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Evidence Based Medicine Leads to Mediation of Symptoms of Mimics of Hypothyroidism

Evidence Based Medicine Leads to Mediation of Symptoms of Mimics of Hypothyroidism

Evidence Based Medicine is a modern, scientific alternative to the eminence based medicine. Currently, eminence based medicine is ignoring the mimics of hypothyroidism. Consequently, those patients are seemingly doomed to a life of chronic suffering with the symptoms of hypothyroidism, constant exhaustion, hypo-metabolism, hyper-cholesterolemia, deformity by myxedema, droopy eye lids, weight gain, etc. Furthermore, these patients are doomed to a life shorted by their greater susceptibility to lifes great killers, diabetes and heart disease.

Evidence Based Medicine (EBM)[1,2] is the conscience, explicit, and judicious use of best evidence in making decisions about the healthcare of patients. EBM is the process of systematically finding, appraising, and using contemporaneous research findings as the basis for clinical decisions. It may be segmented into four potentially iterative efforts[1]

1. Formulate a clear clinical question from a patient’s problem,
2. Search the literature for relevant clinical articles,
3. Evaluate (critically appraise) the evidence for its validity and usefulness, and
4. Implement useful findings in clinical practice.[1]

The clinical practices upon the mimics of hypothyroidism have exemplified the following point:

For decades people have been aware of the gaps between research evidence and clinical practice, and the consequences in terms of expensive, ineffective, or even harmful decision making.[1] Indeed, the clinical practice upon these mimics has been limited to declaring them functional somatoform disorders [3.4] and their symptoms nonspecific.[5,6] These diagnoses have several problems. They are suspect, since millions[7-0] are not likely to be delusional. These diagnostics are illogical,[10] and pending the investigation on the state of medical science[11] below, are also incorrect.

First Formulate

First, we must formulate a clear clinical question from a patient’s problem. Marie, our hypothetical patient, has normal standard thyroid tests [12-19] with or without therapy with levothyroxine sodium. Unfortunately, Marie has continuing symptoms of hypothyridism.

Second Search

Second, we must search the literature for relevant clinical articles. Certainly, a continuing medical education course could be useful. A search finds one by Gossel (Table 1 of 20) and Talking Points on hypothyroidism by Garber.[21] From these we learn :

1. There is a resistance to the cellular reception of thyroid hormones, circa 1967.
2. Triiodothyronine (T3) is largely produced by peripheral conversion of thyroxine (T4), circa 1970.

Further searching finds this quotation that puts a substantial different view upon Maries problem:
T4 . . . is not the active ingredient. T3 is the active ingredient, and it’s the thing that accounts for the thyroid hormone action. As I’ve been reminded many times, there are no intracellular events that we know that can be described by T4 at the level of the nucleus. Only T3. T4 is not the active compound. Likewise, the site of action is in the nucleus. The site of action is not T4 in the plasma. Dr. E. Chester Ridgway[22]

That statement is powerful. It puts a different light on Maries problem. Perhaps, the lack of T3 is
producing the problem. But that is generally not mentioned in the guidelines for hypothyroidism(12 19) and dismissed elsewhere[20,21] On the other hand, Marie isnt getting better.

Further search reveals much more research on both peripheral hormone reception, for example,[23-28] and peripheral metabolism or conversion, for example.[29-39] Unfortunately, we also find some detractions of the use of triiodothyronine (T3), [5, 12 17,40 43] as well as some studies that find T3 replacements useful.[44 48] It is no wonder that Anthony Toft and Geoffrey Beckett were puzzled.[49]

It is extraordinary that more than 100 years since the first description of the treatment of hypothyroidism and the current availability of refined diagnostic tests, debate is continuing about its diagnosis and management.


Third Critically Appraise

As suggested in the third step: we must evaluate and critically appraise the evidence for its validity and usefulness.

Wilsons Syndrome,[5] a position paper by the American Thyroid Association (ATA), claims that no triiodothyronine (T3) containing therapy is needed because the peripheral metabolism or conversion is regulated. In other words, this peripheral process never fails. This is a substantial statement from allopaths, whose entire adult lives have concentrated on somatic failures. Considering the lack of supporting references in Wilsons Syndrome, its counter-intuitive nature, and existing contrary references, [29 39, 40 43] this is a substantially misleading statement.

Wilsons Syndrome, [5] also claims that continuing symptoms are nonspecific in view of Barsky. [6] However, the Barsky subjects may have had hypothyroidism because they were not screened against hypothyroidism. Thus, the ATA wishes to separate continuing symptoms from hypothyroidism with data tainted by hypothyroidism. This is a logical faux pas. Further, nonspecific symptoms are also discredited by Hypothyroidism Presenting with Musculoskeletal Symptoms.[50]

Wilsons Syndrome,[5] continued with this errant logic in depreciating an indicator of hypothyroidism found by a pioneer, Dr. Broda Barnes,[51] the low basal temperature. The citation[52] is of a study that also did not screen out subjects with hypothyroidism. Another logical faux pas.

The papers [40 43] which demonstrate that triiodothyronine (T3) is not effective or useful, support the established thyroxine-only therapy. These papers suffer for several reasons:

1. Many studies were done with subjects who had primary hypothyroidism or had thyroidectomies. The subjects showed little if any benefit with the addition of triiodothyronine (T3) to their therapy in lieu of some of the thyroxine (T4). There were no subjects identified as suffering from deficient peripheral metabolism or deficient hormone reception. Consequently, these results proved nothing for patients suffering from these deficiencies.[10]

2. The low occurrence rate of subjects that have post-thyroid or exo-endocrine deficiencies permitted the authors to round off the low rate of improvement and conclude no improvement.[10]

3. Anecdotally, the triiodothyronine doses were quite low, usually about 5 micrograms per day. This dose in a patient that actually suffers from post-thyroid deficiencies did not produce sustained noticeable benefits. Indeed, that dose is less than 5% to 10% of the usual replacement dose of 50 mcg to 100 mcg daily. In fact, 5 micrograms is the recommended starting dose for more sensitive patients, infants and the elderly. [53]
The papers [44 48] are more positive about the use of a T3 containing hormone replacement. But what
about selecting an approach? A further search turns up two papers, by Baisier, Hertoghe and Eeckhaut,[54] and Brady.[55]

Fourth Implement

The Baisier paper is important because these physicians examined patients with continuing symptoms of hypothyroidism, i.e., the failures of established endocrinology, for their symptoms and for the T3 in their 24-hour urine sample. They produced a clinical algorithm for evaluating symptoms that correlated with further evaluation.

Then, for a more objective measurement, the T3 in the 24-hour urine sample correlated quite well with symptoms.[54] In a follow-up study, they found 40 of the 89 volunteers and treated them with desiccated thyroid with success.[55]

The Brady paper has a diagnostic aid in Table 2. Brady claims that Euthyroid Sick Syndrome and deficiencies in peripheral metabolism or peripheral hormone reception can be differentially diagnosed with the following conditions[55]

T4 Normal or Low Free T4 index Normal or Low

Free T4 Normal or Low

T3 Normal or Low T3 resin uptake Normal or Low

Reverse T4 (rT3) High

TSH Variable,

TRH Normal or low

This set of conditions, particularly a high rT3 in the presence of other hypothyroidism indicators and assays, suggests that the peripheral metabolism or peripheral hormone reception is deficient. Since the dominant hormone in that realm is triiodothyronine (T3), one of the approved several T3 replacements[56] is a logical consideration.

Cautions

Of course, with the administration of any drug, due care must be taken. The manufacturers approved usage recommendations must be considered and followed. Further, for patients requiring a T3 replacement, there probably is not a valid equivalency between a levothyroxine sodium (T4) therapy and a T3-containing therapy because the efficiency of the peripheral metabolism of T4 to T3 probably is not normal.

Conclusion

Evidence Based Medicine (EBM) can, if given a chance, produce a solution to quite unsatisfactory results of extensive hypothyroidism diagnostics and therapy attempts. It can because there are physical reasons for the continuing symptoms. The information about these causes and treatments of these symptoms exists.

Endnotes

1. Rosenberg W, Donald A, Evidence based medicine: an approach to clinical problem-solving, BMJ 1995;310:1122-1126 (29 April)
2. Sackett DL, Rosenberg MC, Muir Gray JA, Haynes RB, Richard WS, Evidence Base Medicine: What It Is and What It Isnt, BMJ, 1996; 312:71-72
3. Weetman AP, Whose Thyroid Hormone Replacement is it Anyway? Clin Endocrinol, 2006;64(3):231-233
4. Salmon P, Peters S, Stanley I, Patients Perceptions of Medical Explanations for Somatisation
Disorders: Qualitative Analysis, BMJ, 1999; 318:372-378
5. Wilsons Syndrome, American Thyroid Association, Nov 1999 updated May 2005
6. Barsky, AJ, MD and Borus, JF. MD, Functional Somatic Syndromes, Ann Intern Med, June 1999, 130(11): 910-921.
7. Saravanan P, Chau F, Roberts N, Vedhara K, Greenwood R, Dayan CM, 2002, Psychological Well-Being in Patients on Adequate Doses of L-Thyroxine Results of a Large, Controlled Community-Based Questionnaire Study, Clinical Endocrinology, 2002, 57: 577-585
8. Turner S, Hypothyroidism Patient Survey Results, Thyroid Patient Advocacy-UK, http://www.tpa-uk.org/tpauk_hypothyroidsurvey.php
9. Patients Petition for Better Diagnosis and Treatment Choice for Hypothyroid Patients, International Hormone Society, http://inthormonesociety.org
10. Pritchard EK, The Linguistic Etiologies of Thyroxine-Resistant Hypothyroidism, Thyroid Science www.thyroidscience.com click on debate.
11. Sharpe M, Carson A, Unexplained Somatic Symptoms, Functional Syndromes, and Somatization: Do We Need a Paradigm Shift?, Ann Intern Med, 2001, 134:926-930
12. Baskin, HJ, MD, Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hyperthyroidism and Hypothyroidism, Am Assoc Clin Endocrinol, 2002, Rev 2006
13. Levy EG, Ridgway EC, Wartofsky L, Algorithms for Diagnosis and Management of Thyroid Disorders, www.thyroidtoday.com 2004.
14. The American Thyroid Association provides links to several hypothyroidism related guidelines: Use of Laboratory Tests in Thyroid Disorders, Treatment Guidelines for Patients with Hyperthyroidism and Hypothyroidism, and Guidelines for Detection of Thyroid Dysfunction.
15. Levy EG, Hypothyroidism Treatment Failure: Differential Diagnosis, www.thyroidtoday.com 2004.
16. Vanderpump MPJ, Ahlquist JAO, Franklyn JA, et al., Consensus Statement for Good Practice and Audit Measures in the Management of Hypothyroidism and Hyperthyroidism, BMJ, August 1996
17. Garber JR, Hennessey JV, Lieberman JA, Morris CM, Talbert RI, Managing the Challenges of Hypothyroidism, Supplement to J of Fam Pract, 2006, www.jponline.com
18. Kaplan MM, Clinical Perspectives in the Diagnosis of Thyroid Disease, Clin Chem, 1999, 45:8(B) 1377-1383
19. UK Guidelines for the Use of Thyroid Function Tests, The Association for Clinical Biochemistry, British Thyroid Association, British Thyroid Foundation, 2006, www.british-thyroid-association.org/guidelines.htm
20. Gossel, TA, Endocrinology Continuing Education accredited by the Accreditation Council for Continuing Medical Education (ACCME), 2005
21. Garber JR, HypothyroidismTalking Points 2006, AACE
22. Ridgway EC, Food and Drug Administration Joint Public Meeting on Bioequivalence of
Levothyroxine Sodium, Monday, May 23, 2005, pages 144-145
23. Sakurai A, Takeda K, Ain K, et al., Generalized Resistance to Thyroid Hormone Associated with a Mutation in the Ligand-Binding Domain of the Human Thyroid Hormone Receptor ?, Proc. Natl. Acad. Sci, November1989, 86:8977-81.
24. Refetoff S, Weiss RE, Usala SJ, The Syndromes of Resistance to Thyroid Hormone, Endocr Rev, 1993, 14(3):348-399
25. Weiss RE, Refetoff S, Treatment of Resistance to Thyroid Hormone Primum Non Nocere, J Clin Endocr Metabol, 84(2):401-404.
26. Pohlenz J, Weiss RE, Macchia PE, et al., Five New Families with Resistance to Thyroid Hormone not Caused by Mutations in the Thyroid Hormone Receptor b Gene, J Clin Endocr Metabol, 84(11):3919-28
27. Yen PM, Sugawara A, Refetoff S, Chin WW, New Insights on the Mechanism(s) of the Dominant Negative Effect of Mutant Thyroid Hormone Receptor in Generalized Resistance to Thyroid Hormone, Am Soc Clin Invest, November 1992, 90:1825-31
28. Jameson JL, Editor, Hormone Resistance Syndromes, Humana Press, 1999
29. Visser TJ, Leonard JL, Kaplan MM, Larsen PR, Kinetic Evidence Suggesting Two Mechanisms for Iodothyronine5′-deiodination in Rat Cerebral Cortex, Proc. Natl Acad Sci. USA, August 1982, 79:5080-84
30. Kaplan MM, Utiger, RD, Iodothyronine Metabolism in Rat Liver Homogenates, J Clin Invest, February 1978, 61:459-471
31. Hidal JT, Kaplan MM, Characteristics of Thyroxine 5′-Deiodination in Cultured Human Placental Cells Regulation by lodothyronines, September 1985, J Clin Invest, 76:947-955
32. Kaplan MM, Yaskoski KA, Maturational Patterns of lodothyronine Phenolic and Tyrosyl Ring Deiodinase Activities in Rat Cerebrum, Cerebellum, and Hypothalamus, J Clin Invest, April 1981, 67:1208-1214
33. Braverman LE, Ingbar SH, Keinwem S, Conversion of Thyroxine (T4) to Triiodothyronine (T3) in Athyreotic Human Subjects, The J Clin Invest, 1970, 49
34. Danzi S, Ojamaa K, and Klein I, Triiodothyronine-Mediated Myosin Heavy Chain Gene Transcription in the Heart, Am J Phys Heart Circ Physiol, Feb 27, 2003
35. Eisenstein Z, Hagg S, Braverman LE, et al., Effect of Starvation on the Production and Peripheral Metabolism of 3,3′,5′ Triiodothyronine in Euthyroid Obese Subjects, J Clin Endocrinol Metab, 1978, 47(4): 889-893
36. Nomura S., et al. Reduced Peripheral Conversion of Thyroxine to Triiodothyronine in Patients with Hepatic Cirrhosis, J of Clin Invest, Sept 1975, 56(3): 643-652.
37. Bianchi R, Mariani G, Molea N, Vitek F, Cazzuola F, Carpi A, Mazzuca N, Toni MG, Peripheral Metabolism of Thyroid Hormones in Man. Direct Measurement of the Conversion Rate of Thyroxine to 3,5,3′-Triiodothyronine (T3) and Determination of the Peripheral and Thyroidal Production of T3., J. Clin Endocrinol Metab., 1983 June; 56(6):1152-63
38. Kelly G, Peripheral Metabolism of Thyroid Hormones: A Review, Alt Med Rev, 2000, 5(4): 306-
333. (Includes large bibliography on peripheral metabolism.)
39. Danforth E, Burger AG, Ingbar SH, Braverman L, et al., Dietary-Induced Alterations in Thyroid Hormone Metabolism during Overnutrition, J Clin Invest, November 1979, 64: 1336-47
40. Sawka, AM, Gerstein, HC, Marriott, MJ, MacQueen GM, and Joffe, RT, Does a Combination Regimen of Thyroxine (T4) and 3,5,3′-Triiodothyronine Improve Depressive Symptoms Better Than T4 Alone in Patients With Hypothyroidism? Results of a Double-Blind, Randomized, Controlled Trial, J Clin Endocrinol Metabol, 2004, 89(3); 1486-7
41. Siegmund W, Spieker K, Weike AI, Giessmann T, Modess C, Dabers T, Kirsh G, Sanger E, Engle G, Hamm AO, Nauck M, Meng W., Replacement Therapy with Levothyroxine Plus Triiodothyronine (Bioavailable Molor Ratio 14:1) is not Superior to Thyroxine Alone to Improve Well-Being and Cognitive Performance in Hypothyroidism, Clin Endocrinol, 2004 June;60(6);750-757
42. Walsh, Dr. John P., Combined Thyroxine/Liothyronine Treatment Does Not Improve Well-Being, Quality of Life, Or Cognitive Function Compared to Thyroxine Alone: A Randomized Controlled Trial in Patients with Primary Hypothyroidism, J Clin Endocrinol Metabol, 88(10):4543-50.
43. Clyde, Patrick W, MD, Combinination Levothyroxine/Liothyronine Shows No Obvious Benefit Over Levothyroxine Alone in Patients With Primary Hypothyroidism, JAMA, December 2003 as reported by Joene Hendry of Doctors Guide.
44. Gaby AR, Sub-Laboratory Hypothyroidism and the Empirical use of Armour Thyroid, Alt Med Rev, 2004, 9(2)
45. Danzi S and Klein I, Potential Uses of T3 in the Treatment of Human Disease, Clin Cornerstone, 2005, 7(S2): S9-S15
46. Bunevacius, R MD PhD, Kacanavicius, G MD PhD, Zalinkinevicius, R MD, Prange, A MD, Effects of Thyroxine as Compared with Thyroxine plus Triiodothyronine in Patients with Hypothyroidism, NEJM, Feb 11, 1999, 340:424-429
47. Bente C, Appelhof EF, Ellie MW, et al., Combined Therapy with Levothyroxine and Liothyronine in Two Ratios, Compared with Levothyroxine Monotherapy in Primary Hypothyroidism: a Double-Blind, Randomized, Controlled Clinical Trial, J Clin Endocrinol Metabol, 90(5):2666-2674.
48. Hertoghe T, Lo Cascio A., Hertoghe J. Considerable improvement of hypothyroid symptoms with two combined T3-T4 medication in patients still symptomatic with thyroxine treatment alone. Anti-Aging Medicine, Ed. German Society of Anti-Aging Medicine-Verlag 2003- 2004; 32-43
49. Toft A, Beckett G, BMJ 2003 (8 Feb); 326:295-296
50. Golding DN, Hypothyroidism Presenting with Musculoskeletal Symptoms, Annals of Rheumatgic Diseases, 1970, 29(10)
51. Barnes, B MD, Hypothyroidism: The Unsuspected Illness, Harper & Row, 1976
52. Mackowiak, et al., A Critical Appraisal of 98.6 Degrees F, the Upper Limit of the Normal Body Temperature, and other Legacies of Carl Reinhold August Wunderlich, JAMA, 1992, 268:1578-80
53. Federal Drug Administration NDA 10-379 for Cytomel, a synthetic triiodothyronine replacement.
54. Baisier, WV, Hertoghe, J., Beekhaut, W., Thyroid Insufficiency? Is Thyroxine the Only Valuable
Drug?, J Nutr and Environ Med, September 2001, 11(3):159-166
55. Brady, D, Functional Thyroid Disorders, Part I, Dynamic Chiropractic, March 20, 2000, 18(7), Table 2
56. Food and Drug Administration accepted or approved and indicated triiodothyronine (T3) containing hormone replacements:

[TABLE=”width: 100%”]
[TR]
[TD] Replacement Manufacturer[/TD]
[TD] Replacement Name[/TD]
[TD] Approval / Acceptance[/TD]
[/TR]
[TR]
[TD] Forest Laboratories, Inc.
909 Third Avenue, 23rd Floor
New York, NY 10022
[/TD]
[TD] Armour
Thyrolar
[/TD]
[TD] Desiccated thyroid was
Manufactured prior to 1937
NDA 16-807
[/TD]
[/TR]
[TR]
[TD] King Pharmaceuticals, Inc.
501 Fifth Street
Bristol, TN 37620
[/TD]
[TD] Cytomel[/TD]
[TD] NDA 10-379[/TD]
[/TR]
[TR]
[TD] Western Research Laboratories
2404 West 12th Street, Suite 4
Tempe, AZ 85281
[/TD]
[TD] Westhroid
Nature-throid
[/TD]
[TD] Desiccated thyroid was
Manufactured prior to 1937
[/TD]
[/TR]
[/TABLE]

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