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Thyroid Dysfunction: Clinical Overview
Hypothalamic-Pituitary-Thyroid Axis Physiology T 4 T3 – – TSH Adapted from Merck Manual of Medical Information. ed. R Berk...
Hypothalamic-Pituitary-Thyroid Axis Clinical Utility of TSH Hypothalamus Pituitary  Thyroid Gland T 4      T 3   Liver  T...
Mild Hypothyroidism & Mild Thyrotoxicosis Definitions TSH FT 4 Euthyroidism Overt Hypothyroidism Mild Overt Thyrotoxicosis...
Distribution of TSH Values by Race/Ethnicity (NHANES III) Lab reference range defined from values in “normal” population: ...
Hypothyroidism & Thyrotoxicosis Prevalences Data from the National Health and Nutrition Examination Survey (NHANES) III. H...
Thyroid disease is more prevalent than which of the following: <ul><li>A. Asthma </li></ul><ul><li>B. Heart disease </li><...
Thyroid Disease: Relative to Other  Diseases in the United States 1. Canaris GJ, et al.  Arch Intern Med . 2000;160:526-53...
Mild Hypothyroidism & Mild Thyrotoxicosis Common Causes <ul><li>Mild Hypothyroidism </li></ul><ul><li>Autoimmune thyroidit...
Mild Hypothyroidism & Mild Thyrotoxicosis Common Causes <ul><li>Mild Hypothyroidism </li></ul><ul><li>Autoimmune thyroidit...
Diagnosis and Treatment
Cost-Effectiveness of TSH Screening q. 5 yrs vs Other Preventive Medical Practices 0 Most cost- effective 20 40 60 80 100 ...
Screening: Recommendations <ul><li>Various societies and authors disagree about population-based screening </li></ul><ul><...
Diagnostic Algorithm 1. Adapted from: Singer PA, Cooper DS, et al. Treatment guidelines for patients with hyperthyroidism ...
Diagnosis: TPO Antibodies Sieiro Netto L, et al.  Am J Reprod Immunol.  2004;52:312-316. Lazarus JH.  Minerva Endocrinol ....
Levothyroxine Therapy <ul><li>LT 4  is the synthetic version of the naturally-occurring hormone thyroxine (T 4 )   </li></...
Starting Therapy <ul><li>Otherwise healthy, < 60 yrs, no cardiac Hx: </li></ul><ul><ul><ul><li>~1.7   g/kg/day </li></ul>...
Maintenance <ul><li>Periodic monitoring essential to ensure appropriate dosing and consistent effect </li></ul><ul><li>Onc...
Combined T 4 /T 3  Therapy Summary of Studies Bunevicius.  N Engl J Med . 1999 Feb 11;340(6):424-9. Bunevicius.  Int J Neu...
T 3  and T 4  /   T 3  Therapy <ul><li>T 3  has a very short half-life </li></ul><ul><li>Liothyronine </li></ul><ul><ul><l...
Suboptimal Thyroxine Therapy What Causes It? <ul><li>Mild Hypothyroidism </li></ul><ul><li>Low Rx dose </li></ul><ul><li>P...
<ul><li>Mild Hypothyroidism </li></ul><ul><li>Low Rx dose </li></ul><ul><li>Poor compliance </li></ul><ul><li>Drug interac...
According to current guidelines, what TSH range should I treat my hypothyroid patients to: <ul><li>A. 1 – 5.5  mU/L </li><...
Treatment Target <ul><li>The TSH target for hypothyroid patients is generally considered to be .5 – 2.0 mu/L </li></ul>Thy...
How Common Is Suboptimal Thyroxine Therapy? <ul><li>a. 1%  </li></ul><ul><li>b. 10%  </li></ul><ul><li>c. 20%  </li></ul><...
How Common Is Suboptimal Thyroxine Therapy? Excessive Thyroxine Therapy Inadequate Thyroxine Therapy 30% 20% 10% Ross,  19...
Potential Reasons to Increase LT 4  Dose <ul><li>Decreased L-T4 Absorption </li></ul><ul><li>Malabsorption Syndromes </li>...
Carr D, et al.  Clin Endocrinol . 1988;28:325-333.   Suboptimal Thyroxine Therapy  Impact of Small Thyroxine Dose Changes ...
1 0 8 6 4 2 0.2 . 1 - 50 -25 + 2 5 +50 TSH mU/L T 4  (  g/day) Dose +75 Normal TSH range Above-normal TSH Below-normal TS...
<ul><li>Clinical Consequences of Elevated and Decreased TSH </li></ul>
Mild Hypothyroidism & Mild Thyrotoxicosis Consequences <ul><li>Mild Hypothyroidism </li></ul><ul><li>↑  Cholesterol </li><...
Consequences of Hypothyroidism ↑ Cholesterol When  Mild & Overt Canaris GJ, et al.  Arch Intern Med.  2000;160:526-534. 7....
1.4 1.25 1.13 0.95 0 0.5 1 1.5 2 2.5 3 Subclinical Hypothyroid Euthyroid Triglycerides (mmol/L) CRP mg/L Kvetny J et al.  ...
Consequences of Hypothyroidism Abnormal Lipid Profile Modified from Frankyn JA. In: Braverman LE, Utiger RD, eds.  Werner ...
Effect of LT 4  Rx on Total Cholesterol  in Subclinical Hypothyroidism <ul><li>LT 4  tx may lower LDL but does not appear ...
Levothyroxine Effect on Cholesterol * * * p<0.05 Monzani F, et al.  J Clin Endocrinol Metab.  2004;89:2099-2106. TC   10%...
Consequences of Mild Hypothyroidism  Atherosclerosis  Odds Ratio (95% CI) †   Aortic Atherosclerosis Myocardial Infarction...
Consequences of Mild Hypothyroidism   Ischemic Heart Disease Imaizumi M.  JCEM . 2004;89(7):3365-3370.  <ul><li>2293 contr...
Consequences of Mild Hypothyroidism   Cardiac Function IVRT = isovolumic relaxation time; MVQ = mitral valve flow velocity...
Mild Hypothyroidism during Pregnancy
Subclinical Hypothyroidism and Pregnancy Outcomes <ul><li>17,298 tested women </li></ul><ul><li>404 with subclinical hypot...
Consequences of Mild Hypothyroidism   Fetal Death 0.9% 3.8% 0 1 2 3 4 5 Maternal TSH   6 mU/L Maternal  TSH <6 mU/L <ul><...
5% 19% 0 5 10 15 20 25 Consequences of Mild Hypothyroidism   Fetal Brain Development <ul><li>Children of women with untrea...
<ul><li>TSH testing recommended in 1 st  trimester </li></ul><ul><li>To maintain euthyroid state, LT 4  dose may need to b...
<ul><li>N  N (%) pregnancies w/   TSH   </li></ul><ul><li>Kaplan (1992)  42 27 (64%) </li></ul><ul><li>Girling (1992)  33...
<ul><li>Cardiac arrhythmias, especially a trial fibrillation </li></ul><ul><li>↑   CV mortality </li></ul>Mild Thyrotoxico...
Consequences of Mild Thyrotoxicosis Atrial Fibrillation Adapted from: Sawin CT, et al.  N Engl J Med . 1994;331:1249-1252....
Consequences of Mild Thyrotoxicosis Cardiovascular Mortality <ul><li>1191 UK persons  </li></ul><ul><ul><li> 60 years  </...
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Thyroid Dysfunction: Clinical Overview

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Thyroid Dysfunction: Clinical Overview

  1. 1. Thyroid Dysfunction: Clinical Overview
  2. 2. Hypothalamic-Pituitary-Thyroid Axis Physiology T 4 T3 – – TSH Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997. Pituitary Thyroid Gland Hypothalamus TRH T 4  T 3 Liver T 4 T 3 Heart Liver Bone CNS TR Target Tissues
  3. 3. Hypothalamic-Pituitary-Thyroid Axis Clinical Utility of TSH Hypothalamus Pituitary Thyroid Gland T 4  T 3 Liver T 4 TRH T 4 T3 TSH <ul><li>TSH reflects tissue thyroid hormone actions </li></ul><ul><li>TSH as an index of therapeutic success and potential toxicity </li></ul>T 3 – – Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997.
  4. 4. Mild Hypothyroidism & Mild Thyrotoxicosis Definitions TSH FT 4 Euthyroidism Overt Hypothyroidism Mild Overt Thyrotoxicosis Mild
  5. 5. Distribution of TSH Values by Race/Ethnicity (NHANES III) Lab reference range defined from values in “normal” population: 0.4 – 5.5 mU/L Data from the National Health and Nutrition Examination Survey (NHANES) III. Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.
  6. 6. Hypothyroidism & Thyrotoxicosis Prevalences Data from the National Health and Nutrition Examination Survey (NHANES) III. Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499. 0.3 4.3 0.5 0.7 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Mild Overt Mild Overt Prevalence, % Hypothyroidism Thyrotoxicosis Individuals with TSH >2.5 mU/L are at risk for overt hypothyroidism during a 20-year follow-up Vanderpump et al. Clinical Endocrin. 1995;43(1):55-68.
  7. 7. Thyroid disease is more prevalent than which of the following: <ul><li>A. Asthma </li></ul><ul><li>B. Heart disease </li></ul><ul><li>C. Diabetes </li></ul><ul><li>D. All of the above </li></ul>www.accessdata.fda.gov/scripts/cder/ob/docs/temptn.cfm ?
  8. 8. Thyroid Disease: Relative to Other Diseases in the United States 1. Canaris GJ, et al. Arch Intern Med . 2000;160:526-534. 2. National Center for Health Statistics. Fast stats A-Z. Available at: http://www.cdc.gov/nchs/ fastats/default.htm. Accessed February 16, 2006. 3. U.S. Census Bureau Web site. 1997 Population Profile of the United States, p23-194. Available at: http:// www.census.gov/prod/3/98pubs/p23-194.pdf. Accessed February 16, 2006. 4. AACE Thyroid Task Force. Guidelines. Endocr Pract. 2002;8:458-469. Arthritis 33.0 Asthma 17.6 Diabetes 10.0 COPD 9.6 Thyroid Disease Hypothyroidism Nodules 21.3 Heart Disease 15.0 0 5 10 15 20 Cases (millions) 1,2,3,4 25 35 30
  9. 9. Mild Hypothyroidism & Mild Thyrotoxicosis Common Causes <ul><li>Mild Hypothyroidism </li></ul><ul><li>Autoimmune thyroiditis </li></ul><ul><li>Previous thyroid surgery and/or 131 I therapy for thyrotoxicosis </li></ul><ul><li>Mild Thyrotoxicosis </li></ul><ul><li>Graves’ disease </li></ul><ul><li>Nodular goiter </li></ul>
  10. 10. Mild Hypothyroidism & Mild Thyrotoxicosis Common Causes <ul><li>Mild Hypothyroidism </li></ul><ul><li>Autoimmune thyroiditis </li></ul><ul><li>Previous thyroid surgery and/or 131 I therapy for thyrotoxicosis </li></ul><ul><li>Inadequate thyroxine therapy </li></ul><ul><li>Mild Thyrotoxicosis </li></ul><ul><li>Graves’ disease </li></ul><ul><li>Nodular goiter </li></ul><ul><li>Excessive thyroxine therapy </li></ul>
  11. 11. Diagnosis and Treatment
  12. 12. Cost-Effectiveness of TSH Screening q. 5 yrs vs Other Preventive Medical Practices 0 Most cost- effective 20 40 60 80 100 Least cost- effective Dollars (1994 $ thousands) Cholesterol screening of asymptomatic population Breast cancer screening: women aged 65 to 74 y Hypertension screening: women aged 40 y Hypertension screening: men aged 40 y Hypothyroidism: men aged 35 y Exercise for CHD prevention Smoking cessation Hypothyroidism: women aged 35 y Flu vaccine: adults aged 45 to 65 y Breast cancer screening: women aged 40 to 74 y Adapted from Danese MD et al. JAMA . 1996;276:285.
  13. 13. Screening: Recommendations <ul><li>Various societies and authors disagree about population-based screening </li></ul><ul><li>The AAFP recommends screening high-risk populations: </li></ul><ul><ul><li>women with a family hx of thyroid disease </li></ul></ul><ul><ul><li>women >35 yo </li></ul></ul><ul><ul><li>pregnant women </li></ul></ul><ul><ul><li>abnormal physical exam </li></ul></ul><ul><ul><li>diabetic patients </li></ul></ul><ul><ul><li>Hx of autoimmune disorder </li></ul></ul><ul><li>The American Thyroid Association indicates that screening is justifiable in men > 35 yo as well (q 5 years) </li></ul>Surks. JAMA . 2004 Jan 14;291(2):228-38. American Academy of Family Physicians. Subclinical Thyroid Disease. Available at: http://www.aafp.org/afp/20051015/1517.pdf Accessed February 16, 2006. The American Thyroid Association Web site. American Thyroid Association Guidelines for Detection of Thyroid Dysfunction. Available at: http://thyroid.org/professionals/publications/documents/GuidelinesdetectionThyDysfunc_2000.pdf. Accessed February 16, 2006.
  14. 14. Diagnostic Algorithm 1. Adapted from: Singer PA, Cooper DS, et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. ATA. JAMA . 1995;273:808-12. 2. Nat’l. Academy of Clinical Biochemistry. Laboratory Med. Practice Guidelines. Lab. support for the diagnosis and monitoring of thyroid disease. 2002. TSH 0.3 to 3.5  U/mL Euthyroid TSH <0.3  U/mL Hyperthyroid? TSH 3.5-9.0  U/mL, NL free T4 TSH >9.0  g/mL, LOW free T4 Suspect Hypothyroid? Test TSH,free T4 Overt Hypothyroidism Mild Thyroid Failure REPEAT TSH and Treat
  15. 15. Diagnosis: TPO Antibodies Sieiro Netto L, et al. Am J Reprod Immunol. 2004;52:312-316. Lazarus JH. Minerva Endocrinol . 2005 Jun;30(2):71-87. Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499. Hak AE, et al. Ann Intern Med . 2000;132:270-278. <ul><li>~10% of NHANES population had TPO+ antibodies </li></ul><ul><li>Potential indicator of autoimmune thyroid failure </li></ul><ul><li>Risk of miscarriage higher in women with TPO+ antibodies </li></ul><ul><li>Screening for TPO+ab warranted pre-conception </li></ul><ul><li>TPO+ab may be associated with CV risks </li></ul>Prevalence of antibodies
  16. 16. Levothyroxine Therapy <ul><li>LT 4 is the synthetic version of the naturally-occurring hormone thyroxine (T 4 ) </li></ul><ul><li>Physicians use TSH to individualize the optimal LT 4 dose </li></ul><ul><li>Small changes in LT 4 dose can cause significant changes in TSH levels </li></ul><ul><li>LT 4 is provided in 12 dosage strengths that differ by as little as 9% </li></ul>Food and Drub Administration Web site. Active Ingredients. Available at: http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm. Accessed February 16, 2006.
  17. 17. Starting Therapy <ul><li>Otherwise healthy, < 60 yrs, no cardiac Hx: </li></ul><ul><ul><ul><li>~1.7  g/kg/day </li></ul></ul></ul><ul><ul><ul><li>8 week F/U TSH, 25  g dose increments </li></ul></ul></ul><ul><li>Older patients, > 60: require 20-30% less </li></ul><ul><ul><ul><li>50  g/day </li></ul></ul></ul><ul><ul><ul><li>6 week F/U TSH, 12-25  g dose increments </li></ul></ul></ul><ul><li>Congenital hypothyroidism </li></ul><ul><ul><ul><li>Initiate therapy with 10-15  g/kg/day </li></ul></ul></ul><ul><ul><ul><li>Usually 50  g/d X 1 week, then 37  g/d </li></ul></ul></ul><ul><li>Pediatric hypothyroidism </li></ul><ul><ul><ul><li>Initial dose: 25-50  g/day X 2-4 weeks </li></ul></ul></ul><ul><ul><ul><li>Titration: 25  g increments Q 4- 8 weeks </li></ul></ul></ul>American Thyroid Association Web site. Treatment Guidelines for Patients with Hyperthyroidism and Hypothyroidism. Available at: http://thyroid.org/professionals/publications/documents/GuidelinesHyperHypo_1995.pdf. Accessed February 16, 2006. Hennessey J. Endocrinologist . 13(6):479-487, Nov/Dec 2003. Sperling. Pediatric Endocrinology, Second Edition. Saunders, Philadelphia: 175-177. Foley. Congenital Hypothyroidism, Acquired Hypothyroidism in Infants, Children, and Adolescents. The Thyroid, 8th Edition . Braverman & Utiger eds. pp.977-988.
  18. 18. Maintenance <ul><li>Periodic monitoring essential to ensure appropriate dosing and consistent effect </li></ul><ul><li>Once TSH normalized: </li></ul><ul><ul><li>Visit frequency decreased to Q 6-12 months </li></ul></ul><ul><li>TSH should be measured at least annually </li></ul><ul><li>Re-measure TSH (in 8-12 weeks) following: </li></ul><ul><ul><li>Dosage, type or brand of thyroxine change </li></ul></ul>Singer et al. JAMA. 1995;273:808-812.
  19. 19. Combined T 4 /T 3 Therapy Summary of Studies Bunevicius. N Engl J Med . 1999 Feb 11;340(6):424-9. Bunevicius. Int J Neuropsychopharmacol . 2000 Jun;3(2):167-174. Walsh et al. J Clin Endocrinol Metab . 2003 Oct;88(10):4543-50. Sawka et al. J Clin Endocrinol Metab . 2003 Oct;88(10):4551-5. Clyde. JAMA . 2003 Dec 10;290(22):2952-8. Same Same Lower Higher Higher Same SHBG Cholesterol Same Same Same Same Same Same Same Improved Improved Cognitive Mood 2.0 vs 2.1 1.8 vs 1.7 3.1 vs 1.5 0.7 vs 0.8 0.5 vs 0.8 TSH T4/T3 vs T4 16 wks 15 15 wks 25 10 Wks 10 5 wks 12.5 5 wks 12.5 Duration T3 Dose 44 67% 40 100% 110 85% 11 100% 33 48% N Thyroiditis Clyde JAMA Sawka JCEM Walsh JCEM Bunevicius JIN Bunevicius NEJM
  20. 20. T 3 and T 4 / T 3 Therapy <ul><li>T 3 has a very short half-life </li></ul><ul><li>Liothyronine </li></ul><ul><ul><li>Synthetic </li></ul></ul><ul><ul><li>T 3 is more biologically active that LT 4 </li></ul></ul><ul><ul><li>No indication for the use of T3 alone </li></ul></ul><ul><li>Thyroid extract </li></ul><ul><ul><li>Porcine-derived </li></ul></ul><ul><ul><li>T 4 and T 3 </li></ul></ul>RxList Web site. Liothyronine Sodium Indications. Available at: http://www.rxlist.com/cgi/generic3/liothyronine_ids.htm. Accessed February 16, 2006. The American Thyroid Association Web site. Thyroid Hormone Treatment FAQ. Available at: http://thyroid.org/patients/brochures/HormoneTreatmentFAQ.pdf. Accessed February 16, 2006.
  21. 21. Suboptimal Thyroxine Therapy What Causes It? <ul><li>Mild Hypothyroidism </li></ul><ul><li>Low Rx dose </li></ul><ul><li>Poor compliance </li></ul><ul><li>Drug interaction </li></ul><ul><li>Dietary interference with absorption </li></ul><ul><li>Pregnancy </li></ul><ul><li>↓ Residual gland function </li></ul><ul><li>Formulation switch </li></ul>
  22. 22. <ul><li>Mild Hypothyroidism </li></ul><ul><li>Low Rx dose </li></ul><ul><li>Poor compliance </li></ul><ul><li>Drug interaction </li></ul><ul><li>Dietary interference with absorption </li></ul><ul><li>Pregnancy </li></ul><ul><li>↓ Residual gland function </li></ul><ul><li>Formulation switch </li></ul>Suboptimal Thyroxine Therapy What Causes It? <ul><li>Mild Thyrotoxicosis </li></ul><ul><li>High Rx dose </li></ul><ul><li>Factitious ingestion </li></ul><ul><li>Aging with ↓ requirement for LT 4 </li></ul><ul><li>Nonsuppressed endogenous gland function </li></ul><ul><li>Stopping estrogen therapy </li></ul><ul><li>Formulation switch </li></ul>
  23. 23. According to current guidelines, what TSH range should I treat my hypothyroid patients to: <ul><li>A. 1 – 5.5 mU/L </li></ul><ul><li>B. 0.5 – 4.5 mU/L </li></ul><ul><li>C. 0.5 – 2.0 mU/L </li></ul><ul><li>D. 1 mU/L </li></ul>www.accessdata.fda.gov/scripts/cder/ob/docs/temptn.cfm ?
  24. 24. Treatment Target <ul><li>The TSH target for hypothyroid patients is generally considered to be .5 – 2.0 mu/L </li></ul>ThyroidToday Web site. Hypothyroidism Treatment Failure: Differential Diagnosis. Available at: http://www.thyroidtoday.com/ExpertOpinions/S320%20Hypothyroidism%20Differential%20Diagnosis.pdf. Accessed February 16, 2006.
  25. 25. How Common Is Suboptimal Thyroxine Therapy? <ul><li>a. 1% </li></ul><ul><li>b. 10% </li></ul><ul><li>c. 20% </li></ul><ul><li>d. 40% </li></ul>?
  26. 26. How Common Is Suboptimal Thyroxine Therapy? Excessive Thyroxine Therapy Inadequate Thyroxine Therapy 30% 20% 10% Ross, 1990 Parle, 1993 Canaris, 2000 Hollowell, 2002 27% 21% 14% 18% 18% 22% 15% 18% 10% 20% 30% Ross DS, et al. JCEM. 1990;71:764-769. Parle JV, et al. Br J Gen Pract. 1993;43:107-109. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. Hollowell J, et al. JCEM. 2002;87:489-499.
  27. 27. Potential Reasons to Increase LT 4 Dose <ul><li>Decreased L-T4 Absorption </li></ul><ul><li>Malabsorption Syndromes </li></ul><ul><ul><li>Jejunoileal Bypass Surgery </li></ul></ul><ul><ul><li>Short Bowel Syndrome </li></ul></ul><ul><ul><li>Cirrhosis </li></ul></ul><ul><li>Drugs or Diet </li></ul><ul><ul><li>Cholestyramine </li></ul></ul><ul><ul><li>Aluminum Hydroxide </li></ul></ul><ul><ul><li>Sucralfate </li></ul></ul><ul><ul><li>Ferrous Sulfate </li></ul></ul><ul><ul><li>Calcium Carbonate </li></ul></ul><ul><ul><li>Cation-Exchange Resin </li></ul></ul><ul><ul><li>High Fiber Diet </li></ul></ul><ul><ul><li>Infants Fed Soybean Formula </li></ul></ul><ul><ul><li>? Excess Soybean in Adults </li></ul></ul><ul><ul><li>Achlorhydria </li></ul></ul><ul><ul><li>? Proton Pump Inhibitors </li></ul></ul><ul><ul><li>? H-2 Blockers </li></ul></ul><ul><li>Increased Biliary Excretion </li></ul><ul><li>Phenytoin sodium </li></ul><ul><li>Rifampin </li></ul><ul><li>Phenobarbital </li></ul><ul><li>Carbamazepine </li></ul><ul><li>Decreased Deiodination of T 4 to T 3 </li></ul><ul><li>Amiodarone </li></ul><ul><li>Increased TBG </li></ul><ul><li>Pregnancy </li></ul><ul><li>BCP </li></ul><ul><li>Estrogens </li></ul><ul><li>Hepatitis </li></ul><ul><li>Hereditary </li></ul><ul><li>Unknown </li></ul><ul><li>Sertraline </li></ul>ThyroidToday Web site. Hypothyroidism Treatment Failure: Differential Diagnosis. Available at: http://www.thyroidtoday.com/ExpertOpinions/S320%20Hypothyroidism%20Differential%20Diagnosis.pdf. Accessed February 16, 2006.
  28. 28. Carr D, et al. Clin Endocrinol . 1988;28:325-333. Suboptimal Thyroxine Therapy Impact of Small Thyroxine Dose Changes 1 0 8 6 4 2 0.2 . 1 - 50 -25 + 2 5 +50 TSH mU/L T 4 (  g/day) Dose <ul><li>21 hypothyroid adults with normal TSH on thyroxine </li></ul><ul><li>Dose changed by 25 µg q. 6 weeks </li></ul>+75 Optimum
  29. 29. 1 0 8 6 4 2 0.2 . 1 - 50 -25 + 2 5 +50 TSH mU/L T 4 (  g/day) Dose +75 Normal TSH range Above-normal TSH Below-normal TSH Optimum Carr D, et al. Clin Endocrinol . 1988;28:325-333. Suboptimal Thyroxine Therapy Impact of Small Thyroxine Dose Changes
  30. 30. <ul><li>Clinical Consequences of Elevated and Decreased TSH </li></ul>
  31. 31. Mild Hypothyroidism & Mild Thyrotoxicosis Consequences <ul><li>Mild Hypothyroidism </li></ul><ul><li>↑ Cholesterol </li></ul><ul><li>↑ Atherosclerotic cardiovascular disease and MI risk </li></ul><ul><li>↑ Miscarriage risk </li></ul><ul><li>Impaired fetal development </li></ul><ul><li>Inadequate TSH suppression in thyroid cancer patients </li></ul>
  32. 32. Consequences of Hypothyroidism ↑ Cholesterol When Mild & Overt Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 Mean Total Cholesterol Level, mmol/L 280 270 260 250 240 230 220 210 200 (mg/dL) >10-15 <0.3 0.3-5.1 >5.1-10 >15-20 >20-40 >40-60 >60-80 >80 TSH, mlU/L Abnormal TSH Level Euthyroid 5.41 (209) 5.78 (223) 5.85 (226) 5.93 (229) 6.16 (238) 6.19 (239) 6.99 (270) 6.92 (267) * P <0.003 compared with euthyroid * * * * * * * * 5.59 (216)
  33. 33. 1.4 1.25 1.13 0.95 0 0.5 1 1.5 2 2.5 3 Subclinical Hypothyroid Euthyroid Triglycerides (mmol/L) CRP mg/L Kvetny J et al. Clin Endocrinology . 2004;61:232-238. Consequences of Hypothyroidism CRP and Lipids N=1212 Danish subjects mean age 42 years 963 euthyroid TSH 0.6-2.8mU/L 249 with subclinical hypothyroid TSH 2.81- 10mU/L P=0.01 P<0.01
  34. 34. Consequences of Hypothyroidism Abnormal Lipid Profile Modified from Frankyn JA. In: Braverman LE, Utiger RD, eds. Werner & Ingbar's The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:833-836. T 4 Therapy     Hypothyroid State     Triglycerides HDL-cholesterol LDL-cholesterol Total cholesterol
  35. 35. Effect of LT 4 Rx on Total Cholesterol in Subclinical Hypothyroidism <ul><li>LT 4 tx may lower LDL but does not appear to affect HDL or TG </li></ul>Danese M et al. JCEM. 2000;85(9):2993-3001. Jaeschke (n=31) Caron (n=29) Miura (n=15) Nilsson (n=29) (n=18) Nystrom (n=17) Paoli (n=15) Cooper (n=33) Franklyn (n=11) Arem (95) (n=14) Arem (90) (n=13) Powell (n=15) Bogner (n=7) Bell Overall (n=238) 0.5 0.0 -0.5 -1.0 -1.5 -2.0 Change in Total Cholesterol, mmol/L -0.20(7.9mg )
  36. 36. Levothyroxine Effect on Cholesterol * * * p<0.05 Monzani F, et al. J Clin Endocrinol Metab. 2004;89:2099-2106. TC  10% LDL  13%
  37. 37. Consequences of Mild Hypothyroidism Atherosclerosis Odds Ratio (95% CI) † Aortic Atherosclerosis Myocardial Infarction Euthyroid 1.0* 1.0* Mild Hypothyroidism (TSH >4.0) 1.7 (1.1-2.6) 2.3 (1.3-4.0) Hak AE, et al. Ann Intern Med . 2000;132:270-278 . *Reference risk † Adjusted for age N=1149 women 0 0.5 1 1.5 2 2.5 3 3.5
  38. 38. Consequences of Mild Hypothyroidism Ischemic Heart Disease Imaizumi M. JCEM . 2004;89(7):3365-3370. <ul><li>2293 controls (no Hx of thyroid disease) </li></ul><ul><li>257 pts with mild hypothyroidism (TSH>5.0 mU/L; nl FT4) </li></ul><ul><li>Mild hypothyroidism was associated with the prevalence of MI after adjustment for age and sex (odds ratio 2.6; 95% CI [1.2-5.6]) </li></ul><ul><li>Significantly more deaths from nonneoplastic disease in men with subclinical hypothyroidism at 6 years. </li></ul>Controls (men) controls A B Overall survival Overall survival 1.00 .95 .90 .85 .80 .75 .70 1.00 .95 .90 .85 .80 .75 .70 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years of follow-up Years of follow-up Men with subclinical hypothyroidism Controls (men) Women with subclinical hypothyroidism controls
  39. 39. Consequences of Mild Hypothyroidism Cardiac Function IVRT = isovolumic relaxation time; MVQ = mitral valve flow velocity; PEP = preejection period; LVET = left ventricular ejection time. Biondi B, et al. J Clin Endocrinol Metab. 1999;84:2064-2067. Monzani F, et al. J Clin Endocrinol Metab. 2001;86:1110-1115. Normalization Normalization T 4 Therapy Effect ↓ — Hypo (vs Control) Echo PEP/LVET — Systolic Function ↓ ↓ Hypo (vs Control) IVRT, MVQ IVRT, A wave, MVQ Diastolic Function Normalization — T 4 Therapy Effect 20 hypo, 20 control 10 hypo, 30 control Number Monzani, 2001 Biondi, 1999 Parameter
  40. 40. Mild Hypothyroidism during Pregnancy
  41. 41. Subclinical Hypothyroidism and Pregnancy Outcomes <ul><li>17,298 tested women </li></ul><ul><li>404 with subclinical hypothyroidism (2.3%) </li></ul><ul><ul><li>TSH < 10 mU/L 88% </li></ul></ul><ul><ul><li>TSH > 10mU/L 12% </li></ul></ul><ul><li>Increased risk of placental abruption and pre-term delivery </li></ul><ul><li>Increased incidence of respiratory distress syndrome </li></ul>Casey et al. Obstet Gynecol. 2005; 105:239.
  42. 42. Consequences of Mild Hypothyroidism Fetal Death 0.9% 3.8% 0 1 2 3 4 5 Maternal TSH  6 mU/L Maternal TSH <6 mU/L <ul><li>TSH > 6 mU/L in 2.2% of mothers with singleton pregnancies (n = 9403) </li></ul><ul><li>Fetal death rate 4x greater with high TSH </li></ul><ul><li>Other pregnancy complications were equivalent </li></ul>Rate of Fetal Death and Thyroid Deficiency ( P <0.001) Allan WC, et al. J Med Screen. 2000;7:127-130.
  43. 43. 5% 19% 0 5 10 15 20 25 Consequences of Mild Hypothyroidism Fetal Brain Development <ul><li>Children of women with untreated hypothyroidism during pregnancy: </li></ul><ul><ul><li>Averaged 7 points lower on IQ testing* </li></ul></ul><ul><ul><li>Had a significant percentage (19%) of IQ  85 </li></ul></ul>IQ Scores of  85 Control Children Children of Mothers with Untreated Hypothyroidism ( P <0.005) *Full-scale Wechsler Intelligence Scale for Children. Haddow JE, et al. N Engl J Med . 1999;341:549-555.
  44. 44. <ul><li>TSH testing recommended in 1 st trimester </li></ul><ul><li>To maintain euthyroid state, LT 4 dose may need to be increased during pregnancy 1 </li></ul><ul><li>Maternal hypothyroidism during gestation may result in a variety of fetal complications 1,2 </li></ul>Mild Hypothyroidism and Pregnancy 1 Idris I et al. Clin Endocrinol . 2005;63:560-565. 2 Pop. Clin Endocrinol (Oxf). 2003 Sep;59(3):280-1.
  45. 45. <ul><li>N N (%) pregnancies w/  TSH </li></ul><ul><li>Kaplan (1992) 42 27 (64%) </li></ul><ul><li>Girling (1992) 33 7 (21%) </li></ul><ul><li>McDougal (1995) 20 20 (100%) </li></ul><ul><li>Caixas (1999) 41 19 (46%) </li></ul><ul><li>Abalovich (2002) 95 66 (70%) </li></ul><ul><li>Chopra (2003) 13 6 (46%) </li></ul><ul><li>Alexander (2004) 19 17 (89%) </li></ul>L-T4 Dosage Adjustment in Pregnancy OVERALL 263 162 (61%) Kaplan. Postgrad Med.1993 Jan;93(1):249-52, 255-6, 260-2. Girling JC, deSwiet M. Br. J Obstet Gynaecol . 1992 May;99(5):368-70. Caixas. J Clin Endocrinol Metab . 1999 Nov;84(11):4000-5. Abalovich. Thyroid . 2002 Jan;12(1):63-8. Chopra. Metabolism . 2003 Jan;52(1):122-8. Alexander EK. N Engl J Med . 2004 Jul 15;351(3):241-9.
  46. 46. <ul><li>Cardiac arrhythmias, especially a trial fibrillation </li></ul><ul><li>↑ CV mortality </li></ul>Mild Thyrotoxicosis Consequences
  47. 47. Consequences of Mild Thyrotoxicosis Atrial Fibrillation Adapted from: Sawin CT, et al. N Engl J Med . 1994;331:1249-1252. 30 25 20 15 10 5 0 0 Incidence of Atrial Fibrillation (%) Years N=2007 pts > 60 TSH  0.1 mU/L TSH >0.1 – 0.4 mU/L 1 2 3 4 5 6 7 8 9 10 Normal TSH (>0.4 – 5.0 mU/L)
  48. 48. Consequences of Mild Thyrotoxicosis Cardiovascular Mortality <ul><li>1191 UK persons </li></ul><ul><ul><li> 60 years </li></ul></ul><ul><ul><li>No thyroid meds </li></ul></ul><ul><li>Assessments </li></ul><ul><ul><li>Serum TSH in 1988-89 </li></ul></ul><ul><ul><li>10-year mortality </li></ul></ul><ul><li>Results </li></ul><ul><ul><li>Low TSH in 6% </li></ul></ul><ul><ul><li>TSH correlated with CV mortality </li></ul></ul><ul><ul><li>Hazard ratio for TSH <0.5 at 2 years: </li></ul></ul><ul><ul><ul><li>All-cause death: 2.1 </li></ul></ul></ul><ul><ul><ul><li>CV death: 3.3 </li></ul></ul></ul>Parle JV, et al. Lancet. 2001;358:861-865. <0.5 <0.5 2.1–5.0 1.3–2.0 0.5–1.2 100 95 90 85 80 75 70 65 0 1 2 3 4 5 6 7 8 9 10 0 Years of Follow-up Survival from Circulatory Disease TSH (mU/L) 2.1–5.0 1.3–2.0 0.5–1.2

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