brain PCT levels could be an alternative to serum PCT for the diagnosis of postmortem sepsis.
2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Keywords:
Procalcitonin
PCT
Post mortem chemistry
Trauma model
Septic model
Freezing death

1. Introduction
In practical casework, the pathologist is often confronted with
Systemic Inammation Response Syndrome (SIRS) e.g in trauma,
hypothermia) and sepsis as possible causes of death. However,
autopsy ndings and histological imaging are often unspecic and
therefore not conclusive for their diagnosis.1
Postmortem biochemistry and molecular biology were used
importantly to investigate the systemic pathophysiological changes
involved in the process of death that cannot be detected by
morphological methods and these may be called pathophysiological vital reactions.2,3
Procalcitonin (PCT) is the precursor of the calcitonin hormone,
which is responsible for calcium homeostasis and it is a peptide
that composed of 116 amino acids. It is produced by parafollicular

* Corresponding author. Department of Forensic Medicine & Clinical Toxicology,

Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
E-mail addresses: dr_afafattia@hotmail.com (A.M. Attia), dr_hendatta@hotmail.
com (H.M. Abo El-Atta), mohh_elsherbiny@yahoo.com (M. El-sherbiny).

cells of the thyroid gland and by the neuroendocrine cells of the

lung and intestine. The blood level of procalcitonin rises in a
response to any pro-inammatory stimulus, to be above the limit of
detection (10 pg/mL) in clinical assays in healthy individual. It rise
with infection especially bacterial origin while viral or noninfectious inammations does not raise it signicantly. The blood
levels of procalcitonin may rise to a level 100 mg/L with severe
systemic infection.4
Systemic inammation and immune responses are involved in
deaths due to trauma and disease.5 In forensic practice, one of the
essential roles of legal medicine is to provide a different approaches
to difculties that may face medicine and law as a forensic
pathologist may face a lot of limitations regarding the precise
diagnosis of septic or traumatic deaths.6
Postmortem diagnosis of sepsis may be difcult due to nonspecicity of macroscopic and routine histological ndings; in
addition, when clinical data on a deceased previous medical history
are not available during medico-legal autopsy.7 Meanwhile, traumatic deaths could happen without notable fatal injuries to organs
or soft tissues as well as there may be a difculty to determine
traumatic injuries that were developed whilst the victim was alive.8

http://dx.doi.org/10.1016/j.jm.2015.08.011
1752-928X/ 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

A.M. Attia et al. / Journal of Forensic and Legal Medicine 37 (2016) 28e32

Postmortem biochemistry of body uids and tissues may provide an understanding of the death process and its systemic
pathophysiological changes that cannot be discovered by the
ordinary morphological methods.3
The present study aims to estimate the postmortem levels of
PCT rise in the serum and some organs (kidney, liver, brain) of
animal induced septic death model; and whether such rise is
similar to other causes of death models such as traumatic,
drowning and freezing death models or not.
2. Material & methods

29

instructions by supplier. The optical density will be measured

under 450 nm wave length with assay range: 6e2000 pg/ml.
2.2. Methods
1 Induction of traumatic death model9:
The anaesthetized rabbit has to be secured in a stereotactic
frame. A round steel disc (1 cm diameter, 3 mm thickness) is xed
by surgical cement onto the central area of the skull. A 450 g weight
is dropped from a height of 1 m onto the center of the steel disc.
2 Induction of Infection death model10:

2.1. Study design

The experimental study was performed on 60 male rabbits, their
weights ranged from 1.8 to 2.0 kg. They were reared in clean
capacious metal cages under suitable laboratory conditions (as
good aeration, lightening and a constant room temperature about
24
C). The animals allowed to have free access to water and
standard rabbit fodder (25.1% proteins, 3.8% fat, 18.05% cellulose); at
Animal House of Medical Experimental Research Center, Faculty of
Medicine, Mansoura University.
According to Egyptian/European Union legislation (86/609/EEC),
the experimental animals were housed, handled, and euthanized.
The Ethical Committee of the Mansoura Faculty of Medicine
approved the present experimental protocols.
2.1.1. Animals were divided into four groups
1 Group 1 (traumatic induced death model):
Fifteen rabbits were assigned as a trauma model induced death.
2 Group 2 (infection induced death model):
Fifteen rabbits were assigned as a septic model induced death.
3 Group 3 (drowning induced death model):
Fifteen rabbits were assigned as a drowning model induced
death.
4 Group 4 (freezing induced death model):
Fifteen rabbits were assigned as a trauma model induced death.
At the end of the study, all rabbits were sacriced by decapitation. Postmortem blood samples were collected (2 ml) directly after
death of each rabbit. Each blood sample was centrifuged immediately and sera were stored at 20
C.
Kidneys, livers and brains were collected from all animals and
rapidly frozen at 20
C.
Procalcitonin was
measured
using
enzyme
linkedimmunosorbent assay Kit in serum and organs (kidney, liver and
brain) samples. Cat No. 201-12-0978 Sun Red Bio-technology
Company. All analyses were performed in accordance with

Rabbits exposed to an endotoxic shock after they were received

an intravenous solution of 200 ml lipopolysaccaride (LPS) at
different concentrations.
3 Induction of drowning death model:
It was done by immersing the animal cage in a basin lled with
water till the animal was died.
4 Induction of freezing death model:
It was done by exposing the animals to a (20
C) environment
till death.
2.2.1. Statistical analysis
The data were analyzed by using SPSS (statistical package for
social science) program version 16. The data were expressed as
mean and standard deviation. On way ANOVA (F test) was done to
compare between the studied groups. Post Hoc benferroni test was
done to study the difference between each two groups. Signicance
was considered at p value less than 0.05.
3. Results
The levels of procalcitonin (PCT) in all tested samples of
different causes of deaths are highly signicantly increased as
shown in Table 1 and Fig. 1.
In trauma induced model, PCT levels obtained from liver samples were the highest among other organs in the same group followed by the kidney's levels (Fig. 1).
Meanwhile, in infection induced model, the PCT levels were
highly elevated in all tested samples in comparison to the other
groups. The levels in the liver samples were the highest compared
to other organs in the same group followed by the brain's levels
(Fig. 1).
In drowning induced model, the PCT in the brain samples
showed the highest elevated levels compared to other organs in the
same group followed by the kidney's levels (Fig. 1).
In freezing induced model, the PCT levels showed increase in all
tested samples but were less than other groups. The levels in the
liver samples were the most elevated compared to other organs
followed by the brain's levels (Fig. 1).

Table 1
Procalcitonin levels (pg/ml) in serum, kidney, liver and brain samples of different models of death in rabbits (n 60).
Death model

Serum (mean SD)

Trauma
Infection
Drowning
Freezing

593.12
1684.87
589.35
194.09

240.6
873.18
326.91
45.43

Kidney (mean SD)

917.34
1831.73
861.43
189.31

80.77
26.15
120.35
16.92

Liver (mean SD)

1309.58
2103.8
809.44
651.72

105.24
107.67
72.44
214.02

Brain (mean SD)

672.62
1922.32
1294.46
358.16

46.33
83.45
202.94
109.76

30

A.M. Attia et al. / Journal of Forensic and Legal Medicine 37 (2016) 28e32

2500
2000
1500

Serum
Kidney

1000

Liver
500

Brain

Freezing

Infecon

Drowning

Trauma

Fig. 1. Procalcitonin levels (pg/ml) in serum, kidney, liver and brain samples of
different models of death in rabbits (n 60).

There was highly signicant difference between groups as

regards serum, kidney, liver and brain PCT levels using ANOVA test
(Table 2).
Post Hoc multiple comparisons test for PCT levels showed signicant differences between groups in most of the liver, brain and
kidney samples, while PCT serum blood samples were signicant
only between trauma and infection groups (Table 3).
4. Discussion
The aim of the present work is to investigate the postmortem
levels of procalcitonin (PCT) in the serum and some organs (kidney,
liver, brain) in animal induced deaths models (traumatic, infection,
drowning and freezing).

Table 2
ANOVA test between the procalcitonin levels (pg/ml) in all test groups (trauma,
infection, drowning and freezing induced death models).
Death model

Trauma

Serum
Kidney
Liver
Brain

26.526 (p < 0.0001)

1242 (p < 0.0001)
347.398 (p < 0.0001)
462.303(p < 0.0001)

Infection

Drowning

Freezing

ANOVA test between all variances.

Table 3
Post Hoc Multiple Comparisons test for procalcitonin levels in all test groups (serum,
kidney, liver & brain) (n 60).
Groups

Serum PCT levels

Trauma
Infection
Drowning
Freezing
Kidney PCT levels
Trauma
Infection
Drowning
Freezing
Liver PCT levels
Trauma
Infection
Drowning
Freezing
Brain PCT levels
Trauma
Infection
Drowning
Freezing

Std. Error

Sig.

95% condence interval

Lower bound

Upper bound

176.00056E2
1.7600056E2
1.7600056E2

.000
1.000
.164

1.573154E3
477.641018
82.374351

610.353649
485.159685
880.426351

2.7066933E1
2.7066933E1
2.7066933E1

.000
.261
.000

988.422030
18.126697
653.993970

840.353970
129.941364
802.062030

4.9573696E1
4.9573696E1
4.9573696E1

.000
.000
.000

929.810990
364.551010
522.267677

658.621010
635.740990
793.457656

4.5588089E1
4.5588089E1
4.5588089E1

.000
.000
.000

1.374391E3
746.535475
189.763858

1.125005E3
497.148525
439.150808

The post-mortem determination of biochemical parameters, in

many of forensic studies has been established as useful in diagnosis
of the underlying cause of death.11
The present study showed highly signicant increase in PCT
levels in all tested samples due to different causes of death. In
trauma induced model, the PCT levels showed signicant increase
in all tested samples. Liver samples were the highest elevated levels
compared to other organs in the same group followed by the
kidney's levels.
Chiesa et al.12 and Joram et al.13 described a few situations
where PCT can be elevated by non-bacterial causes including,
neonates <48 h of life which is considered a physiological elevation,
the rst days after a major trauma, major surgical intervention,
severe burns, treatment with drugs stimulating the release of proinammatory cytokines, patients with invasive fungal infections,
acute attacks of plasmodium falciparum malaria, patients with
prolonged or severe cardiogenic shock, prolonged severe organ
perfusion anomalies, small cell lung cancer, medullary C-cell carcinoma of the thyroid.
Pelinka et al.14 found that both serum PCT and S100B are associated with mortality after traumatic brain injury (TBI), however,
S100B increases than PCT earlier and markedly in non-survivors.
They observed that the difference in PCT between septic and
non-septic patients was not signicant. Thus, they concluded that
the prediction of sepsis in TBI patients should not depend on
neither PCT nor S100B.
Wojtaszek et al.15 found an increase in PCT serum levels that
observed in multiple trauma patients depending on the kind of
injury. The highest levels were measured on the 2nd day following
trauma. PCT concentration remained unchanged during the 1st day
after injury.
According to the study of Wanner et al.16 that involved 405
trauma patients and monitored the potential of PCT in them, they
concluded that PCT is a predictive indicator of sepsis after trauma
and it act as an independent predictor of multiple organ failure in
the early posttraumatic phase and also they stated that PCT is not a
predictor of sepsis.
Wanner et al.16 and Stiletto et al.17 stated that multi-trauma
patients manifested with an increase in PCT serum concentration,
which depended on the severity of the injury. Peak values were
observed in the rst 24 h and around the 3rd day following trauma.
The PCT high levels during the rst days after injury are believed to
be a prognostic factor in severe systemic inammatory response
syndrome (SIRS), infection or multiple organ dysfunction syndrome
(MODS).
In the present study, and regarding the infection induced model,
the PCT showed the highest levels in all tested samples in comparison to the other groups, where levels from liver samples
showed the highest elevated levels than other organs in the same
group followed by the brain's levels.
Regarding the association of procalcitonin to sepsis, Redl et al.18
reported that PCT is both a marker and a mediator of sepsis.
Meanwhile, further experimental studies have shown that PCT
differs signicantly between survivors and non-survivors in a
sepsis model and this supports the hypothesis that the liver is the
main source of PCT production.19
In non-trauma patients, several clinical studies report that PCT is
a good diagnostic and prognostic marker of sepsis.20e22
In contrast, decreasing PCT levels were associated with a higher
probability of survival because PCT predict the outcome of septic
shock poorly.23 Moreover, Andermahr et al.24 and Lewejohann
et al.25 stated that PCT is not superior to other markers.
Maier et al.26 stated that serum PCT signicantly increased after
abdominal trauma in severe multiple traumatized patients and
supported other diagnostic methods such as ultrasound and CT

A.M. Attia et al. / Journal of Forensic and Legal Medicine 37 (2016) 28e32

scan. Elevated levels of PCT are indicative of traumatic impact as it

elevated during the rst 2 days after trauma rather than the
ongoing sepsis, In addition, surgery, massive transfusion, and
intensive care therapy might inuence the PCT levels.
Maruna et al.27 and Morgenthaler et al.28 stated that procalcitonin produced from neuroendocrine cells in lung, liver or
kidney during inammation and it elevated in patients with
bacterial infection. PCT is undetectable (<.01 ng/ml) in the serum
of healthy individuals and a level of >0.5 ng/ml is considered
abnormal.29
Several biomarkers have been established in several studies for
their ability to diagnose sepsis of bacterial origin, PCT has been
indicated as the best biomarker.30
Elevated concentrations of PCT during severe bacterial infections are commonly observed in patients who had already
undergone total thyroidectomy. In patients with sepsis, nonneuroendocrine parenchymal cells, such as liver and splenic area,
are stimulated to produce and secrete large amounts of PCT but it is
still debated.31e33
In addition, Tsokos et al.34 was originally investigated the role of
PCT in postmortem diagnosis of sepsis in forensic pathology. They
measured postmortem serum PCT levels in septic and control cases.
They observed increased PCT levels in all septic cases and normal
concentrations in most control cases.
The probability determine PCT levels in other body uid were
investigated by Schrag et al.,35 and they reported promising results
with vitreous and pericardial uid PCT concentrations in septic
cases.
In the present work, regarding the drowning group, the PCT
levels showed signicant increase in all tested samples. Their levels
in the brain were the highest compared to other organs of the same
group followed by the kidney's levels. Meanwhile, the freezing
group, the PCT levels showed increase in all tested samples but the
levels were less than other groups. The levels obtained from liver
samples showed the most elevated levels compared to other organs
followed by the brain's levels.
As a debate of using the biomarkers plasma C-reactive protein
or PCT levels as diagnostic criteria for sepsis using more than 2
standard deviations (SD) above the normal value was declared
despite being a part of the inammatory variables which,
together with infection, constitute a denition of sepsis.36,37 As well
there is evidence that low PCT levels can be used to assist critical
care clinicians to discontinue empiric antibiotics in those patients
who appear septic, but have no subsequent evidence of infection.38
Besides, although PCT has an established role as a septic biomarker,
it has limitations, as it rises transiently in patients with non septic
conditions such as trauma, surgery, heatstroke and it may not be
detectable in certain cases of sepsis.
To our knowledge, this is the rst experimental study to determine the serum level of prolactin after death; and no other studies
had compared the PCT level in different types of death such as
drowning and freezing deaths.
Procalcitonin (PCT) is a very stable protein ex vivo, even at room
temperature and PCT concentrations do not differ in arterial and
venous blood samples from living persons. In addition, repeated
freezing and thawing of the blood samples does not signicantly
inuence PCT concentrations in these specimens.4
In the present study, Post Hoc multiple comparisons test for PCT
levels showed signicant differences between groups in most of
liver, brain and kidney samples, while PCT serum blood samples
were signicant only between trauma and infection groups.
In healthy individuals, all the PCT produced in C-cells is converted to calcitonin, so that circulating PCT concentrations are
below detection levels of 0.1 ng/mL (0.1 mg/L). In patients with
sepsis, PCT concentration may increase up to 5000 to 10,000 times

31

with calcitonin still in the reference range. No enzymes in blood can

break down the PCT circulating molecule.32,39
Even though PCT is not produced by circulating blood cells, its
synthesis seems to be closely dependent on the cytokines involved
in initiating the inammatory cascade. Procalcitonin can be
detected after 3e4 h in response to bacterial endotoxins and peaks
at 6e8 h with a half-life of approximately 24e30 h.39,40
Further experimental studies have shown that PCT differs
signicantly between survivors and non-survivors in a sepsis
model18 and they support the hypothesis that the liver is the main
source of PCT production.19
5. Conclusion
The results of the present study conrm that procalcitonin is
allowing a differentiation between sepsis and non-sepsis related
deaths; its level may rises from twice up to eight times higher in
septic conditions compared to non septic causes. In addition, liver,
kidney and brain procalcitonin could be an alternative to the serum
procalcitonin for the diagnosis of postmortem sepsis.
Conict of interest
Authors declare that there is no conict of interest with anyone.
Funding
None declared.
Ethical approval
None declared.
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