Abstract
Objectives: To analyze the clinical profile
of juvenile hyperthyroidism at presentation, their treatment
outcome; predictors of remission and relapse. Methods:
Retrospective analysis of medical records of 56 patients with
juvenile hyperthyroidism seen over a period of 16 years. A cohort
of 38 females and 18 males with mean (± SD) age of 14.9 ± 3.4
years (range 3 to 18 years) was analyzed. Results: Majority
of patients was in the age group of 12-16 years. Common symptoms
observed at presentation were weight loss (82.1%), excessive
sweating (78.6%), heat intolerance (76.8%), increased appetite
(73.2%) and diarrhea in 48.2%. In addition, accelerated linear
growth was observed in 7.1% of patients. Goiter was present in
98.2% of children; 94.5% of which was diffuse and 4.8% was
multinodular. The mean (( SD) T3 was 4.8 + 3.4 ng/mL (N,
0.6-1.6), T4 was 218 ± 98 ng/mL (N, 60-155) and TSH was 0.44 ±
0.36 (N, 0.5-5.5 µIU/mL). TMA positivity seen in 36.9% of
patients. All patients were treated with carbimazole; subsequently
4 patients required thyroidectomy and one required radioactive
iodine ablation. Mean (±SD) duration of follow-up in our patients
was 4.9 + 3 years, ranging between 1.6 to 16 years and mean
(± SD) duration of treatment was 34.4 + 22.6 months (range
12 to 120 months). Mean (±SD) duration to achieve euthyroidism was
5.2 + 4.7 months, ranging between 1-33 months. On intention
to treat analysis, remission with carbimazole was achieved in
47.6%, remaining patients failed to achieve remission with drug
treatment. Conclusion: Graves’ disease is the commonest
cause of juvenile hyperthyroidism. Carbimazole is safe, effective,
cheap, and easily available form of therapy. It is occasionally
associated with serious side effects but requires prolonged follow
up.
Key words: Graves’ disease, Hyperthyroidism, Remission,
Relapse
Hyperthyroidism in childhood and adolescence
is less common compared to adult population(1). Graves’ disease (GD) is
the most common cause of hyperthyroidism in children as well as in
adults and accounts for 10-15% of all childhood thyroid diseases(2).
Hashimoto’s disease is quite common in adolescents and sometimes can
cause transient hyperthyroidism, which can be confused with GD. Other
less common causes of hyperthyroidism in children and adolescents
include benign toxic adenoma, thyroid stimulating hormone (TSH)
secreting pituitary adenoma or rarely pituitary resistance to thyroid
hormones and McCune-Albright syndrome(2,3).
The clinical profile of hyperthyroidism varies with
age. Children have certain symptoms and signs, like hyperkinetism,
accelerated linear growth, poor scholastic performance, and weight gain,
which are uncommon in adults(4). The diagnosis of hyperthyroidism is
easily confirmed by thyroid function tests and radioactive iodine uptake
if required. Treatment modalities for hyperthyroidism in adults include
long-term anti thyroid drugs, ablative therapy including surgery and
radioiodine. However, the treatment of hyperthyroidism in children is
controversial, and all treatment modalities are associated with
potential complications(5). The objective of the present study was to
analyze the clinical profile of juvenile hyperthyroidism at
presentation, treatment outcome; predictors of remission and relapse.
Subjects and methods
In this retrospective analysis, data of 84 patients
were retrieved from the records of Thyroid Clinic at Nehru Hospital,
Post Graduate Institute of Medical Education and Research, Chandigarh,
North India, from 1986 to 2002. Inclusion criteria were age less than 18
years at presentation and duration of follow up of at least 12 months
after achieving a maintenance dose for a period of at least one year.
The diagnosis of hyperthyroidism was made on the basis of clinical
criteria and confirmed by elevated serum T3 (N, 0.6-1.6 ng/mL) and/or T4
(N, 60-155 ng/mL) and suppressed TSH (<0.5 (IU/mL). The diagnosis of
Graves’ disease (GD) was based on diffuse goiter with increased
radioactive iodine up-take. Thyroid hormone profile was performed by
radioimmunoassay (RIA). Radioactive iodine uptake (RAIU) study was
performed at 24 hrs (N, 15-25%) and thyroid microsomal antibody (TMA)
was estimated by immuno-fluorescence technique. Fine needle aspiration
cytology (FNAC) was also performed in some of these patients. Bone age
was estimated by Greulich’s and Pyle’s chart(6). Patients treated with
block replacement therapy and patients with follow up of less than 12
months were excluded from the study. Therapy with carbimazole was
initiated with a dose of 0.6 to 0.8 mg/Kg body weight and continued till
euthyroidism was achieved. The dose was titrated at 3 monthly intervals
and a maintenance dose (5 mg) was continued for 12 months. We defined
remission as clinical and biochemical euthyroidism for at least 1 year
after antithyroid drug withdrawal and relapse as recurrence of symptoms
within one year after stopping the drug(7,8). During follow up, time to
achieve euthyroidism, total duration of follow up, number of relapses,
complications of medical therapy, radioiodine and surgery were recorded.
Out of 84 patients, fifty-six patients met the inclusion criteria and
included in the study.
Statistical Analysis
The SPSS package version 10.1, 1999 (SPSS Inc
Chicago, IL) was used for data analysis. Data are expressed as Mean ± SD
or as percentages and P value of <0.05 was considered as significant.
Chi square test was used for comparing categorical variables and
non-parametric tests (Mann Whitney test) used for comparing continuous
variables. Spearman’s R coefficient was used for the correlation
analysis between the parameters determined in the study. Regression
analysis was used to determine factors in frequency outcome. Intention
to treat analysis was used to calculate remission rate.
Results
The details of age and sex distribution are given in
Table I. Their age ranged from 3 to 18 years with mean (± SD) of
14.9 ± 3.4 years (Median age 16 years) and female to male ratio of
2.1:1. The symptoms and signs observed at presentation are summarized in
Table II. Family history was recorded in all patients. A positive
family history was obtained in 5 (8.9%) patients. First-degree relatives
were involved in 3 patients (two had GD, one had hypothyroidism).
TABLE I
Age and Sex Distribution of Children with Hyperthyroidism.
|
Age group |
Male |
Female |
Total |
|
<5 |
0 |
1 |
1 |
|
> 5-10 |
4 |
2 |
6 |
|
>10-15 |
6 |
14 |
20 |
|
>15 |
8 |
21 |
29 |
|
Total |
18 |
38 |
56 |
Table II
Comparison of Symptoms and Signs in Juvenile Hyperthyroidism.
|
Symptoms and signs |
Present study
(%) |
Lafranchi, et al. (2)
(%) |
Raza, et al. (12)
(%) |
|
Goiter |
98.2 |
99 |
98 |
|
Weight loss |
82.1 |
54 |
54 |
|
Tachycardia |
80.0 |
83 |
95 |
|
Excessive sweating |
78.6 |
49 |
41 |
|
Tremor |
78.2 |
61 |
51 |
|
Heat intolerance |
76.8 |
33 |
27 |
|
Palpitation |
76.8 |
34 |
- |
|
Increased appetite |
73.2 |
60 |
47 |
|
Exaggerated DTR |
63.6 |
- |
- |
|
Eye involvement |
58.9 |
66 |
71 |
|
Dyspnea on effort |
60.7 |
- |
- |
|
Diarrhea |
48.2 |
13 |
27 |
|
Menstrual disturbance |
33.3 |
- |
- |
|
Sleep disturbance |
30.4 |
- |
22 |
|
Thyroid bruit |
20.0 |
53 |
84 |
|
Murmur |
10.9 |
- |
- |
|
Increased linear growth |
7.1 |
- |
|
|
Proximal muscle weakness |
5.4 |
- |
|
|
Anxiety |
5.4 |
80 |
- |
The mean (± SD) values of T3, T4, TSH and RAIU are
given in Table III. Significantly high titre of TMA (1:80
dilutions) was seen in 36.9% of patients. Fine needle aspiration
cytology (FNAC) was performed in 22 patients and findings were
consistent with colloid goiter in 36%, lymphocytic infiltration with
follicular destruction (23%) followed by fire and flare appearance (23%)
and benign thyroid aspirate (18%).
TABLE III
Subjects and Parameters.
|
Parameters |
(Mean ± SD) |
|
Age at presentation (years) |
14.9 ± 3.4 |
|
Lag time for diagnosis (months) |
7.04 ± 7.54 |
|
Duration of follow up (years) |
4.9 ± 3.0 |
|
Thyroid function tests at presentation |
|
|
T3 (ng/mL) |
1.8 ± 3.4 |
|
T3 (ng/mL) |
218.5 ± 98.6 |
|
TSH (µIU/mL) |
0.44 ± 0.36 |
|
Radioiodine uptake (%) |
55.6 ± 19.7 |
|
Initial dose of carbimazole (mg/day) |
26.3 ± 5.6 |
|
Maintenance dose of carbimazole (mg/day) |
10 ± 1.7 |
|
Duration of treatment (months) |
34.4 ± 22.6 |
|
Duration of achieve euthyroidism (months) |
5.2 ± 4.7 |
All 56 patients received carbimazole in doses of 0.6
to 0.8 mg/kg body weight, in a single dose as initial treatment along
with non-iodized salt. Subsequent doses were titrated at 12 weeks
interval according to clinical and hormonal profile. The Mean (± SD)
duration of treatment was 34.4 ± 22.6 months (range 12 to 120), duration
to achieve euthyroidism was 5.2 ± 4.7 months (range 1 to 33) and
duration of follow up was 4.9 ± 3.0 years (range 1.6 to 16 years).
Remission was achieved in 71.4%, however on intention to treat analysis,
remission was achieved in 40 (47.6%) patients; relapse was recorded in 5
(9%) patients. Remaining patients either lost to follow up or could not
achieve euthyroidism and continued with medications. Younger ages, male
sex, low heart rate at onset were associated with higher percentage of
remission. However, these were not statistically significant (Table
IV).
Table IV
Remission and Patient Characteristics.
|
Parameter |
Remission |
No-remission |
P
value |
|
No. |
(%) |
No. |
(%) |
|
Age group <5 |
- |
|
1 |
(100) |
0.176 |
|
>5-10 |
6 |
(100) |
- |
0.325 |
|
|
>10-15 |
17 |
(73.9) |
6 |
(26.1) |
0.729 |
|
>15 |
17 |
(65.4) |
9 |
(34.6) |
0.351 |
| Sex |
|
|
|
|
|
|
Male |
15 |
(83.3) |
3 |
(16.7) |
0.175 |
|
Female |
25 |
(65.8) |
13 |
(34.2) |
0.175 |
|
Heart rate |
|
|
|
|
|
|
<110 per minute |
18 |
(90.0) |
2 |
(10.0) |
0.057 |
|
>110 per minute |
22 |
(62.9) |
13 |
(37.1) |
0.057 |
|
BMI |
16.66 ± 2.83 |
(73.3) |
16.70 ± 3.15 |
(26.7) |
0.962 |
|
T3 (mean ± SD) ng/mL |
4.7 ± 3.67 |
5.03 ± 2.09 |
0.790 |
|
T4 (mean ± SD) ng/mL |
210.1 ± 103.0 |
237.1 ± 88.8 |
0.384 |
|
RAIU, 24h (mean ± SD) |
56.26 ± 20.19 |
54.08 ± 19.09 |
0.737 |
Four patients were subjected for sub-total
thyroidectomy when they remained hyperthyroid for a period of more than
18 months despite of receiving 60 mg carbimazole daily. No surgical
complication was reported in these patients except in one who developed
transient hypocalcemia. Out of 56 patients, one developed
agranulocytosis after three years of carbimazole therapy. Subsequently,
she received ablative dose of radioiodine.
Discussion
Diffuse toxic goiter remains the most common cause of
hyperthyroidism in children. The disorder is rare before the age of 3
years, increases progressively and reaches peak by adolescence(9). Onset
of hyperthyroidism in majority of the children in our cohort was between
12 and 16 years of age. Although age at onset as early as 1.1 years has
been reported, Mokhashi, et al. and others reported onset of
hyperthyroidism in majority of children around 9 years of age(10,11).
Hyperthyroidism is more common in female children with reported female
to male ratio as high as 5:1(10). Girls to boys ratio in our study was
2.1:1.
The weight loss, tachycardia, tremor and excessive
sweating were frequently present in our patients as reported by
others(2). The high incidence of symptoms and signs in our study was
probably related to late presentation (delayed diagnosis). Presence of
goiter was comparable in either sex; however, females had large goiter
compared to males (P <0.05). Exophthalmos was recorded in 30.9% of our
cohort, which is comparable to other studies(11). Behavioral problems
like nervousness, irritability, excessive crying and hyperactivity were
reported in various other series but these were not recorded in most of
our patients. However, features like thyroid acropachy, pretibial
myxedema (dermopathy), thyroid storm, and periodic paralysis are rare in
children and were not present in our patients.
Both autosomal recessive and dominant modes of
inheritance have been postulated in genetics of hyperthyroidism. Raza et
al(12) and Vadiya, et al.(13) have reported a positive family
history in 30% and 37% of their patients respectively while only 9% of
patients had the same in our study.
Thyroid hormonal profile of our patients was
comparable to others(11). RAIU at 24-hours ranged from 35.9% to 75.3% in
our study, as compared to 41% to 86% in the series by Saxena, et al.(14).
High RAIU at 24 hr substantiated the diagnosis of GD and excludes the
possibility of subacute thyroiditis. In our cohort, 36.9% of patients
had significantly high titre of thyroid microsomal antibodies (TMA).
However, others reported it in 41.6% and 50% respectively(11,14). High
titers of TMA in these patients represents immune mediated disease
process. FNAC evidence of lymphocytic infiltration in patients with
hyperthyroidism is well known(15). Vaidya, et al,(13) reported
that 4% of patients with hyperthyroidism had evidence of thyroiditis on
FNAC. In our patients it was even higher (23%), probably due to the
universal salt iodination program in our country. The universal salt
iodination program has been associated with increasing incidence of
thyroiditis due to increased expression of major histocompatibility
Class II (MHCII) antigen from thyroid follicular cells and alterations
in structure of thyroglobulin, thereby becoming more antigenic. When
FNAC was compared in girls and boys, lymphocytic infiltration (18% vs.
4.5%) and fire flare appearance (18% vs. 0%) were more common in
girls.
We used carbimazole as the first line therapy in all
patients similar to other studies (10,12). Remission with drug treatment
is variable in various studies ranging from 33-64%(11,16,17), in our
study it was achieved in 47.6% of patients. Girls took longer time to
achieve euthyroidism and low remission rate compared to boys. This may
be due to larger goiter size in girls. Among them furing follow up, 6.9%
of patients developed hypothyroidism.
Children are relatively refractory to the antithyroid
drugs and side side effects are more common(12). The overall incidence
of side effects of drug in our series was 1.8%, which was much lower
than in other pediatric series(11,17).
Block replacement therapy (BRT) using methimazole
initially and later combined with L-thyroxine has been tried to achieve
long term remission in patients with GD. Some studies in adults with GD
have shown the beneficial effect of combination of methimazole and L-thyroxine
in decreasing the incidence of recurrence, however others have refuted
it(18). Raja, et al.(12) used BRT in juvenile hyperthyroidism and
showed that it was more convenient than the titration regimen pertaining
to dose adjustment and visits to hospital per year (P <0.001).
The thyroid surgery and radioiodine ablation are
second line treatment modalities in management of juvenile
hyperthyroidism. In Europe thyroidectomy (subtotal, near total, total)
is often the therapy of choice in children and adolescents with GD,
after a recurrence, during or after antithyroid drug treatment (ATD), or
in those who cannot tolerate ATD (2,19). Of the 56 patients in our
study, only 4 patients underwent subtotal thyroidectomy and only one had
transient hypocalcemia. However, Raza, et al.(12) more commonly
documented transient hypocalcemia (59%) and vocal cord palsy (7.6%). In
our patients final outcome in form of hypothroidism was comparable to
others(12). Radioiodine ablation is less frequently used in Europe in
contrast to those of American centers. In our series only one patient
received radioiodine ablation when she developed agranulocytosis. At
last follow-up after 2 years of radioiodine ablation she was remained
euthyroid.
Predictors for early remission of childhood
hyperthyroidism are small goiter, higher BMI, low heart rate, low
radioiodine uptake and low T3, T4(5,20). Frequent relapses are seen in
T3-predominent GD, and those who receive either low doses or short
course of anti thyroid drugs. Patients with younger age, male sex, with
higher BMI, lower heart rate (<110 per minute) and relatively low T3, T4
levels achieved higher percentage of remission in our study, however it
was not statistically significant. Other causes of delayed remission in
children compared to adults may be poor compliance with drug and
immunomodulatory effects of puberty.
In conclusion, Carbimazole is effective, inexpensive,
cheap, easily available and rarely associated with serious side effects;
therefore we recommend this as first line therapy. However, it requires
frequent and prolonged follow-up. Surgery can be used as second line
therapy, if hyperthyroidism is not controlled with optimum doses of
carbimazole and associated with pressure symptoms. Radio-iodine ablation
treatment seems to be safe and effective but our experience with the
same is limited.
Contributors: SB conceived & designed the study along
with AB. SB, AB and PV were also involved in acquisition, analysis and
interpretation of data, along with SRM. All authors were involved in
drafting the article. SB shall serve as guarantor.
Funding: None.
Competing interests: None stated.
