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A Clinical Approach to Thyroid Insufficiency: Beyond the TSH/T4 Laboratory Paradigm Henry Lindner, MD Hormonerestoration.com Conventional Endocrinology: Missing the Boat Diagnoses and treats only severe hormonal disorders caused by disease. Laboratory Orientation: Uses population reference ranges to define disease and treatment Fails to diagnose if hormone levels are anywhere within the reference range Disease/no disease instead of continuum Blind to the prevalence of moderate functional and age-related hormone Clinical Medicine: vs. Laboratory Primacy of Signs and Symptoms Notes Relative Levels Degrees of Insufficiency Goal=Optimal Clinical Response Primacy of Laboratory Values Reference Ranges Disease/No Disease Goal=Normalization of Lab Values Clinical vs. Biochemical “It is of special interest that some patients with severe biochemical hypothyroidism had only mild clinical signs, whereas other patients with minor biochemical changes had quite severe clinical manifestations.” Zulewski H, Müller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab. 1997 Mar;82(3):771-6. Tests Cannot Be Used Determine Dose Detailed clinical assessments of 148 treated hypothyroid patients by four experienced clinicians “reference ranges for TT4, FT4, and TSH in patients receiving thyroxine replacement are considerably different from the conventional ranges;” “We consider that biochemical tests of thyroid function are of little, if any, value clinically in patients receiving thyroxine replacement.” “Further adjustments to the dose should be made according to the patient's clinical response.” Fraser WD, Biggart EM, O'Reilly DS, Gray HW, McKillop JH, Thomson JA. Are Clinical Trumps All “The ultimate test of whether a patient is experiencing the effects of too much or to little thyroid hormone is not the measurement of hormone concentration in the blood but the effect of thyroid hormones on the peripheral tissues” Greenspan FS, Rapoport B. 1991 Tests of thyroid function. In: Greenspan FS, ed. Basic and clinical endocrinology, 3rd ed. London: Appleton & Lange, Prentice Hall International; 211. The Meaning of the Reference Range Reference Range=95% of the population; NOT the optimal range for any person! Male testosterone: 250-1000ng/dL 4x! Female testosterone: 0.0-76ng/dL ! Free T4: 0.6-1.8g/dL 3x! Free T3: 2.3-4.2pg/ml 2x! Far too broad, does not define optimal Prevalence of Thyroid Insufficiency 19.7% of the non-diagnosed persons found to have “subclinical hypothyroidism” Kvetny J, Clin Endocrinol (Oxf). 2004 Aug;61(2):232-8 47.5% of blood donors had thyroid disease by serum testing and ultrasound. FT4 RR with normal US was 1.0-1.6 ng/dL Kratzsch J, Clin Chem. 2005 Aug;51(8):14806 Reference Range View vs. Physiology Euthyroid Ref. Range View Signs and Symptoms Hypothyroid Optimal Hyperthyroid Physiological View 0 Lower Limit Upper Limit Serum Hormone Levels Continuum: Weight vs. Free T4 Within the RR 4082 people in Denmark Reference Range: 9.8-20.4 nmol/l J Clin Endocrinol Metab July 2005, 90(7):4019-4024 Continuum: Higher FT4 and FT3 Levels within the RRs are Better: FT3 in upper third of range50% reduction of incidence of severe atherosclerosis Auer J, Clin Cardiol. 2003 Dec;26(12):56973 Lower cholesterol, triglycerides, Creactive protein, homocysteine and lipoprotein(a) Lower blood pressure, arterial dilatation TSH/T4 RR Nomenclature Primary hypothyroidism: FT4 with TSH Central hypothyroidism: FT4 and TSH Subclinical hypothyroidism: FT4 and TSH Primary hyperthyroidism: FT4 with TSH Subclinical hyperthyroidism: FT4 with TSH Problems “Subclinical” could have high or low-RR FT4! Laboratory, not a clinical classification system! Ignores actual FT4 levels within RR! TSH/T4 Thyroidology The TSH is always right—the perfect guide for diagnosis and treatment. Treat with T4 only because T4-to-T3 conversion is always perfect. The T3 level is irrelevant for diagnosis or treatment. Thyroid hormone resistance is rare and always involve high hormone levels. Exceptions are rare and can be ignored for practical purposes. Indicators of Thyroid Insufficiency First Rank—Signs and Symptoms Second Rank—FT4 and FT3 levels Third Rank—TSH TSH is indirect—a measure of H-P activity only, not of thyroid hormone effects througout the body. No Caption Found McDermott, M. T. et al. J Clin Endocrinol Metab 2001;86:4585-4590 The Rotterdam Study (9 ). Analysis of the relationship between subclinical hypothyroidism (SCH) and myocardial infarctions in this study revealed an attributable risk of 60% (SCH contributed to 60% of the myocardial infarctions in the 124 women who had SCH) and a population attributable risk of 14% (SCH was involved in 14% of all myocardial infarctions in the entire group of 1149 women). These risks were similar to those associated with the major recognized cardiovascular risk factors—hypercholesterolemia, hypertension (BP), smoking, and diabetes mellitus. Hak AE, Pols HAP, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly Copyright ©2001 The Endocrine Societywomen: the Rotterdam Study. Ann Intern Med. 2000; 132:270-78. Thyropause Endocr Rev. 1995 Dec;16(6):686-715. Universal Hypothalamic-Thyrotroph Dysfunction with Aging 120 100 80 60 40 20 0 TSH B-19yrs 20-39yrs 40-59yrs 60-79yrs 80-99yrs TSH response to low T4 (2.7-3.2g/dL) Thyroid. 2007 Feb;17(2):139-44. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000 Feb 28;160(4):526-34. The Colorado Thyroid Disease Prevalence Study (2 ). Shown are the age- and gender-specific Thyroid Hormones T4 T3 Maintain metabolic rate, mood, and energy Thyroid gland production controlled by thyroid stimulating hormone (TSH) from pituitary T4 (Synthroid, Levoxyl) is the bioidentical prohormone, must be converted to active T3 in tissues throughout the body. Thyroid gland makes T4 and T3; We should restore both hormones Thyroid hormone resistance can arise by Thyroid Insufficiency until Proven Otherwise Mental fog Fatigue, depression, anxiety Cold extremities Aches and pains Hair loss, esp. in women Weight gain Constipation Puffy ankles and face Elevated cholesterol Diagnosing Thyroid Insufficiency Listen to the patient Always check free T4 and free T3 levels and consider possibility of hormone resistance TSH diagnostic only if elevated--thyroid gland failure Don’t overlook moderate thyroid insufficiency caused by H-P dysfunction (TSH within RR, hormone levels below mid-point of RR). Always consider a trial of adequate thyroid Symptomatic Patient: Diagnosis? TSH FT4 FT3 0 Lower Limit Upper Limit Symptomatic Patient: Diagnosis? TSH FT4 FT3 0 Lower Limit Upper Limit Symptomatic Patient: Diagnosis? TSH FT4 FT3 0 Lower Limit Upper Limit Symptomatic Patient: Diagnosis? TSH FT4 FT3 0 Lower Limit Upper Limit Symptomatic Patient: Diagnosis? TSH FT4 FT3 0 Lower Limit Upper Limit The Fatigue, Fibromyalgia, and Depression Epidemic Pre-1970s: Docs treated symptoms with T3 and T4 (desiccated porcine thyroidArmour) Post-1970s: Docs treat TSH using T4 only! Doses lowered by 30-50%! TSH “normalizing” T4 doselow freeT3 , weight gain, persistence of symptoms People with fatigue, fibromyalgia, and depression often have central thyroid Thyroid Optimization is Safe Eliminating symptoms by raising T4 and T3 into the upper half of the RR, or partially suppressing TSH does not cause: cardiac abnormalities J Clin Endo Metab. 2000 Jan;85(1):159-64 bone loss Horm Res. 2005;64(6):293-8. Epub 2005 Nov 1 muscle wasting Am J Phys Endol Metab. 2005 Jun;288(6):E106773 In hyperthyroidism, both T4 and T3 levels are above the RR 24hrs/day. Symptoms are sensitive indicators: hot Bone Loss Thyroid hormone increases metabolism including rate of bone turnover. If losing bone, will lose bone faster If gaining bone, will gain bone faster Most women>30yr old are losing bone Giving low dose T4 to hypothyroid women increases bone loss. For More Information HR essays and hundreds of abstracts at www.hormonerestoration.com. Contact me: [email protected]