Thyroid Science 6(3):1-5, 2011	www.ThyroidScience.com
Case Reports

Development of Postpartum Graves' Hyperthyroidism

in a Woman with Hashimoto's Hypothyroidism

Cindy Huang, MD, Diane Fresca, MD

Dragana Jokic, MD, and Xiangbing Wang, MD, PhD

Division of Endocrinology, Metabolism & Nutrition, Department of Medicine,

UMDNJ- Robert Wood Johnson Medical School, New Brunswick, NJ 08093-0019

Corresponding Author: Xiangbing Wang, MD, PhD FACE

Division of Endocrinology, Metabolism & Nutrition

Robert Wood Johnson University Hospital-UMDNJ

MEB 384B, 1 RWJ Place, P.O.box 19. New Brunswick, NJ 08903

Phone (732) 235-7751 Fax (732) 235-7069 E-mail: wangx9@umdnj.edu

Received: February 9, 2011

Accepted: February 30, 2011

Abstract. Transformation of Hashimoto's hypothyroidism to Graves' hyperthyroidism is extremely rare, but does occur. The course and severity of autoimmune thyroid diseases are altered during pregnancy and the postpartum period. We report the clinical course, laboratory findings, and treatment of a female patient with Hashimoto hypothyroidism. She had a past medical history of Hashimoto hypothyroidism and had been on LT4 replacement therapy for two years. Six-months postpartum, however, she developed Graves' hyperthyroidism. LT4 was discontinued, and the patient was started on methimazole, 30 mg daily. Methimazole was discontinued one month later due to severe side effects, and 131 radioiodine therapy was applied. We suggest that patients with preexisting Hashimoto's hypothyroidism are not immune to developing Graves' disease. When such pa
tients have unexpected symptoms and changes in thyroid function tests, especially during pregnancy or in the postpartum state, this unlikely diagnosis should be entertained and treated accordingly.

Keywords Autoimmune thyroid disease • Graves' disease • Hashimoto's • Hyperthyroidism • Hypothyroidism • LT4 • Methimazole

Introduction

Hashimoto thyroiditis and Graves' disease are the most two common autoimmune thyroid diseases. They are generally thought to be discrete entities. The autoantibodies thyroid peroxidase (TPO) and thyroglobulin (Tg) are the classic markers of Hash
imoto's thyroiditis, a condition in which thyroid lym
phocytic infiltration and thyrocyte damage may prog
ress to hypothyroidism.

Graves' disease is caused by autoantibodies that induce thyrotoxicosis by mimicking the action of TSH and activating the TSH receptor. Reports show
ed that antibodies that either stimulate or block TSH receptors in Graves' disease patients were present in concentrations similar to those in Hashimoto thyroid
itis.[1] Studies also show a link between Graves' dis
ease and Hashimoto thyroiditis.[2]

The course and severity of autoimmune thyroid diseases are altered during pregnancy and the post
partum period. The thyroidal response to a fluctuat
ing immune status, combined with changes in thyroid economy during pregnancy, may result in a need to adjust the treatment regimen for thyroid disease dur
ing pregnancy. These and other not yet completely elucidated factors lead to partial tolerance and a dominant T-helper subset 2 (Th2) immune profile, which explains the positive influence of pregnancy on the clinical course of many (albeit not all) autoim
mune diseases and, characteristically, the generalized improvement of thyroid autoimmune diseases during pregnancy.

Patients with Hashimoto's hypothyroidism who are on thyroid hormone replacements are frequently observed to have an increased requirement for levo
thyroxine early in pregnancy. This, however, is not true of all patients.[3,4]

Graves' disease usually improves during preg
nancy but flares up after delivery. Due to the pro
found autoimmune modifications that occur post-
delivery, it is understandable that the postpartum period has been associated with a greater frequency of onset, recurrence, or exacerbation of thyrotoxico
sis from Graves' disease and postpartum thyroidi
tis.[5] Spontaneous conversion from hypothyroidism to hyperthyroidism, although not common, has been reported before.[6-10] Development of Graves' disease in the first trimester of pregnancy and later stages of pregnancy has also been reported.[8,10,11]

Spontaneous transformation from Hashimoto hypothyroidism to postpartum Graves' hyperthyroid
ism , however, has not previously been reported. We report a patient with a 2-year history of Hashimoto hypothyroidism and replacement therapy who devel
oped Graves' hyperthyroidism 6- months postpartum.

Case Presentation

A 34-year-old female presented to the emergency department with complaints of palpitations and diz
ziness that was worsening. Three months previously, she had undergone a work up for fatigue following a miscarriage in June 2005. At that time, her TSH was < 0.1 mIU/L, her free T4 was within range at 1.0 ng/dL, and her 123 Iodine uptake and scan showed a 6-hour RAI uptake of 9.7% and 24-hour RAI uptake of 13% with patchy and heterogeneous activities. The patient was sent to an endocrinologist for evaluation.

After five months of observation, when her TSH rose to 32 mIU/L and her free T4 dropped to 0.8 ng/dL, the patient was diagnosed with Hashimoto's thyroiditis.

Anti-TPO antibodies at that time were positive at 67.7 IU/mL. Two months after initiation of treatment with LT4, 100 g daily, her TSH dropped to 0.032 mIU/L and her free T4 elevated to 2.13 ng/dL. Her LT4 dose was subsequently decreased to 50 g daily. Two months later, the patient became euthyroid and remained stable until becoming pregnant in August 2006.

During her first trimester, her TSH rose to 98 mIU/L and her LT4 was increased back to 100 g daily. However, her thyroid function tests again normalized, and she remained euthyroid through her third trimester. She had an uncomplicated delivery. Postpartum, she remained on 100 g of LT4 until she presented to her endocrinologist on September 2007 with symptoms of thyrotoxicosis.

At this time, her TSH was undetectable and her free T4 was markedly elevated at 10.44 ng/dL. A 123 iodine uptake and scan revealed a homogenous 4-
hour uptake of 66% and a 24-hour uptake of 73%. LT4 was discontinued, and the patient was started on methimazole, 30 mg daily.

The patient's thyrotoxic symptoms persisted four weeks after she initiated methimazole, and she devel
oped skin rashes, nausea, dizziness, and had episodes of syncope. Because of this, she sought treatment at our emergency department.

Upon admission, her TSH was undetectable, her

Table 1. Time course of TFTs, 123 Iodine uptake, thyroid antibodies and treatments.
Date	TSH	Free T4	24 hour RAI Uptake	TPO	TSI	LT4 Dose
6/05	< 0.01	1.0	13%	None
10/05	31.19	0.8	67.7	Start	Start 100 g
12/05	0.032	2.13	100 g
2/06	0.009	1.79	100 g
4/06	0.86	1.24	50 g
7/06	0.71	1.31	50 g
8/06

(1st trimester)	98.070	0.97	50 g
9/07

(6 months post partum)	0.049	10.44	73%	100 g, off T4 and start Tapazole
10/07	< 0.01	2.02	Off Tapazole
11/07	< 0.01	1.03	357%	131RAI therapy
2/7/08	15.38	0.94	50 g
4/7/08	0.288	1.23	88 g
7/14/08	0.228	1.33	88 g
Reference ranges: 123Iodine uptake, 24 hour 15-35%; TPO Ab, < 30 IU/mL; TSI, 0-129%; TSH, 0.35-5.50 mIU/mL; FreeT4, 0.61-1.76 ng/dL.

free T4 was 2.02 ng/dL, and her thyroid stimulating immunoglobulin (TSI) level was elevated at 357%. Methimazole was discontinued due to her skin rashes and because she had transaminase elevations greater than two times the upper limit of normal. She was hydrated with intravenous fluid and administered propranolol and prednisone while waiting for 131 RAI therapy.

Seven days after discontinuing methimazole, the patient received 10 mCi of 131I during her admission for definitive treatment. One month later at outpatient follow-up, the patient was found to be clinically eu
thyroid with a reference range free T4. Three month later, however, the patient complained of fatigue, dry skin, and was found to be clinically hypothyroid. Her TSH was high at 15.38mIU/L, and her free T4 was low in its reference range at 0.94 ng/dL. Treatment with LT4 was then reinitiated (Table 1).

Discussion

Hyperthyroidism is known to occur early in the course of Hashimoto's thyroiditis and is commonly termed "Hashitoxicosis."[12] At this time, the inflamed thyroid gland leaks preformed hormone. In patients who have already entered the hypothyroid phase of Hashimoto's thyroiditis, the injured thyroid gland has lost its synthetic ability and the patient needs life long replacement therapy. Affected patients are not ex
pected to subsequently develop hyperthyroidism.

In the case we report here, however, the clinical course and treatment are unique. The patient was ini
tially noted to have subclinical hyperthyroidism with low 123I uptake in June 2005, which indicated Hash
itoxicosis. Four months later, she developed hypothy
roidism and had elevated TPO antibodies. She began T4 replacement therapy. This, of course, was the typ
ical course for a patient with Hashimoto hypothyroid
ism.

During the first trimester of her pregnancy, her LT4 replacement dose had to be increased. This indi
cated that she had reduced thyroid reserve because Hashimoto's thyroiditis had injured or destroyed her thyroid gland.

Six months postpartum, she developed typical signs and symptoms of hyperthyroidism. She was found to have a high 123I uptake, high TSI titer, low TSH, and a high free T4. These findings confirmed the diagnosis of Graves' hyperthyroidism.

The patient was treated with methimazole. How
ever, she developed skin rashes and liver toxicity one month later. Because of this, Methimazole was dis
continued and propranolol was used to control her hyperthyroidism while waiting for 131RAI thera
py.[13,14]

Spontaneous conversion from hypothyroidism to hyperthyroidism, as in the patient we describe here, is not common, although it has been reported be
fore.[6-11] Some of the described changes in clinical course that researchers have reported were associated with pregnancy or previous treatment with antithy
roid medications; others occurred spontaneously. Nearly all of the patients in these cases expressed more than one type of thyroid auto-antibody concom
itantly or over time. These observations are in ac
cordance with a series of studies from the 1990's. These studies established that the same patient may express one or more different TSH receptor antibod
ies in addition to anti-TPO or anti-thyroglobulin anti
bodies.[15-17]

Factors influencing the relative concentrations of each antibody and how the different antibodies inter
act with one another are likely responsible for the prevailing clinical manifestations. Spontaneous trans
formation from Hashimoto hypothyroidism to Grave
s' hyperthyroidism postpartum, however, has never been reported before. The etiology of Graves' disease in a postpartum-patient already on replacement for Hashimoto's hypothyroidism remains to be elucidated at the present time.

Our patient had both positive TSI and positive TPO antibodies at two different points in her clinical course. She had Hashimoto hypothyroidism and had already been on replacement for two years. She also had a sufficiently reduced thyroid reserve to require an increase in LT4 replacement during her first tri
mester of pregnancy. There should not have been enough thyroid hormone in reserve in her thyroid gland to respond to the stimulating antibodies post
partum.

Literature review revealed several case reports describing patients who transitioned from one form of autoimmune thyroid disease to another. [15-17] It ap
pears that the course and severity of autoimmune thyroid disease are altered during or in the post
partum period. The pregnant woman's immune state may have changed from predominant anti-TPO anti
body or thyroid-binding inhibiting immunoglobulin (TBII) to TSI.[16-18] Serum levels of TBII and TSI have been shown to consistently decrease or disap
pear during pregnancy and increase after deliver
y.[15-18] Progesterone (P) and estrogen (E) exert these immuno-modulating effects. Whereas progesterone decreases reactivity of both the humoral and cellular arms of the immune system, estrogen exerts opposite effects. Because pregnancy is characterized by an overall increase in the P:E ratio, the reactivity of both arms of the immune system is inhibited.[9] Thyroid autoantibodies and antibodies directed against other tissues are partially suppressed during pregnancy and are exacerbated after delivery. The precise mechan
ism of these immune effects remains obscure. Pre
sumably, the rapid reduction in immune suppressor function of the P:E ratio following delivery leads to the reestablishment and exacerbation of these con
ditions.[20-22]

The postpartum rebound of thyroid autoimmune diseases is a striking example of this phenomenon.[22] We suggest that our patient had thyroid hormone in reserve in her thyroid gland for two reasons: her anti-
TPO antibody level was low and did not completely destroy her thyroid gland, and her relatively low LT4 dosage before pregnancy allowed thyroid hormone production to proceed. During her pregnancy and postpartum period, her autoimmune status changed predominant to TSI (359%). The antibodies may have stimulated her remaining thyroid gland to pro
duce enough thyroid hormone to produce Graves' hyperthyroidism six months postpartum.

Conclusion

We report a case of Graves' hyperthyroidism that developed in a woman with Hashimoto's hypo
thyroidism six month postpartum. Transformation of Hashimoto's hypothyroidism to Graves' hyperthy
roidism is extremely rare. However, patients with Hashimoto's hypothyroidism are not immune to the development of Graves' disease. When such patients have unexpected symptoms and changes in thyroid function tests that characterize hyperthyroidism, es
pecially during pregnancy or the postpartum state, this unlikely diagnosis should be entertained and treated accordingly.

References

1.	Morgenthaler, N.G., Ho, S.C., and Minich, W.B.: Stimulating and blocking thyroid-stimulating hor
mone (TSH) receptor autoantibodies from patients with Graves' disease and autoimmune hypothy
roidism have very similar concentration, TSH re
ceptor affinity, and binding sites. J. Clin. Endo
crinol. Metab., 92:1058-1065, 2007.

2.	McLachlan, S.M., Nagayama, Y., Pichurin, P.N., et al.: The link between Graves' disease and Hash
imoto's thyroiditis: a role for regulatory T cells. Endocrinology, 148:5724-5733, 2007.

3.	Kaplan, M.M.: Monitoring thyroxine treatment during pregnancy. Thyroid, 2:147-152, 1992.

4.	Mandel, S.J., Larsen, P.R., and Seely, E.W.: In
creased need for thyroxine during pregnancy in women with primary hypothyroidism. N. Engl. J.Med., 323:91-96, 1990.

5.	Mino, N., Mori, H., Iwatani, Y., et al. High prev
alence of transient post-partum thyrotoxicosis and hypothyroidism. N. Engl. J. Med., 306:849-852, 1982.

6.	Takasu, N.,Yamada, T., Sato, A. et al. Graves's dis
ease following primary hypothyroidism due to Hash
imoto's disease: Studies of eight case. Clin. Endo
crinol., 33: 687-698, 1990.

7.	Ruchala, M., Szczepanek, E., Skiba, A., et al.: Graves' hyperthyroidism following primary hypo
thyroidism due to Hashimoto's thyroiditis in a case of thyroid hemiagenesis: case report. Neuroendo
crinol. Letters, 29:55-58, 2008

8.	Lu, R., Burman, K.D., and Jonklaas, J.: Transient Graves' hyperthyroidism during pregnancy in a pa
tient with Hashimoto's hypothyroidism. Thyroid, 15:725-729, 2005.

9.	Bando, Y., Nagai, Y., Ushiogi. Y., et al.: Develop
ment of Graves' hyperthyroidism from primary hy
pothyroidism in a case of thyroid hemiagenesis. Thy
roid, 9:183-7, 1999.

10.	Gola, M., Doga, M., Mazziotti, G., et al.: Develop
ment of Graves' hyperthyroidism during the early phase of pregnancy in a patient with pre-existing and long-standing Hashimoto's hypothyroidism. J. Endocrinol. Invest., 29:288-290, 2006.

11.	Volpe, R., Ehrlich, R., Steiner, G., et al.: Graves' disease in pregnancy years after hypothyroidism with recurrent passive-transfer neonatal Graves' dis
ease in offspring: therapeutic considerations. Am. J. Med., 77:572-578,1984.

12.	Nabhan, Z.M., Kreher, N.C., and Eugster, E.A.: Hashitoxicosis in children: clinical features and na
tural history. J. Pediatrics, 146:533-536, 2005

13.	Wang, X., Wu, H., and Chao, C.: Effect of pro
pranolol on calcium, phosphorus and magnesium metabolism in Graves' disease. Metabolism, 41:552-
555, 1992.

14.	Toscano-Zukor, A.M. and Wang, X.: Overt hyper
thyroidism in metastatic gestational trophoblastic disease. The Endocrinologist, 17:211-213, 2007

15.	Dayan, C.M. and Daniels, G.H.: Chronic autoim
mune thyroiditis. N. Engl. J. Med., 335:99-107, 1996.

16.	Kohn, L.D., Suzuki, K., Hoffman, W.H., et al.: Characterization of monoclonal thyroid stimulating and thyrotropin binding-inhibiting autoantibody from a Hashimoto's patient whose children had in
trauterine and neonatal thyroid disease. J. Clin. Endocrinol. Metab., 82:3998-4009, 1997.

17.	Kung, A.W. and Jones, B.M.: A change from stim
ulatory to blocking antibody activity in Graves, dis
ease during pregnancy in patient with Graves' dis
ease. J. Clin. Endocrinol. Metab., 83:5871-5874, 2003.

18.	Geenen, V., Perrier de Hauterive, S., Puit, M., et al.: Autoimmunity and pregnancy: theory and practice. Acta Clin. Belg., 57: 317–324, 2002.

19.	Sridama, V., Pacini, F., Yang, S.L., et al.: Decreas
ed level of helper T cells: a possible cause of im
munodeficiency in pregnancy. N. Engl. J. Med., 307:352-356, 1982.

20.	Stagnaro-Green, A., Roman, S.H., Cobin, R.H., et al.: A prospective study of lymphocyte-initiated im
munosuppression in normal pregnancy: evidence of a T-cell etiology for postpartum dysfunction. J. Clin. Endocrinol. Metab., 74:645-663, 1992.

21.	DeGroot, L.J. and Quintans, J.: The causes of auto
immune thyroid disease. Endocr. Rev., 10:537-562, 1989.

22.	Amino, N., Tada, H., Hidaka, Y., et al.: Postpartum autoimmune thyroid syndrome. Endocr. J., 47:645-
655, 2000.

23.	Momotani, N., Noh, J., Oyanagi, H., et al.: Antithy
roid drug therapy for Graves' disease during preg
nancy: optimal regimen for fetal thyroid status. N. Engl. J. Med., 315:24–28, 1986.