CCNM 2021 Dr. Saunders Adrenal and Thyroid Testing PDF

Lab Series: Adrenal and Thyroid Testing Paul Richard Saunders, PhD, ND, R HOM Canadian College of Naturopathic Medicine Canadian College of Homeopathic Medicine National University of Health Sciences Dundas Naturopathic Centre September 27, 2021...

Lab Series: Adrenal and Thyroid Testing Paul Richard Saunders, PhD, ND, R HOM Canadian College of Naturopathic Medicine Canadian College of Homeopathic Medicine National University of Health Sciences Dundas Naturopathic Centre September 27, 2021  Outline Adrenal Pathway Hormones Addison Cushing Adrenal Fatigue and Support Thyroid Pathway Hormones Hypothyroid Hashimoto Thyroiditis Subclinical hypothyroid Thyroid Cancer Hyperthyroidism Graves Thyroid support Adrenal Pathway  Cholesterol Adrenal cortex---largest portion of the gland Zona glomerulosa---aldosterone, mineralocorticoid; renin-angiotensin system, requires Ca, stimulated by ACTH from anterior pituitary Zona fasciculata---glucortocoids: 11-deoxycorticosterone, corticosterone, cortisol; release contolled by ACTH from anterior pituitary Zona reticularis---androgens, DHEA sulfate, androstenedione, testosterone; release is stimulated by ACTH from anterior pituitary Cholesterol---stored in vesicles, but also synthesized de novo in adrenal cortex; from circulating lipoproteins; cholesterol to pregnanalone to progesterone to aldosterone  Cholesterol---stored in vesicles, but also synthesized de novo in adrenal cortex; from circulating lipoproteins; Endocrin Integ:Adrenal.2001. 300 mg from diet, 600 mg synthesized qd; LDL + HDL cholesterol to pregnenolone to progesterone to aldosterone Pregnenolone to 17-OH pregnenolone to cortisol Pregnenolone to 17-OH pregnenolone to DHEA to estrone (E1) Pregnenolone to 17-OH pregnenolone to DHEA to androstenediol to testosterone to estradiol (E2) Cortisol Progesterone DHEAS (sulfated) Estrone, E1 One OH group Estradiol, E2 Estriol, E3 Testosterone Vitamin D Digitalis spp. Glycyrrhizin  Panax quinquefolius protopanaxadiol  Dihydrotestosterone (DHT)--- Metabolite of testosterone---male characteristics Binds more tightly to androgen receptors May be elevated in women with hair loss, hirsutism, PCOS, post- chemotherapy,….  Test Options--- Cholesterol---whole panel Cortisol--- saliva (2-5 points) serum AM and PM (2 points, same day) DHEA, DHEA-S Aldosterone Progesterone Estradiol Testosterone DHT Electrolytes  DHEA Lab Value Clin Endocrin.1998;49(4):421-432. Clin Endrocrin.200;53(5):561-568. J Urban Health.2019;96:632-643. Mid-range or above Low DEHA in Female---pituitary, Hirsutism Deeper voice Irregular menstruation Acne Vertex hair loss Increased muscularity Obesity in victimized African-North Americans Long-term cancer risk  Males Acta Cardiol.2003;58(5):403-410. Cancer Epid Biom Prev.2000;139:5-7, 73-89. Crit Care.2015;19(1):231. Ann Epidemiol.2006;16(7):510-515. Cardiovascular Dz Colon CA Subarachnoid aneurysm Aging  Adrenal Insufficiency---Addison Disease J Intern Med.2009;265(5):514-529. Deficiency of cortisol Deficiency of aldosterone Abdominal pain, vomit, muscle weakness, fatigue, mood and personality changes, low BP, tanned patches, goitre, vitiligo, eosinophilia Addison originates in adrenal gland---80% autoimmune, 20% idiopathic Adrenal insufficiency may also arise from pituitary, lack of ACTH or Corticotropic Releasing Hormone (CRH), or both; Sheehan Syn-necrosis at childbirth or CRH from brain tumor, withdrawal from steroids  Cortisol Roles Reprod Fertil Devel.1994; 6:1412-150. Regulate glucose Regulate metabolism Reduce inflammation Memory formation Salt-water balance and thus BP Fetal development during pregnancy---LU maturation-surfactant; LV gluconeogenesis; Gut maturation; Thyroid--tri-iodothyronine; catecholamines for labor, delivery, life outside the uterus; KI maturation; Nerve maturation  Addison #1 cause in the developed world Endocrinol.1955;56(1):24-29. Arch Biochem Biophys.1952;36(1):237-239. J Intern Med.2009;265(5):514-529. Destruction of adrenal cortex against enzyme 21-hyroxlyase or CYP450c1, 1922 Biosynthesis of aldosterone and cortisol from progesterone, from CYP21A2 Other organs may be affected---thyroid, pancreas Adrenal Destruction---adrenal-leukodystrophy metastasis---LU cancer, Hemorrhage Infection---TB, histoplasmosis, coccidioidomycosis Amyloidosis  Adrenal Insufficiency Risks Robbins Pathology,2019. NIH.2007. No 90-3054. Ann Intern Med.2009;51:350-354. TB, AIDS, metastatic cancers Amyloidosis, fungal infection, hemochromatosis, sarcoidosis Type 2 autoimmune polyglandular syndrome---T1D, hyperthyroid/Graves, hypothyroid/Hashimoto, and may include hypogonadism, premature ovarian failure, celiac, autoimmune gastritis, pernicious anemia Steroids > 1 week suppress adrenal function---  Steroids > 1 week suppress adrenal function Inj Proced.2010.ISBN.9780387765952. Joint Bone Spine.2010.doi.10.1016/j.bspin.2009.12.010. glucocorticoids suppress CRH and ACTH over time the glands atrophy (shrink in size) recovery can take months Stress---physical, illness, emotional can lead to adrenal insufficiency Steroid joint injections can have similar effect Genetic mutations are rare---DAX-1, Triple A, glycerol kinase deficiency Smith-Lemli-Opitz Syn—impaired delivery of cholesterol, impaired absorption of fat & fat-soluble vitamins from diet  Lab Findings to Assist In the Probable Origins JAMA.2005;294(19):2528. J Clin Endocrin.2001.doi.10.1210/jc.86.7.2909. Hypothalamus (3rd) All low---CRH, ACTH, DHEA, DHEA-s, cortisol, aldosterone, renin, Na, K Pituitary (2nd) Low---ACTH, DHEA, DHEA-S, cortisol, renin, Na High---CRH Normal---aldosterone, K Adrenal (1st) Low---cortisol, aldosterone, Na High---CRH, ACTH, DHEA, DHEA-S, renin, K  Cushing Syndrome Endocrin Metab Clin.2011;40(2):379-391. Prolonged glucocorticoid exposure, elevation Presentation---high BP, abdominal obesity with thin legs and arms, stretch marks, round reddish face, adipose lump between shoulder blades, weak muscles, weak bones, acne, fragile or slow to heal skin Women---hirsutism, irregular menstruation Other—changeable mood, headaches, chronic fatigue sx Medications---chronic prednisone, pituitary tumor, ectopic tumors  Cushing Test Steps Neuroendocrin.2010.82.Suppl 1:1-5. Review medications Cortisol in urine, saliva or blood Dexamethasone suppression test or 24 h urine cortisol If abnormal then night cortisol If night cortisol elevated, then ACTH CT adrenal, MRI pituitary (may be < 2 mm diameter) 2-3 per million per year; esp. 20-50 yo; Female:Male (3:1) Harvey Cushing, MD, 1932, Am Neurosurgeon Occurs in cats, dogs, horses  Other Signs and Symptoms Am J Med.2005;118(12):1340-1346. Insomnia Reduces libido Impotence—male Amenorrhea Oligomenorrhea Infertility Metabolic syndrome---hyper pigmentation of skin folds (acanthosis nigrians), Ht Dz, Insulin resistance Hypertension Obesity Elevated triglycerides Depression and anxiety Increased urination + increased thirst high Na, low K Osteoporosis True Cushing rare; “Clinical Cushing” common  Adrenal Fatigue Adrenal Fatigue Allergy Asthma Proc.2012;33 Suppl 1(3):S100-102. Sci Based Med.2010.Oct 28. S Afr Med J.2018;108(9):724-725. BMC Endocrin Disord.2016;16(1):48. Pseudo science term of alternative medicine from ~1998 2016 Systematic Review 3470 articles 58 studies accepted---33 in healthy, 25 in symptomatic Conflicting results Heterogenous studies Poor quality of assessments Terms not endorsed by endocrinologists False premises Inappropriate/invalid conclusions NOT a medical condition It is still a myth  Adrenal Nutrition---Testable Options Vitamin C B5 B6 Zinc, Zn RBC Magnesium, Mg RBC Thyroid Pathway  Thyroid – Adrenal Relationship Townsend Lett.2021.454:44-49. Adrenals are essential to human metabolism Thyroid sets the thermostat of our metabolism Adrenal is the furnace Decreased adrenal leads to long-term hypothyroidism If the thyroid is corrected, adrenal demands usually increase Thus---treat adrenal and thyroid together, concurrently Risks of thyroid treatment---increased fertility, menstrual cycles resume/improve, allergies may be more prominent  Lab Tests--- Townsend Lett.2021.454:44-49. TSH Free T4 Free T3, total T3 Reverse T3, rT3 Antibodies---TPO-Ab, Tg-Ab, TR-Ab, TSI (LATS), THS-Ab Timing---midway between Thyroid dosing or fasting or consistent by patient; i.e. mid-dose Basal (axilla) temperature---indicative of low metabolic rate, not diagnostic Retest if treating---3 months, 6 months; 12 months if stable  Thyroid Antibodies--- Rarely return to normal Vary with time, diet, life stressors TPO, Tg-Ab---suggestive of Hashimoto TPO, TSH-Ab---suggestive of Graves, Graves can have Ab of Hashimoto  Thyroid Stimulating Hormone, TSH 6 h ½ life Median TSH is 1.5, reference range + 2 standard deviations or 0.4 – 2.9; yet often 4.5 or 5.0; Ontario do not treat until 10.0; statistically 3.0 is elevated TSH! Adult guidelines are to treat if > 10; subclinical is 5-10 TSH and low free T4 Children---0.4 – 2.0 T2, 3,5-Diodothyronine  T4, Tetraiodothyrine Pre-hormone Prin Pract Med.1901.W Osler.p.843. ½ life 6-7 days Peaks 3 h after one dose, thus > q 12 h dosing; Wm. Osler, MD, dosed desiccated q 8 h in 1901 Malabsorption of T4 is statistically insignificant, rarely clinically significant If not Ab then T4 is nutritional support, if thyroiditis, progressive dose changes must be monitors and adjusted as necessary Pregnancy---can double T4 and T3 requirements, Monitor! Some 16% do poorly on just T4 therapy---daily T4 if too high can elevate rT3  T3, Triiodothyronine Active hormone ½ life of 24-48 h, peaks at 2.5 h, lowest at 12 h Thermostat of metabolism Effect ~ 4x that of T4, but only 1/40 that of T4 levels  T3 Roles SSRI + T3 refractory depression, bipolar II Increases serotonin in the brain Increases rate of protein turnover Fetal and infant development Blood pressure, pulse rate Breakdown of cholesterol, number of LDL receptors Glucose metabolism  rT3 Non-stimulatory, not retro-converted Adaptive down regulation to injury/trauma, illness, starvation, psychological distress Ratio of total T3 to rT3  rT3---Endocrinology.1959;64:466-468. J Vet Med A Physiol Clin Med.2002;49:121-124. J Nutr.2004;134:2301-2306. J Endocrinol.2016;2157583. 3-iodothronamine (3-TIAM)---causes hypothyroidism, rT3 precursor of 3- TIAM Aggravated---dexamethasone, adrenaline Deactivates 5’-deiodinase enzymes (T4 to T3) Type-2, Type-1 AIDS---low rT3 leads to weight loss Normal production ratio---T4 90%, rT3 9%, T3 0.9%; tT3/rT3 ~ 10-14 (US values); 95% of rT3 from T4—monitor doses if T4 too high, not good long- term Low rT3 suggestive of low T4 Elevated rT3 suggestive of hypothyroidism  Hypothyroidism Physiol Res.2008;57 Suppl 1:s109-117. Thy res.2018;11:2. Pharmacol Ther.2017;173:135-145. Failure of gland to fully function---R/O Nutritional issues Underactive thyroid Female > Male Newborn---jaundice, large protruding tongue, difficult respiration, hoarse cry, umbilical hernia, constipation, poor muscle tone, excess sleep; delayed permanent teeth, delayed puberty, poor mentation Pseudo-hypothyroidism---from excess I intake; WHO says I at 1-200 mg/d is replete  Risk factors--- Cleveland Clinic.Hypothyroidism. Hormones.2011;10:117-124. J Endofrinol.1995;146:475-483. Female > 60 yo Autoimmune disease(s) Iodine deficiency Family history Post-partum Bacterial or viral infection—reduction of TSH release and peripheral T3 or euthyroid sick syndrome Distress---physical, emotional, anxiety, as above Starvation High carbohydrate diet Chemotherapy Adrenal hormones, HRT (estrogen), caffeine, stimulants Deficiency of type 2 deiodinase, mutation--16% of UK, NW Europeans  Hashimoto Thyroiditis J Clin Endocrinol Metab.1978;46:859-862. T-cell mediated destruction Antibodies react w/ thyroid peroxidase enzyme (TPO-Ab) and thyroglobulin (Tg- Ab), the protein source for thyroid hormone NHANES III---13% have circulating thyroid Ab Autopsy---lymphatic thyroiditis in 50% female, 20% male; likely intra-thyroidal cytokines Pregnancy---may need up to 45% more thyroid support, Am Thy Assoc recommends testing q4 weeks Elevated Ab risk for miscarriage; thus want TSH of < 4.0 (better 2.0) Oral contraceptive, Ovarian replacement hormones stimulate LV to make more thyroid binding proteins; test and thyroid replacement often needs to go up; recheck when OCP or HRT is withdrawn  Subclinical Hypothyroidism Endocr Pract.2013;19:175. JAMA.2018;320:1349-1359. Monitor regularly Rarely benefit from T4 alone Have higher rates of dysfunction, death vs healthy controls Trials, Reviews, Meta-analyses show little to no benefit from T4 alone No trials have used T3 as a treatment arm! Consider T4 + T3 as treatment  Resistance to Thyroid Hormone (RTH) (rare) J Clin Invest.2012;122:3035-3043. Best Pract Res Clin Endocrinol Metab.2017;31:241-253. Refetoff Syn---mutated thyroid hormone receptor, rare Alpha > Beta, Beta less severe Elevated TSH, T3, T4, low rT3 + goiter T4 may benefit if symptomatic, surgery leads to return of goiter Visser Syn---defective MCT8 transporters Severe neurodevelopmental disabilities, seen in infancy Low T4, TSH ~ 6.0, high total & free T3, low rT3 Poor response to treatment  Dysfunctional deiodination of T4 Endotext.2015;PMID: 25905294 9 families known Defect of selenoprotein synthesis Clinical hypothyroidism Children with delayed growth, mental, neuro development Fatigue, muscle weakness, Raynauds, vertigo, hearing loss, UV sensitive skin, infertility Normal size thyroid gland Low T3, high T4, rT3, ~ normal TSH Tx-–T3 beneficial DIO2 mutation---16% UK J Clin Endocrinol Metab.2009;94:1623-1629. Normal childhood, development Unmasked when given T4 Best w/ T3 + T4 Tx  Thyroid Cancer Thyroid gone (surgery) and/or ablated (I131) Least tolerant of daily T4 Beneficial to use divided dosing, q12 h or q8 h Once stable for 2+ week Test Often make no or little T3, thus need it to be stable, energetic Conventional Tx---push T4 to lower TSH Tx goal---low TSH  Hyperthyroidism--- Mayo Clinic.Hyperthyroidism. Int J Endocrinol Metab.2012;10:490-496. Silent—enlarge, painless, likely autoimmune Subacute—viral or bacterial infection Post-partum---esp. w/i 6 months of delivery Nodules on thyroid increase production 1.2% of USA, Canada Female 10x more often Higher risk > 60 yo Graves 1% of USA, Canada  Risk Factors for Hyperthyroidism Mayo Clinic.Hyperthyroidism. Family thyroid history Pernicious anemia, B12 deficient T1D Addison Medications---amiodarone > 60 yo Pregnant in last 6 mo Thyroid surgery, goiter  Graves Disease Mayo Clinic.Graves Disease. Stimulating and destructive reactions B-lymphocytes release Ab that bind to TSH receptors, thus the cells respond exactly as they do to TSH, TSH Receptor Antibodies (TR-Ab or TSI, formerly LATS) Most Grave patients make destructive Ab as in Hasimoto (TPO-Ab, Tg- Ab) Can quickly flip between hyper- and hypo- and hyper-thyroiditis  Nutritional Requirements for Thyroid Function---Supportive Tests Cereus.2020;12(10:e11008. Endocr Metab Immune Disord Drug Target. Mol Cell Endocrin.2012;355:240-248. Iodine--- worsened by perchlorates; thiocynates--tobacco smoke, food Selenium, Se-RBC Iron D3 B12 A Magnesium Manganese Boron Copper (serum, urine) Protein---tyrosine Sleep---polysomnography, wrist actigraphy  Chemical Interference MedScape.2021.Thy Disrupt. Perchlorates---jet fuel, prevent static cling plastic/paper; I uptake Thiocyanates—cigarette smoke, nitrate fertilizer Ag organophosphate pesticides---adult, in utero Flame retardants---adult, in utero Perfluoroalkyl substances---non-stick cooking, water resistant clothing; T4, T3 Excess iodine---pseudo-hypothyroidism, TSH resistant Lithium---to 10 mg seem safe, Therapeutic dose (bi-polar) -> hypothyroidism Biotin > 5 mg Steroids Oral contraceptive Hormone replacement therapy  Summary Adrenal is the furnace, Thyroid is the thermostat Testing options are multiple What is critical to diagnosis What is critical to ongoing care What can the patient afford given that ND care is out of pocket What can the clinician suspect from history & physical examinations and Tx effectively Medical history is essential Physical examination is essential Family history is informative, suggestive Medications—past and present---are suggestive and often indicative  Treatment---start low, go slow, monitor regularly, consistently Tx---consider BID, TID dosing Follow-up on the out of range Be wary of the unexpected Discussion and Consent are essential and critical  Discussion & Questions Thank you