https://dx.doi.org/10.24016/2023.v9.327
ORIGINAL ARTICLE
Brief review of pathophysiological disorders as consequence of
psychological stress
Breve revisión de los
trastornos fisiopatológicos como consecuencia del estrés psicológico
Francisco López-Naranjo1,
Rebeca Córdova-Moreno1; Ivo Heyerdahl-Viau1*
1 Universidad
Autónoma Metropolitana, Mexico City, Mexico.
* Correspondence: ivoheyerdahl@gmail.com
Received: May
04, 2023 | Revised: August 15, 2023 | Accepted: September
20, 2023 | Published Online: September 25, 2023.
CITE
IT AS:
López-Naranjo, F.,
Córdova-Moreno, R., & Heyerdahl-Viau, I. (2023). Brief review of
pathophysiological disorders as consequence of psychological stress. Interacciones, 9, e327. https://dx.doi.org/10.24016/2023.v9.327
ABSTRACT
Background: Psychological stress is a reaction to an unexpected
situation that favours adaptation and response to the event. However, when
psychological stress is chronic or very intense, it can induce changes in
various systems and tissues, causing diseases or aggravating existing ones. Objective:
To briefly analyse the pathophysiological conditions caused by
psychological stress. Method: A narrative review of the scientific
literature on pathophysiological conditions as a consequence of psychological
stress was performed. Results: Psychological stress can induce various
conditions at the gastrointestinal, immune and cardiovascular levels. This is
mainly due to the neurobiological and endocrine response because when faced
with a stressful stimulus, a deregulated release of glucocorticoids and
catecholamines is generated, altering the normal physiology of the organism.
Gastrointestinal disorders are mainly due to goblet cell dysfunction, resulting
in intestinal hyperpermeability, inflammation and infection. Changes at the
immune level lead to an increase in inflammatory
responses but a decrease in the protective activities of the immune system.
Finally, cardiovascular conditions include atherosclerosis, increased blood
pressure and stroke. Conclusion: Psychological stress can induce real
physiological pathologies and, in some cases, fatal ones. Some of the molecular
mechanisms involved in these pathologies have already been studied and
identified. Knowledge of these molecular mechanisms can help clinicians and therapists
to improve the treatment and therapy of patients.
Keywords: Psychological
Stress, Glucocorticoids, Immunity, Cardiovascular Diseases, Brain-gut Axis.
RESUMEN
Introducción: El estrés psicológico es una respuesta a una
situación inesperada que favorece la adaptación y la respuesta ante dicho
evento. Sin embargo, cuando el estrés psicológico es crónico o muy intenso, se
pueden desencadenar afecciones en diversos sistemas y tejidos, generando
enfermedades o empeorando las ya existentes. Objetivo: Analizar
brevemente las afecciones fisiopatológicas causadas por el estrés psicológico. Método:
Se realizó una revisión narrativa con la literatura científica sobre las
afecciones fisiopatológicas debidas al estrés psicológico. Resultados: El
estrés psicológico puede desencadenar diversas afecciones a nivel
gastrointestinal, inmunitario y cardiovascular. Esto se debe principalmente a
la respuesta neurobiológica y endócrina, ya que ante estímulos estresores, se
genera una liberación desregulada de glucocorticoides y catecolaminas que
alteran la fisiología normal del organismo. Las afecciones a nivel
gastrointestinal se deben principalmente a la disfunción de las células
caliciformes, dando como consecuencia hiperpermeabilidad
intestinal, inflamación e infecciones. Las alteraciones a nivel inmunitario
generan un aumento en las respuestas inflamatorias pero una reducción en las
actividades protectoras del sistema inmune. Por último, las afecciones
cardiovasculares incluyen ateroesclerosis, aumento de la presión arterial y
derrames cerebrales, entre otros. Conclusión: El estrés psicológico
puede causar patologías fisiológicas reales y, en algunos casos, mortales.
Algunos de los mecanismos moleculares implicados en estas patologías ya han
sido estudiados y establecidos. Conocer estos mecanismos moleculares puede
ayudar a los médicos y terapeutas a mejorar el tratamiento y la terapia del
paciente.
Palabras
claves: Estrés Psicológico, Glucocorticoides, Inmunidad, Enfermedades
Cardiovasculares, Enfermedades Inflamatorias del Intestino.
BACKGROUND
Throughout the life of the human being, events occur that do not turn
out as expected; sometimes they are better, but at other times, they are worse,
and can lead to psychological stress and frustration. Psychological stress is a
physiological response to an unexpected or unfavorable
event for the person who perceives it. This response favors
an adaptation for a better action and response to the situation (Piqueras
Rodríguez et al., 2009). Therefore, stress may have a protective effect in the
short run, during minutes or hours, when the individual needs to stay alert
(Antoni y Dhabhar, 2019). However, when this response
is very intense or chronic, it may lead to negative emotions such as fear,
anxiety, anger, and sadness (Piqueras Rodríguez et al., 2009).
Since the human being is predisposed to adaptation, the emotional
perception to adverse situations and the intensity and duration of their
reaction to them depends, among other factors, on the discrepancy between what
has been achieved and what is expected based on previous experiences and
learning (Mustaca, 2018). When these states are very
intense or chronic, they can affect the person's quality of life by contracting
mental illness or physical disorders (Piqueras Rodríguez et al., 2009).
Psychological stress was already frequent worldwide, but this and other
mental disorders have increased because of the COVID-19 pandemic (Cooke et al.,
2020; Nochaiwong et al., 2021), affecting general
population, including health professionals as well (Mathur et al., 2020), and
some opinions suggest that COVID-19 related stress may continue even after the
pandemic is over (Łaskawiec et al., 2022).
However, and unfortunately, due to modern lifestyles and social demands
and expectations, the impacts of psychological stress are greatly
underestimated (Güler et al., 2019; Izawa et al., 2016; Nakamura-Taira et al.,
2018), and there is an urge to raise greater awareness in this regard.
Therefore, it is important to inform the population about the importance of
psychological stress and the influence it can have on people's health. Among
these pathologies are gastrointestinal conditions (He et al., 2018), immune
system affections (Ilchmann-Diounou & Menard,
2020) and cardiovascular conditions (Vancheri et al., 2022), which can have an
important clinical impact on people. Therefore, we consider it necessary to
carry out a brief narrative review on this topic aimed at psychologists,
doctors, community pharmacists and even patients or anyone interested in the
topic.
This review aims to briefly describe pathophysiological disorders such
as gut, cardiovascular, and immune system affections as consequence of
psychological stress and some of the involved mechanisms according to recent
scientific research.
METHODS
This article is a brief narrative review on the pathophysiological
consequences of psychological stress. To this end, a non-systematized
bibliographic search of specialized scientific literature was carried out in
databases such as PubMed, Google Scholar and SciELO
using key words such as “psychological stress”, “pathophysiological disorders”,
“stress and stressors”, “gut health”, “immune system”, “cardiovascular system”
and “neurobiology of stress”. Only refereed scientific publications were
considered. Those in English language published in the last five years (from
2018 to March 2023) were prioritized, although the inclusion of some older
articles and in Spanish language was also allowed as they were previously
identified. Original research articles were included, as well as other
narrative and systematic reviews. Likewise, to complement some definitions,
sources were consulted from official websites such as the World Health
Organization (WHO) site.
RESULTS
Stress and stressors
According to the World Health Organization, stress is “a state of worry
or mental tension generated by a difficult situation” (World Health
Organization, 2023). This typically occurs when an individual feels unable to
cope with an adverse situation or negative environmental stimulus (Epel et al.,
2018; Huh et al., 2021). Each individual has a different response to these
situations, so it is important to take into account the concept of “perceived
stress”, which is the way in which an individual understands the amount of
stress to which they are exposed (Huh et al., 2021) so that the individual
produces psychological and emotional responses to these situations, such as the
appearance of overwhelming sensations, anxiety or a feeling of loss of control
and insufficiency (Epel et al., 2018).
Therefore, psychological stress response is subjective and its
measurement and perception complex, because it involves external stressors and
the individual`s abilities to cope with them, which varies among individuals
(Vancheri et al., 2022). So, an individual may have a response against a real
or perceived (but not real) threat to the well-being which may be exacerbated
(van der Sluis & Hoekstra, 2020). This response is acute when the
experience it is brief but intense, or chronic when it is constant in time.
Acute psychological stress may be a result of quick events, such as an
interview, an accident, or natural disasters such as earthquakes and
hurricanes, among others, whereas chronic stress is the result of long term or
repetitive exposure to stressors or stressful situations, such as prolonged
family or job-related problems, low socioeconomic status, diseases, or
loneliness, among others (Vancheri et al., 2022). Therefore, acute stress may
be beneficial in some situations because its response may help the individual
to adapt to an adverse situation in a moment of need, but chronic stress is
considered harmful because it can produce some pathophysiological disorders as
a result (Antoni & Dhabhar, 2019).
Sex and age differences against psychological stress
Regarding sex and age differences, it is difficult to establish a
correlation with psychological stress because it depends on very personal or
specific circumstances. For example, COVID-19 pandemic increased psychological
stress in general population; a study conducted in China during the pandemic
stablished that unemployment increased psychological stress, but it was also
found that people under 45 years old and females were found to be more affected
by this circumstance (Yan et al., 2021). In another study conducted also in
China, it was shown that psychological stress was correlated with an increase
for hypertension in women, but not in men (Hu et al., 2015).
Altogether, this suggest that women are more vulnerable against
psychological stress than men. However, as it was mentioned before, it is
difficult to establish a clear general correlation, as it was shown in a review
study in which the authors concluded that despite many research articles
suggest that there is in indeed a stronger link in women between stress and
sleep with inflammation because of hormone differences, in some cases,
methodologies of measurement are poor and the results are largely mixed (Dolsen
et al., 2019). The same can be said about age differences, as different events
affect people differently. For example, in a study, it was established that
young adults were indeed more vulnerable to stress during COVID-19 pandemic due
to isolation (Birditt et al., 2021), but other
situations or circumstances in life such as retirement can cause great stress
to older people, and it has been established that men are more vulnerable to it
(Berezina et al., 2019).
Neurobiology and endocrinology of psychological stress
When the human being is exposed to a stressor, acute stress is caused
because the nervous systems immediately respond by activating the sympatho-adrenal medullary system (SAMS) which then causes
the release of catecholamines (Turner et al., 2020). At the same time, there is
also an activation of the limbic-hypothalamo-pituitary
adrenal axis (LHPAA), causing a secretion of high levels of corticotropin
releasing factor (CRF) from hypothalamus. CRF then binds in the pituitary
gland, resulting in the production of adrenocorticotropic hormone (ACTH), which
then stimulates the production of stress hormones such as glucocorticoids,
including cortisol and corticosterone that affects immunity and hearth health
as described later (van der Sluis and Hoekstra, 2020).
Several neurotransmitters are also involved in psychological stress
response. One of the most important ones is dopamine. Dopamine is a
neuromodulator because it modulates sensitivity to other neurotransmitters. For
example, it modulates the influence of glutamate in other neurons (Wise & Robble, 2020). Acute stressors induce a pronounced
activation of the dopamine system, and it has been seen that children with
traumas have elevated urinary dopamine metabolites and that acute psychosocial
stressors induce greater dopamine release in people with low self-reported
maternal care. It is interesting that even after a single stress exposure,
long-lasting changes in the dopamine system may occur in a similar way to that
induced by addictive drugs and that a long-term exposure to psychological
adversity is related to a diminished dopaminergic function (Ap Bloomfield et
al., 2019).
On the other hand, the excitatory neurotransmitter glutamate, and the
inhibitory neurotransmitter gammaaminobutyric acid
(GABA) are also important. Basolateral amygdala (BLA) is a region of the brain
that plays an important role in fear learning and memory, and it consist of 80%
of excitatory neurons (glutamatergic neurons) and 20% of inhibitory neurons
(GABAergic neurons). It has been shown that acute stressors induce higher
expression of glutamate receptors in BLA and a large increase in excitatory
neurotransmitter glutamine pool which can cause acute and chronic nerve cell
injuries, causing degeneration and death of glutamatergic neurons. In fact,
similarly to what happens with the dopamine system, prolonged stress causes a
low expression of glutamine receptors and glutamine response overall, causing a
biochemical imbalance and BLA structural changes, therefore causing behavioural
disorders (Wang et al., 2021). Interestingly, GABAergenic
response seems to be the opposite; a study carried with magnetic resonance
spectroscopy method on healthy human subjects showed that prefrontal GABA
decreased by 18% in a threat-of-shock condition relative to the safe condition,
showing a rapid presynaptic down-regulation of GABAergic neurotransmission in
response to acute psychological stress. This makes sense, because GABA is the
main inhibitory neurotransmitter and GABA receptor agonists that enhance GABA
transmissions such as benzodiazepines are used as anxiolytics (Hasler et al.,
2010).
Norepinephrine is another important neurotransmitter involved in
psychological stress responses. Locus coeruleus (LC) is the main norepinephrine
secretor in the brain. Norepinephrine is secreted by the LC during acute stress
which activates BLA and all that it entails, as previously described (Giustino
et al., 2020). Furthermore, it has been reported that norepinephrine released
by daily stressed young adults induces vasoconstriction, which may lead to
cardiopathies (Greaney et al., 2020) as described later.
Overall, this means that the brain transduces the emotional stimuli
(stressor) perceived by the person (stress perception) into hemodynamic,
neuroendocrine and immune changes to generate a “fight or flight” response
(stress response) (Vancheri et al., 2022). However, this response produces an
energy expenditure and metabolism for an activity that may not eventuate, which
is why the response is considered “metabolically unjustified” (Turner et al.,
2020).
Psychological stress measurement
As it was mentioned earlier, psychological stress measurement is complex
because it depends on subjective perceptions. However, they are reliable tools
available for this purpose. The simplest ones are self-report questionaries,
such as the Perceived Stress Scale (PSS-10), the Job Content Questionnaire, the
Job Stress Survey, the Coping Strategy Indicator, the Stress and Coping Process
Questionnaire, the Coping Inventory for Stressful Situations, among many
others. The PSS-10 is the most used tool to measure perception of stress for
clinical and research purposes. It was developed by Cohen, Kamarck
and Memelstein in 1983, and it contains 10 questions
on current levels of perceived stress; six items measure stress itself and four
measure coping strategies to it (Frisone et al., 2021).
However, there are other tools which may be more objective because they
rely on technology to measure stress via bio-signals evaluation, imageology or
biomarkers and metabolites detection. For example, as it was mentioned before,
nuclear magnetic resonance can be useful to measure neurotransmitters related
to perceived stress (Hasler et al., 2010). Similarly, heart activity measurement
tools such as electrocardiogram, blood volume pressure, heart rate and heart
rate variability measurements are useful to detect perceived stress on patients
and how stress affects their cardiovascular system. However,
electroencephalogram (EEG) is probably the most used technique to detect
changes in neuronal activity associated with external stimuli, therefore, it is
useful to measure stress responses, especially by measuring the EEG asymmetry
index because it reveals emotional arousal; most research studies support the
statement that under stress conditions there is generally greater frontal right
alpha activity in relation to the left alpha activity (Giannakakis et al.,
2022).
However, now days technological advances can be exploited even further
in various exciting ways. For example, there is a lot of promising research
regarding real-time stress monitoring using wearable devices. Such instruments
would be very beneficial, not only for regular patients, but also for people
with especially dangerous or stressful occupations such as firefighters, police
officers, athletes, soldiers, among others (Parlak, 2021). For example, in a
study, scientist developed a wearable instrument to measure EEG asymmetry index
in human subjects to study stress in real time. This instrument was built with
off-the shelf instruments and dry electrodes. Its response was compared with
standardized stress test, observational questionnaires, and performance
measurements. It reached more than 90% accuracy (Arpaia et al., 2020). On the
other side, one of the most promising approaches in this regard is real-time
cortisol measurement. This has been successfully reported in several research
works, and it has been reached mainly via development of immune-electrochemical
sensors using enzymes or antibodies. These devices detect and measure cortisol
on saliva and other human fluids (Parlak, 2021).
Effect of psychological stress on gut
Microbiota is the set of microorganisms that coexist on human surfaces
and cavities. These includes bacteria, archaea, bacteriophages, eukaryotic
virus, and fungi. These microorganisms, especially bacteria, are mutualistic
organism, therefore, they have several important functions that brings benefit
to human health; they train host immunity, digest some food, modify drug and
toxin structures, regulate gut endocrine action and neurological signalling,
among other activities (Fan & Pedersen, 2020).
However, gut microbiota is not directly in contact with gastrointestinal
epithelium; it lies on a layer of mucus that creates a coat, protecting
intestinal tissue from bacteria and other biological and mechanical stress
(Paone & Cani, 2020). In addition, this mucus layer also provides nutrients
and adhesion for microbe growth (He et al., 2018). The main constituent of this
mucus layer are mucins, which are large, complex, glycosylated proteins
produced and secreted by goblet cells (Paone & Cani, 2020).
Goblet cells produce mucins in response of nervous stimuli (via a
brain-gut axis), and it has been shown that acute stress increases mucus
release (He et al., 2018). This acute stimulus enhances the mucosal barrier and
protects a leaky epithelium against microbial infection, but on the long term,
it has been shown that exaggerated and prolonged stimulation of goblet cells
reduces their numbers and, therefore, decreases mucus secretion (Söderholm et
al., 2002). Additionally, the protective function of the mucus layer is also
reduced because psychological stress also alters O-glycosylation of mucins,
resulting in flattening of the layer and a consequent loss of cohesion (He et
al., 2018). All of this results in intestinal hyperpermeability, a consequent
intestinal inflammation and possible infection (Söderholm et al., 2002; Wei et
al., 2019). That’s why psychological stress may produce gastrointestinal
symptoms.
Additionally, as it was mentioned before, LHPAA stimulation releases
CRF, which increases oxidative damage in the colon, leading to inflammatory
responses and increasing intestinal permeability and bacterial translocation.
It also causes to microbiota dysbiosis, which leads to gastrointestinal
diseases such as irritable bowel syndrome (Zhang et al., 2023).
Effect of psychological stress on immune system
Immune system activates inflammatory response in a hostile environment
to preserve cellular and organ integrity. Therefore, it is a natural and
necessary response against biotic and abiotic stress. However, alterations of
immune system due to diseases may cause an insufficiency or an overactivity.
Insufficient response may cause immunodeficiency, resulting in infections and
cancer, while an overactivity may lead to autoimmune disorders (Kjekshus, 2015).
When glucocorticoids are released after a stressful situation, they can
modulate immune response; it has been established that they attenuate immune
responses and inflammatory processes by attenuating signalling pathways of the
inflammatory process, diminishing leukocyte transmigration, and decreasing
levels and production of chemo-attractants that are important for immune cells
to fight infectious agents (Ilchmann-Diounou &
Menard, 2020). They also cause apoptosis of B and T lymphocytes, causing
adaptive immune deficiency (Xu et al., 2020). This is why glucocorticoids are
used as pharmacological agents to treat immune-related disorders, such as
autoimmune diseases in which the organism has exaggerated immune responses (Ilchmann-Diounou & Menard, 2020). However, when
considering chronic stress, these immune alterations may lead to chronic
infection, chronic inflammatory autoimmune diseases or even cancer.
Additionally, stress-induced sympathetic adrenergic signalling can inhibit
immune responses in infection diseases (Bae et al., 2019).
Nevertheless, it has also been established in animal models and in
humans that stressful events and stress-related disorders such as
post-traumatic stress disorder is associated with an increase in
pro-inflammatory markers, such as various interleukins (Il) and TNFα, among
others. This obviously leads to an exaggerated immune response and damage in
several tissues, including intestinal barrier which produces intestinal hypopermeability
(Ilchmann-Diounou and Menard, 2020), aggravating gut
health described in the previous section.
Overall, this means that stress is related to an up-regulation of
inflammation and a down regulation of protective immunity; a combination of
factors that can lead to serious damage on an individual’s health and can also
aggravate other preexisting diseases such as cancer, since affected immune
cells may not control cancer cells effectively and may act as stromal cells
(Antoni & Dhabhar, 2019).
Effect of psychological stress on cardiovascular system
The most common cardiovascular disease (CVD) is atherosclerosis or
coronary artery disease (CAD). This disease consists of lipid accumulation and
inflammation of large arteries, and can lead to other cardiovascular affections
and stroke (Björkegren & Lusis, 2022).
Chronic stress is related to increase of CVD due to acceleration of
atherosclerosis. This is because greater amygdala activity caused by stress is
associated with carotid artery intima-media thickness, enhanced blood pressure
reactions and inflammatory responses. Besides, there is a maladaptation of the
neuroendocrine pathways involved in the response to stress (Vancheri et al.,
2022).
Additionally, because of the LHPAA stimulation, stress also favours
glucocorticoids secretion from adrenal glands, accelerating atherosclerosis
(Björkegren & Lusis, 2022). This is because glucocorticoids reduce nitric
oxide concentration, which is a key driver of vasodilation. Glucocorticoids can
also promote vascular contractility via regulation of various expression
factors of enzymes and proteins involved in vascular contractility (Macleod et
al., 2021). This also explains why corticosteroid therapy is associated with
CAD (Björkegren & Lusis, 2022).
Acute stress can also have cardiovascular consequences; as it was
mentioned before, seconds after the exposure to the stressor, a large
sympathetic nervous system activity is produced, causing release of
catecholamines adrenaline and noradrenaline into circulation, therefore causing
an increase in hearth rate and blood pressure and peripheral microvascular
constriction. This circumstance also favours atherosclerosis development.
Besides, significant acute stress may trigger cardio-pathological events such as
angina, arrhythmias, stress cardiomyopathy, myocardial infarction, stroke, or
sudden death (Vancheri et al., 2022).
There is also clinical evidence in real patients: in a study carried in
Sweden with data from 1987 to 2013, it was observed that stress related
disorders are associated with several CVDs independently of family background
or psychiatric comorbidities (Song et al., 2018). These findings show the
importance of stress related disorders awareness because these pathologies may
affect anyone regardless of their family history of diseases.
CONCLUSIONS
Psychological stress can cause real physiological pathologies, and not
just psychological perception of somatic symptoms as some people may believe.
Some of the molecular mechanisms involved in these physiological pathologies
caused by psychological stress have already been studied and established.
Knowing these molecular mechanisms may help physicians and therapists to
improve patient`s treatment and therapy. This is important because this is a
case of a disorder that causes other disorders, and in some cases, fatal ones.
This is why psychological stress must not be overlooked or underestimated by
patients nor physicians.
ORCID
Francisco López-Naranjo: https://orcid.org/0000-0002-2140-7382
Rebeca Córdova-Moreno: https://orcid.org/0000-0002-6755-1240
Ivo Heyerdahl-Viau:
https://orcid.org/0000-0002-8252-2552
AUTHORS' CONTRIBUTION
Francisco López-Naranjo: Conceptualization, investigation, writing, review,
supervision, and approval of the final version.
Rebeca Córdova-Moreno: Review, supervision, and approval of the final
version.
Ivo Heyerdahl-Viau: Conceptualization, methodology investigation, writing,
editing, translation, and approval of the final version.
FUNDING SOURCE
This study did not receive funding.
CONFLICTO
DE INTERESES
The authors declare that there were no conflicts of
interest in the collection of data, analysis of information, or writing of the
manuscript.
ACKNOWLEDGMENTS
Not applicable.
REVIEW PROCESS
This study has been reviewed by
external peers in double-blind mode. The editor in charge was David Villarreal-Zegarra. The review process is included
as supplementary material 1.
DATA AVAILABILITY
STATEMENT
Not applicable.
DISCLAIMER
The authors are
responsible for all statements made in this article.
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