Thyroid Dysfunction: Clinical Overview

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  • This diagram illustrates the hypothalamic-pituitary-thyroid axis. The hypothalamus synthesizes thyrotropin-releasing hormone (TRH). TRH stimulates the anterior pituitary gland to produce thyroid-stimulating hormone (TSH). TSH stimulates the thyroid gland to produce the thyroid hormones thyroxine (T 4 ) and triiodothyronine (T 3 ). In the liver, T 4 is converted to T 3 , which is active in target tissues including the heart, liver, bone, and central nervous system (CNS). Levels of T 4 and T 3 in the blood in turn regulate the levels of TRH and TSH via a negative feedback loop: If levels of T 4 and T 3 are sufficient, amounts of TRH and TSH are reduced. If levels of T 4 and T 3 are too low, formation and secretion of TRH and TSH are increased. This negative feedback loop is most important in control of thyroid hormone levels.
  • This schematic is intended to illustrate the relationship between TSH and T 4 levels in euthyroidism, mild and overt hypothyroidism, and mild and overt thyrotoxicosis. When both TSH and T 4 are in the normal range, the patient is euthyroid. Mild hypothyroidism consists of a normal T 4 with a elevated TSH. In overt hypothyroidism both TSH and T 4 are out of the normal range. Mild thyrotoxicosis consists of a normal T 4 with a below-normal TSH. In overt thyrotoxicosis both TSH and T 4 are out of the normal range. Note: Schematic is not drawn to scale.
  • This slide shows the prevalence of mild and overt hypothyroidism and thyrotoxicosis in the US population as a whole.
  • To put hypothyroidism in perspective, it is one of the most prevalent common diseases in the US. When thyroid nodules are included, thyroid disease surpasses all of chronic diseases except arthritis. 1,2,3 Because thyroid disorders are so common, knowing more about the diagnosis, consequences, and treatments are important to primary care physicians. Hypothyroidism, which affects a greater number of patients than many other serious diseases, is best diagnosed through TSH testing. 4 References Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med . 2000;160:526-534.. National Center for Health Statistics. Fast stats A-Z. Available at: http://www.cdc.gov/nchs/fastats/default.htm. Accessed January 6, 2003. U.S. Bureau of the Census, Current Population Reports, Series P23-194. Population Profile of the Untied States: 1997 . US Government Printing Office, Washington, DC. 1998. Available at: http://www.census.gov/prod/3/98pubs/p23-194.pdf. Accessed December 23, 2002. AACE Thyroid Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 2002;8:458-469
  • Using a computerized decision model, investigators compared the cost-effectiveness of TSH screening with no TSH screening. “TSH screening” meant adding a serum TSH measurement to serum cholesterol screening at 5-year periodic health examinations. The cost-effectiveness of TSH screening was compared with that of other preventive medical practices. Results showed that, although TSH screening raises costs, its cost-effectiveness ratio is comparable to that of other preventive measures, such as screening for breast cancer in women aged 40 to 74 years and hypertension in men aged 40 years. Danese MD et al. JAMA. 1996;276:285.
  • Identifying patients who should be evaluated for hypothyroidism is based on the patient’s age, history of hypothyroidism, signs and symptoms of the disease, certain laboratory and physical findings, and other clinical clues. 1 Once the clinical suspicion of thyroid failure has been aroused, a logical first step is to measure TSH. 1 Rarely is the TSH low in the presence of a high clinical suspicion of thyroid deficiency. In such a case, however, the patient should be referred to an endocrinologist for evaluation of possible hyperthyroidism or pituitary disease. 1 If the TSH is normal (euthyroid), other causes of the signs and symptoms, including central hypothyroidism, should be sought. 1 If the TSH is elevated, further testing is warranted to determine if the hypothyroidism is overt or subclinical. 1-2 References Ridgway EC, editor. Hypothyroidism: the hidden challenge. A CME monograph from the University of Colorado School of Medicine. Parsippany, NJ: Health Learning Systems. 1996. Demers LM, Spencer CA, eds. Laboratory Medicine Practice Guidelines: Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease. From the The National Academy of Clinical Biochemistry website: www.nacb.org/thyroid_lmpg.htm 3/12/2002.
  • Dosage must be established for each patient individually. (’97 FR Notice; II) Physicians rely of the results of a TSH (thyroid stimulating hormone) test to establish the optimal amount of replacement therapy. (’01 FDA CP Response, p8, parag. 3) Generally, the initial dose is small. The amount is increased gradually until clinical evaluation and laboratory tests indicate that an optimal response has been achieved. (’97 FR Notice; II) In order to allow for fine adjustments of dose, which are necessary due to levothyroxine sodium’s narrow therapeutic range, levothyroxine sodium products are marketed in an unusually large number of dosage strengths. (’01 FDA CP Response, p8, parag. 1)
  • The large number of drugs may interact with levothyroxine, including antacids, bile acid sequestrants, ferrous sulfate, carbamazepine, hydantoins, phenobarbital, and rifampin.
  • Dosage must be established for each patient individually. (’97 FR Notice; II) Physicians rely of the results of a TSH (thyroid stimulating hormone) test to establish the optimal amount of replacement therapy. (’01 FDA CP Response, p8, parag. 3) Generally, the initial dose is small. The amount is increased gradually until clinical evaluation and laboratory tests indicate that an optimal response has been achieved. (’97 FR Notice; II) In order to allow for fine adjustments of dose, which are necessary due to levothyroxine sodium’s narrow therapeutic range, levothyroxine sodium products are marketed in an unusually large number of dosage strengths. (’01 FDA CP Response, p8, parag. 1)
  • As shown on the next slide, the correct answer is approximately 40%.
  • This slide presents data from 4 different studies showing that suboptimal thyroxine therapy, resulting in TSH levels outside the reference range, is very common. Ross et al retrospectively analyzed serum TSH and free T 4 levels of 460 consecutive clinic visits. 1 Of hypothyroid patients on replacement therapy, 14% had subnormal TSH, and 18% had high TSH. In the Parle et al study, prescribing records of 18,944 patients in 4 general practices in the United Kingdom were examined. 2 Of these, 97 patients were being prescribed thyroxine and agreed to have their TSH tested. Among these patients, TSH was abnormally high in 27% and abnormally low in 21%. The Canaris et al study population was 25,862 participants attending a statewide health fair. 3 Of the 1525 subjects who were taking thyroid medication, 22% had a suppressed TSH and 18% an elevated TSH. The NHANES III population reported by Hollowell et al included 17,353 subjects. 4 Of the 820 subjects in the population who self-reported thyroid disease or who were taking thyroid medication, 15% had biochemical evidence of hypothyroidism; 18%, thyrotoxicosis. 1. Ross DS, et al. J Clin Endocrinol Metab. 1990;71:764-769. 2. Parle JV, et al. Br J Gen Pract. 1993;43:107-109. 3. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. 4. Hollowell J, et al. J Clin Endocrinol Metab. 2002;87:489-499.
  • This study has important implications for titrating levothyroxine replacement therapy. In this study by Carr and colleagues, hypothyroid patients who were receiving an optimum LT 4 replacement dose that had been titered to put their TSH into the reference range had their LT 4 dose adjusted by 25  g increments every 6 weeks. In this graph each dot represents 1 patient. The green rectangle in this slide indicates a range of 0.5 mU/L to 4.1 mU/L. Note that an increase in LT 4 caused TSH suppression in the majority of patients. In the elderly patients studied by the Framingham study, such a TSH suppression increased the risk of atrial fibrillation. Conversely, a dose reduction of only 25  g produced an elevated TSH that potentially could have consequences such as a rise in cholesterol. Clearly the individualization of levothyroxine dose justifies the need for the multiple dose strengths currently available. Carr D, McLeod DT, Parry G, Thornes HM. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol (Oxf) . 1988;28:325-333.
  • ASCVD = atherosclerotic cardiovascular disease; MI = myocardial infarction.
  • This slide shows the linear relationship between total cholesterol and serum TSH in the Canaris et al study. The highlighted bars on the right side of the graph indicate the elevated cholesterol levels in subjects with very high TSH. However, as shown in the bar that is highlighted in gold, even those with modest TSH elevations have higher total cholesterol than those with normal TSH. All mean cholesterol levels were significantly different from the mean cholesterol level of the euthyroid subjects. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med . 2000;160:526-534.
  • 7564 (3374 men/4190 women) underwent biennial health exams since 1958 as f/up of bomb survivors by Radiation Effects Research Foundation (RERF). Baseline was considered Oct 1984-April 1987, during which 2856 subjects agreed to be screened for thyroid disease. In the baseline cross-sectional analysis, subclinical hypothyroidism was associated with ischemic heart disease independent of other risk factors (age, systolic blood pressure, BMI, cholesterol, smoking, or DM) (odds ratio 2.5; CI 95% in total population; OR=4.0 CI 95% in men only). Ischemic heart disease was considered to be angina pectoris or myocardial infarction. Cerebrovascular event was defined as intracranial hemorrhage and cerebral infarction. Fasting blood samples were used for thyroid function test (T4 and TSH) as well as autoantibody tests.
  • This study determined that hypothyroid pregnancies result in a higher percentage of fetal deaths. Only 0.9% of euthyroid women experienced fetal death after 16-18 weeks of pregnancy. 3.8% of women with a TSH  6 mU/L suffered this consequence. Among women with TSH elevations  10mU/L, the percentage of fetal death rose to 8.1%. Other complications did not increase as a result of hypothyroidism. Since TSH testing was done in this study during the second trimester of pregnancy, it has been concluded that thyroid function testing must be done during the first trimester of pregnancy and that all pregnant women must be tested and, if found to be hypothyroid, be treated immediately to prevent these outcomes. Allan WC, Haddow JE, Palomaki GE, et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen . 2000;7:127-130.
  • Children aged 9 to 11 were tested for intelligence, attention, language, reading ability, school performance, and visual-motor skills. It was found that children of untreated hypothyroid women averaged 7 points lower on IQ tests than the control children. In addition, 19% of children in this group scored 85 or lower on IQ tests, as compared with 5% among control children. According to the Weschsler scale, IQ below 85 is subnormal, probably leading to poor intellectual development and limited job prospects. Background information on the Wechsler Scale for the presenter: 85-99 IQ Low Normal 100-114 Upper Normal 115-129 Bright 130-144 Gifted 145-159 Highly Gifted 160+ Profoundly Gifted Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med . 1999;341:549-555.
  • In this study, 1191 persons aged 60 or older and not on thyroxine or antithyroid medication were tested for TSH in 1988-89. In 1999, vital statistics were recorded and cause of death was ascertained for those who had died. TSH level was correlated with cardiovascular (CV) mortality. Those with a low TSH had a higher overall mortality than those with normal TSH. CV mortality was 3 times higher in those with TSH <0.5 mU/L. Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. 2001;358:861-865.

Transcript

  • 1. Thyroid Dysfunction: Clinical Overview
  • 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. Hypothalamic-Pituitary-Thyroid Axis Clinical Utility of TSH Hypothalamus Pituitary Thyroid Gland T 4  T 3 Liver T 4 TRH T 4 T3 TSH
    • TSH reflects tissue thyroid hormone actions
    • TSH as an index of therapeutic success and potential toxicity
    T 3 – – Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997.
  • 4. Mild Hypothyroidism & Mild Thyrotoxicosis Definitions TSH FT 4 Euthyroidism Overt Hypothyroidism Mild Overt Thyrotoxicosis Mild
  • 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. 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. Thyroid disease is more prevalent than which of the following:
    • A. Asthma
    • B. Heart disease
    • C. Diabetes
    • D. All of the above
    www.accessdata.fda.gov/scripts/cder/ob/docs/temptn.cfm ?
  • 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. Mild Hypothyroidism & Mild Thyrotoxicosis Common Causes
    • Mild Hypothyroidism
    • Autoimmune thyroiditis
    • Previous thyroid surgery and/or 131 I therapy for thyrotoxicosis
    • Mild Thyrotoxicosis
    • Graves’ disease
    • Nodular goiter
  • 10. Mild Hypothyroidism & Mild Thyrotoxicosis Common Causes
    • Mild Hypothyroidism
    • Autoimmune thyroiditis
    • Previous thyroid surgery and/or 131 I therapy for thyrotoxicosis
    • Inadequate thyroxine therapy
    • Mild Thyrotoxicosis
    • Graves’ disease
    • Nodular goiter
    • Excessive thyroxine therapy
  • 11. Diagnosis and Treatment
  • 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. Screening: Recommendations
    • Various societies and authors disagree about population-based screening
    • The AAFP recommends screening high-risk populations:
      • women with a family hx of thyroid disease
      • women >35 yo
      • pregnant women
      • abnormal physical exam
      • diabetic patients
      • Hx of autoimmune disorder
    • The American Thyroid Association indicates that screening is justifiable in men > 35 yo as well (q 5 years)
    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. 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. 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.
    • ~10% of NHANES population had TPO+ antibodies
    • Potential indicator of autoimmune thyroid failure
    • Risk of miscarriage higher in women with TPO+ antibodies
    • Screening for TPO+ab warranted pre-conception
    • TPO+ab may be associated with CV risks
    Prevalence of antibodies
  • 16. Levothyroxine Therapy
    • LT 4 is the synthetic version of the naturally-occurring hormone thyroxine (T 4 )
    • Physicians use TSH to individualize the optimal LT 4 dose
    • Small changes in LT 4 dose can cause significant changes in TSH levels
    • LT 4 is provided in 12 dosage strengths that differ by as little as 9%
    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. Starting Therapy
    • Otherwise healthy, < 60 yrs, no cardiac Hx:
        • ~1.7  g/kg/day
        • 8 week F/U TSH, 25  g dose increments
    • Older patients, > 60: require 20-30% less
        • 50  g/day
        • 6 week F/U TSH, 12-25  g dose increments
    • Congenital hypothyroidism
        • Initiate therapy with 10-15  g/kg/day
        • Usually 50  g/d X 1 week, then 37  g/d
    • Pediatric hypothyroidism
        • Initial dose: 25-50  g/day X 2-4 weeks
        • Titration: 25  g increments Q 4- 8 weeks
    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. Maintenance
    • Periodic monitoring essential to ensure appropriate dosing and consistent effect
    • Once TSH normalized:
      • Visit frequency decreased to Q 6-12 months
    • TSH should be measured at least annually
    • Re-measure TSH (in 8-12 weeks) following:
      • Dosage, type or brand of thyroxine change
    Singer et al. JAMA. 1995;273:808-812.
  • 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. T 3 and T 4 / T 3 Therapy
    • T 3 has a very short half-life
    • Liothyronine
      • Synthetic
      • T 3 is more biologically active that LT 4
      • No indication for the use of T3 alone
    • Thyroid extract
      • Porcine-derived
      • T 4 and T 3
    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. Suboptimal Thyroxine Therapy What Causes It?
    • Mild Hypothyroidism
    • Low Rx dose
    • Poor compliance
    • Drug interaction
    • Dietary interference with absorption
    • Pregnancy
    • ↓ Residual gland function
    • Formulation switch
  • 22.
    • Mild Hypothyroidism
    • Low Rx dose
    • Poor compliance
    • Drug interaction
    • Dietary interference with absorption
    • Pregnancy
    • ↓ Residual gland function
    • Formulation switch
    Suboptimal Thyroxine Therapy What Causes It?
    • Mild Thyrotoxicosis
    • High Rx dose
    • Factitious ingestion
    • Aging with ↓ requirement for LT 4
    • Nonsuppressed endogenous gland function
    • Stopping estrogen therapy
    • Formulation switch
  • 23. According to current guidelines, what TSH range should I treat my hypothyroid patients to:
    • A. 1 – 5.5 mU/L
    • B. 0.5 – 4.5 mU/L
    • C. 0.5 – 2.0 mU/L
    • D. 1 mU/L
    www.accessdata.fda.gov/scripts/cder/ob/docs/temptn.cfm ?
  • 24. Treatment Target
    • The TSH target for hypothyroid patients is generally considered to be .5 – 2.0 mu/L
    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. How Common Is Suboptimal Thyroxine Therapy?
    • a. 1%
    • b. 10%
    • c. 20%
    • d. 40%
    ?
  • 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. Potential Reasons to Increase LT 4 Dose
    • Decreased L-T4 Absorption
    • Malabsorption Syndromes
      • Jejunoileal Bypass Surgery
      • Short Bowel Syndrome
      • Cirrhosis
    • Drugs or Diet
      • Cholestyramine
      • Aluminum Hydroxide
      • Sucralfate
      • Ferrous Sulfate
      • Calcium Carbonate
      • Cation-Exchange Resin
      • High Fiber Diet
      • Infants Fed Soybean Formula
      • ? Excess Soybean in Adults
      • Achlorhydria
      • ? Proton Pump Inhibitors
      • ? H-2 Blockers
    • Increased Biliary Excretion
    • Phenytoin sodium
    • Rifampin
    • Phenobarbital
    • Carbamazepine
    • Decreased Deiodination of T 4 to T 3
    • Amiodarone
    • Increased TBG
    • Pregnancy
    • BCP
    • Estrogens
    • Hepatitis
    • Hereditary
    • Unknown
    • Sertraline
    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. 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
    • 21 hypothyroid adults with normal TSH on thyroxine
    • Dose changed by 25 µg q. 6 weeks
    +75 Optimum
  • 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.
    • Clinical Consequences of Elevated and Decreased TSH
  • 31. Mild Hypothyroidism & Mild Thyrotoxicosis Consequences
    • Mild Hypothyroidism
    • ↑ Cholesterol
    • ↑ Atherosclerotic cardiovascular disease and MI risk
    • ↑ Miscarriage risk
    • Impaired fetal development
    • Inadequate TSH suppression in thyroid cancer patients
  • 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. 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. 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. Effect of LT 4 Rx on Total Cholesterol in Subclinical Hypothyroidism
    • LT 4 tx may lower LDL but does not appear to affect HDL or TG
    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. Levothyroxine Effect on Cholesterol * * * p<0.05 Monzani F, et al. J Clin Endocrinol Metab. 2004;89:2099-2106. TC  10% LDL  13%
  • 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. Consequences of Mild Hypothyroidism Ischemic Heart Disease Imaizumi M. JCEM . 2004;89(7):3365-3370.
    • 2293 controls (no Hx of thyroid disease)
    • 257 pts with mild hypothyroidism (TSH>5.0 mU/L; nl FT4)
    • 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])
    • Significantly more deaths from nonneoplastic disease in men with subclinical hypothyroidism at 6 years.
    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. 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. Mild Hypothyroidism during Pregnancy
  • 41. Subclinical Hypothyroidism and Pregnancy Outcomes
    • 17,298 tested women
    • 404 with subclinical hypothyroidism (2.3%)
      • TSH < 10 mU/L 88%
      • TSH > 10mU/L 12%
    • Increased risk of placental abruption and pre-term delivery
    • Increased incidence of respiratory distress syndrome
    Casey et al. Obstet Gynecol. 2005; 105:239.
  • 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
    • TSH > 6 mU/L in 2.2% of mothers with singleton pregnancies (n = 9403)
    • Fetal death rate 4x greater with high TSH
    • Other pregnancy complications were equivalent
    Rate of Fetal Death and Thyroid Deficiency ( P <0.001) Allan WC, et al. J Med Screen. 2000;7:127-130.
  • 43. 5% 19% 0 5 10 15 20 25 Consequences of Mild Hypothyroidism Fetal Brain Development
    • Children of women with untreated hypothyroidism during pregnancy:
      • Averaged 7 points lower on IQ testing*
      • Had a significant percentage (19%) of IQ  85
    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.
    • TSH testing recommended in 1 st trimester
    • To maintain euthyroid state, LT 4 dose may need to be increased during pregnancy 1
    • Maternal hypothyroidism during gestation may result in a variety of fetal complications 1,2
    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.
    • N N (%) pregnancies w/  TSH
    • Kaplan (1992) 42 27 (64%)
    • Girling (1992) 33 7 (21%)
    • McDougal (1995) 20 20 (100%)
    • Caixas (1999) 41 19 (46%)
    • Abalovich (2002) 95 66 (70%)
    • Chopra (2003) 13 6 (46%)
    • Alexander (2004) 19 17 (89%)
    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.
    • Cardiac arrhythmias, especially a trial fibrillation
    • ↑ CV mortality
    Mild Thyrotoxicosis Consequences
  • 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. Consequences of Mild Thyrotoxicosis Cardiovascular Mortality
    • 1191 UK persons
      •  60 years
      • No thyroid meds
    • Assessments
      • Serum TSH in 1988-89
      • 10-year mortality
    • Results
      • Low TSH in 6%
      • TSH correlated with CV mortality
      • Hazard ratio for TSH <0.5 at 2 years:
        • All-cause death: 2.1
        • CV death: 3.3
    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