CME INDIA Case Presentation by Dr. Richa Agnihotri, MBBS, DGO, DNB (Obs & Gynae), FGES (lap surgeon), Balaji Soni Hospital and Life Care Clinic, Jaipur.

CME INDIA Case Study

24-year, 8 weeks Primi – No symptoms: T3/T4/TSH Report dated 02/12/2021

Asymptomatic 8 Weeks Primi with Hyperthyroid Range: To Treat or Not?

FT4/TSH/FT3 report dated 13/12/2021

Asymptomatic 8 Weeks Primi with Hyperthyroid Range: To Treat or Not?

How to proceed?

CME INDIA Case Discussion:

Dr. V. P. Youmash, Assistant Professor, KAPV Medical College, Trichy TN:

  • TSH may normally get suppressed during first trimester of pregnancy due to structural similarity with betahcg and many will have subclinical hyperthyroidism. If pt symptomatic, antithyroid drugs can be initiated based on anti-TPO antibody

Dr. Venkatesh Molio, Maregoan, Goa:

  • TRAB thyroid receptor antibodies if patient is asymptomatic
  • If symptoms start: PTU preferred
  • But watch for hepatotoxicity, Agranulocytosis

Dr. Prabhat Agarwal, Agra:

  • PTU 100 TDS
  • Because first trimester
  • If tsh is below than .05, then it’s pathological, as taught by my teacher

Dr. Om Lakhani, DNB, Endocrinologist, Ahmedabad:

  • Get TSH receptor antibody done. it is available with most labs in India now including national chains like Lal path lab.
  • If positive start PTU till end of 1st trimester and then switch to carbimazole after 12 weeks.
  • No role of Anti TPO antibody. It is a common misconception. It is a nonspecific antibody.
  • Looks more like Graves’ disease then gestational thyrotoxicosis but with an availability of TSH receptor antibody in most place it is always a good idea to get it tested and documented.
  • Dose is PTU- 50 mg TDS if someone decides to start.
  • The goal is to keep the T3 and T4 close to upper limit of normal range for the specific trimester. overtreatment is as bad as under treatment.
  • It is a tight rope in pregnancy and we must tread carefully.
  • The normal ranges for fT3 and ft4 mentioned are not pregnancy ranges. they are non-pregnancy ranges. always a good idea to look at pregnancy ranges published from local data or if available from the lab.
Asymptomatic 8 Weeks Primi with Hyperthyroid Range: To Treat or Not?
  • These are trimester specific values from Dr Rajesh Rajput’s paper (Conclusion- “Existing results for trimester-specific reference intervals for thyroid hormones are inconsistent and cannot be extrapolated due to differences in ethnicity, maternal iodine status, laboratory assay method, and rigor for selection of reference population. Thus, the establishment of reference intervals in each region is of great importance.” Ref-3).
  • The patient’s Free T3 and total t3 from the corrected range in this patient is actually normal. Though T3 assays are famously unreliable. all the more reason to check the TRAb.

Dr. N. K. Singh:

  • So, you opine not to start PTU NOW.
  • TRab-To be done.Then accordingly started.
  • Some members want to know why TRab is so important in this case.

Dr. Om Lakhani, DNB, Endo.:

  • Yes
  • The differential diagnosis here are three for all practical purposes:
    1. Gestational thyrotoxicosis (which is because of high HCG in first trimester) and basically variation of normal.
    2. Graves’ disease.
    3. Toxic nodule / toxic multi nodular goitre.
  • Number 3 in most cases can be determined by clinical examination, so it is either 1 or 2 which are practically the DD with 1 more common than 2.
  • Gestational thyrotoxicosis – does not need treatment while Graves’ diseases needs to be carefully treated during pregnancy.
  • Now, TRAb is a specific test for the diagnosis of Graves’ disease. So if TRAb is positive it is suggestive of Graves’ and treatment needs to be started.
  • If TRAb is negative and there it is most likely to be Gestational thyrotoxicosis in which case there is no indication for any treatment – basically need to wait and watch.

Dr. Premchand Singh, Internist, RIMS, Manipur:

Asymptomatic 8 Weeks Primi with Hyperthyroid Range: To Treat or Not?
Table: Ref (4)

  • There is a definite difference in the thyroid reference range across various countries and also within the Indian population due to its ethnic origin.
  • Our study concludes the following reference intervals for TT3, TT4, and TSH for each trimester of pregnancy (TT3 [88.28–176.8, 102.24–233.27 and 88.46–205.49 ng/dl], TT4 [6.49–13.75, 7.9–16.06 and 7.77–15.3 µg/dl] and TSH [0.21–1.82, 0.72–1.71 and 0.69–1.93 IU/ml]) for the pregnant Indian women of Manipur state (Ref 4).
  • We also emphasize, there is a definite difference in the trimester specific reference range of thyroid hormones within country like India due to its ethnic variation.

CME INDIA Learning Points

  • It must be appreciated that during pregnancy, the thyroid gland increases in size by 10% in iodine replete countries. But in areas of iodine deficient countries 20% to 40%
  • Production of the thyroid hormones, thyroxine (T4), and triiodothyronine (T3), increases by nearly 50%, in conjunction with a separate 50% increase in the daily iodine requirement.
  • Up to 18% of all pregnant women are thyroid peroxidase antibody (TPOAb) or thyroglobulin antibody (TgAb) positive. Increasingly, data suggest that TPOAb positivity adversely modulates the impact of maternal thyroid status (especially hypothyroidism) on the pregnancy and the developing fetus (ATA2017).
  • Largest decrease in serum TSH is observed during the first trimester. It is due to elevated levels of serum hCG directly stimulating the TSH receptor and thereby increasing thyroid hormone production.
  • A reduction in the lower TSH reference range is observed during pregnancy in almost all studies. In a small percentage of women, TSH can be undetectable (<0.01 mU/L), and yet still represent a normal pregnancy.
  • While addressing the clinical importance of a reduced serum TSH during pregnancy, it must be appreciated to note that subclinical hyperthyroidism has not been associated with adverse pregnancy outcomes. Obviously a maternal TSH concentration that is low but detectable is likely not clinically significant.
  • Ideally, reference ranges for thyroid function in pregnancy are established locally at the population level in pregnant women without thyroid disease.
  • ATA-2017 says: When local reference ranges are not available, the lower reference range for TSH can be reduced by 0.4 milliunits/L and the upper reference range for TSH can be reduced by 0.5 milliunits/L in the late first trimester of pregnancy (1).
  • Beyond the first trimester, TSH normalizes towards the nonpregnant reference ranges, and nonpregnant reference ranges can be used.
  • Reference ranges for total T4 and total T3 also should be adjusted for pregnancy. The upper reference range limits for total T4 and total T3 can be increased by approximately 50% after 16 weeks of gestation.
  • Before 16 weeks of gestation, there is a gradual increase in total T4 and total T3 compared with nonpregnant adults. These adjustments to total T4 and total T3 reference ranges are necessary to account for the increase in thyroid-binding globulin in pregnancy. (1)
  • Drug of choice: Pregnant women with overt hyperthyroidism should be treated with antithyroid drugs.
    • Either propylthiouracil or methimazole can be used to treat pregnant women with overt hyperthyroidism.
    • The choice of medication is dependent on trimester of pregnancy, response to prior therapy, and whether the thyrotoxicosis is predominantly T4 or T3.
    • Methimazole typically is avoided in the first trimester because it has been associated with a rare embryopathy characterized by oesophageal or choanal atresia as well as aplasia cutis, a congenital skin defect.
    • Propylthiouracil generally is prescribed for control of hyperthyroidism in the first trimester. After the first trimester, either methimazole or propylthiouracil can be used for treatment of hyperthyroidism.
    • In rare cases, propylthiouracil results in clinically significant hepatotoxicity
    • Usually transition to methimazole after the first trimester is scientific.
    • Remember that a transition from propylthiouracil to methimazole may result in a period of poor control of hyperthyroidism.
    • Both medications have known adverse effects that must be weighed against each other and discussed with the patient.
    • Propylthiouracil decreases T4 to T3 conversion and is used preferentially for T3-predominant thyrotoxicosis.
    • Transient leukopenia occurs in up to 10% of pregnant women who take thioamide drugs, but this situation does not require therapy cessation.
    • In less than 1% of patients who take thioamide drugs, however, agranulocytosis develops suddenly and mandates discontinuation of the drugs. The development of agranulocytosis is not related to dosage, and because of its acute onset, serial leukocyte counts during therapy are not helpful.
    • Alert – if fever or sore throat develops, women are instructed to discontinue use of the medication immediately and report for a complete blood count
    • If propylthiouracil is selected, an oral dosage of 100–600 mg daily, divided into three doses, may be initiated, depending on clinical severity. A typical dose in the average patient is 200-400 mg daily.
    • If methimazole is used, an initial daily dosage of 5–30 mg orally, divided into two doses, is recommended (although the frequency may be reduced to one daily dose as maintenance therapy is established).
  • The goal of treatment
    • Use lowest possible thioamide dose to maintain free T4 levels slightly above or in the high-normal range, regardless of TSH levels.
    • In women with predominantly T3 thyrotoxicosis, total T3 should be monitored.
    • Beta-blockers can be used as adjunctive therapy for symptomatic palpitations. Adrenergic β blocking agents, such as propranolol 20–40 mg every 6–8 h may be used for controlling hyper-metabolic symptoms. In the vast majority of cases the drug could be discontinued in 2 to 6 weeks. Long term treatment with propranolol has been associated with intrauterine growth restriction, fetal bradycardia and neonatal hypoglycemia.
  • Antithyroid drugs and risk of foetal hypothyroidism
    • Propylthiouracil and carbimazole /methimazole, both cross the placenta and are capable of causing foetal hypothyroidism and goitre.
    • Fetal goitre can be easily picked up by ultrasonography which should be done by an experienced ultrsonologist. This helps us to know the foetal thyroid status accurately so that timely dose interventions can be made in the drugs being offered to the mother.
    • Close monitoring of thyroid function, roughly once a month, is important because the need for antithyroid treatment often declines through preg-nancy, and in the mid-trimester it may occasionally be discontinued.
    • One should use the minimal dose of Antithyroid medication
    • The level of free T4 should be monitored in pregnant women being treated for hyperthyroidism, and the dose of antithyroid drug (thioamide) should be adjusted accordingly to achieve a free T4 at the upper end of the normal pregnancy range.
  • Thyroid Auto-antibodies
    • Three principal thyroid autoantigens are involved in Autoimmune thyroid disease. These are thyroperoxidase (TPO), thyroglobulin (Tg) and the TSH receptor.
    • TSH receptor autoantibodies (TRAb) are heterogeneous and may either mimic the action of TSH and cause hyperthyroidism as observed in Graves’ disease (alternatively, antagonize the action of TSH and cause hypothyroidism.)
    • TPO antibodies (TPOAb) appear involved in the tissue destructive processes associated with the hypothyroidism observed in Hashimoto’s and atrophic thyroiditis. During pregnancy, the presence of TRAb is a risk factor for fetal or neonatal thyroid dysfunction as a result of the transplacental passage of maternal TRAb.
    • The pathologic role of TgAb remains unclear.
  • TSH Receptor Anti-body Test
    • TSH Receptor stimulating antibodies are most closely associated with disease pathogenesis in all forms of Autoimmune thyrotoxicosis (Graves’ disease), Hashitoxicosis & Neonatal Thyrotoxicosis.
    • This test is recommended for:
    • Diagnosis of clinically suspected Graves’ disease (Extra thyroidal manifestation of Graves’ disease, Endocrine Exophthalmus, Pretibial Myxedama, Thyroid acropachy) in patients with normal thyroid function tests.
    • Determining risk of Neonatal thyrotoxicosis in a pregnant female with active or past history of Graves’ disease.
    • Differential diagnosis of Gestational Thyrotoxicosis versus First trimester manifestation or recurrence of Graves’ disease.
    • Assessing the risk of Graves’ disease relapse after antithyroid therapy.

CME INDIA Tail Piece

  • At present no Anti Thyroid medication started. TRab was planned. Report awaited.

References:

  1. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum [published erratum appears in Thyroid 2017;27:1212]. Thyroid 2017;27:315–89. (Level III)
  2. Thyroid disease in pregnancy. ACOG Practice Bulletin No. 223. American College of Obstetricians and Gynecologists. Obstet Gynecol 2020;135:e261–74.
  3. Rajput R, Singh B, Goel V, Verma A, Seth S, Nanda S. Trimester-specific reference interval for thyroid hormones during pregnancy at a Tertiary Care Hospital in Haryana, India. Indian J Endocrinol Metab. 2016;20(6):810-815. doi:10.4103/2230-8210.192903
  4. Jebasingh FK, Salam R, Meetei TL, Singh PT, Singh NN, Prasad  L.  Reference  intervals in  evaluation  of maternal  thyroid function  of Manipuri women. Indian J Endocr Metab 2016;20:167-70
  5.  Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis [published erratum appears in Thyroid


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