Indian Pediatrics 1998; 35:967-973

R.K. Marwaha, R. Sankar, M. Magdum, V.S.Nijahvan, C.M. Khanna, C.B. Jaggi, V. Ambardar, N.S. Maharda, R.P. Walia and S.K. Jain

From the Department of Endocrinology and IDD Epidemiology, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi 110 054, India.

Reprint requests: Lt. Col. R. Sankar, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi 110 054, India.

Manuscript received: June 30, 1997; Initial review completed: September 28, 1997;
Revision accepted: April 22, 1998

 

Objective: To determine the clinical, biochemical, ultrasonological and cytomorphological features in goitrous juvenile chronic lymphocytic thyroiditis(CLT) Setting: Tertiary referral center for thyroid disorders. Subjects: A total of 455 children were evaluated for goiter. Of these 122 children had features of CLT in FNAC and were further studied.  Methods: All subjects were subjected to detailed clinical examination. The thyroid functional status was assessed by estimation of serum concentration of thyroid hormones (thyroxine and triiodothyronine) and thyrotropin (TSH). In addition the antithyroid antibody titers were measured. Ultrasonological and cytomorphological characteristics in these patients were also evaluated. Results: The mean age at presentation was 12.5 years (SD 3.93). The male: female ratio was 1:7.7. Thyroid functional status as assessed by serum thyroxine and thyrotropin levels revealed, euthyroidism in 67 (54.9%), hypothyroidism in 30 (24.6%), subclinical hypothyroidism in 22 (18%) and hyperthyroidism in 3 (2.5%). Thyroid antimicrosomal antibodies were detected in significant titers in 90 (73.8%) and antithyroglobulin was positive in 71 (58.2%). The positivity of the antimicrosomal and antithyroglobulin antibodies were much higher in subjects with hypothyroidism and was detected in 86.5% and 69.2%, respectively. The mean urinary iodine excretion was 74.1 µg/g of creatinine (SD 31.4) indicating mild iodine deficiency. Fine needle aspiration cytoloty (FNAC) revealed features of chronic lymphocytic thyroiditis. Hurthle cell changes was seen in only 12% of the cases. The epithelium was more often hyperplastic and vacuolation of the cytoplasm and peripheral vacuolations were seen frequently. Giant cells and epithelioid cells were seen in many cases. Conclusions: In any child presenting with firm goiter, a diagnosis of CLT should be excluded. Many subjects with juvenile CLT have biochemical evidence of hypothyroidism but only few symptoms or clinical features.

Key words: Hypothyroidism, Thyroiditis.
 

CHRONIC lymphocytic thyroiditis (CLT) was first reported in 1912 by Hashimoto(1). He described lymphocytic infiltrate, fibrosis, epithelial cell atrophy and eosinophilic changes in some parenchymal cells of the thyroid glands of four patients. Subsequently, many studies have documented the occurrence and natural history of CLT in childhood(2-4). In non- iodine deficient areas juvenile CL T is the commonest cause of thyroid enlargement in children and adolescents(5). The prevalence and pattern of CLT in childhood and adolescence in India is not known. We report here the clinical, biochemical and cytomorphological features observed by us in 122 children with CLT.

Subjects and Methods

The Institute of Nuclear Medicine and Allied Sciences, Delhi, has a Department of Thyroidology which is a tertiary referral center; nearly 15,000 subjects are referred for evaluation of thyroid diseases every year. All those presenting with goiter are subjected to detailed history, clinical examination, ultra-sonological assessment of thyroid volume and echotexture, FNAC of the thyroid gland and measurement of the thyrotropin and thyroid hormone levels in serum.

In the period from June 1994 to December 1994, a total of 455 children were evaluated for goiter in one Unit of the Institute. Of these 122 children had features of CLT in FNAC. They were further studied to determine the clinical presentation, biochemical thyroid status, antibody levels and cytomorphological features. The inclusion criteria therefore were presence of goiter and cytomorphological features suggestive of chronic lymphocytic thyroiditis on FNAC.

Goiter was graded as per the WHO / UNICEF /ICCIDD Joint consultation recommendations(6): (i) Grade 0: No palpable or visible goiter; (ii) Grade I: A mass in the neck that is consistent with an enlarged thyroid that is palpable but not visible when the neck is in the normal position. It moves upwards in the neck as the subject swallows. Nodular alterations(s) can occur even when the thyroid is not enlarged; (iii) Grade II: A swelling in the neck that is visible when the neck is in a normal position and is consistent with an enlarged thyroid when the neck is palpated. Clinical features suggestive of hyper or hypothyroidism were carefully looked for.

Serum total thyroxine (T4) and total triiodothyronine (T3) levels were measured by radio immuno assay (RIA) and serum thyrotropin (TSH) level was measured by immunoradiometric assay (IRMA). The RIA and IRMA kits were obtained from Bhabha Atomic Research Center, Bombay.

Antibody titers were measured by RPHA test using Serodia^R kits. Titers of 1:400 were regarded as significant for both anti-thyroglobulin and anti-microsomal antibodies. Casual urine samples were collected and urinary iodine level was estimated by the Sandell-Kolthoff reaction(7). Utlrasonological examination was carried out using short focus real time 7.5 mHz transducer with a water bath. Both lobes were evaluated in transverse and sagittal planes. Surrounding structures were also evaluted(8,9). For inter and intra group comparisons, Students 't' -test was used.

Results

Clinical Features

A total of 122 children were studied. The age and sex distribution of the children studied is shown in Table I. There were 14 boys and 108 girls. The average age at presentation was 12.5 years (SD 3.93).

 

TABLE I

Age and Sex Distribution of the Children Studied.

	Age groups
Sex	6-10	11-14	15-19	Total
Males	6	7	1	14
Females	26	41	41	108
	32	48	42	122

Of the 122 subjects studied, 102 (83.6%) presented with asymptomatic goiter, 12 (9.8%) with pain and 8 (6.6%) with symptoms suggestive of hypothyroidism. In 86 (70.5%) there was grade ~I goiter and the remaining 36 (29.5%) had grade I goiter. In 71 (58.2%) the thyroid gland was firm in consistency and in the remaining it was soft. The surface was smooth in majority with scalloped margins and in few typical granular feel could be appreciated. Regional lymph nodes were felt in 16 (13.1%) subjects. Clinically, features of hypothyroidism were seen in 8 (6.6%) and the remaining were clinically euthyroid. None had features of gross hypothyroidism or myxoedema.

Laboratory Findings

TSH: The mean serum TSH was 29.8 µu/ml (SO 39.2), whereas the median was 6 µu/ml , indicating that a number of subjects had high TSH. A total of 52 (42.6%) had TSH value more than 5 µu/ml. Of these, 20 subjects had TSH more than 100 µu/mL The mean TSH for those with biochemical hypothyroidism (low T4. and elevated TSH) was 68.7 µu/ml (SO 33.4).

T4: The mean T4 was 7.1 µu/dl (SO 6.4). The mean T4 in the 52 subjects with elevated TSH was 4.6 µu/ dl (SO 3.4). In these 52 subjects T4 was low in 57.7% (n = 30), in the low normal range < 8 µu/ dl) in 26.9% (n=14) and in the normal range in the remaining. A total of 30 subjects, thus had biochemical hypothyroidism with elevated TSH and low T4, and 14 subjects had subclinical hypothyroidism (elevated ISH and normal T4).

Antibodies: Antimicrosomal antibodies were detected in significant titers in 90 (73.8%). The titers ranged from 1:400 to 1:2621400 dilution. Of the 52 subjects with TSH >5 µu/ml antimicrosomal antibodies was positive in 86.5% (n = 45) and this difference compared to the overall antibody positivity was statistically significant (p <0.05) (Table II).

Antithyroglobulin antibodies were detected in significant titers in 71 (58.2%). Of the 52 subjects with elevated. TSH, antithyroglobulin antibodies was positive in 69.2% (n = 36) and this difference compared to the overall antithyroglobulin positivity was statistically significant (p <0.05).

Ultrasound: The echo pattern was hypoechoic in 52 (43%) and was normal in 70 (57%). Distinct single nodule was detected in 4 (3.3%).

Urinary Iodine: The mean urinary iodine excretion was 74.13 µg/ g of creatinine (SD 31.4). In 31 (25.4%) the urinary iodine excretion was less than 25 µg/ g of creatinine; in 21 (17.2%) it was above 100 µg/ g of creatinine. The urinary iodine excretion in the subjects studied is shown in Table III.

FNAC: All 122 subjects had cyto-morphological features suggestive of chronic lymphocytic thyroiditis. The major features seen were lymphoplasmacytic in- filtration, hyperplastic follicular epithelium and marked cytoplasmic and peripheral vacuolation. Hurthle cells were seen only in 12% cases and giant cells and epitheloid cells were seen in 23% cases.

 

TABLE II

Prevalence of Anti-Thyroid Antibodies

	All subjects		Subjects with TSH >10 µu/ml
AIM	-ve	32 (26.2%)	7 (13.5%)
	+ve	90 (73.8%)	45 (86.5%)
ATG	~ve	51 (41.8%)	16 (30.8%)
	+ve	71 (58.2%)	36 (69.2%)

AIM = Anti-microsomal antibody
ATG = Anti-thyroglobulin antibody

TABLE III

Urinary Iodine Excretion

	Urinary iodine in Ilg/ g of creatinine
	< 25	26 - 75	76 - 100	> 100
Number of subjects	31	30	40	21
Percentage	25.4	24.6	32.8	17.2

Discussion

The incidence of juvenile chronic lymphocytic thyroiditis, once considered rare is reported to be increasing (10,11). The incidence varies depending on the geographical location, type of study, and sex of . the patient(4,12). In non-iodine deficient regions juvenile CL T is the most common cause of thyroid enlargement in children and adolescents(13). Its incidence in regions where environmental iodine deficiency continues to be a public health problem is not known.

Hashimoto's thyroiditis is autoimmune in origin Roitt and Doniach(14) in 1956 showed the association of antibodies to thyroglobulin in the sera of patients with Hashimoto's thyroiditis. Since then, antibodies to the microsomal fraction of the thyroid cell, as well as to a colloid antigen, to T4, T3 and the TSH receptor, have all been described with the disorder(15,16).

A current popular theory for the pathogenesis of CLT is that it is a disorder of immune surveillance. In the pathogenesis, both cell mediated and antibody mediated mechanisms are implicated(17). It is believed that there is dysfunction of "suppressor" T lymphocytes, allowing a clone of "thyroid-specific helper" T lymphocytes to prolierate and provide help to B cells to produce circulating thyroid antibodies to thyroid antigens, resulting in destruction of thyroid cells(17,18).

What precedes these events awaits further study. In this context the potential role the environment may play has attracted lot of attention. Iodine ingestion is increasingly implicated in the possible generation of the autoimmune response(19-21). Studies in genetically susceptible animals have shown that potassium iodide supplements lead to a significant increase in thyroid autoantibody titers in blood as well as lymphocytic infiltration of the thyroid(22). The apparent sensitivity to iodides agrees with the clinical observation of an increasing prevalence of CLT in industrialized, iodine sufficient countries. Our study, .from an area with moderate to mild iodine deficiency, show that nearly 25% of the children who presented with goiter, had juvenile CL T. This shows clearly that considerable work remains to clarify the role of iodine ingestion and the quantity and the duration required to induce autoimmune thyroiditis. Avail- able evidence at the most indicates an association and no causal relationship has been established.

Rallison et al.(12) investigated the role of iodine as a possible etiological factor in juvenile CL T. They studied the incidence of juvenile CL T in Utah and in Arizona, areas with different iodine intake, and there was no significant difference in the prevalence of thyroiditis in the two areas. A survey of subjects potentially exposed to fallout radiation did not reveal a higher incidence of thyroiditis among those exposed than unexposed(23).

CLT in adults is nearly always associated with positive antimicrosomal anti- bodies, and positive antirnicrosomal anti-bodies can be detected in sera of approximately 90% or more of cases(16,24). Juvenile CLT may not be accompanied by the high titers of antithyroidantibodies(25). We found high titers of both antimicrosomal and anti-thyroglobulin antibodies in 73.8% and 58.2% subjects, respectively. The positivity of these antibodies was more in those with chemical hypothyroidism. There was a positive correlation between the anti-microsomal antibody titers and the TSH levels in those with hypothyroidism.

It is not clear what proportion of patients with juvenile CLT develop hypo-thyroidism. Many studies suggest that 20% to 50% of patients with juvenile CL T develop hypothyroidism(3,26,27). However, some workers(12,13) report that juvenile CLT may be self-limiting and spontaneous recoveries do occur.

We noticed biochemical hypothyroidism in 24.6% and another 18% were sub-clinically hypothyroid. None of these children had any clinical features of hypothyroidism, only few patients showed subtle signs of hypothyroidism on careful clinical examination(13). Therefore bio-chemical evaluation of thyroid function is essential in children with juvenile CL T.
The role of thyroid hormone for the development of the central nervous system is well established(28,29). The developmental effects of thyroid hormones are manifest in every organ and tissue. In both sexes thyroid hormone influences sexual development. In hypothyroid state, pubertal development may be either accelerated or delayed and onset of puberty may be followed by anovulatory cycles(30). As shown in our study in juvenile CLT there is an overwhelming preponderance for girls and bulk of them are in the age group 9 to 16 years. Since there is gross discrepancy between the clinical and biochemical thyroid functional status, it is mandatory that thyroid functional status is assessed by estimation of thyroid hormone levels in children suspected of having CLT.

Our study from an area with mild to moderate iodine deficiency indicates that in nearly 25% of the children presenting with goiter, CLT is the underlying cause for the goiter. Although the prevalence and natural history of juvenile CL T has been described from many regions with iodine sufficiency, its epidemiology in iodine deficient environment needs further studies. The role of iodine in initiating or amplifying the autoimmune damage to the thyroid gland, the proportion of patients with juvenile CL T who have spontaneous recovery and the proportion who develop' permanent hypothyroidism needs to be prospectively studied.