Real Pregnancy or Uncontrolled Hypothyroidism?

Transcription

1 Real Pregnancy or Uncontrolled Hypothyroidism? Christie G. Turin 1,MD; Anisha Gupta 1, MD; Susan Samson 1,2, MD; Mandeep Bajaj 1,2, MBBS Baylor College of Medicine, Houston, TX 1 ; CHI-St. Luke s Episcopal Health System, Houston, TX 2

2 Outline 1. Objectives 2. Case presentation 3. History of TSH 4. TSH structure 5. TSH assay 6. β-hcg & TSH assay cross reactivity 7. Pregnancy and hypothyroidism 8. Conclusions

3 Objectives

4 Objectives To illustrate a case of a young woman of reproductive age with typical hypothyroid symptoms and a false home and in-hospital pregnancy test To present the history of the development of the TSH assay and how it has changed over time To differentiate TSH from other structurally-similar hormones To demonstrate a case of false positive pregnancy tests due to crossreactivity of hcg with TSH on modern IMCA assays To recognize the presence of other non-hcg substances that could affect the hcg level

5 Case Presentation

6 Case Presentation History of Present Illness 27-year-old woman originally from Turkey with history of hypothyroidism presented with progressive fatigue, cold intolerance, constipation, and weight gain, shortness of breath. Reported a positive home pregnancy test with a delayed menstrual cycle (LMP 7 weeks ago) Past Medical History Hypothyroidism since 2009 Past Surgical History Denies previous surgical history Social History Denies tobacco, alcohol, or illicit drugs use

7 Physical Exam T: 98.5 F HR: 56 bpm BP: 113/71mmHg RR:18 SpO2: 100% General appearance: resting, in no acute distress Neck: no thyromegaly, no JVD, no LAD Cardiovascular: bradycardic, regular rhythm, no murmurs Respiratory: CTAB, no rales Gastrointestinal: soft, non-tender, non-distended, BS + Pelvic: no vaginal bleeding Extremities: no lower extremities edema Neurological: AAOx4, no focal deficits

8 Labs and Imaging Laboratory TSH uiu/ml Free T4: 0.67 ng/dl hcg 262 miu/ml Endovaginal Ultrasound No intrauterine gestational sac

9 Follow up Patient was started on IV levothyroxine Repeat hcg 194mIU/mL, continued to downtrend No signs of vaginal bleeding Discharged to home on oral levothyroxine 300 mcg daily (5mcg/kg/day). Down-titrated to 200 mcg (2.8 mcg/kg/day) TSH improved to 0.6uIU/mL, hcg undetectable Patient resumed a normal menstrual cycle with normalization of thyroid function

10 History of TSH

11 History of TSH 1926: Eduard Uhlenhuth from the University of Maryland, first to demonstrate that the anterior lobe of the pituitary gland secreted a thyroid stimulator s: Determination of primary structure of TSH : Elucidation of the crystal structure of the closely related human chorionic gonadotropin (hcg) 3 1.Uhlenhuth E. Br J Exp Biol. 1927; 5: Magner JA. Endocr Rev. 1990; 11: Lapthorn AJ. Nature. 1994; 369:

12 TSH Structure

13 TSH Structure 28-kD to 30-kD glycoprotein synthesized by thyrotrophic basophils in the adenohypophysis Composed of two non-covalently linked subunits: α and β α chain is shared by hcg, LH, FSH Biological specificity of each glycoprotein hormone is conferred by the β chain Szkudlinski. Physiol Rev Apr;82(2):

14 TSH and hcg Both glycoproteins have a common α-subunit and there is a 38% sequence identity between the hcg β- subunit and TSH β-subunit. 1 Szkudlinski. Physiol Rev Apr;82(2):

15 TSH Assay

16 TSH Assay 1965: radioimmunoassay (RIA) of htsh. Detection limit of ~1mIU/L 1,2 1984: immunoradiometric assay (IMA) with better sensitivity and short incubation times 3. Uses a combination of monoclonal antibodies targeting different TSH epitope(s) in a sandwich format. Detection limit as low as mIU/L 1990s: Third-generation of TSH IMAs, achieving sensitivity of 0.01mIU/L 1. Utiger RD. J Clinc Invest. 1965; 44: Ridgeway EC. Mayo Clin Proc. 1988; 63: Seth J. Br Med J (Clin Res Ed). 1984; 289(6455):

17 TSH Assay Immunoradiometric assay (IMA): TSH in patient s serum is added to tube with monoclonal TSHantibodies. Labeled anti- TSH antibodies are added, which are detected after binding occurs. Picture obtained from: Stanley. Essentials of Immunology & Serology

18 TSH Assay Different non-isotopic signals Immunoenzymometric assays (IEMA) used enzyme Immunofluorometric assays (IFMA) used fluorophors Immunochemiluminometric assays (ICMA) used chemiluminescent molecules Immunobioluminometric assays (IBMA) used bioluminescent signal molecules Current TSH assays are automated ICMAs, achieving a functional sensitivity 0.01 miu/l. Currently considered standard of care Hay ID. Clin Chem 1991; 37:

19 TSH hcg Cross Reactivity

20 hcg assay 1966: Midgley described the first radioimmunoassay for hcg however, it didn t differentiate between hcg and LH 1972: Vaitukaitis, Braunstein, and Ross developed a specific radioimmunoassay which specifically measured β-subunit of hcg Vaitukaitis JL. Am J Obstet Gynecol Jul 15;113(6):751-8.

21 TSH and hcg Cross Reactivity β-hcg assay has a mean analytical specificity of <10% cross reactivity with TSH ** Cross reactivity was calculated as % interference (β-hcg supplemented with 100 miu/l TSH)** More information available in:

22 Other causes of false hcg elevation Interference by other non-hcg substances: 1, 2 Heterophilic antibodies Nonspecific protein binding hcg-like substances Trophoblastic or non-trophoblastic neoplasms Boscato LM. Clin Chem 1988;34: Hussa RO. Obstet Gynecol 1985;65:211-9.

23 Pregnancy and Hypothyroidism

24 Pregnancy and Hypothyroidism Women with hypothyroidism have decreased fertility: difficulties conceiving, increased risk of abortion. Increased risk of maternal complications: gestational hypertension, anemia, abuptio placenta and postpartum hemorrhage. Increased risk of neonatal complications: preterm birth, low birth weight, respiratory distress Abalovich M. Thyroid. 2002;12:63-66

25 Pregnancy and Subclinical hypothyroidism Two parallel, randomized, placebocontrolled trials including women with subclinical hypothyroidism or hypothyroxinemia Subclinical hypothyroidism: 97 vs 94 IQ score (p: 071) Hypothyroxinemia: 94 vs 91 IQ score (p: 0.30) No significant effect on neurodevelopmental outcomes in children whose mothers had received thyroxine treatment. N Engl J Med Mar 2;376(9):

26 Conclusions

27 Conclusions 1. A low quantitative β-hcg without evidence of pregnancy could be explained by the cross reactivity that this test has with the TSH assay (which may occur when TSH level is above 100 miu/l). 2. A downtrending β-hcg level was noted as the hypothyroidism was treated, consistent with a false-positive pregnancy test. 3. Levothyroxine therapy in early stages of pregnancy in patients with hypothyroidism is imperative to multiple maternal and neonatal complications.

28 References

29 References 1. Uhlenhuth E, et al. The anterior lobe of the hypophysis as a control mechanism of the function of the thyroid gland. Br J Exp Biol. 1927; 5: Magner JA, et al. Thyroid-stimulating hormone: biosynthesis, cell biology, and bioactivity. Endocr Rev. 1990; 11: Lapthorn AJ, et al. Crystal structure of human chorionic gonadotropin. Nature. 1994; 369: Szkudlinski, et al. Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Structure-Function Relationships. Physiol Rev Apr;82(2): Utiger RD, et al. Radioimmunoassay of human plasma rhyrotropin. J Clinc Invest. 1965; 44: Ridgeway EC, et al. Thyrotropin radioimmunoassays: Birth, life, and demise. Mayo Clin Proc. 1988; 63: Seth J. A sensitive immunoradiometric assay for serum thyroid stimulating hormone: a replacement for the thyrotrophin releasing hormone test? Br Med J (Clin Res Ed) Nov 17; 289(6455): Casey BM, et al. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med Mar 2;376(9): Hay ID, et al. American Thyroid Association Assessment of Current Free Thyroid Hormone and Thyrotropin Measurements and Guidelines for Future Clinical Assays. Clin Chem 1991; 37: Vaitukaitis JL, et al. A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obstet Gynecol Jul 15;113(6): Total β-hcg.available at: Boscato LM, et al. Heterophilic Antibodies: A Problem for All Immunoassays. Clin Chem 1988;34: Hussa RO, Rinke ML, Schweitzer PG. Discordant Human Chorionic Gonadotropin Results: Causes and Solutions. Obstet Gynecol 1985;65: Abalovich M, et al. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid. 2002;12:63-66

30 Thank you