1. 1 Bryan R. Haugen, MD Associate Professor of Medicine University of Colorado Health Sciences Center Past consulting: Abbott Laboratories

2. 2 A 62 year-old woman presented with classic symptoms of hypothyroidism Fatigue, weight gain, constipation Fatigue, weight gain, constipation TSH 28 mU/L (0.5-5), T4 8  g/dl (4-12) She was started on 0.1 mg levothyroxine once a day

3. 3 62 year-old hypothyroid woman (TSH 28 mU/L) Eight weeks later: Symptoms improved, but still has significant fatigue –TSH 7 mU/L (0.5-5), T4 9  g/dl (4-12) –Levothyroxine increased to 0.125 mg a day ( 25%) Eight weeks later: Minimal fatigue, new insomina –TSH 0.08 mU/L

4. 4 Sensitivity of TSH to Change in Dosage of Levothyroxine TSH (  IU/mL) 108 6 4 2 0.2 1 -50-25+25+50+75 Optimum T 4 (mcg) Carr D, et al. Clin Endocrinol. 1988;28:325. Upper limit of normal Lower limit of normal

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6. 6 Long-term effects of a low TSH Increased risk of atrial fibrillation (3-fold)Increased risk of atrial fibrillation (3-fold) –Sawin, New Engl J Med 331:1249, 1994 Reduced exercise capacity and cardiac functionReduced exercise capacity and cardiac function –Mercuro, J Clin Endo Metab 85:159, 2000 Decreased BMD and increased fracture risk (3-4x)Decreased BMD and increased fracture risk (3-4x) –DeRosa, Clin Endo 47:529, 1997 –Bauer, Ann Int Med 134:561, 2001 Increased all cause mortality (2-fold), CV mortalityIncreased all cause mortality (2-fold), CV mortality –Parle, Lancet 358:861, 2001

7. 7 Incidence of Atrial Fibrillation (%) 3025 20 15 10 5 0 Low Thyrotropin Years 012345678910 High Thyrotropin Normal Thyrotropin Slightly Low Thyrotropin Serum Thyrotropin Values at Baseline Sawin CT et al. New Engl J Med. 1994;331:1249.

8. 8 62 year-old hypothyroid woman –TSH 0.08 mU/L on 0.125 mg LT4 LT4 decreased to 0.112 mg a day ( 10%) Seven weeks later: She felt well with no complaints –TSH 1.6 mU/L

9. 9 Summary Serum TSH and patient symptoms, not serum T4, are therapeutic endpointsSerum TSH and patient symptoms, not serum T4, are therapeutic endpoints True normal range for TSH is quite narrow (0.5 – 2 mU/L)True normal range for TSH is quite narrow (0.5 – 2 mU/L) Small changes in administered levothyroxine (10-20%) result in significant changes in TSHSmall changes in administered levothyroxine (10-20%) result in significant changes in TSH Abnormal TSH has consequencesAbnormal TSH has consequences –Burden on the patient –Burden on the healthcare system