Thyroid Science 6(11):CR1-5, 2011	www.ThyroidScience.com
Case Reports

Autoimmune Thyroiditis: Correlation of

Cytomorphology with Drug History and Clinical Implications

Somanath Padhi, MD,1* Renu G'Boy Varghese, MD, DNB1

Anita Ramdas,1 MD, Kulwant Singh, MD,1

Jayaprakash Sahoo, MD, DM,2

Mark C Arokiaraj, MD, DM,3

Department of 1Pathology, 2Endocrinology, and 3Cardiology,

Pondicherry Institute of Medical Sciences,

Ganapathychettykulam, Kalapet, Puducherry, India, 605014

*Corresponding Author: Dr Somanath Padhi, MD

Assistant Professor, Department of Pathology

Pondicherry Institute of Medical Sciences

Kalapet, Puducherry, India, 605014

Phone: 91 0413 2656271 Fax: 91 0413 2656273

Email: somanath.padhi@gmail.com

Received: July 25, 2011

Accepted: August 1, 2011

Abstract. Background: The cytopathologist plays an important role in the evaluation of thyroid cytomor
phology in various neoplastic and non-neoplastic conditions. However, thyroid cytomorphology and the clin
ical implications of drug usage have rarely been discussed. Nonetheless, drugs used for different non-thyroid conditions may influence the hypothalamic-pituitary-thyroid axis and cause diverse cytomorphological pat
terns on aspiration smears. Clinicians should be informed of the presence or absence of specific underlying thyroid abnormalities detected on cytosmears which may warrant complete drug withdrawal, dose reduction, or change to different drug combinations. Besides these outcomes, interpreting thyroid cytomorphology, without a prior knowledge of antithyroid drug therapy, can be challenging and lead to misdiagnoses of neoplasm or malignancy. Cases: We present the thyroid cytomorphology of 3 different patients, each of whom was receiving a different drug (amiodarone, carbimazole, and carbamazepine) with biochemical, se
rological, and ultrasound correlations. We also briefly review the relevant literature. We conclude that a pro
per drug history is important while interpreting thyroid cytology in different clinical settings.

Keywords • Amiodarone • Carbimazole • Carbamazepine • Cytomorphology • Drugs • Thyroid

Introduction

Thyroid autoimmunity encompasses two ex
tremes: at one end, the diffuse hyperplasia and hyper
functioning gland of Graves' disease; and at the other, total destruction of the gland with hypothyroidism (as in Hashimoto's thyroiditis).

Hashimoto thyroiditis is the most common cause of hypothyroidism in iodine sufficient areas of the world.[1] Fine needle aspiration cytology of thyroid is a safe and accurate procedure for the initial evaluation of thyroiditis. This is especially true when correlated with serology, hormone profile, colour Doppler ul
trasonography, and radionuclide parameters.[2-6]

However, drug induced cytological changes in thyroid fine needle aspiration, their diagnostic pit
falls, and clinical implications are rarely described in the literature.

Amiodarone, a class III antiarrythmic drug, pro
duces thyroid dysfunction (both hyper and hypothy
roidism) in its users with or without underlying thy
roid abnormalities. Amiodorone-induced hypothy
roidism is amenable to thyroid replacement therapy whereas amiodarone-induced thyrotoxicosis (type 1 & 2) leads to a difficult therapeutic approach. Proper evaluation of thyroid function is, therefore, important both prior to the start and during amiodarone use in cardiology practice.[7-10] Even more problematic is the scenario of unnecessary overdiagnosis of a neoplasm or malignancy in fine needle aspiration smears in patients of untreated Graves' disease or those receiv
ing radioiodine ablation or antithyroid drugs (carbi
mazole, a pro-drug converted after absorption to the active form, methimazole.).[11-15]

An association of autoimmune thyroiditis during the course of or following antiepileptic therapy is rare, and that after carbamazepine therapy has not been reported in English literature. However, there

Table 1. Clinical characteristics, prescribed drugs, cytological diagnosis of goitre and impact on further management in three different patients.
Age/sex

Department

Primary Diagnosis

Drug therapy	Secondary presentation

(duration)	Cytological diagnosis	New therapy	Remark
48/M	Cardiology

CRHD, MR, AF x 6 months

tab amiodarone 200 mg x 6 months	Diffuse goitre x 1month

Palpitation, hand tremor, weight loss x 15 days	Diffuse toxic goitre	C+P+D

stoppage of amiodarone	Withdrawal of amiodarone due to risk of development of type 1 AIT[7,8]
40/M	Endocrinology

Graves' disease x 1 year

Tab carbimazole 20 mg x 1 year	Reduction in size of goitre, weight loss, heat intolerance present	Toxic goitre,

Autoimmune thyroiditis	Tab carbimazole 20mg contd.	TIC, suspicion of neoplasm, diagnostic

pitfall.[12,15]
26/F	Neurology

Seizure disorder x 9 years

Tab carbamazepine (Cz) 200 mg TDS x 9 years	Diffuse Goitre (L > R) x 2years

Cold intolerance, menorrhagia, hoarseness of voice, weight gain x 2 months	Hashimoto thyroiditis	Cz+T	Possible association of autoimmunity[16] (significance ?)
Abbreviations: M; males, F; female, CRHD; chronic rheumatic heart disease, MR; Mitral regurgitation, AF; atrial fibrillation, TDS; three times daily, mg; milligram, L; left, R; right, C; Carbimazole, P; Propranolol, D; Digoxin, Cz; Carbamazepine, T; L-Thyroxine (50 microgram), AIT; Amiodarone induced thyrotoxicosis, TIC; therapy induced changes in cytosmear.

are reports to suggest that anticonvulsants may in
duce or exacerbate autoimmune mechanisms in cer
tain thyroid diseases, the exact pathogenesis of which still not known.[16]

The aim of the present article is to highlight var
ious issues related to drug therapy and thyroid cy
tomorphology. By doing so, we hope to create aware
ness among cytopathologists and guide clinicians to more effective patient management.

Case Histories

The 3 cases described in this report involved clinical presentation and fine needle aspiration cy
tology of the thyroid glands from three different pa
tients (2 male, 1 female). Each patient received a different category of drug (1 antiarrythmic, 1 anti
thyroid, and 1 antiepileptic). The cytologies are pre
sented in Table 1 and 2, respectively.

Discussion

Amiodarone, a class III antiarrythmic drug, has a strong structural resemblance to the thyroid hor
mones. It contains two iodine atoms, which constitute 37.5% of its mass. Daily intake of 200 mg of ami
odarone increases the iodine level in the circulation 20-to-40 times compared to the general population. The excessive load of iodine causes alteration in thy
roid hormone metabolism. Thyroid dysfunction, both

hypothyroidism and hyperthyroidism occurs in up to 25% of users. Amiodarone-induced hypothyroidism occurs more commonly in females in iodine sufficient areas. Their hypothyroidism results from the Wolf- Chaikoff effect with blockage of hormone secretion or as a consequence of chronic autoimmune thyroiditis due to iodine excess. The patient with amiodorone-
induced hypothyroidism should undergo thyroid hor
mone replacement therapy. Amiodarone withdrawal is not always necessary.[7,8]

Amiodarone may induce autoimmune thyrotoxi
cosis more commonly in males in iodine deficient areas 4 months to 3 years after initiating therapy. Type 1 amiodarone-induced thyrotoxicosis is defined as hyperthyroidism occurring in patients with underlying thyroid disease, with or without positive thyroid hor
mone (Jod-Basedow effect). Patients do not have peroxidase antibody titre. The hyperthyroidism is due to increase synthesis and release of thyroid hormone.

Type 2 amiodarone-ind uced thyrotoxicosis is a drug-induced destructive thyroiditis that occurs in patients without underlying thyroid disorder. Anti-
thyroid drugs such as propylthiouracil/methimazole with withdrawal of amiodarone are the treatment of choice in type I and type 2 amiodarone-induced thy
rotoxicosis. Patients respond rapidly to glucocorticoid therapy.[7-10]

In view of potential interaction of amiodarone with the thyroid gland and consequent therapeutic implications, interpretation of thyroid cytomorphol-

Table 2. Cytomorphology of thyroid, hormone profile, serology, ultrasound finding in three different patients on medications for different conditions.
Cases/drug

Cytomorphology	Serology	Thyroid hormone	CD-USG thyroid	Diagnosis

1

Amiodarone

(antiarrythmic)	Cellular, pseudopapillae, fire flare, dense cytoplasm, paravacuolar granules, thin colloid, no inflammation.

Anti TPO + ve	Hyperthyroid

(undetectable serum TSH)	B/L enlarged gland, heterogonous echotexture,

Increased colour flow	Diffuse Toxic Goitre

Suggestive of GD[6]

(Figure-1A,B)
2

Carbimazole

(antithyroid)	Cellular, monolayer sheet, microfollicles pseudopapillae, plenty of bare nuclei, sudden bizarre pleomorphic nuclei, coarse chromatin, occasional paravacuolar granules, mild Hurthle cell change, minimal lymphocytes, absent colloid.	Anti TPO + ve

Euthyroid	Not available at the time of FNAC	Therapy induced changes, suspicious of neoplasm.[11-15]

(Figure 2)
3

Carbamazepine

(antiepileptic)	Moderate cellularity, Prominent Hürthle cell change, folliculolysis, giant cells, epitheloid cells, prominent lymphocytic infiltration, crushed tissue fragment,[4] scant thick colloid.	Anti TPO + ve	Hypothyroid

(elevated TSH)	B/L asymmetrically enlarged gland, nodular outline, heterogenous echotexture, no calcification.

Decreased blood flow	Hashimoto thyroiditis.[2-4]

(Figure-3A,B,C)
Abbreviations: TPO; thyroid peroxidase antibody, TSH; thyroid stimulating hormone, CD-USG; Colour Doppler ultrasonography, B/L; bilateral, FNAC; fine needle aspiration cytology, GD; Graves' disease.

Figure 1A. Cytosmears from thyroid in Case 1 showing sheets of follicular epithelial cells with marginal vacuoles (fire flare appearance) over a background of thin colloid (Papanicolaou stain, 400X). These features are that of a hyperfunctioning state and with a positive serology suggestive of Graves' disease

ogy is important. Cytological features such as fire- flare appearance of the thyrocytes, dense cytoplasm, paravacuolar granules with thin colloid are sug
gestive of a hyperfunctioning state, whereas Hürthle cell morphology, folliculolysis, lymphocytic infil
tration, epitheloid cells, plasma cells, and scant to absent colloid are strongly suggestive of Hash
imoto's hyperthyroiditis.[2-6] The presence of pos
itive serology, undetectable serum TSH, and cyto
morphology was suggestive of hyperthyroidism in Case 1. Complete withdrawal of the drug was nec
essary to prevent possible development of type 1 autoimmune thyrotoxicosis.

Worrisome cellularity and nuclear atypia in Graves' disease, with or without prior therapy, can be a potential a source of misdiagnosis of neoplasm. Irradiated follicular epithelial cells, following ra
dioiodine therapy, may show focal regenerative cellular and nuclear atypia, oxyphil or squamous metaplasia or cytoplasmic vacuolization. Bizarre cells with markedly enlarged and cells with nuclear pseudo inclusions may lead to a false positive di
agnosis of malignancy. Similar morphology has be
en described in patients with untreated Graves' dis
ease or those receiving carbimazole therapy.[11-15]

Figure 1B. Bluish green paravacuolar cytoplasmic granules in thyroid follicular epithelial cells indicative of hyperfunctioning state. No evidence of thyroiditis was seen (Leishmann stain, 400X).

Figures 3A, 3B, and 3C. Moderately cellular cytosmears from thyroid in Case-3 showing (A) intense lymphocytic infiltration into the epithelial cells, (B) Hürthle cell change), and (C) crushed cellular fragments with epitheloid cells over a hem
orrhagic background devoid of colloid. These cytological fea
tures are diagnostic of autoimmune thyroiditis (Hashimoto thy
roiditis) (Leishmann, 200X, 400X).

Figure 2. Changes suspicious of neoplasm induced

by therapy.

Demonstrating nucleolar features with toludine blue stain can be helpful in these cases.[12] Obtaining a drug possible development of type 1 amiodarone-
induced history with serological, hormonal, and radio
logical correlation can avoid unnecessary misdiag
nosis as in Case 2.

Association of autoimmune thyroiditis with the use of antiepileptic drugs has been rarely documented in the research literature.[16,17] Goitrous hypothyroidism with increased anti-thyroglobulin antibodies and anti-
microsomal antibodies has been reported in two ado
lescent girls 1-to-3 years following antiepileptic (etho
suximide) therapy. Replacement of ethosuximide with valproate in one, and discontinuation of therapy with thyroxine replacement in the other, led to reduced an
tibody titres with restoration of euthyroid status.[16]

In a recent study by Allison Gandey et al.,[17] it was found that 32% of patients with epilepsy taking antiepileptic drugs in mono or polytherapy have thy
roid hormone abnormalities. From a study of 300 epileptic patients, "the most relevant," report, "was the increase of thyroid stimulating hormone (TSH) in patients taking valproate monotherapy (61.5%; TSH level > 6.6; p < 0.001)." It is an increase, they cau
tion, that can lead to subclinical hypothyroidism. Forty-eight percent of carbamazepine users and 17% phenytoin users had thyroid abnormalities. Carba
mazepine in polytherapy significantly decreased thy
roxine levels below 62.01 (p = 0.008). These obser
vations suggest that anticonvulsants may induce or exacerbate autoimmune mechanisms in certain thyroid diseases. Autoimmune thyroiditis following the use of carbamazepine in a young female (case 3) in the pre
sent series may just be an association, the clinical significance of which is yet to be ascertained. Hence, more cases with similar findings must be studied in order to reach a rational conclusion.

Conclusion

To conclude, interpretation of thyroid cytomor
phology can be challenging in various clinical settings. Obtaining a proper drug history is essential while in
terpreting cytosmears in order to guide the clinicians for better therapy options.

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