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Thyroid IN My Mind with Expanded Appendix


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Dr. Cady returned to IMMH in Orange County to deliver this talk on September 28, 2017. This is his fifth presentation on this topic to the Integrated Medicine and Mental Health conference.

In this presentation, Dr. Cady reviews common misconceptions about the evaluation of the thyroid axis, dosing concerns, actual studies on patients and real-world clinical data. A large appendix and reference is included at this end of this presentation for things which were not able to be covered in the time allotted. These include the role of thyroid hormone on cognition, the role of thyroid hormone in head injury, and an exploration of the role of thyroid hormone in possibly preventing, and possibly actually treating Alzheimer's disease (as one of MANY targeted pharmaceutical, nutraceutical and integrative modalities.)

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Thyroid IN My Mind with Expanded Appendix

  1. 1. Thyroid IN My Mind Louis B. Cady, MD
  2. 2. CONTINUING MEDICAL EDUCATION COMMERCIAL DISCLOSURE REQUIREMENT I, Louis B. Cady, MD, have the following commercial relationships to disclose: •Speaker honoraria received from: • Immunolaboratories, Great Plains Diagnostic Labs, LABRIX •Speaker’s bureaus (active) for: • Allergan (Aventis), Lundbeck, NEOS, Shire, Takeda, Vaya Pharma •Historical data – speaker’s bureau for Arbor, Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Glaxo-Smith Kline, Janssen, McNeil, Pfizer-Roerig, Sanofi~aventis, Searle, Sepracor, Shionogi, Sunovion, Wyeth-Ayerst •Distributor – Pharmanex supplements & Biophotonic scanner Louis B. Cady, MD
  3. 3. Attention class!! Cady Wellness Institute app – Apple “app” store or Google Android store Where (else!) to get “the slides” Louis B. Cady, MD
  4. 4. Review on: “How to get the MOST out of this presentation”: Louis B. Cady, MD
  5. 5. 4
  6. 6. Per HDRS – 17, remission in: 15.9% on Li 24.7% on T3 Per QIDS-SR16, remission in: 13.2% on Li 24.7% for T3 * * Fava & Covino: Augmentation/Combination Therapy in STAR*D Trial, Medscape Psychiatry LEVEL III RESULTS: Louis B. Cady, MD
  7. 7. Prange’s postulate: • 1963 case where hyperthyroid patient became toxic when imipramine was introduced. – Preclinical theories: • thyroid hormone enhances noradrenergic receptor sensitivity • Perhaps modest amounts of T3 might accelerate imipramine’s antidepressant activity without producing toxicity. Prange AJ. Paroxysmal auricular tachycardia apparently resulting from combined thyroid-imipramine treatment. Am J Psychiatry 119:994-995, 1963. Louis B. Cady, MD
  8. 8. Prange proceeds… • Placebo controlled study of 20 depressed (but non-refractory) patients, a more rapid onset of antidepressant action was observed in the imipraime-T3 group vs. placebo. Prange AJ, et al. Enhancement of imipramine antidepressant activity by thyroid hormone. Am J Psychiatry 126:457-469, 1969. Louis B. Cady, MD
  9. 9. Open studies commenced • THE STUDIES: – Earle BV. Thyroid hormone and tricyclic antidepressants in resistant depression. Am J Psychiatry 126:1667-1669, 1969 – Ogura C, et al. Combined thyroid (tri-iodothyronine) tricyclic antidepressant treatment in depressive states. Folia Psychiatrica et Neurologica Japonica 28:179-186, 1974 – Banki CM. Triiodothyronine in the treatment of depression. Orv Hetil 116:2543-2546, 1975. – Tsutsui S et al. Combined therapy of T3 and antidepressants in depression. J Int Med Res 7:138-146, 1979. – Schwartz G et al. Normal thyroid function in desipramine nonresponders compared to responders by the addition to L-tri-iodothyronine. Am J Psychiatry 141:1614-1616, 1984 • THE FINDINGS: – “When T3 was added to TCA’s for treatment- refractory depressed patients, there was a favorable outcome in about two-thirds of the cases.” • Charney DS et al. Treatment of Depression, Chapter 28 in: Textbook of Psychopharmacology, American Psychiatric Press, Inc. © 1995. Louis B. Cady, MD
  10. 10. Thyroid augmentation known to be useful in refractory depression • 292 patients and eight studies aggregated. – (Medline data base 1966 – May 1995.) • Patient treated with T3 augmentation – twice as like to respond as controls – (RR 2.09; 95% confidence interval) • Improvements in depression scores were moderately large (effect size 0.62, P<0.001) Louis B. Cady, MD Aronson R et al. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996 Sep;53(9):842-8.
  11. 11. 5HT joins NE • 2002 - New findings: – Thyroid hormones increase 5HT neurotransmission in the cortex by increasing 5HT2 sensitivity, and by reducing 5HT1A autoreception sensitivity in the raphe – Changes in gene expression of brain and neurotrophins thought to be responsible. Bauer M et al. Thyroid hormones, serotonin and mood of synergy and significance in the adult brain, Mol Psychiatry 7:140-156, 2002. Louis B. Cady, MD
  12. 12. For resistant depression: “The best-documented augmentation strategies involve inexpensive medicines (e.g., lithium or thyroid hormones) and response, if it occurs, is often within 2 weeks.” - Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 2004 (Chapter 14, Mood Disorders) Louis B. Cady, MD
  13. 13. Where are we in the literature? THYROID Louis B. Cady, MD
  14. 14. Dangers of HYPERthyroidism• Depression • Anxiety disorders (10-20%) • Hyperthyroid dementia/cognitive impairmenet (5- 10%) • Hypomania or mania (2-5%) • Psychosis (2-5%) From: Neuropsychiatry of Neurometabolic & Neuroendocrine Disorders – Kaplan & Sadock Comprehensive Textbook of Psychiatry – Ch 2.14 612-13. Louis B. Cady, MD
  15. 15. “Hypothyroidism depression” 7/31/2017 965 citations Louis B. Cady, MD
  16. 16. “SUBCLINICAL Hypothyroidism depression” 7/31/2017 – 139 citations Louis B. Cady, MD
  17. 17. “subclinical hypothyroidism depression children” 7/31/2017 5 citations
  18. 18. CONCLUSIONS: This is the first study to demonstrate associations between CBCL-DP [Child Behavior Checklist Dysregulation Profile] and subclinical hypothyroidism. Louis B. Cady, MD
  19. 19. “schizophrenia subclinical hypothyroidism” – 7 results 5/26/2017• “These findings render possible the diagnosis of subclinical hypothyroidism in neuroleptic-treated schizophrenic patients.” Martinos A et al. Effects of six weeks’ neuroleptic treatment on the pituitary-=thyroid axis in schizophrenic patients. Neuropsychobiology. 1986; 16 (2-3):72-7. • The depressives and schizophrenics showed subclinical or chemical hypothyroidism while the manic showed slightly higher values for T(3), and T(4), when compared to normal control subjects. • Boral GC . Thyroid function in different psychiatric disorders. Indian J Psychiatry. 1980 Apr, 22(2):200 – 2 Louis B. Cady, MD
  20. 20. Louis B. Cady, MD “subclinical hypothyroidism bipolar disorder” 5/26/2017 42 citations • “Thyroid abnormalities occur frequently in patients with BD regardless of treatment.” [Lambert CG et al. Bipolar Disord. 2016 May;18(3):247-60] • Patients with SCH had poorer performance than patients without SCH in measures of verbal memory, attention, language, and executive functions. [Martino DJ, et al. Subclinical hypothyroidism and neurocognitive functioning in bipolar disorder. J Psychiatr Res. 2015 Feb;61:166-7] • “There is no significant association between hypothyroidism and bipolar disorder.” Menon B. Hypothyroidism and bipolar affective disorder: is there a connection. Indian J. Psychol Med. 2014 Apr;36(2):125-8 • Hypothyroidism, either overt or more commonly subclinical, appears to the commonest abnormality found in bipolar disorder. Chakrabarti S. Thyroid functions and bipolar affective disorder. J Thyroid Res. 2011;2011; 2011:306367.
  21. 21. Pause for background… Louis B. Cady, MD
  22. 22. Louis B. Cady, MD
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  24. 24. [ - accessed August 2015 and 08 20 2016] • “Thyrotropin (Thyroid-Stimulating Hormone or TSH). Measuring TSH is the most sensitive indicator of hypothyroidism.” (hunh?!) – accessed 9/5/2011 • “…blood tests for measuring levels of TSH and free thyroxine (T4) are the only definitive way to diagnose hypothyroidism” – 10/6/2012 Louis B. Cady, MD
  25. 25. Louis B. Cady, MD accessed 7/31/2017
  26. 26. Louis B. Cady, MD
  27. 27. Factors for production of thyroid hormones: •Iron, iodine, tyrosine, Zn, Se, E, B2, B3, B6, C, D Factors affecting T4 to REVERSE T3 (RT3): •STRESS, trauma, low calorie diet, inflammation, toxins, infections, liver/kidney dysfxn, certain Rx Factors that INHIBIT proper T4 production: •STRESS •Infection, trauma, radiation, Rx •Fluoride •Toxins: pesticides, Hb, Cd, Pb •Celiac disease T4 T3 requires Se and Zinc!T4 T3 requires Se and Zinc! T4 Factors that improve cellular sensitivity to thyroid hormones: •Vitamin A •Exercise •Zinc Louis B. Cady, MD
  28. 28. “the foot soldier” “the evil twin” Selenium required! FEEDBACK INHIBITION CORTISOL 80% of T4 converted in the liver Iodine required (65% of T4)
  29. 29. Conventional medical practice: -Only TSH is typically considered. -You get T4 if you’re lucky. -Ill-considered: “T7”, Total T4, Total T3, %T3 uptake -You DON’T get Free T3 or Rev T3 Conventional medical practice: -Only TSH is typically considered. -You get T4 if you’re lucky. -Ill-considered: “T7”, Total T4, Total T3, %T3 uptake -You DON’T get Free T3 or Rev T3 ? ? Louis B. Cady, MD ?
  30. 30. Why Reverse T3? • Hibernating bears can: – Lower temperature 9 – 11 degrees Farenheit – Reduce their metabolism by 75% – Drop heart rate from 55 to 9 bpm • Rev T3 thought to “hibernate” humans Louis B. Cady, MD
  31. 31. What causes elevation in Rev T3? • High Cortisol (emotional stress) or high copper • Nutritional starvation • Heavy metal toxicity – mercury, lead, cadmium* • Selenium or Zinc deficiency* • And high dose of thyroxine (T4) – a “pro-hormone” –iatrogenic!) *Integrative tip: hair analysis is an inexpensive and effective screen. Also RBC-Selenium and RBC Zinc. Louis B. Cady, MD
  32. 32. “Euthyroid sick syndrome” • Stages: – EARLY: • Normal TSH, Normal T4, but LOWER T3 – LATE: • T4 also goes down • Pro-inflammatory cytokines promote this via direct activity on the thyroid gland, as well as by inhibition of peripheral response for conversion of T4 to T3, especially in the liver. Papanicolaou DA. Euthyroid sick syndrome and the role of cytokines. Rev Endocr Metab Disord 1(1-2):43-48, 2000. Louis B. Cady, MD
  33. 33. Caloric Deprivation and Non- Thyroidal Illness Causes Low T3 • “The effects of the low T3 syndrome at the tissue level are in many instances comparable to those seen in hypothyroidism.” • “These effects are considered to constitute a beneficial adaptive mechanism in situations in which the organism is endangered.” Hennemann G, Docter R, Krenning EP. Causes and effects of the low T3 syndrome during caloric deprivation and non-thyroidal illness: an overview. Acta Med Austriaca. 1988;15(1):42-45. Louis B. Cady, MD
  34. 34. And you can’t tell by “looking” • Patients with biochemically severe hypothyroidism may present with only mild clinical manifestations • Some patients with moderate changes in thyroid hormones may present with severe signs of tissue hypothyroidism. Meier C, Trittibach P, Guglielmetti M, et al. Serum thyroid stimulating hormone in assessment of severity of tissue hypothyroidism in patients with overt primary thyroid failure: cross sectional survey. BMJ. 2003 Feb 8;326(7384):311-312.
  35. 35. Key review article! [Schroeder AC et al. Front Encorinol (Lausanne). 2014;5:40. / ) • Thyroid hormones effect on brain relates to balance of T4 and T3. • Thyroid receptor alpha1 = 70-80% of all TR expression in adult vertebrate brain. Louis B. Cady, MD
  36. 36. What does Thyroid receptor alpha1 bind? Louis B. Cady, MD Effectively: -These genes make THR alpha -THR Alpha is a nuclear receptor for tri-iodothyronine [T3]. -“[This receptor] has been shown to mediate the biological activities of thyroid hormone.” Source: Gene ID: 7067, updated 9-Jul-2017
  37. 37. What does the literature show? Louis B. Cady, MD
  38. 38. Aim: evaluate biological factors assoc. with suicide attempts in naturalistic sample 439 patients with major depression, bipolar and psychotic disorders consecutively assessed in the ER of an Italian Hospital (Jan 2008-Dec 2009) Suicide attempters were 2.27 times less likely to have higher Free T3 values than non-attempters (odds ratio = 0.44; 95% CI; p=0.01) (prolactin level differences failed to reach significance)
  39. 39. Best augmenting strategies available: -Lithium -Thyroid hormone -Anti-anxiety medications -Atypical antipsychotics. Louis B. Cady, MD
  40. 40. 63 patients with “subclinical hypothyroidism” HAM-D and MADRS scales with serum TSH Free T4, free T3 TPO AB and Tg-AB levels “This study suggests the importance of a psychiatric evaluation in patients affected by subclinical hypothyroidism.” Prevalence of depressive symptoms in this population was 63.5% Hunh? Louis B. Cady, MD
  41. 41. Aim: Evaluate relationship of subclinical hypothyroidism and cognition in the elderly. - 337 outpatients; {177 = men; 160 = women} “Patients with subclinical hypothyroidism had a probability about 2 times greater (RR = 2.028, p<0.05) of developing cognitive impairment.” MMSE scores were SIGNIFICANTLY lower in subclinical hypothyroid patients compared to euthyroid (p<0.03)
  42. 42. An opposing view: • “Thus, any abnormal thyroid function tests in psychiatric patients should be viewed with skepticism. Given the fact that thyroid function test abnormalities seen in non-thyroidal illness usually resolve spontaneously, treatment is generally unnecessary, and may even be potentially harmful.” • Dicerman AL, Barnhill JW. Abnormal thyroid function tests in psychiatric patients: a red herring? Am J Psychiatry. 2012 Feb;169(2):127-33 Louis B. Cady, MD
  43. 43. What are the TYPES of hypothyroidism (from the top down)? • Tertiary hypothyroidism – deficiency in hypothalamus – not enough TRH • Secondary hypothyroidism –pituitary isn’t kicking out enough TSH “your thyroid labs are ‘just fine’” • PRIMARY hypothyroidism – where thyroid gland can’t make thyroid hormone – This is the only one that high TSH is good for diagnosing!! • Low TSH • Low TSH Your doc is happy!!  • HIGH TSH (finally!) Louis B. Cady, MD
  44. 44. Review of all hypothyroid patients in a private practice in Belgium between May 1984 and July1997 • 24 hour urine Free T3 correlates better with clinical status of hypothyroid patients, and even better than T4 by RIA. • Conclusions: In this study symptoms of hypothyroidism correlate best with 24 h urine free T3 Baisier WV et al. 2000, Vol. 10, No. 2 , Pages 105-113
  45. 45. • Early 20’s college student • Weight gain, fatigue, brain fog • Saw “numerous” MD’s asking for help • Told “nothing is wrong with your thyroid; your labs are fine.” (permission granted to use photos & data) Louis B. Cady, MD
  46. 46. A physician’s wife. “Fatigued” “No sex drive.” Louis B. Cady, MD
  47. 47. ♦ Depressed mood 100% ♦ Reduced energy: 97%3 ♦ Fatigue or loss of energy: 94%94%2 ♦ Impaired concentration: 84%3 ♦ Tiredness: 73%1 ♦ Hypersomnia: 10%–16%4 (Insomnia) Useful Target Symptoms in MajorUseful Target Symptoms in Major DepressionDepression 1. Tylee et al. Int Clin Psychopharmacol 1999;14:139-151. 2. Maurice-Tison et al. Br J Gen Pract 1998;48:1245-1246. 3. Baker et al. Comp Psychiatry 1971;12:354-65. 4. Horwath et al. J Affect Disord 1992;26:117-25. 5. Reynolds and Kupfer. Sleep 1987;10:199-215. Louis B. Cady, MD
  48. 48. A FEW common symptoms of hypothyroidism (adapted from multiple sources) • Depression, fatigue • Concentration problems • Poor cognitive performance • Lack of motivation • Reduced libido • Psychosis – “myxedema madness” • Exacerbation of bipolar symptoms  • Cold intolerance • Weight gain • Slowed relaxation phase of DTR’s • Brittle hair/fingernails • Decreasing eyebrows • HIGH blood pressure • Constipation Louis B. Cady, MD
  49. 49. “Data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few.” (JAMA 2004) “Data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few.” (JAMA 2004) Louis B. Cady, MD
  50. 50. Subclinical hypothyroidism in the US– what’s the latest?As of August 6, 2015 • Synthesis: treat only those with TSH >10 – Hennessey JV Espaillat R. Diagnosis and management of Subclinical Hypothyroidism in Elderly Adults: A Review of the Literature. J Am Geriatr Soc. 2015 Jul 22. epub ahead of print • Synthesis: SCH [TSH >/= 4.5- 19.99] associated with hip and other fractures. – Blum MR et al. Subclinical thyroid dysfunction and fracture risk: a meta- analysis. JAMA. 2015 May 26;3(20):2055-65. • Synthesis: Treatment of SCH [TSH 4-11] improved risk of coronary heart dz risks. “Direct evidence on the benefits and harms of screening remains unavailable.” – Rugge JB et al. Screening for and treatment of thyroid dysfunction: An evidence review for the US. Rockville (MD) Agency for Healthcare Research and Quality (IS);2014 Oct. Report No. 15-05217-EF-1.
  51. 51. As of August 21, 2016NEW LITERATURE – AUGUST 2016 – “Association between serum thyrotopin levels and mortality among euthyroid adults in the United States. [Inoue K et al. Thyroid. 2016 Aug 18 [Epub ahead of print] •Population – NHANES III study . N = 12,584 adults>/= 20 years of age. •Associations between TSH tertiles (high, medium, and low) and mortalities (all cause, cardiovascular and cancer) •Mean followup = 19.1 years with 3,395 deaths. •Increase risk of all-cause mortality found in high normal TSH compared to medium normal TSH group. ( Low normal compared to medium also had higher all cause mortality). •“This study indicated that the normal range of TSH levels may require reevaluation.” Louis B. Cady, MD
  52. 52. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THYROID DYSFUNCTION CASE FINDING. [Hennessy JV. Endoc Pract. 2016 Feb;22(2):262-70 We recommend that thyroid dysfunction should be frequently considered as a potential etiology for many of the nonspecific complaints that physicians face daily. The application and success of safe and effective interventions are dependent on an accurate diagnosis. We, therefore, advocate for an aggressive case-finding approach, based on identifying those persons most likely to have thyroid disease that will benefit from its treatment. Louis B. Cady, MD
  53. 53. This is it in a nutshell…1. 70% of older patient with TSH > than 4.5 mIU/L were within their age- specific reference range. 2. From the “Conclusion” statement: “TSH distribution progressively shifts toward higher concentrations with age. The prevalence of SCH may be significantly overestimated unless an age-specific range for TSH is used.”
  54. 54. How much subclinical hypothyroidism? • 4 – 8.5% of US population (for TSH> 5.1!!) – Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4 and thyroid autoantibodies in the United States population (1988–1994): National Health and Nutrition Examination Survey (NHANES III) J Clin Endocrinol Metab. 2002;87:489–99. – Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado Thyroid Disease Prevalence Study. Arch Int Med. 2000;160:526–3 • UK study (2011): 8% of women over 50 and men over 65 have under-active thyroid and 100,000 could benefit from treatment – BBC News 2011 - January 24 Louis B. Cady, MD
  55. 55. More studies • 24.2% of an adult female population in Puerto Rico = hypothyroid – Vonzales-Rodriguez LA, et al. Thyroid dysfunction in an adult female population: A population-based study of Latin American Vertebral Osteoporosis Study (LAVOS) - Puerto Rico site. P R Health Sci J. 2013 Jun; 32(2):57-62. Louis B. Cady, MD
  56. 56. “But the doctor told me my thyroid was fine.” • Can be “wnl” but suboptimal. • TSH frequently only thing checked. • Nothing known about Free T4 or Free T3. • Free T4 can be converted to Reverse T3 under stress (cortisol) • Free T4 can be underconverted to T3 (Se def). • Can have normal levels (or slightly elevated levels) of everything and have auto-immune thyroid disease. Louis B. Cady, MD
  57. 57. Definition of “normal labs”: “When your lab values are as crappy as everyone else’s.” - Neal Rouzier, MD (World Link Medical Seminar II – Spring 2011) Louis B. Cady, MD
  58. 58. Modern Medicine’s Paradigm: 2 Standard Deviations – “if you are not sick, then you must be well.” “NORMAL” OPTIMAL TSH: {<2 0r <1 per some experts) TSH = 0.45 4.12 source: Percentile (2.5th% 97.5th % NHANES III Louis B. Cady, MD
  59. 59. Average (normal) or optimal? • Would you like an normal wife (husband) or an optimal one? • Would you like a “normal” marriage or an exciting and optimal one? • Would you like a “normal” medical practice or an incredible, exciting, and (optimal!!) stimulating one? • Would you like “normal” thyroid labs or OPTIMAL ones? Louis B. Cady, MD
  60. 60. So what are people doing out there? What does the literature say? Louis B. Cady, MD
  61. 61. Dr. Imre Zs-Nagy, MD – one more time! Archives of Gerontology and Geriatrics, Volume 48, Issue 3, May-June 2009, 271-275 "[The] gerontological elite has instead sought to obfuscate the facts ... the reason for this is nothing less than an abject fear ... to avert their loss of control, power, prestige, and position in the multi-billion dollar industry of gerontological medicine.” Prof. Dr. Imre Zs.-Nagy, MD - part of the gerontology movement for four decades; founder and Editor-in-Chief of the Archives of Gerontology and Geriatrics
  62. 62. “Subtle deficits in specific cognitive domains (primarily working memory and executive function) likely exist in subclinical hypothyroidism and thyrotoxicosis, but these are unlike to cause major problems in most patients.” (Endocrinol Metab Clin North Am. 2014 Jun) “Subtle deficits in specific cognitive domains (primarily working memory and executive function) likely exist in subclinical hypothyroidism and thyrotoxicosis, but these are unlike to cause major problems in most patients.” (Endocrinol Metab Clin North Am. 2014 Jun) “Patients with mild thyroid disease and significant distress related to mood or cognition most likely (??) have independent diagnoses that should be evaluated and treated separately.” “Patients with mild thyroid disease and significant distress related to mood or cognition most likely (??) have independent diagnoses that should be evaluated and treated separately.” Louis B. Cady, MD
  63. 63. So what does the American Association of Clinical Endocrinologists (ACEE) say? • “The upper limit of TSH should remain at 4.5 mIU/L, rather than 3.0-3.5 as some other organizations have suggested.” • “Routine T4 treatment for patients with TSH between 4.5 and 10mIU/L is not warranted.” – statements/subclinical.pdf retrieved August 25, 2014 Louis B. Cady, MD
  64. 64. Lab values – one more time…”4.5” is where the American Assn. of Clin. Endocrinologists wants the highest level of TSH TSH = 0.45 4.12 source: % = (2.5th% 97.5th % NHANES III 4.5 is the upper limit they want – this is at c. the 99th % Louis B. Cady, MD
  65. 65. 70 patients- ages 18-65 years of age. w/ primary hypothyroidism on stable T4 for 6 months. 70 patients- ages 18-65 years of age. w/ primary hypothyroidism on stable T4 for 6 months. Randomized to either dessicated thyroid extract (DTE) or T4 for 16 months, then crossed over for another 16 months. Randomized to either dessicated thyroid extract (DTE) or T4 for 16 months, then crossed over for another 16 months. RESULTS: - “No differences in symptoms” and neurocognitive measures. RESULTS: - “No differences in symptoms” and neurocognitive measures. BUT: -DTE patients lost 3 lbs! -48.6% of patients (n=34) PREFERRED DTE. -Those patients preferring DTE lost 4 lbs during the DTE treatment and subjective symptoms were all significantly better while taking DTE as per general health questionnaire-12 and thyroid symptom questionnaire. BUT: -DTE patients lost 3 lbs! -48.6% of patients (n=34) PREFERRED DTE. -Those patients preferring DTE lost 4 lbs during the DTE treatment and subjective symptoms were all significantly better while taking DTE as per general health questionnaire-12 and thyroid symptom questionnaire.
  66. 66. “Conclusions”: - DTE therapy did not result in a significant improvement in quality of life; however, DTE caused modest weight loss and nearly half (46.8%) of the study patients expressed preference for DTE over L-T4. DTE therapy may be relevant for some hypothyroid patients.” [Can you believe it????] “Conclusions”: - DTE therapy did not result in a significant improvement in quality of life; however, DTE caused modest weight loss and nearly half (46.8%) of the study patients expressed preference for DTE over L-T4. DTE therapy may be relevant for some hypothyroid patients.” [Can you believe it????]
  67. 67. Kelly, T. An examination of myth: a favorable cardiovascular risk-benefit analysis of high-dose thyroid for affective disorders. J Affect Disord. 2015 May 15;177:49-58 CONCLUSION: The cardiovascular risks of HDT appear to be low. HDT is at least as safe as or safer than many psychiatric medications. It is effective and well tolerated. CONCLUSION: The cardiovascular risks of HDT appear to be low. HDT is at least as safe as or safer than many psychiatric medications. It is effective and well tolerated. CONCLUSION: High circulating levels of thyroid hormone is not the cause of the sequelae of hyperthyroidism. The reluctance to using high dose thyroid is unwarranted. CONCLUSION: High circulating levels of thyroid hormone is not the cause of the sequelae of hyperthyroidism. The reluctance to using high dose thyroid is unwarranted. Kelly, T et al. Elevated levels of circulating thyroid hormone do not cause the medical sequelae of hyperthyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jun 11;71:1-6.
  68. 68. Thyroid “by the numbers.” 1. Review this lecture. 2. Go get good training. (Neal Rouzier, MD) 3. PSYCHIATRISTS! Acknowledge that “T3 augmentation” is in your literature and it is your RIGHT TO PRACTICE IT. (Consider “HDT”!) 4. Therapists/other practitioners: wake up! Don’t fall into trap of “blaming” the functionally hypothyroid patient. REFER! 5. Start LOW. 6. Go SLOW. 7. Test test test test test. – MUST GET BASELINE (which typically hasn’t been done). – If you are unsure or nervous, TEST. – MONITOR THE THERAPY. 1. Explain “Goldilocks and the Three Bears” to your patients and start LOW, giving them some flexibility.
  69. 69. Useful aphorisms to remember • It’s difficult to be euthymic without being euthyroid. • Depression can start in the NECK. • John Earl Shoaff: “The difference between success and failure is about a half dozen things.” Louis B. Cady, MD
  70. 70. Framework: • Decide where in the literature you want to be. • Do you want to practice the way things “used to be” or do you want to practice evidence based medicine? – [or just blindly listen to the specialty societies who parrot from the past?] • Do you want your patient to be “normal” or “optimal”? • And can you live with yourself and your decision? Louis B. Cady, MD
  71. 71. Dx: • TSH • Free T4 • Free T3 • Reverse T3 • If indicated: – Anti-thyroid antibodies (anti-TPO) – Anti-thyroglobulin antibodies – Thyrotropin receptor antibodies (TRAb’s) • We typically do not do: – Total T4, Total T3, or thyroid reuptake Test! Test! Test! Louis B. Cady, MD
  72. 72. Rx: • Synthroid ® (levothyroxine) • Cytomel ® (Tri-iodothyronine – “T3”) – Instant release (cheap!) – Compounded in SR capsule (easier dosing) • Armour® thyroid (brand or generic) = T4 + T3 • Naturethroid & Westhroid = T4 + T3 – better tolerated in some Louis B. Cady, MD
  73. 73. “Sit down before fact as a little child, - Thomas H. Huxley Louis B. Cady, MD be prepared to give up every preconceived notion, follow humbly wherever … nature leads, or you shall learn nothing.”
  74. 74. Louis B. Cady, MD Cady Wellness Institute 4727 Rosebud Lane – Suite F Newburgh, IN 47630 USA Office (812) 429-0772 Available on Apple “app store” and Google Android store. Louis B. Cady, MD
  75. 75. Appendix with holistic references Louis B. Cady, MD
  76. 76. Must have iodine to make T4! Source: Office of Dietary Supplements, NIH accessed 8/11/2013 Louis B. Cady, MD
  77. 77. Sources/locations of deficiency: • Chlorinated or fluorinated drinking water • Not using iodized salt • Consumption of NaCL in processed foods • Consumption of soy & “goitrogens” - cabbage, broccoli, cauliflower and Brussels sprouts • Being pregnant • People living with iodine deficient soils & eating local foods Louis B. Cady, MD
  78. 78. North America 85% South America 76% Asia 76% Africa 74% Europe 72% Australia 55% % Mineral depletion from the soil during the past 100 years, by continent Source: UN Earth Summit Report 1992
  79. 79. - Selenium is one of the factors that may affect the risk of cognitive decline. In selenium deficiency the brain remains selenium replete the longest suggesting that Se plays an important role in brain functions. - Results from this study: “Low Se status is a risk factor for cognitive decline even after taking into account vascular risk factors.” Louis B. Cady, MD
  80. 80. SELENIUM DEFICIENCY in FASEB: • “Adaptive dysfunction of selenoproteins from the perspective of the ‘triage’ theory: why modest selenium deficiency may increase risk of diseases of aging.” Foundation of American Societies for Experimental Biology McCann, J, Ames BM. FASEB J. 2011 Jun;25(6):1793-814. Louis B. Cady, MD
  81. 81. As of August 20, 2016 • “Low selenium status is associated with increased risk of thyroid disease. Increased selenium intake may reduce the risk in areas of low selenium intake.” – Wu Q et al. Low population selenium status is associated with increased prevalence of thyroid disease. J Clin Endocrinol Metab. 2015 Nov;100 (11):4037-47. • “We demonstrated …the beneficial effects obtained by selenomethionine treatment on patients affected by subclinical hypothyroidism.” – Nordio M. Combined treatment with myo-inositol and selenium ensures euthryoidism in subclinical hypothyroidism patients with autoimmune thyroiditis. J Thyroid Res. 2013;2013:424163 Louis B. Cady, MD
  82. 82. • “Iron deficiency impairs thyroid hormone synthesis by reducing activity of heme-dependent thyroid peroxidase.” – Zimmermann MB, Kohle J. Thyroid. 2002 Oct;12 (10):867-78 – Subclinical hypothyroidism assoc. with Fe deficiency. – Nekrasova TSA, 2013 Kloin Med (Mosk).2013; 91 (9):29-33. – Fe deficiency assoc with Thyroid microsomal antibody levels. – Wang YP et al. J Formos Med Assoc. 2014 Mar;113(3):155-60. – Fe salts + T4 worked best. – Ravanbod M et al. Am J Med. 2013 May;126(5):420-4. Consider IRON deficiency Louis B. Cady, MD 135 citations search on “iron deficiency hypothyroidism” as of 6/19/2017
  83. 83. • Cognition • Head injury recovery • Alzheimer’s disease prevention Other areas of interest advertised in lecture synopsis Louis B. Cady, MD
  84. 84. Cognition: maternal low thyroid and ADHD in kids• Known impact of thyroid hormone deficiency in pregnancy can affect ADHD symptoms in children – “Generation R” Study in Rotterdam – 4,997 eligible mother-child pairs studies (with data on maternal thyroid levels) identified – Of these, 3,873 visited a Generation R research center for assessments. • “Maternal hypothyroxinemia (n-127) in early pregnancy was associated with higher scores for ADHD symptoms in children at 8 years of age” independent of confounding factors. – Modesto T et al. JAMA Pediatr. 2015 Sep;169(9):838-45. Louis B. Cady, MD
  85. 85. Impact of mild maternal thyroid hormone deficiency in pregnancy – the Generation R Study • Congenital hypothryoidism known to cause irreversible brain damage. • Before 12-14 weeks of gestation, maternal thyroid hormone serves as the only source of thyroid hormone for the fetus. – T3 is generated locally from maternal T4 in the fetal brain before mid-gestation. • Iodine deficiency and thyroid autoimmune disorders known as two of the main causes of thyroid deficiency. – Ghassabian A et al. Best Practice and Research Clinical Endocrinology & Metabolism 28 (2014) 221 – 232 Louis B. Cady, MD
  86. 86. Results of Generation R study (cont) • 3,659 maternal child pairs evaluated in this analysis. – Higher results of maternal free T4 in early pregnancy predicted a lower risk of expressive language delay in their children at 2 ½ years. – “Severe hypothyroxinaemia: • predicted a higher likelihood of expressive language delay in children at 1 ½ and 2 ½ years of age. • Also predicted a higher risk of non-verbal delay at 2 ½ years. • Ghassabian A et al. Best Practice and Research Clinical Endocrinology & Metbaolism 28 (2014) 221 – 232 Louis B. Cady, MD
  87. 87. Multiple studies • “Thyroid hormone regulates neurogenesis in the developing and adult brain across different vertebrate species.” – Gothie JD et al. Mol Cell Endocrinol. 2017 May 22. • The development of infant visual attention is related to thyroid hormone during early prenatal period. – Bell MA et al. Am J Clin Nutr. 2016 Sept • Thyroid dysfunction known to occur in autism spectrum disorder and may be related to a blocking folate receptor autoantibody – Frye RE et al. J Neuroendocrinol. 2017 Mar; 29 (3) Louis B. Cady, MD
  88. 88. Experimental induction of hypothyroidism during early postnatal stages in rats. • Hypothyroidism induces at 21 days of age using propyl—2- thiouracil . • Results: – “hypothyroidism triggers a significant dysfunction in learning and memory processes. – “The cognitive impairment was correlated with a reduction in hippocampal plasticity and depression. – Also, decreased glucose utilization and increased oxidative stress observed. – Hypothyroidism in young rat model alters numerous functions at the level of the hippocampus. • Salazr P et a. Biochim Biophys Acta. 2017 April;1863(4):870-883. Louis B. Cady, MD
  89. 89. Other studies in children • Endocrine-disrupting chemicals (EDC’s) and perturb normal levels of hormones required for normal neural circuit development. – Three ubiquitous endocrine disruptors studied [polychlorinated biphenyls, polybrominated diphenyl esters, and bisphenol A.] – Impact of these disrupts goes beyond relative hypothyroidism and affect memory, cognition, and social behavior. – Pinson A et al. Andrology. 2016 Jul;4(4):706-22 Louis B. Cady, MD
  90. 90. Thyroid hormone and aging • Known correlation between increase in TSH during ageing. – Unclear if this is a normal adaptive response associated with senescence or an actual mild thyroid dysfuncion. – Several meta-analyses showed a direct link between subclinical hypothyroidism and cardiovascular events (younger than 65) and cognitive impairment (in those under 75 years of age.) • Pasqualetti G et al. Recent Pat Endocr Metab Immune Drug Discov. 2016 (10(1):4 – 10 Louis B. Cady, MD
  91. 91. “Thyroid function and neuropsychological status in older adults.” • “Cross sectional associations between serum thyroid hormone concentrations and several neuropsychological function domains among men and women aged 55 – 74 years” were reported. • Findings: – Higher thyroid hormone levels associated with improved visuospatial function, as well as tasks of memory and learning. • Shrestha S et al. Physiol Behav. 2016 Oct 1; 164(Pt A):34-9 Louis B. Cady, MD
  92. 92. Thyroid hormone and its function on health status, mood, and cognition in T4 treated subjects • Cross sectional study of 132 otherwise health hypothyroid subjects who received levothyroxine replacement therapy. – Generally, not much difference in health status, mood or cognitive status. – However, on the Iowa Gambling Task (which mimics real life decision-making), subjects with low-normal TSH “made more advantageous decisions than those with high-normal TSH levels.” – “Decision making – which encompasses many executive functions, may be affected.” • Samuel MH et al. Thyroid. 2016 Sep;26(9):1173-84. Louis B. Cady, MD
  93. 93. Thyroid hormone: influences on mood and cognition in adults (the need for a “happy medium”) • “Treatment of over thyroid dysfunction largely resolves associated disturbances in mood and cognitive dysfunction.” – “However, in the setting of overt hypothyroidism subtle detrimental effects on cognition may not be full reversed.” • “Subclinical HYPERthyroidism and higher Free Thyroxine ( Free T4) within the normal range have also been associated with poorer cognitive outcomes.” – Ritchie M, Yeap BB. Maturitas. 2015 Jun;81(2):266-75. Louis B. Cady, MD
  94. 94. Prevalence of thyroid dysfunction and its impact on cognition in older Mexican adults (SADEM study) • 1750 participants evaluated via interviews, TSH, and Free T4 levels. – TSH of 0.4 – 4 was considered euthyroid. – Over hypothyroidism = TSH>4.8 – Overt hyperthyroidism – TSH <0.3 IU/L • Results: – Overall estimated prevalence of thyroid dysfunction in Mexican population was 23.7%. • 15.4% we were classified as subclinical hypothyroidism. – Thyroid dysfunction and cognitive impairment was most evident in overt hypothyroidism [OR=1.261] – Juarez-Decillo T et al. J. Endocrinol Invest. 2017 Mar 25. Louis B. Cady, MD
  95. 95. TSH and cognition in older people (negative study) • 335 home-dwelling older people (>/= 75 yoa) • Cognitive performance evaluated using the Consortium to Establish a Registry of Alzheimer’s Disease battery (CERA- nb) – APO E4 genotype also defined. – Subjects divided into quartiles by TSH. • “Our results do not support the notion that higher TSH concentrations, not even in the range of subclinical hypothyroidism, would adversely affect cognition among older people.” – Ojala AK et al. Age Ageing. 2016 Jan;45(1):155-7 Louis B. Cady, MD
  96. 96. Thyroid hormones are associated with longitudinal cognitive change in urban adult population (positive study) • 1466 of 1602 participants was analytic sample size. • Adults ages 30 – 64 years at baseline visit. • Follow-up between first and second visit ranged from <1 to 8 years • “In sum, higher baseline thyroid stimulating hormone was associated with faster cognitive decline over time among urban US adults, specifically in domains of working memory and visuospatial and/or visuoconstruction abilities.” Beydoun MA et al. Neurobiol Aging. 2015 Nov; 36(11):3056-3066. Louis B. Cady, MD
  97. 97. Head injury considerations Louis B. Cady, MD
  98. 98. Head injury considerations in children • Hypopituitarism: 5 – 7% prevalence in children following TBI. • “The effect of hormonal replacement in patient recovery is important enough to consider baseline screening and reassessment between 6 and 12 months after TBI.” – Cassano-Sancho P. Arch Dis Child. 2017 Jun; 102(6):572-577 Louis B. Cady, MD
  99. 99. Evaluation of pituitary function for extended periods s/p TBI • 24 children s/p TBI evaluated. – Mean age 9.5 (+/- 3.1) years – Follow-up times were 29.4 (+/-9.8) months. – TSH, Free T4, Free T3, IGF-1, sodium, FSH, LH, E2 in girls, Total testosterone in both girls and boys – No children found with hormonal deficiencies. • Conclusion was that some pituitary dysfunction may present in the late period, “therefore, all cases should be followed up at outpatient clinics for a longer period” – Aylanc H, et al. J Neurosci Rural Pract. 2016 Oct-Dec;7(4):537-543 Louis B. Cady, MD
  100. 100. TBI in childhood research • The more severe the trauma, the greater the risk of progressive reduction in long- term serum TSH. – Heather N et al. Clin Endocrinol (Oxf). 2016 Mar;84(3):465-7. Louis B. Cady, MD
  101. 101. Thyroid hormone treatment activates protective pathways following neuronal injury• TBI in rats showed to be associated with reduction in T4 and T3. • A single dose of levothyroxine (T4) one hour post-injury, increased serum T4 and NORMALIZED serum T3 levels. – Expression of genes important for thyroid actin in the brain (MCT8 and Type 2 deiodinase) diminished after injury but were partially restored with T4 treatment. • The findings from both in vitro and in vivo studies support a role of thyroid hormone in activating pathways important for neuronal protection and promotion of neuronal recovery after injury. – Li J et al. Mol Cell Endocrinol. 2017 Sep 5;452:120-130. Louis B. Cady, MD
  102. 102. Emerging pharmacotherapy for treatment of TBI – targeting hypopituitarism and inflammation • Large body of evidence suggests that TBI may adversely affect pituitary function – both acutely and chronically. • The time interval between injury and effect “is one of the major factors responsible for variations in the prevalence of hypopituitarism reported.” • “euthyroid sick” syndrome reviewed – Paterniti I et al. Expert Opin Emerg Drugs. 2015;20(4):583-96. Louis B. Cady, MD
  103. 103. “Thyroid hormone in the frontier of cell protection, survival and functional recovery” • Thyroid hormones exerts important actions on cellular energy metabolism. • Enhances homeostatic potential including antioxidant, antiapoptotic, anti-inflammatory and cell proliferation responses. • Psych uses: – Reduce cognitive side effects of lithium – Improves response to ECT in bipolar patients. • Videla LA et al. Expert Rev Mol Med. 2015 May 25;17:e10. Louis B. Cady, MD
  104. 104. Somatotropic and thyroid hormones in the acute phase of subarachnoid haemorrhage. • Complicated hospital course was associated with a deeper fall in TSH and T3 concentrations. • “Low concentrations of TSH and T3 were connected to worse SAH [subarachnoid haemorrhage] grade and poor outcome.” – Implications for treatment? No conclusions given. – Zetterling M et al. Acta Neurochir (Wien). 2013 Nov;155(11):2053-62. Louis B. Cady, MD
  105. 105. Exogenous T3 administration provides neuroprotection in a murine model of traumatic brain injury.• Thyroid hormones noted to be decreased in patients with brain jury. • Controlled cortical impact injury (CCI) [widely used experimentally] was used in adult male mice. • Tx with T3 (1/2 MICROgrams/100 grams body weight IP) one hour after TBI resulted in a significant improvement in motor and cognitive recovery after CCI. • 24 hours after brain trauma, T3 treated mice showed significantly lower number of apoptotic neurons. • T3 significantly enhanced post-TBI expression of BDNF and GDNF compared to control vehicle. – Crupi R et al. Pharmacol Res. 2013 Apr;70(1):80-9. Louis B. Cady, MD
  106. 106. Multiple hormonal derangements seen as determinant of cognitive decline in older men • Thyroid, cortisol, and anobolic hormones [DHEA- S, testosterone, and IGF-1] noted to decline with age. • Frailty related to consequences of cognitive impairment and cognitive decline. • Correlation with changes of thyroid hormone and anabolic hormones in older men was found. – Maggio M et al. J Nutr Health Aging. 2012 Jan;16(1):40-54. Louis B. Cady, MD
  107. 107. The role of thyroid hormone Prevention/attenuation of Alzheimer’s disease? Louis B. Cady, MD
  108. 108. Thyroid hormone levels an in-vivo Alzheimer’s disease pathologies • Study evaluated TSH with two AD specific biomarkers (cerebral amyloid beta burden and glucose metabolism. – 148 individuals – PET scan, T3, Free T3, Free T4 and TSH levels measured. – Al patients were clinically euthyroid. But… • Independent negative associations were found between serum fT4 levels and global cerebral Aβ deposition after controlling for the effects of age, gender, and the apolipoprotein E ε4 (APOEε4) genotype. (no other thyroid hormones showed a relationship) – Choi HJ et al. Alzheimers Res Ther. 2017 Aug 17;9(1):64. Louis B. Cady, MD
  109. 109. Effects of Thyroid Hormones and their Metabolites on Learning and Memory in Normal and Pathological Conditions. • “The available literature suggests that both classical and non- classical thyroid hormones act as neuroprotective agents in the brain areas related to learning and memory. Their role in these areas supports the idea that they may be involved in the development of Alzheimer's disease.” • CONCLUSION: Thyroid hormones produce significant neurological effects, act as neuroprotective agents and might be considered as future diagnostic and therapeutic tools for Alzheimer's disease. – Accorroni A et al. Curr Drug Metab. 2017;18(3):225-236. Louis B. Cady, MD
  110. 110. • “…levothyroxine replacement therapy with vitamin E supplementation may ameliorate cognitive deficit in PTU-induced hypothyroidism [experimental model of hypothyroidism] through the decrease of oxidative stress status.” • Note: BOTH were used. – Pan T, et al. Endocrine. 2013 Apr;43(2):434-9.
  111. 111. Thyroid hormone prevents cognitive deficit in a mouse model of Alzheimer's disease. • Study examined feasibility of using T4 as a therapeutic agent of Alzheimer’s disease. – Mice injected IP with amyloid beta-peptide to produce AD animal model. • IP injection of levothyroxine prevented their cognitive impairment and improved their memory function. – Fu AL et al. Neuropharmacology. 2010 Mar-Apr;58(4- 5):722-9. Louis B. Cady, MD
  112. 112. Selenium and selenoproteins in health and disease. • Selenoproteins – involved in redox regulation of intracellular signaling, redox homeostasis, and thyroid hormone metabolism. – Reduced expression of selenoproteins directly linked to thyroid hormone metabolism defects (specifically – deficiency of deodinases) • Selenoprotein deficiencies have been linked to some forms of cancer, Alzheimer’s disease, cardiovascular disease, and life span. – Papp LV et al. Antioxid Redox Signal. 2010 Apr 1;12(7):793-5. Louis B. Cady, MD
  113. 113. And now – more research and reading is in your future! • This review has merely scratched the surface of all of these topics. • My thanks to everyone who attended my lecture at IMMH 2017 (Orange County) and my best wishes for the future! Louis B. Cady, MD