Download Stress pathophysiology

Stress pathophysiology
Content of the practical =
examination questions
• Stress and General adaptation syndrome characteristics, phases, regulatory
mechanisms. Eustress. Distress.
• Psychosomatic disturbances. Iatrogenic
diseases.
• Pain and stress.
Stress-reaction (general adaptation syndrome) is
common both for humans and animals
Dental Fear
It is estimated that as many as
75% of US adults experience some
degree of dental fear, from mild to
severe.
Approximately 5 to 10 percent of
U.S. adults are considered to
experience dental phobia; that is,
they are so fearful of receiving
dental treatment that they avoid
dental care at all costs
What is stress?
• Physiological or biological stress is an
organism's response to a stressor such as
an environmental condition or a stimulus.
Stress is a body's method of reacting to
a challenge.
• Stressor – any influence which is a
THREAT to psychological or biological
homeostasis
Constancy of the Internal
Environment (Homeostasis)
1. Constancy in an open system, such as our bodies
represent, requires mechanisms that act to maintain this
constancy.
2. Steady-state conditions require that any tendency
toward change automatically meets with factors that
resist change. An increase in blood sugar results in
thirst as the body attempts to dilute the concentration of
sugar in the extracellular fluid.
Cannon W.B. (1932). The wisdom of the body (pp. 299–300). New York: W.W. Norton.
Homeostasis (cont.)
3. The regulating system that determines the homeostatic
state consists of a number of cooperating mechanisms
acting simultaneously or successively. Blood sugar is
regulated by insulin, glucagon, and other hormones that
control its release from the liver or its uptake by the tissues.
4. Homeostasis does not occur by chance, but is the result
of organized self-government.
Cannon W.B. (1932). The wisdom of the body (pp. 299–300). New York:
W.W. Norton.
History of research
As a young medical student, Selye
noticed that patients with diverse disease
conditions had many signs and
symptoms in common. He observed that
“whether a man suffers from a loss of
blood, an infectious disease, or
advanced cancer, he loses his appetite,
his muscular strength, and his ambition
to accomplish anything; usually the
patient also loses weight and even his
facial expression betrays that he is ill.”
Selye referred to this as the “syndrome
of just being sick.”
Selye noted a triad:
• adrenal cortex enlargement,
• atrophy of the thymus gland and
other lymphoid structures
• development of bleeding ulcers in
the stomach and duodenal lining.
• appeared in rats he was using for his studies.
These same three changes developed in
response to many different or nonspecific
experimental challenges.
Other definitions of stress?
• Stress results from the ‘interaction between, or misfit of,
environmental opportunities and demands, and
individuals needs and abilities, and expectations, elicit
reactions’.
• In its negative sense, stress is defined as “physical,
mental or emotional strain or tension; a condition or
feeling experienced when a person perceives that
demands exceed the personal and social resources that
individuals are able to mobilize
•
Levi L. 1987 Definitions and the Conceptual Aspects of Health in Relation to Work. In
Psychosocial Factors at Work and Their Relation to Health. R. Kalimo, M.A.
El-Batawi and C.L. Cooper, eds. WHO, Geneva.
Sutherland V.J. and C.L. Cooper.
1990 Understanding Stress: A Psychological Perspective for Health Professionals.
London: Chapman and Hall.
Types of stress
• Acute vs chronic
• Acute stress is defined as a single exposure on the scale
of minutes to hours without cycles of recovery and reexposure
• Physical (burns, trauma, noise, infection),
• Psychological (emotional) – all factors that
demand significant changes of behavior
Eustress vs Distress
• Selye indicated that not all stress was detrimental;
hence, he coined the terms eustress and distress.
• Eustress - mild, brief, and controllable -perceived as
positive stimuli to emotional and intellectual growth and
development. Distress - severe, protracted, and
uncontrolled situations of psychological and physical
distress that are disruptive of health
Classic Stages of Stress
• Stage 1 Alarm
• Shock phase (1): During this phase, the body can endure
changes such as hypovolemia, hypoosmolarity,
hyponatremia, hypochloremia, hypoglycemia - the stressor
effect. This phase resembles Addison's disease. The
organism's resistance to the stressor drops temporarily
below the normal range and some level of shock (e.g.
circulatory shock) may be experienced.
• = prevalent effects of the stressor
• Can lasts seconds-days, if stressor is
tolerable → phase 2 or if stressor is small,
phase 1 is not registered
Stress: Stage1 Alarm (phase 2)
• Antishock phase:
• When the threat or stressor is identified or realized, the
body starts to respond and is in a state of alarm. During
this stage, the locus coeruleus/sympathetic nervous
system is activated and catecholamines such as
adrenaline are being produced,
The result is:
• increased muscular tonus,
• increased blood pressure due to peripheral
vasoconstriction and tachycardia,
• and increased glucose in blood.
• There is also some activation of the HPA axis, producing
glucocorticoids (hence the fight-or-flight response.
• cortisol, aka the S-hormone or stress-hormone).
Stress Stage 2
• Resistance
• increased secretion of glucocorticoids play a major role,
intensifying the systemic response—they have lypolytic,
catabolic and antianabolic effects: increased glucose, fat
and aminoacid/protein concentration in blood. Moreover,
they cause lymphocytopenia, eosinopenia, neutrophilia
and polycythemia. In high doses, cortisol begins to act
as a mineralocorticoid (aldosteron) and brings the body
to a state similar to hyperaldosteronism. Although the
body begins to try to adapt to the strains or demands of
the environment, the body cannot keep this up
indefinitely, so its resources are gradually depleted.
Stress Stage 3
Recovery or Exhaustion:
• Recovery stage follows when the system's compensation
mechanisms have successfully overcome the stressor
effect (or have completely eliminated the factor which
caused the stress). The high glucose, fat and aminoacid
levels in blood prove useful for anabolic reactions,
restoration of homeostasis and regeneration of cells.
Exhaustion
• Exhaustion is the alternative third stage in the
GAS model.
• All of the body's resources are eventually depleted and
the body is unable to maintain normal function. The initial
autonomic nervous system symptoms may reappear
(sweating, raised heart rate, etc.). If stage three is
extended, long-term damage may result (prolonged
vasoconstriction results in ischemia which in turn leads
to cell necrosis), as the body's immune system becomes
exhausted, and bodily functions become impaired,
resulting in decompensation.
PRE - START
of stress
Stressors
Physical
1) harmful environmental stimuli (fumes, high levels of
radiation, unfavorable climate, cold or hot climate, etc.);
2) Disturbances of physiological processes in the body, such
as in various diseases, including - infectious, physical
overload, etc.;
Psychological
3) the need for rapid information processing, ie work in a
shortage of time;
4) work in terms of risk to their own lives or the lives of others;
5) perceived threat to life;
6) isolation and imprisonment;
7) ostracism (exile, persecutions), pressure group;
8) lack of control over events;
9) lack of purpose in life;
10) deprivation - lack of stimuli.
11) the threat of "death" of one of the inner psychic parts
Stressors
of civilized
people:
are the acute
or chronic?
Holmes- Rahe Stress Inventory
Evolutionary role of stress:
what do you need to survive?
CNS mechanism of stress
Brain cortex
Stimulus  receptor
Reticular formation
Hypothalamus
Limbic system
Threat = Stress
Parasympathetic
activation
1 Sympathetic activation (150 ms – minutes - hours)
2 Adrenaline reaction (sec – minutes – hours … 10 times longer then 1st)
3 ACTH – cortisol + TTH + STH + aldosterone + vasopressin +
angiotensinogen (appr 10 sec. - hours – days – weeks)
ACTH
• ACTH is recepted not only by cells of the
adrenal glands, but by many nerve cells of the
brain, and one of its important functions is to
consolidate memory, ie transfer information from
short-term to long-term memory. Low/moderate
levels of stress in most cases improves memory,
while a high level - on the contrary, worsen.
Glucocorticoids,
GABA and opioids 
reduce the secretion
ACTH  CRH 
serotonin,
acetylcholine, IL
1 and IL6.
Structure of adrenal gland
•
https://upload.wikimedia.org/wikipedia/commons/thumb/c/ca/1818_The_Adrenal_Glands.jp
g/600px-1818_The_Adrenal_Glands.jpg
Mechanism of steroid hormones’ action
Hypothalamic-PituitaryAdrenal Axis.
The response to
stress begins in the
brain. The hypothalamus
is the control center in
the brain for
many hormones
including corticotropinreleasing hormone
(CRH). ACTH,
Adrenocorticotropic
hormone.
Stress Interactions
PHYSIOLOGIC EFFECTS OF
CATECHOLAMINES
PHYSIOLOGIC EFFECTS OF CATECHOLAMINES (cont.)
PHYSIOLOGIC EFFECTS OF CORTISOL
Carbohydrate and
lipid metabolism
Diminishes peripheral uptake and utilization of glucose;
promotes gluconeogenesis in liver metabolism cells; enhances
gluconeogenic response to other hormones; promotes lipolysis
in adipose tissue
Protein metabolism Increases protein synthesis in liver and decreases protein
synthesis (including immunoglobulin synthesis) in muscle,
lymphoid tissue, adipose tissue, skin, and bone; increases
plasma level of amino acids; stimulates deamination in liver
Anti-inflammatory
effects (systemic
effects)
Proinflammatory
effects (possible
local effects)
High levels of cortisol used in drug therapy suppress
inflammatory response; inhibit proinflammatory activity of
many growth factors and cytokines; however, over time some
individuals may develop tolerance to glucocorticoids,
causingan increased susceptibility to both inflammatory and
autoimmune disease
Cortisol levels released during stress response may increase
proinflammatory effects
PHYSIOLOGIC EFFECTS OF CORTISOL
(Immune effects)
Treatment levels of glucocorticoids are immunosuppressive; thus, they are
valuable agents used in numerous diseases;
the T-cell or innate immunity system is particularly affected by these larger
doses of glucocorticoids with suppression of Th1 function or innate
immunity; stress can cause a different pattern of immune response; these
nontherapeutic levels can suppress innate (Th1) and increase adaptive
(Th2) immunity—the so-called Th1 to Th2 shift; several factors influence
this complex physiology and include long-term adaptations, reproductive
hormones (i.e., overall, androgens suppress and estrogens stimulate
immune responses), defects of hypothalamic-pituitary-adrenal axis,
histamine generated responses, and acute vs. chronic stress; thus stress
seems to cause a Th2 shift systemically whereas locally, under certain
conditions, it can induce proinflammatory activities and by these
mechanisms may influence onset or course of infections and
autoimmune/inflammatory, allergic, and neoplastic diseases
PHYSIOLOGIC EFFECTS OF CORTISOL (cont.)
Digestive function
Promotes gastric secretion
Lipid metabolism
Lipolysis in extremities and lipogenesis in face and trunk
Urinary function
Enhances excretion of calcium
Connective tissue
function
Muscle function
Decreases proliferation of fibroblasts in connective tissue
(thus delaying healing)
Maintains normal contractility and maximal work output for
skeletal and cardiac muscle
Bone function
Decreases bone formation
Vascular
Maintains normal blood pressure; permits increased
system/myocardial responsiveness of arterioles to constrictive action of
function
adrenergic stimulation; optimizes myocardial performance
Central nervous
system function
Somehow modulates perceptual and emotional functioning;
essential for normal arousal and initiation of daytime activity
Possible synergism Suppresses maternal immune system to prevent rejection of
with estrogen in fetus?
pregnancy?
Levels of cortisol and melatonin cycle
throughout the day
“Trier Social Stress Test” (TSST). The researchers asked
the participants to conduct a 5-minute speech task and a 5minute mental arithmetic task in front of an audience.
Effect of Corticotropin-Releasing Hormone (CRH)—Mast
Cell—Histamine Axis, Cortisol, and Catecholamines
on the Th1/Th2 Balance—Innate and Adaptive Immunity.
3 phase: Somatotropin +
Thyrotropin
• ST  somatomedin insulin resistance  
Glucose+FFA
• TT T3+T4  sensitivity of tissues to
Epi+NorEpi  Energy production 
 heart contractility 
 blood pressure

OTHER HORMONES THAT INFLUENCE
THE STRESS RESPONSE
β-Endorphins (endogenous opiates)
Pituitary and hypothalamus
Growth hormone (GH, somatotropin)
Anterior pituitary gland
Oxytocin Hypothalamus
Testosterone Leydig cells in testes
Estrogen Ovaries
Substance P (SP) Produced by a
neuropeptide classified as tachykinin
(increases heart rate subsequent to
lowering blood pressure) found in brain, as
well as nerves innervating secondary
lymphoid tissues
Activates endorphin (opiate) receptors on peripheral sensory nerves, leading to
pain relief or analgesia Hemorrhage increases levels to inhibit blood pressure or
delay compensatory changes that would increase blood pressure1
Affects protein, lipid, and carbohydrate metabolism Counters effects of insulin
Involved in tissue repair May participate in growth and function of immune system 2
Levels increase after a variety of stressful stimuli (cardiac catheterization,
electroshock therapy, gastroscopy, surgery, fever, physical exercise) Increased
levels associated with psychologic stimuli (taking examinations, viewing violent or
sexually arousing films, certain psychologic performance tests) Prolonged stress
(chronic stress) suppresses growth hormone
Promotes bonding and social attachment In animals associated with reduced
hypothalamic-pituitary-adrenal (HPA) activation levels and reduced anxiety4
Regulates male secondary sex characteristics and libido Levels decrease after
stressful stimuli (anesthesia, surgery, marathon running, mountain climbing)5
Decreased by psychologic stimuli; however, some data indicate that psychologic
stress associated with competition (e.g., pistol shooting) increases both
testosterone and cortisol levels, especially in athletes older than 45 years6
Markedly reduced in individuals with respiratory failure, burns, and congestive heart
failure7 Decreased levels occur during aging and are associated with a lower
cortisol responsiveness to stress-induced inflammation8
Works in concert with oxytocin, exerting a calming effect during stressful situations9
SP increases in response to stress; receptors for SP are found on membranes of
both T and B cells, mononuclear phagocytic cells, and mast cells; proinflammatory
activity induces release of histamine from mast cells during stress response;
causes smooth muscle contraction, causes macrophages and T cells to release
cytokines, and increases antibody production
OTHER HORMONES THAT INFLUENCE
THE STRESS RESPONSE
Melatonin Produced by pineal gland
Increases during stress response; release is suppressed by light and increased in
the dark; receptors have been identified on lymphoid cells, possibly higher density
of receptors on T cells than B cells; suppression of lymphocyte function by trauma
was reversed by melatonin10
Prolactin Anterior pituitary gland;
numerous extrapituitary tissue sites
Increases in response to many stressful stimuli (including procedures such as
gastroscopy, proctoscopy, pelvic examination, and surgery)3 Requires more
intense stimuli than those leading to increases in catecholamine or cortisol levels
Levels show little change after exercise
Somatostatin (SOM) Produced by
sensory nerve terminals found in and
released from lymphoid cells and
hypothalamus
Vasoactive intestinal peptide (VIP) Found
in neurons of central nervous system
(CNS) and in peripheral nerves
Natural killer (NK) function and immunoglobulin synthesis are decreased by SOM;
growth hormone secretion decreased by SOM
Calcitonin gene–related peptide (CGRP)
Found in spinal cord motor neurons and
in sensory neurons near dendritic cells of
skin and in primary and secondary
lymphoid tissues
CGRP receptors are present on T and B lymphocytes; thus it is likely that CGRP
can modulate immune function; CGRP may enhance acute inflammatory
response because it is a vasodilator; maturation of immune B lymphocytes is
inhibited by CGRP; IL-1 is inhibited by CGRP, which is important for activation of
T cells; it has been shown to interfere with lymphocyte activation
Neuropeptide Y (NPY) Present in
neurons of CNS and in neurons
throughout body; co-localized in nerve
terminals in lymphatic tissues with
norepinephrine
Lymphocytes have receptors for NPY and thus may modulate their function; 11
several lines of evidence suggest that NPY is a neurotransmitter and
neurohormone involved in stress response; increased levels of NPY occur in
plasma in response to severe or prolonged stress; it may be responsible for
stress-induced regional vasoconstriction (splanchnic, coronary, and cerebral); it
may also increase platelet aggregation2
VIP increases during stress; VIP-containing nerves are located in both primary
and secondary lymphoid tissues, around blood vessels, and in gastrointestinal
tract; VIP receptors are on both T and B cells; VIP may influence lymphocyte
maturation; cytokine production by T cells is modified by VIP; B cells and antibody
production are influenced by VIP
Stress-limiting systems
Reduce the intensity of their effects on
target organs. These mechanisms include:
• GABA-ergic system
• Endogenous opioids
• Prostaglandins,
• Antioxidant system and
• Parasympathetic nervous system.
Factors, affecting adaptation to stress
Diagnosis of Stress
• Heart rate variability testing - defines the state of
stress regulatory systems by measuring RR
intervals during long time (>5 min)
• The content in blood / urine / saliva of:
glucocorticoids / catecholamines and their
metabolites
• The questionnaires and inventories, scales
to determine anxiety and anxiety
Psychosomatic diseases
Psychologic stress may cause or exacerbate
(worsen) several disease states, which are
called PSYCHOSOMATIC (≠in ICD10 or DSM-V)
In 1950 Alexander published a work that described seven
conditions thought particularly to have a psychosomatic aspect.
These were reverently referred to as the "Holy Seven" in the
following years.
1) gastric ulceration, 2) ulcerative colitis,
3) bronchial asthma, 4) essential hypertension,
5) eczema,
6) hyperthyroidism and
7) rheumatoid arthritis
Psychoneuroimmunology
• 1975 - The possibility of conditional reflex
regulation of the immune system
• The animals were given water with
saccharin and immunosuppressants,
producing a conditioned reflex.
• After a while immunosuppression observed
when giving water with saccharin, even
without immunosuppressive drugs
http://www.stress.org/stress-effects/
50 common signs
and symptoms of stress
1. Frequent headaches, jaw clenching or pain
2. Gritting, grinding teeth
3. Stuttering or stammering
4. Tremors, trembling of lips, hands
5. Neck ache, back pain, muscle spasms
6. Light headedness, faintness, dizziness
7. Ringing, buzzing or “popping sounds
8. Frequent blushing, sweating
9. Cold or sweaty hands, feet
10. Dry mouth, problems swallowing
11. Frequent colds, infections, herpes sores
12. Rashes, itching, hives, “goose bumps”
13. Unexplained or frequent “allergy” attacks
14. Heartburn, stomach pain, nausea
15. Excess belching, flatulence
Stress-related diseases
Stress-related disease
Stress  Pain
Symptoms of TMJ problems
Some people notice that when stressed,
they grind their teeth - particularly at night and this can put pressure on the TMJ.
The usual symptoms of TMJ problems are
pain, which may be felt as earache, clunking
of the jaw, or limitation of movement,
causing difficulty in opening the mouth.
Other symptoms that may arise are swelling
of the joint, headaches, neck pain and
tinnitus.
Psychosocial factors in TMJ dysfunction
• Emotional stress (anxiety, depression, anger) may increase pain by
causing autonomic, visceral and skeletal activity and by reduced
inhibition via the descending pathways of the limbic system.
• The interactions of these biological systems have been described as
a vicious "anxiety-pain-tension" cycle which is thought to be
frequently involved in TMD.
• stress and anxiety  grinding of teeth + sustained muscular
contraction in the face  pain  further anxiety  prolonged
muscular spasm at trigger points+ vasoconstriction, ischemia and
release of pain mediators.
• The pain discourages use of the masticatory system (a similar
phenomenon in other chronic pain conditions is termed "fear
avoidance" behavior), which leads to reduced muscle flexibility,
tone, strength and endurance. This manifests as limited mouth
opening and a sensation that the teeth are not fitting properly
•
https://en.wikipedia.org/wiki/Temporomandibular_joint_dysfunction
Personal traits TMJD
• Persons with TMD have a higher prevalence of
psychological disorders than people without TMD.
People with TMD have been shown to have higher levels
of anxiety, depression, somatization and sleep
deprivation, and these could be considered important
risk factors for the development of TMD. In the 6 months
before the onset, 50–70% of people with TMD report
experiencing stressful life events (e.g. involving work,
money, health or relationship loss). It has been
postulated that such events induce anxiety and cause
increased jaw muscle activity. Muscular hyperactivity has
also been shown in people with TMD whilst taking
examinations or watching horror films.
•
https://en.wikipedia.org/wiki/Temporomandibular_joint_dysfunction
Mouth Ulcers
The exact cause of most mouth ulcers is unknown. Stress or
tissue injury is thought to be the cause of simple mouth ulcers.
http://www.webmd.boots.com/oral-health/guide/mouth-ulcers
Stress ulcer
• - single or multiple mucosal defects which
can become complicated by upper
gastrointestinal bleeding during the
physiologic stress of serious illness.
Ordinary peptic ulcers are found
commonly in the gastric antrum and the
duodenum whereas stress ulcers are
found commonly in fundic mucosa and can
be located anywhere within the stomach
and proximal duodenum.
Psychological Stress 
Inflammation
• Appels A. 2000 - anxiety and depression cause
increased production of inflammatory cytokines,
particularly IL-6 (the level of which is
prognostically important in morbidity, mortality,
aging).
• During anxiety disorders the number of
receptors for IL-2 is reduced in lymphocytes 
an increase in sick days due to acute respiratory
infections (La Via MF 1996).
Connection between psychology
and specific immunity
• Kemeny M, 1989 Depressive symptoms
are associated with a decrease in the
number of T-helper cells which provide Tcell immunity (MD-8) that is developed to
increase the frequency of herpes relapse
after 6 months.
Stress and immunity
• Students who responded to the session with
more anxiety, more often demonstrated lack of
response to immunization against hepatitis B.
• During the session wound on the oral mucosa
healed by 40% longer.
• In individuals who care for disabled immunity
disorders can last for years. E.g. level of
antibodies against pneumococcus is falling
faster after immunization
Stress and leukocytes
• Studying the effect of stressful intensive care
unit (ICU) shifts on medical residents, biologist
Matthias Nahrendorf of Harvard Medical School
in Boston recently found that blood samples
taken when the doctors were most stressed out
had the highest levels of neutrophils and
monocytes.
http://www.sciencemag.org/news/2014/06/how-stress-can-clog-your-arteries
Stress and atherosclerosis
In mice living with chronic stress, (Nahrendorf)
atherosclerotic plaques more closely resemble
plaques known to be most at risk of rupturing and
causing a heart attack or stroke. When the
scientists blocked the β3 adrenoreceptor, though,
stressed mice not only had fewer of atherosclerotic
plaques, but also had reduced levels of the active
immune cells in their plaques, pinpointing β3 as a
key link between stress and atheroscelerosis
http://www.sciencemag.org/news/2014/06/how-stress-can-clog-your-arteries
Iatrogenic disease
• Iatrogenic disease is defined as any medical,
therapeutic, diagnostic, or prophylactic action
that, unintentionally, causes symptoms that need
treatment, call for hospital admission, increase
hospital stay, cause permanent incapacity or
injury, or lead to death.
• Can you propose some examples?
The diseases we cause: Iatrogenic illness in a department of internal
medicine Sofia Madeira, Miguel Melo, João Porto, Sílvia Monteiro, J.M. Pereira de
Moura, M.B. Alexandrino J.J. Alves Moura
European Journal of Internal Medicine 18 (2007) 391–399
Causes of iatrogenesis include:
• side effects of possible drug interactions
• complications arising from a procedure or
treatment
• medical error
• negligence
• unexamined instrument design[clarification
needed]
• anxiety or annoyance in the physician or
treatment provider in relation to medical
procedures or treatments
• unnecessary treatment for profit
Additional sources
http://www.stress.org/education/
http://www.drlam.com/articles/adrenalexhaustion.asp
1. Amico JA et al: J Neuroendocrinol 16(4):319–324, 2004.
2. Rabin BS: The nervous system—immune system connection. In Stress,
immune function, and health: the connection, New York, 1999, Wiley-Liss.
3. Rohleder N et al: J Neuroimmunol 126(1-2):69–77, 2002.
4. Marucha PT, Kiecolt-Glaser JK, Favagehi M: Psychosom Med 60(3):362–
365, 1998.
5. Chesnokova V, Melmed S: Endocrinology 143(5):1571–1574, 2002.
6. Guezennec CY et al: Int J Sports Med 16(6):368–372, 1995.
7. Bauer-Wu SM: Clin J Oncol Nurs 6(3):167–170, 2002.
8. Bauer-Wu SM: Clin J Oncol Nurs 6(4):243–246, 2002.
9. Repka-Ramirez MS, Baraniuk JN: Clin Allergy Immunol 17:1–17, 2002.
10. Maestroni GJ: Adv Exp Med Biol 460:396, 1999.
11. Petito JM, Huang Z, McCarthy DB: J Neuroimmunol 54:81, 1994.
Thank you for
attention!