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Journal of the Anatomical Society of India

Carbimazole Induced Thyroid Histopathy in Albino Rats during Development

Author(s): Zaidi T.M., Khan A.A, Hasan B.M. and Faruqi A.N.

Vol. 53, No. 2 (2004-07 - 2004-12)

J.N. Medical College, A.M.U., Aligarh. U.P.

Abstract:

Although personal preference may affect the choice of the antithyroid drug, almost all of them are known to cross the placental barrier as well as secreted into the milk. Thus, they affect the thyroid status of the developing fetus and the newborn. The present study was carried out on twelve pregnant albino rats; 6 control and 6 experimental. The experimental female rats received carbimazole in an oral dose of 5 mg/250g/d, from 10th day of pregnancy to 21st day of lactation. At the end of experiment the pups were perfused and fixed with 10% formalin. The thyroid glands were dissected out and processed for paraffin sections and light microscopic observations. As compared to control, the thyroid gland of pups from experimental group revealed overall shrinkage though its general cytoarchitecture remained intact. Most of the follicles were very much reduced (<1/ 4th of control) with scanty homogenous colloidal material. The follicular cells were cuboidal compared to flattened/low cuboidal in control. The number of follicular were cells/follicles were also reduced. None of the follicles revealed absorptive vesicle. It was concluded that carbimazole administered even in therapeutic dose during pregnancy and lactation resulted into alteration of the thyroid microstructure of newborn, suggestive of functional hypothyroidism.

Key words: Thyroid, Hypothyroidism, Hyperthyroidism, Antithyroid drugs

Introduction:

Thyroid gland is a unique endocrine gland being largest, superficially located and being amenable to physical examination and biopsy.The thiourelene therapy is a mainstay of the treatment of hyperthyroidism occurring during pregnancy. Marchant et al (1977) demonstrated transplacental passage of propylthiouracil and methimazole after single dose given to normal women. Gardner et al (1986) reported higher cord serum propylthiouracil concentration than maternal serum propylthiouracil concentration during treatment of hyperthyroidism. Likewise, propylthiouracil when administered orally, the fetus directly benefits from maternal ingestion. This however, also predisposes the fetus to hypothyroidism Dussault et al (1993). For many years the breast-feeding was forbidden if antithyroid drugs were used Larsen et al (1992). It had been well established that both methimazole and propylthiouracil are transferred into breast milk, Low et al (1979) and Cooper et al (1984). It is generally noticed that with the higher dose of methionamide the risk of developing hypothyroidism also increases. Carbimazole is a carbethoxy derivative of methimazole which is converted into methimazole in the body and commonly used in India as antithyroid drug. The present study was aimed to find the light microscopic changes in the thyroid of pups from carbimazole-exposed albino rat mothers.

Material and Methods:

In the present study 12 pregnant albino rats withaverage weight of 200 ± 20 g, were obtained from theanimal house of J.N. Medical College, A.M.U., Aligarh. They were divided into two groups (control and experimental) having six animals each. The experimentalanimals were adminstered carbimazole in an oral dose of 5mg/250gm/day in single daily dose. The controlgroup received only normal diet and water. The treatment was continued from10th day of pregnancy to 21st day of lactation. At the end of experiment the 6 pups (weighing 30 ± 5 g) from each group were killed andperfused with 10% buffered fomalin. The thyroid glandswere dissected out and processed for paraffin embedding. The sections of 8-10 micrometer were stained with haematoxylin and eosin for observation under light microscope.

Observations:

The control group showed large aggregation of follicles having oval, circular or irregular shapes (Fig. 1). Most of the follicular cross-sections had 20-30 flattened/ low cuboidal follicular cells having scanty cytoplasm. The follicles possessed copious amount of homogenous, eosinophilic colloid material (Fig. 2). The colloid near luminal aspect of follicular cells was associated with absorptive vesicles suggesting resting stage of normal functioning thyroid gland. The interlobular stroma appeared less dense (Fig. 1) but individual follicles were surrounded by network of small blood vessels (Fig. 2). The para follicular cells were in the form of clumps having large round nuclei and eosinophilic cytoplasm (Fig. 2). The experi-mental group showed relatively small sized aggregation of follicles. Most of the follicles were markedly small (Fig. 3) having only 810 cuboidal follicular cells (Fig. 4). Follicles were mostly rounded and filled with scanty colloid material or completely devoid of colloid (Fig. 5). No absorptive vesicles were observed near luminal aspect of the follicular cells. Stroma between the lobules appeared more dense (Fig. 3) but less vascular. Squamous metaplasia of thyroid follicular epithelium, LiVolsi and Merino, (1978) and cartilage, skeletal muscle or adipose tissue, Finkle and Goldman (1973), were not found within the thyroid parenchyma.

Discussion:

Thionamide, an antithyroid drug of the same group as that of carbimazole, used during pregnancy and lactation is known to suppress the thyroid status of both mother and fetus suggesting that even the therapeutic dose taken during pregnancy can induce hypothyroidism, Momotani et al (1986). Histological findings in the present study included small, shrunken lobules, comprising of microfollicles which were either partially filled or completely devoid of colloid and lined by cuboidal epithelium. The follicles also lacked absorptive vesicles. These features suggested markedly suppressed functional status of the thyroid gland. Quite similar observations have been made by Michael et al (1991) in propylthiouracil treated Bufo regularis tadpoles. These tadpoles developed collapsed follicles, partially devoid of colloid, and folded cuboidal epithelia. It may be emphasized that drug-induced microscopic features of thyroid neither matched with classical description of hypothyroidism nor with hyperthyroidism, Govan et al (1986). In fact it consisted some features of hypo and some of the hyperthyroidism. In other words, it has its own characteristic microsturcture. Surprisingly, literature dealing with drug-induced microsturcture of thyroid remain scanty.

Fig. 1

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Thyroid from control showing normal lobules, large follicles of variable shapes completely filled with colloid. Poorly defined stroma. H&E, X40

Fig. 2

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Thyroid from control showing large follicles filled with abundant colloid, absorptive vesicles and flattened follicular cells. H&E, X400

Fig. 3

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Thyroid gland from experimental showing small lobules, small round follicles and relatively prominent stroma compared to control. H&E, X40

Fig. 4

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Thyroid from experimental showing microfollicles, scanty colloid, cuboidal follicular cells and absence of absorptive vesicles. H&E, X400

Fig. 5

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Thyroid from experimental showing small round follicles, each lined by 10-12 cuboidal follicular cells. Some of follicles completely devoid of colloid. H&X, X1000

Though methimazole-induced developmental hypoplasia and functional hypothyroidism, when not reversible are known, to cause severe embryopathies in fetuses, Karlsson et al (2001). However, in the present study it could not be ascertained whether Carbimazole induced various histomorphological changes were reversible or not. Foetal thyroid status was found to be inversely proportional to maternal drug dose of carbimazole, Mortimer et al (1990). In contrast to this Momotani et al (1997), Gardner et al (1986) and Cheron et al (1981) did not find any significant correlation between Propylthiouracil doses and foetal thyroid status. Though there is significant correlation between foetal thyroid status with the maternal thyroid status; there is also profound individual variation in the maternal doses necessary to maintain similar functional status of thyroid. This suggests that there is a lack of relationship between maternal doses and fetal thyroid status. Some times as the pregnancy progresses the dose of antithyroid drug is either reduced or stopped completely by the end of pregnancy which requires continuous monitoring of the thyroid function to avoid foetal hypothyroidism Joel et al (2001). This may explain the lack of correlation between dose of methionamide and maternal or fetal thyroid function Momotani et. al. (1997).

Refetoff et al, (1974) reported individual variability in response to thionamide in two sets of dizygotic twins born to mothers treated with thionamides during gestation, which he explained that it might be due to individual variation of either placental barrier or TSH receptor antibodies of mother and fetus. Neurophysiological outcome in early treated congenital hypothyroidism have shown Gardener et al (1986) and

Momotani et al (1986) that intellectual retardation if ever occurred was due to severe hypothyroidism Simons et al (1994) and Dubuis et al (1996). It was unusual for the transient or mild hypothyroidism to produce such changes Mc Carroll et al (1976) Eisenstein et al (1992).

It was concluded that carbimazole can be administered both during pregnancy and lactation with guarded prognosis. However, the potential risk of thyroid dysplasia persists and if the change remained irreversible then it may lead to permanent hypothyroidism and other associated congenital anomalies.

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