Stress: An Overview of its Overwhelming Physiological
Effects
Presented by: Dr. Ron Grabowski, R.D., D.C. February, 2019
Objectives Participants will be able to correlate how stress affects
cholesterol and blood pressure.
Participants will be able to diagnose nutritional deficiencies and
treat comorbidities associated with stress.
Participants will learn specific Nutrient-Drug Interactions that
impact our health.
Definition Stress as a specific medical term was first defined by the
endocrinologist Hans Selye in 1936 as the physiological
adaptive responses to perceived (psychological) or real
(physical) threats (“stressors”) to an organism. J Physiol Pharmacol 2011; 62:591-599
Exp Neurol 2012; 233: 49-67
50 Common Signs and Symptoms of Stress
(The American Institute 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
16. Constipation, diarrhea, loss of control
17. Difficulty breathing, frequent sighing
18. Sudden attacks of life threatening panic
19. Chest pain, palpitations, rapid pulse
20. Frequent urination
21. Diminished sexual desire or performance
22. Excess anxiety, worry, guilt, nervousness
23. Increased anger, frustration, hostility
24. Depression, frequent or wild mood swings
25. Increased or decreased appetite
26. Insomnia, nightmares, disturbing dreams
27. Difficulty concentrating, racing thoughts
28. Trouble learning new information
29. Forgetfulness, disorganization, confusion
30. Difficulty in making decisions
31. Feeling overloaded or overwhelmed
32. Frequent crying spells or suicidal thoughts
33. Feelings of loneliness or worthlessness
34. Little interest in appearance, punctuality
35. Nervous habits, fidgeting, feet tapping
36. Increased frustration, irritability, edginess
37. Overreaction to petty annoyances
38. Increased number of minor accidents
39. Obsessive or compulsive behavior
40. Reduced work efficiency or productivity
41. Lies or excuses to cover up poor work
42. Rapid or mumbled speech
43. Excessive defensiveness or suspiciousness
44. Problems in communication, sharing
45. Social withdrawal and isolation
46. Constant tiredness, weakness, fatigue
47. Frequent use of over-the-counter drugs
48. Weight gain or loss without diet
49. Increased smoking, alcohol or drug use
50. Excessive gambling or impulse buying
Aldosterone Synthesis
JRSM Cardiovasc Dis. 2014 Jan-Dec.
Cholesterol and Aldosterone
JRSM Cardiovasc Dis. 2014 Jan-Dec;
Aldosterone Aldosterone has shown to increase the excretion of
magnesium in both urine and feces, and that this could lead to
a severe depletion of muscle magnesium.
BMJ - 1963
Brain-Gut Axis Brain conveys the neural, endocrine and circulatory messages
to the gut via brain-gut axis reflecting changes;
Corticotrophin Releasing Hormone (CRH)
Mast cells activity
Neurotransmission at the autonomic nerves system
Intestinal barrier function
All affecting the pathogenesis of colitis and human IBD.
Brain-Gut Axis The effect of stress on inflammatory bowel disease (IBD) might
be mediated by autonomic nervous system and hypothalamic
pituitary adrenal axis.
These nervous pathways are part of the so called "brain-gut
axis" which links gastrointestinal integrity and functions to
central nervous system acting through the increase
of intestinal permeability, bacterial translocation and cytokines
network.
Curr Pharm Des. 2017 Feb 28
IBS Irritable bowel syndrome (IBS) is a chronic continuous or
remittent functional gastrointestinal (GI) disorder affecting,
statistically, 11.2% of the global population. Clin Gastroenterol Hepatol 2012; 10: 712-721.e4
Impact of Psychological Stress on
Irritable Bowel Syndrome (IBS) Currently non-pharmacological approaches and
pharmacological strategies that target on stress-related
alterations;
Antidepressants
Antipsychotics
Miscellaneous agents
5-HT synthesis inhibitors
Selective 5-HT reuptake inhibitors
World J Gastroenterol.2014 Oct 21;20(39):14126-31
Psychological Stress and NSAIDs Psychological stress exacerbates NSAID enteropathy and
increased intestinal permeability.
Psychological stress has shown to induce changes in the ileal
microbiota that were characterized by increases in the total
number of bacteria and the proportion of Gram-negative
bacteria.
J Gastroenterol.2017 Jan;52(1):61-71.
Human Studies – Stress
Glutamine Levels Decrease:
Surgery
Starvation
Severe burns
Trauma
Severe infections
Psychological stress
Exercise
Significant reduction in L-Glutamine concentrations in the
muscle.
Hypothalamus-Pituitary Axis Stress triggers the hypothalamus-pituitary axis and the
activation of the autonomic nervous system;
Increases
Cortisol levels
Proinflammatory cytokines such as tumor necrosis factor-alpha,
interleukin-8, interleukin-1beta and interleukin-6.
Curr Neuropharmacol. 2016;14(8):892-900
Hippocampus The hippocampus is vulnerable to zinc deficiency and
neuropsychological symptoms associated with enhanced HPA axis
activity are observed in zinc-deficient animals.
J. Neurosci. Res. 2001, 63, 447–452.
Brain Res. Rev. 2009, 62, 33–34.
The hippocampus is a major target of glucocorticoids and is
enriched with corticosteroid receptors.
Mol. Neurobiol. 2011, 44, 167–174
Eur. J. Pharmacol. 2008, 583, 312–321
Glucocorticoid receptors are markedly activated after exposure
to stress.
Trends Neurosci. 2008, 31, 1–7.
Zinc & HPA Zinc deficiency elevates the hypothalamo-pituitary-
adrenocortical (HPA) axis activity, followed by an increase in glucocorticoid secretion from the adrenal cortex, which is involved in stress response.
J. Am. Coll. Nutr. 1995, 14, 11–17.
J. Nutr. 2002, 132, 974–979.
J. Am. Med. Assoc. 1992, 267, 1244–1252.
The continuous increase in plasma corticosterone concentration is observed after daily administration of a zinc-deficient diet.
Behav. Brain Res. 2007, 177, 1–6.
Life Sci. 2008, 82, 909–914.
Metabolic Syndrome Abdominal obesity
Insulin resistance
Dyslipidemia
Hypertension
In the US, over 40% of people older than 60 years suffer
from metabolic syndrome.
Magnes Res 2006; 19: 237-43.
Arch Biochem Biophys 2007; 458: 40-7.
Magnes Res 2007; 20: 107-29.
Visceral Fat Stress induced HPA axis activation has been identified to play
an important role in this preferential body fat accumulation
and to stimulate the proinflammatory cytokine secretion by
adipocytes that hold a potentially important pathogenic role. J Allergy Clin Immunol 2005; 115: 911-9.
Metabolic Syndrome and Magnesium
Patients with metabolic syndrome have shown to have lower
intramononuclear cell Mg concentration (which may provide
reliable information about intracellular Mg concentration) as
compared to controls. Am J Hypertens 1993; 6: 123S-134S.
Diabetes Res Clin Pract 2009; 83: 257-62.
Magnesium & Metabolic Syndrome Mg deficiency contributes to other aspects of the metabolic
syndrome:
Hyperlipidemia
Elevated blood pressure
Endothelial dysfunction
Increased thrombosis tendency
Magnes Res 2006; 19: 237-43.
Magnesium Deficiency Modulates
Stress and Inflammation
Mg supplementation has been shown to reduce CRP blood
levels in patients with heart failure. Curr Opin Lipidol 2008; 19: 50-6.
Mg deficiency results in a stressor effect and increases
susceptibility to the physiological damage produced by stress. Artery 1981; 9: 182-9.
J. Magnesium in clinical practice. London: John Libbey.
Renin-Angiotensin-Aldosterone There is growing evidence that enhanced activation of the
renin-angiotensin-aldosterone system is a factor in the
development of insulin resistance, by increasing oxidative
stress.
Stress and NMDA A stress response induces the release of large quantities of
excitatory amino acids, such as aspartate and glutamate.
Released glutamate can bind to different receptors, and N-
methyl-D-aspartic acid (NMDA) activation also causes the
mobilization of free cytosolic Ca.
Mg deficiency in rats induces hyperalgesia involving NMDA
receptors.
Br J Pharmacol 2001; 134: 1227-36.
Endothelium One of the earliest events in the acute response to stress is
endothelium dysfunction.
Endothelial cells actively contribute to inflammation by
elaborating cytokines.
Mg may suppress inflammatory responses by human
endothelial cells through the NFκB pathway.
Front Biosci 2005; 10: 1177-82.
Biochim Biophys Acta 2004; 1689: 13-21.
J Reprod Immunol 2007; 73: 101-7.
Pantothenic Acid Vitamin B5
Anti-grey hair factor
Anti-stress factor
Water regulator (Hyperhidrosis)
Pantothenate
Calcium Pantothenate
Physiological Function
(Pantothenate) Gastrointestinal/Biliary:
Bile production
Metabolic:
As component of Acetyl CoA
It is necessary for the synthesis and metabolism of
fatty acids
Water metabolism regulator
Component of energy storage and release
Essential for production of energy from CHO, fat, and
protein.
Functions in protein modification.
Nervous: Required for myelin sheath formation.
Respiratory: Respiratory pigment synthesis
Stress and Methylation Stress, an anxiety component, induces an increase in adrenal
catecholamines, which increases the demand for methylation
reactions required in norepinephrine and adrenaline synthesis. Lancet 1982
Synthesis of biogenic amines may increase the demand for one-
carbon units for methionine synthesis, derived from choline, as
well as folate-dependent pathways.
Vitamin B12 Vitamin B12 deficiency has been linked to psychiatric
disorders;
Impaired memory
Irritability
Depression
Dementia
Psychosis (rare) Wintrobe's Clinical hematology. 10th ed. Baltimore: Williams & Wilkins, 1999
N Engl J Med. 1988.
Study In a large study of 406 patients with known vitamin B12
deficiency,
98.4 percent had elevated serum methylmalonic acid levels.
95.9 percent had elevated serum homocysteine levels
(defined as three standard deviations above the mean).
Only one patient out of 406 had normal levels of both
metabolites, resulting in a sensitivity of 99.8 percent when
methylmalonic acid and homocysteine levels are used for
diagnosis.
28 percent of the patients in this study had normal
hematocrit levels, and 17 percent had normal mean
corpuscular volumes. Am J Med. 1994
Pyridoxine and Neurotransmitters
Dopamine
Norepinephrine
Serotonin
Tyramine
Tryptamine
Taurine
Histamine
Gamma aminobutyric acid (GABA)
Choline and Anxiety In a large population–based study (5918) of the Hordaland
Health Study, including both sexes and 2 age groups of 46–49
and 70–74 y, choline concentrations were negatively
associated with anxiety symptoms but not with depression
symptoms.
Fatty Acid Composition There is a large body of evidence showing that fatty acid
composition influences the biophysical properties of neuronal
membranes. Prog Clin Biol Res 1988
Fatty acids effects;
Receptor function
Neurotransmitter reuptake
Signal transmission
In animal models of depression, diet has been shown to
influence membrane properties, eg, n-3 PUFA–enriched food
augments serotonin receptor sensitivity. AJCN - 1995
Long-chain PUFAs and
the Human Brain The n–3 and n–6 PUFAs comprise 14% and 17% of the total
FAs in the human brain and are predominantly DHA and
arachidonic acid (AA; 20:4n–6), respectively.
Saturated FAs account for nearly one-third of all FAs;
monounsaturated FAs and other PUFAs account for the
remainder. Prostaglandins Leukot Essent Fatty Acids 2006
Both DHA and AA accumulate rapidly in neural tissues during
the brain growth spurt that occurs during gestation and the
first year of life.
AJCN-2009
Omega-3 Fatty Acids Higher n-3 PUFA concentrations lead to higher membrane
fluidity, which in turn increases serotonin transport. Am J Clin Nutr 1995 and Am J Physiol 1992
Both inflammation and atherosclerosis have been associated
with depression and could link fatty acids and depression.
Biol Psychiatry 1998
J Affect Disord 1996
n-3 vs n-6 Fatty Acids DHA and EPA can be synthesized from the parent n–3 FA alpha-
linolenic acid (ALA) in the liver through a series of elongation and desaturation steps.
There has been recent concerns that the efficiency of this process may be low (8%) because both n–6 and n–3 FAs share and compete for the same enzymes that are used for desaturation and elongation.
n-6 FAs such as linoleic acid are widely present in vegetable oils, seeds, nuts, margarine, grains, eggs, and some meats, whereas n–3 polyunsaturated FAs (PUFAs) are found primarily in canola and soybean oil, flaxseed, walnuts, eggs, some meats, and cold water fish. Am J Clin Nutr 2006
Intakes of n–6 FAs have increased, resulting in a high ratio of n–6:n–3 FA intakes in the diet that may be associated with an increased risk of mental health disorders. Biol Psychiatry 2005 and Am J Clin Nutr 2000