Thyroid Science 5(2):CLS1-3, 2010	www.ThyroidScience.com
Case Report

Thyrotoxicosis in Pregnancy Complicated by

Propylthiouracil-induced Hepatitis

Lajya Devi, MD,1A Rimpy Tandon, MD,2A

Ibha Kumari, MD,2B Anju Huria, MD,2C Poonam Goel, MD2D

1Department of Obstetrics & Gynecology, Guru Gobind Singh Medical College, Faridkot, Punjab

1AAssociate professor, lajja.goyal@rediffmail.com.

2Department of Obstetrics & Gynecology, Government Medical College & Hospital, Sector–32, Chandigarh

2AAssistant Professor, drrimpy@yahoo.com; 2BEx-Senior Lecturer, kumari.ibha@yahoo.com;

2CProfessor & Head, anjuhuria@yahoo.com; 2DProfessor, poonam1302@yahoo.com.

*Corresponding Author: Dr. Rimpy Tandon,

Assistant Professor, Department of Obstetrics & Gynecology,

Government Medical College & Hospital, Sector-32, Chandigarh, drrimpy@yahoo.com

Received: January 19, 2010

Accepted: January 29, 2010

Abstract. Graves' disease is the most common cause of hyperthyroidism during pregnancy. Propylthiouracil (PTU) is the treatment of choice due to its relative safety during pregnancy compared to methimazole. How
ever, rarely, PTU causes serious complications like hepatitis. We report a case of hepatitis possibly related to PTU during pregnancy complicated by thyrotoxicosis.

Keywords • Graves' disease • Hepatitis • Methmazole • Pregnancy • Propylthiouracil • Thyrotoxicosis

Introduction

Hyperthyroidism complicates up to 0.2% of preg
nancies, and Graves' disease accounts for 90%-to-
95% of these cases.[1] Medical treatment with anti
thyroid drugs is the preferred mode of therapy in such situations, as radioactive iodine is contraindicated dur
ing pregnancy.[2]

Propylthiouracil (PTU) is the antithyroid drug often prescribed during pregnancy due to its relative safety compared to methimazole.[3] However, rarely, PTU causes serious complications. One complication is hepatitis that leads to a management dilemma. Withdrawing the drug results in a recurrence of thy
rotoxicosis that may adversely affect the pregnancy.

Case Report

A 22-year-primigravida was seen at 5 weeks of gestation with complaints of palpitation, tremors, and excessive sweating. Examination revealed diffuse thy
roid enlargement and ophthalmopathy. Her pulse was 110 beats per minute and her blood pressure was 150/90 mm of Hg. Her hemoglobin was 12 gm/dL (10.5-to-14 gm/dL) and other cell lines were also with
in their reference ranges. Baseline liver and renal func
tion tests were within their reference ranges. Her TSH level was 0.2 U/mL (0.6-to-4.5 U/mL), her free T3 was 6.3 pg/mL (1.2–to-4.1pg/mL), and her free T4 was 2.96 ng/dL (0.7-to-1.72ng/dL). Thyroid ultraso
nography showed that the gland was diffusely en
larged.

She was started on 50 mg of PTU and 20 mg of propranolol twice each day. Follow-up after 6 weeks revealed persistent symptoms; hence, her daily dose of PTU was increased to 300 mg. The patient finally achieved a euthyroid state with a PTU dose of 600 mg per day. Subsequent follow-ups of the patient till 32 weeks of gestation were uneventful.

At 33-weeks of gestation, jaundice was detected. Laboratory testing showed the following: a total serum bilirubin of 9.4 mg/dL (0.5-to-1.2 mg/dL), conjugated bilirubin of 7.8 mg/dL, serum aspartate aminotrans
ferase of 302 IU/L (5-to- 40 IU/L), alanine amino
transferase of 325 IU/L (5-to-35 IU/L), alkaline phos
phatase 344 IU/L (108-to-306 IU/L), and a prothrom
bin time index of 71% (75%-to-100%). There was no history of any preceding fever.

Viral markers for hepatitis A, B, C and E were negative and HIV serology was non-reactive. Ultraso
nography of the patient's liver and gall bladder was unremarkable.

A diagnosis of PTU-induced hepatitis was made and PTU was withdrawn. The dose of propranolol was increased to 60 mg daily in three divided doses. Fetal well-being was monitored with daily non-stress testing and on alternate days a biophysical profile. Liver function tests showed improvement one week after the patient stopped the use of PTU. However, thyroid function test results showed a reversal of the hyper
thyroid state: her free T4 level was 3.5 ng/dL (0.7-to-
1.72 ng/dL).

At 35-weeks of gestation, the patient complained of loss of fetal movement and features that revealed abruption. Intrauterine fetal death was confirmed with ultrasonography. Labour was induced and the patient delivered a dead fetus weighing 2.4 kg.

Two weeks after delivery, the patient developed palpitations and sweating. Her TSH was abnormally low. She was then treated with radioablation (5 mCi).

Six months after radioablative therapy, she con
ceived again in a euthyroid state. In the second month of pregnancy, she again developed features of Graves' disease. This time, her hyperthyroidism was controlled with 20 mg of NeoMercazole® twice daily. (NeoMer
cazole® is carbimazole, which is completely metab
olised to methimazole, the metabolite that is respon
sible for the drug's clinical effects.) She tolerated the dose well and achieved euthyroid status quickly within 4 weeks. She was closely supervised till term and de
livered a live and healthy baby weighing 2.6 kg at 37-weeks of gestation.

Discussion

The management of thyrotoxicosis in our patient raises important and pertinent issues. Uncontrolled thyrotoxicosis in pregnancy is associated with mater
nal and fetal complications. These include pre-eclam
psia, thyroid crisis, preterm labour, abruptio placen
tae, and fetal death.[2]

Our patient's first pregnancy was complicated with abruptio placentae and still birth. These compli
cations were possibly related to uncontrolled thyro
toxicosis after the patient stopped the use of PTU.

The second issue of importance is whether to use PTU or methimazole to control thyrotoxicosis during preganancy.[4] Both drugs have been used for this purpose. PTU is preferably used in many countries where methimazole is considered to be more often as
sociated with fetal abnormalities like aplasia cutis, oesophageal atresis, choanal atresia, facial abnormal
ities, and mental retardation.[5] However, there is now a consensus that the overall risk of congenital abnor
malities from methimazole is no higher than that re
ported from the use of nonteratogenic drugs.[5]

In our patient's first pregnancy, PTU was asso
ciated with hepatitis. However, methimazole produced no adverse reactions in the mother or the fetus.

The incidence of PTU-induced hepatitis ranges from 0.1%-to-0.2%.[6] It takes the form of allergic hepatitis accompanied by laboratory evidence of hepa
tocellular damage.[6] The occurrence of PTU-induced hepatitis in the third trimester of pregnancy leads to a treatment dilemma. Switching to other thionamides has been tried,[7] but this risks potential cross-reaction and hence should be avoided.[8]

Higher doses of PTU are associated with more ad
verse effects. Most often, hyperthyroidism during pregnancy is controlled with 100-to-450 mg of PTU. Occasionally, however, doses in the range of 600-to-
800 mg/day are required. This is possibly related to poor compliance or altered PTU pharmacodynamics in pregnancy.

Surgery is the treatment option when persistently high doses of PTU are required or thyrotoxicosis re
mains uncontrolled. Surgery should preferably be per
formed in the second trimester.

Our case illustrates the fact that rare side effects of drugs used to control a medical condition in preg
nancy may occur at any time. Hence, these patients' clinical condition should be closely monitored with liv
er function tests.

Our patient was interesting in one more aspect. She developed a hyperthyroid state soon after stopping PTU. Though after the delivery of the dead fetus in her first pregnancy, her hyperthyroid state was con
trolled with radioactive iodine. She then again devel
oped thyrotoxicosis during her second pregnancy. This time, however, her hyperthyroidism was well control
led with methimazole and she delivered a healthy ba
by.

Conclusion

Hepatitis is a rare side effect of PTU, and its occurrence during pregnancy leads to a management dilemma. However, if hepatitis occurs in the second trimester, the option of surgery can be carried out. The available literature indicates that the patient can also
safely use methimazole as was seen in our patient during her second pregnancy.

References

1.	Nader S.: Thyroid disease and other endocrine disor
ders in pregnancy. Obstet. Gynecol. Clin. N. Am., 21:257-285, 2004.

2.	Davis, L.E., Lucas, M.J, Hankins, G.D., et al. Thy
rotoxicosis complicating pregnancy. Am. J. Obstet. Gynecol., 160: 63-70, 1989.

3.	Rosenfeld, H., Ornoy, A., Shechtman, S., et al.: Pregnancy outcome, thyroid dysfunction and fetal goiter after in utero exposure to propylthiouracil: a controlled cohort study. Br. J. Clin. Pharmacol., 68: 609–617, 2009.

4.	Chattaway, J.M and Klepser, T.B. Propylthiouracil versus methimazole in treatment of Graves' disease during pregnancy. Ann. Pharmacother., 41:1018-
1022, 2007.

5.	Inoue, M., Arata, N., Koren, G., et al. Hyperthyroidism during pregnancy. Canadian Family Physician, 55:701-703, 2009.

6.	Cooper DS. Antithyroid drugs. New England J. Med., 352:905-917, 2005.

7.	Kontoleon, P., Illias, I., Koutras, D.A., et al.: Succes
sful treatment with carbimazole of a hyperthyroid pregnancy with hepatic impairment after propylthio
uracil administration: a case report. Clin. Exp. Obstet. Gynecol., 29:304-305, 2002.

8.	Rashid, M., and Rashid, M.H. Obstetric management of thyroid disease. Obstet. Gynecol. Surv., 62: 680688, 2007.