| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Other Original Articles |
Units of Endocrinology (J.A.) and Genetics (T.K.), Hospital Divino Espirito Santo, 9500 Ponta Delgada, Azores-Portugal; and Departments of Medicine (K.D., R.S., S.R., R.E.W.) and Pediatrics (S.R.), University of Chicago, Chicago, Illinois 60637
Address all correspondence and requests for reprints to: Dr. João Anselmo, Endocrinology Unit, Hospital Divino Espirito Santo, 9500 Ponta Delgada-Azores, Portugal, or Dr. Roy E. Weiss, Thyroid Study Unit, MC 3090, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: rweiss{at}medicine.bsd.uchicago.edu
Abstract
We report the occurrence of transient thyrotoxicosis during pregnancy in a subject with resistance to thyroid hormone. Before pregnancy, the subject was euthyroid, with normal serum TSH and elevated levels of free T3 and free T4 caused by a mutation in the TRß gene (R243Q). Beginning at the fourth week of gestation serum levels of free T3 and T4 increased in parallel with an increase in hCG. At 6–7 wk gestation she manifested hypermetabolic features, with mild nausea and vomiting. Peak levels of serum hCG and thyroid hormone concentrations were attained at 12 wk gestation, when serum TSH was fully suppressed. In the following weeks of gestation, thyroid hormone levels declined, with amelioration of the symptoms. A baby boy also affected with resistance to thyroid hormone harboring the same TRß gene mutation was born by normal vaginal delivery.
RESISTANCE TO THYROID hormone (RTH) is an uncommon and usually dominantly inherited disorder characterized by reduced responsiveness of target tissues to thyroid hormones (1, 2). Subjects present with high serum levels of free T3 (FT3) and free T4 (FT4) in conjunction with nonsuppressed TSH. Goiter is the most common clinical abnormality. Although the majority of patients with RTH are clinically euthyroid, we observed signs and symptoms suggestive of hyperthyroidism during the first trimester of pregnancy. In the present work we evaluated thyroid function during pregnancy in a patient with RTH.
Case Report
The subject of this study was a 26-yr-old woman (gravida 2, para
2) belonging to a large Azorean family with RTH (3).
Sequencing the TRß gene from leukocyte-derived DNA revealed a single
nucleotide substitution, with adenine replacing the normal guanine
(CGG
CAG), resulting in a change in
the normal arginine at position 243 to a glutamine (R243Q). The subject
was brought to medical attention 4 yr ago because one of her sisters
was found to have a large goiter and high levels of free thyroid
hormones with normal TSH. This phenotype, suggestive of RTH, lead to
the study of other family members. Her father (recently deceased at the
age of 61 yr) and five of eight siblings (three sisters, aged 28, 25,
and 14 yr, and two brothers, aged 31 and 33 yr) were found to be
affected (Fig. 1
). Informed consent was
obtained from the subject and family members, and all evaluations were
approved by the institutional review board.
|
At 20 yr of age during the first trimester of her first pregnancy she
reported signs and symptoms of hypermetabolism, including weight loss
and mild nausea and vomiting. The symptoms spontaneously subsided. At
that time no thyroid function tests were obtained. Her first son, who
is now 6 yr old, also has RTH (Fig. 1
).
During the subject’s second pregnancy, thyroid function tests were
closely monitored (Fig. 2). At 4 wk
gestation, FT3 and FT4 were
slightly above the elevated prepregnancy levels coincident with the
elevated hCG. Between 6 and 7 wk gestation, the patient started to
complain of anxiety, tremor, tiredness, and palpitations and had a
resting pulse rate above 120 beats/min. She also complained of mild
nausea and occasional vomiting. At 10 and 12 wk gestation serum
concentrations of hCG were 257 and 321 kU/liter, respectively, and the
TSH became undetectable by a third generation TSH assay (ACS
Ciba-Corning Diagnostics, Inc., Medfield, MA). The assay is a
two-antibody chemiluminometric immunoassay with a sensitivity of 0.02
mU/liter. At 10 wk gestation there was no measurable response of TSH to
TSH-releasing hormone (TRH test, 400 µg proterelin, iv). By wk 12 of
gestation the patient had lost 2 kg. A complete blood chemistry panel
revealed no abnormalities in serum electrolytes or liver function
tests. At 16 wk gestation, FT3 and
FT4 had declined, and the symptoms subsided. TSH
remained below normal limits until 28 wk gestation. During the third
trimester thyroid hormone levels were slightly below the prepregnancy
levels, and TSH remained within the normal range.
|
Discussion
Changes in thyroid physiology associated with normal pregnancy can be difficult to distinguish from true hyperthyroidism. Many of the clinical symptoms of hyperthyroidism mimic normal pregnancy. Furthermore, hCG has TSH-mimetic action. During the first trimester of pregnancy, an increase in the serum hCG concentration is associated with an increase in serum FT4 and a reduction in TSH levels. Their respective peak and nadir occur, on the average, at 10 wk gestation. During this time 18% of women have subnormal TSH levels; in half of them the values may be less than 0.05 mU/liter or undetectable. This occurs mainly in those women in whom hCG reaches a value above 50 kU/liter. However in only 11% of these women is FT4 above the upper limit of normal (4).
Little is known about the thyroid hormone physiology in a gravid patient with RTH in whom thyroid hormone levels are elevated before conception. The observations presented in this report demonstrate that, as in pregnant women without RTH, TSH suppression was only transient. Furthermore, during the recovery period, FT4 remained below the pregestational level, albeit above the upper limit of normal for subjects without RTH.
The concentration of FT3 required to suppress serum TSH in subjects with RTH varies according to the severity of the hormonal resistance. Information is based on short-term administration of L-T3 (5). The senior authors of this article observed only one subject with RTH who developed symptomatic autoimmune thyrotoxicosis. In this individual, suppression of serum TSH from 0.6 to less than 0.01 mU/liter was associated with 63% and 54% increases in serum FT4 and FT3, respectively. These incremental changes are slightly higher than those observed in the subject presented herein (28% for FT4 and 37% for FT3).
A TSH with increased biological activity in subjects with RTH is believed to be responsible for the maintenance of high thyroid hormone levels and goiter (6). Nothing is known regarding the biological activity of hCG in subjects with RTH. However, the higher hCG levels reported in the current case compared with those encountered, on the average, in pregnancy, could explain the transient thyrotoxicosis. Indeed, symptomatic gestational hyperthyroidism with serum hCG levels above 100 kU/liter has an overall prevalence of 2.4%, and half of these subjects also have hyperemesis (4). Whether this occurs with higher frequency in subjects with RTH remains to be established.
To our knowledge there is only one other study that examines thyroid hormone physiology in a pregnant subject with RTH (7) and a fetus with the TRß mutation, T377A. This subject was treated before and during pregnancy with 3,5,3'-triiodothyroacetic acid, which did not allow for assessment of thyroid hormone changes. Further studies of pregnant subjects with RTH will clarify the physiology of thyroid hormone in the gravid mother and have implications for the management of the fetus.
Acknowledgments
Footnotes
This work was supported in part by NIH Grants DK-15070, DK-58281, and RR-00035; The Seymour J. Abrams Thyroid Research Center; and Blum-Kovler research funds.
Abbreviations: FT3, Free T3; FT4, free T4; RTH, resistance to thyroid hormone.
Received February 28, 2001.
Accepted May 8, 2001.
References
This article has been cited by other articles:
 |
|
 |
|
  J. Anselmo, D. Cao, T. Karrison, R. E. Weiss, and S. Refetoff Fetal Loss Associated With Excess Thyroid Hormone Exposure JAMA, August 11, 2004; 292(6): 691 - 695. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
