Evaluation and Management of Hypothyroidism in the Primary Care Setting

1. Evaluation and Management of Hypothyroidism in the Primary Care Setting Christopher P. Paulson, Maj, USAF, MC Faculty, Eglin AFB Family Medicine Residency

2. Case Scenario • While precepting residents the following case is presented for your review • 45 yo female with abnormal thyroid labs discovered during an evaluation of mild fatigue of several months duration

3. Case Scenario • Past Med Hx: negative for diabetes, autoimmune disorders, radiation exposure, and known thyroid disease or thyroid surgery • Medications: none • Family Hx: negative for autoimmune disorders and thyroid dysfunction

4. Case Scenario • Labs: • TSH 6.73 (0.46 - 4.68) mIU/ml • FT4 1.32 (0.71 – 2.19) ng/dl • Repeat labs in 6 weeks • TSH 6.82 • FT4 1.27

5. Case Scenario • The patient desires thyroid replacement therapy • The resident inquires about treatment guidelines for subclinical hypothyroidism • How do you respond?

6. Learning Objectives • Identify common risk factors and etiologies of hypothyroidism • Be able to evaluate and initiate appropriate treatment for hypothyroidism • Use an evidence-based approach for population screening and sub-clinical disease management • Apply management guidelines to your patient population

7. Overview of Hypothyroidism • Epidemiology • Etiology • Evaluation and Treatment • Subclinical Disease and Screening Guidelines • Conclusion/Key Points

8. Epidemiology • Incidence of Hypothyroidism • 1% in areas with adequate iodine (U.S.) • Female to Male ratio 8:1 • Incidence increases with age Vanderpump, MP, Tunbridge, WM. The epidemiology of thyroid disease. In: The Thyroid: A Fundamental and Clinical Text, 8th ed, Braverman, LE, Utiger, RD (eds). Lippincott Williams and Wilkins, Philadelphia, 2000. p. 467.

9. Risk Factors Downs Syndrome Turners Syndrome Head and neck radiation exposure Type 1 Diabetes Family history of autoimmune disease History of previous thyroid disorder Presence of other autoimmune disorders Postpartum state Family history of thyroid disorders Epidemiology Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams textbook of endocrinology. 10th edition. Philadelphia: Saunders, 2003; 423-55.

10. Symptoms Fatigue Weight gain Headache Dry Skin Hoarseness of voice Irregular menses Decreased appetite Myalgias Parasthesias Somnolence Lethargy Depression Cold intolerance Epidemiology Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams textbook of endocrinology. 10th edition. Philadelphia: Saunders, 2003; 423-55.

11. Symptoms Fatigue – 90% Weight gain Headache Dry Skin Hoarseness of voice Irregular menses Decreased appetite Myalgias Parasthesias Somnolence Lethargy Depression Cold intolerance Epidemiology Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams textbook of endocrinology. 10th edition. Philadelphia: Saunders, 2003; 423-55.

12. Signs Nonpitting edema Constipation Memory defects Coarse skin Dry skin Brittle nails Bradycardia Ataxia Diminished libido Bleeding tendencies Alopecia Macroglossia Slowed speech Dementia Psychosis Slowed reflexes Epidemiology Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams textbook of endocrinology. 10th edition. Philadelphia: Saunders, 2003; 423-55.

13. Etiology • Primary hypothyroidism (95 – 99%) • Chronic autoimmune thyroiditis (Hashimoto’s) • Goitrous • Atrophic • Iatrogenic • Thyroidectomy • Radioiodine treatment • External beam radiation Farwell, AP, Ebner, SA, editors. Hypothyroidism. In: Noble: Textbook of Primary Care Medicine, 3rd ed, Mosby 2001.

14. Etiology • Primary hypothyroidism • Iodine deficiency (most common world-wide) • Drugs • Lithium, amiodarone, etc • Infiltrative disease - rare • Fibrous thyroiditis (Reidel’s thyroiditis) • Hemochromatosis • Scleroderma • Others Farwell, AP, Ebner, SA, editors. Hypothyroidism. In: Noble: Textbook of Primary Care Medicine, 3rd ed, Mosby 2001.

15. Etiology • Primary hypothyroidism • Congenital • Transient Hypothyroidism • Postpartum • Subacute (granulomatous) thyroiditis • Subtotal thyroidectomy Farwell, AP, Ebner, SA, editors. Hypothyroidism. In: Noble: Textbook of Primary Care Medicine, 3rd ed, Mosby 2001.

16. Etiology • Secondary and Tertiary hypothyroidism • Tumor • Postpartum pituitary necrosis (Sheehan’s) • Hypophysitis • Infiltrating disease • TSH or TRH deficiency • Trauma • Radiation therapy Farwell, AP, Ebner, SA, editors. Hypothyroidism. In: Noble: Textbook of Primary Care Medicine, 3rd ed, Mosby 2001.

17. Etiology • Other • Thyroid hormone resistance – very rare Farwell, AP, Ebner, SA, editors. Hypothyroidism. In: Noble: Textbook of Primary Care Medicine, 3rd ed, Mosby 2001.

18. Evaluation • When to evaluate • Signs or symptoms suggestive of hypothyroidism • Periodic assessment for high risk medications (amiodarone, lithium, etc.) • Screening at risk populations? • Controversial – addressed in screening section

19. Evaluation • Assess risk factors for hypothyroidism • Medications (lithium, amiodarone, etc) • History of head or neck radiation exposure • Presence of Downs or Turners • Family or personal history of autoimmune or thyroid disorders • Type 1 diabetes

20. Evaluation Basic Thyroid Labs TSH FT4 Primary Hypothyroidism Subclinical Hypothyroidism Secondary or Tertiary Hypothyroidism Thyroid Hormone Resistance (pt is clinically hypothyroid)

21. Evaluation • Primary hypothyroidism • Proceed to treatment • Further evaluation generally not indicated • For postpartum hypothyroidism, serial TSH and FT4, treat only if significantly symptomatic

22. Evaluation • Secondary or tertiary hypothyroidism • Image the sellar and suprasellar regions with MRI to evaluate for mass • Screen for other hypothalamic or pituitary disease • Adrenocortical, posterior pituitary, and gonadal dysfunction • Consider consultation

23. Evaluation • Thyroid hormone resistance • Exceedingly rare • If suspected – consultation is appropriate • Subclinical hypothyroidism • Addressed in later section

24. Treatment Guidelines • Standard Replacement Therapy • Synthetic thyroxine (T4) • 1.6 mcg/kg/day – lean body mass • 112 mcg in 70kg adult • Full dose recommended regardless of degree of hypothyroidism • Reassess after 6 weeks with TSH Roos, A, Linn-Rasker, SP, van Domburg, RT, et al. The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med 2005; 165:1714.

25. Treatment Guidelines • Special situations • Elderly patients • Start at 50 mcg/day and increase by 25 mcg/day every 6 weeks until TSH is normalized • Known CAD • Start at 25 mcg/day and increase by 25 mcg/day every 6 weeks until TSH is normalized Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams textbook of endocrinology. 10th edition. Philadelphia: Saunders, 2003; 423-55.

26. Treatment Guidelines • Special situations • Postpartum hypothyroidism • Treat based on moderate or severe clinical symptoms not based on labs • Only 1 in 4 will require treatment • 50 to 100 mcg per day x 12 weeks • Discontinue and recheck thyroid labs 6 wks later Stuckey, BG, Kent, GN, Allen, JR. The biochemical and clinical course of postpartum thyroid dysfunction: the treatment decision. Clin Endocrinol (Oxf) 2001; 54:377.

27. Treatment Guidelines • What about liothyronine (T3) replacement? • Physiologically active • 20% from thyroid directly and 80% from peripheral conversion of T4 • Early studies indicated possible beneficial effects on mood, quality of life, and psychometric functioning

28. Treatment Guidelines • Systematic review of the literature published in 2005 • Levothyroxine (T4) compared with levothyroxine + liothyronine (T3) • 9 controlled trials included • Beneficial results in only a single study • Quality of life, mood, psychometric performance Escobar-Morreale, HF. Treatment of Hypothyroidism with Combinations of Levothyroxine plus Liothyronine. Journal of Clinical Endocrinology and Metabolism. Vol 90, number 8. Aug 2005.

29. Treatment Guidelines • Systematic review of the literature published in 2005 • Increased incidence of side effects with T3 including palpitations, irritability, nervousness, dizziness, and tremor • Overall patient preference for T3 • Not explained by outcome measures • No clear clinical benefit Escobar-Morreale, HF. Treatment of Hypothyroidism with Combinations of Levothyroxine plus Liothyronine. Journal of Clinical Endocrinology and Metabolism. Vol 90, number 8. Aug 2005.

30. Subclinical Hypothyroidism • Generally defined as few or no symptoms of hypothyroidism with an elevated TSH and normal FT4 • Historically unclear recommendations in the literature

31. Subclinical Hypothyroidism • Possible benefits of treatment • Symptom improvement • Prevent progression to overt hypothyroidism • Reduce lipid levels and subsequently lower risk of cardiovascular events • Prevent poor developmental outcomes in children born to women with subclinical disease

32. Subclinical Hypothyroidism • Possible risk of unnecessary treatment • Development of osteoporosis • Increased incidence of atrial fibrillation • Cost

33. Subclinical Hypothyroidism • What does the literature show? • USPSTF review in 2004 • No clear difference in lipid levels or cardiovascular outcomes for subclinical disease • Except for patients with known thyroid disease • No significant symptom improvement with treatment • Except for patients with known thyroid disease www.ahrq.gov/clinic/uspstf/uspsthyr.htm

34. Subclinical Hypothyroidism • What does the literature show? • USPSTF review in 2004 • Poor neurodevelopmental outcomes in children born to women with elevated TSH values in their first trimester • Increase in fetal demise rate • Average IQ at age 7 to 9 was 7 points less (significant) • No studies on whether screening or treatment would impact outcome www.ahrq.gov/clinic/uspstf/uspsthyr.htm

35. Subclinical Hypothyroidism • What does the literature show? • USPSTF review in 2004 • No increased risk of fracture or diminished bone density with levothyroxine treatment • Except in those patients on suppressive therapy • No increased risk of atrial fibrillation with treatment www.ahrq.gov/clinic/uspstf/uspsthyr.htm

36. Subclinical Hypothyroidism • What does the literature show? • Other considerations • Annual rate of progression to overt disease • No autoimmunity <2% • No prior thyroid disease - < 2% • Thyroid antibodies – 5-7% • Elderly with thyroid antibodies – 20-24% www.ahrq.gov/clinic/uspstf/uspsthyr.htm

37. Case Scenario - revisited • Initial labs: • TSH 6.73 • FT4 1.32 • Repeat labs in 6 weeks • TSH 6.82 • FT4 1.27

38. Case Scenario - revisited • The patient desires thyroid replacement therapy • The resident inquires about treatment guidelines for subclinical hypothyroidism • Now, how do you respond? What is the evidence based answer?

39. Case Scenario - revisited • The evidence-based answer • There is no clear indication to treat • Likelihood of progressing on to overt hypothyroidism in this case is very low

40. Screening Guidelines • The American Thyroid Association • Screen ALL adults at age 35 and then every 5 years; more frequent for high risk or symptoms • The American College of Physicians • Screen women older than 50 with at least one symptom www.ahrq.gov/clinic/uspstf/uspsthyr.htm

41. Screening Guidelines • The American Association of Clinical Endocrinologists • Screen women of childbearing age or during the first trimester www.ahrq.gov/clinic/uspstf/uspsthyr.htm

42. Screening Guidelines • The American College of Obstetricians and Gynecologists • Be aware if signs and symptoms of postpartum thyroid dysfunction and evaluate when indicated www.ahrq.gov/clinic/uspstf/uspsthyr.htm

43. Screening Guidelines • AAFP • Recommends AGAINST routine screening in asymptomatic patients younger than age 60 • No recommendation for those over 60 www.ahrq.gov/clinic/uspstf/uspsthyr.htm

44. Screening Guidelines • USPSTF • Evidence is insufficient (I) to recommend for or against routine screening for thyroid disease in adults • Fair evidence that TSH is useful in detecting subclinical disease • Poor evidence that treatment improves clinically important outcomes www.ahrq.gov/clinic/uspstf/uspsthyr.htm

45. Screening Guidelines • USPSTF – Clinical Considerations • Clinicians should be aware of subtle thyroid dysfunction particularly in high risk groups • Elderly • Down Syndrome • Post-partum women • Radiation exposure (>20 mGy) www.ahrq.gov/clinic/uspstf/uspsthyr.htm

46. Screening Guidelines • USPSTF – Clinical Considerations • Subclinical hypothyroidism • Is associated with poor obstetric outcomes and poor cognitive development in children • Evidence for dyslipidemia, atherosclerosis, and decreased quality of life is inconsistent and less convincing www.ahrq.gov/clinic/uspstf/uspsthyr.htm

47. Screening Guidelines • USPSTF – Discussion • No controlled studies showing whether routine screening improved symptoms or health outcomes • 2 of 3 small randomized studies demonstrated no benefit in treating subclinical disease • No trials of treatment of subclinical disease for pregnant women www.ahrq.gov/clinic/uspstf/uspsthyr.htm

48. Screening Guidelines • USPSTF – Discussion • No clear benefit demonstrated on systematic review of the literature for either screening asymptomatic adults or treating subclinical thyroid disease www.ahrq.gov/clinic/uspstf/uspsthyr.htm

49. Conclusion/Key Points • Hypothyroidism is commonly encountered in the primary care setting • Be aware of signs and symptoms of hypothyroidism particularly in populations at risk • There is insufficient evidence to recommend treatment with liothyronine (T3) over levothyroxine (T4)

50. Conclusion/Key Points • There is insufficient evidence for screening asymptomatic patients without a history of thyroid disease • There is no clear benefit in treating subclinical hypothyroidism • Treatment is indicated in pregnancy due to known risk without treatment