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.

Disclaimer Consultant for SpectraCell Laboratories, Houston, Texas

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

Types of Stress

Psychological

Physical Oxidative

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

Stress HPA and SNS

Norepinephrine

Epinephrine

Cortisol

Renal

Renin

Angiotensin

Aldosterone

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

Psychological Stress and GI Tract Intestinal sensitivity

Motility

Secretion

Permeability

Microbiota

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.

Aldosterone and Insulin Resistance

Ann Intern Med. 2009 Jun 2; 150(11): 776–783.

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.

Stress

Pre-Presidency Presidency

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

DHA and Depressive Disorders

AJCN-1/2009

CASE STUDIES

50 year old

Female

Hx: High stress,

depression, and

anxiety

Meds: Zoloft and

Xanax

50 year old

Female

Med Hx: High

stress,

depression, and

anxiety

Meds: Zoloft and

Xanax

50 year old

Female

Med Hx: High

stress,

depression, and

anxiety

Meds: Zoloft and

Xanax

Male

Age: 28

Professional

athlete

Good case for

ordering MTHFR

test

Male

Age: 28

Questions & Answers