|Year : 2015 | Volume
| Issue : 1 | Page : 14-22
Evaluation of etiology, clinical profile and management outcomes in juvenile hypo and hyperthyroidism: A single centre experience
J Venkateswarlu1, Babulreddy Hanmayyagari2, J Nagender1, K Neelaveni1, Rakesh Sahay1, Ramesh Jayanthy1
1 Department of Endocrinology, Osmania General Hospital, Hyderabad, India
2 Department of Endocrinology and Consultant Endocrinologist, Elite Endocrinology Clinic, Hyderabad, Andhra Pradesh, India
|Date of Web Publication||18-Dec-2014|
Dr. J Venkateswarlu
Flat no-204, Sai Sree Apartment, Sivaji Nagar 2nd Lane, Mangamurudonka, Ongole, Andhra Pradesh - 523 002
Source of Support: None, Conflict of Interest: None
Objective: The aim of this study was to evaluate the etiology, clinical profile and response to treatment in physical, sexual and psychological aspects in juvenile hypo and hyperthyroidism. Materials and Methods: 63 patients of newly diagnosed overt hypothyroidism (TSH > 15μIU/ml and T4 < 5.5μg/dl) and 5 patients of hyperthyroidism (TSH < 0.1μIU/ml and T4 > 12μg/dl) in 8-16 years age group presenting with various symptoms are followed for 1-2 years after starting treatment with levothyroxine/carbimazole. Dose was adjusted to maintain TSH/T4 in normal range. The response to treatment is monitored by physical, sexual and intellectual parameters. Results: Among 68 patients, 63 (92.6%) are overt hypothyroid and 5 (7.4%) are hyperthyroid. The age group included was 8-16 years. Among hypothyroid patients, puberty was attained within a year of treatment in patients with delayed puberty. There was improvement in cognitive function with treatment though statistically not significant. Positive TPO antibodies was associated with low T4 and high TSH (P < 0.05). Among hyperthyroid group (5 patients), chief complaints are goitre in 100%, weigt loss in 100% and proptosis in 60% (3 patients). Sexual maturity was appropriate for age Bone age was appropriate for chronological age. There was no significant difference in cognitive function with treatment. Conclusion: In juvenile age group, most common cause for hypothyroidism is Hashimotos thyroiditis and hyperthyroidism is Graves disease. Goitre and growth retardation are commonest mode of presentation of both hypo and hyperthyroidism.TPO antibodies is associated with severe hypothyroidism (low T4 and high TSH). Even hyperthyroid children presents with poor height gain. Height velocity and sexual maturity improve with treatment. Cognitive function was not significantly affected in hypo or hyperthyroidism.
Keywords: Height standard deviation scores, hyperthyroidism, hypothyroidism, intelligent quotient, thyroid peroxidase antibodies
|How to cite this article:|
Venkateswarlu J, Hanmayyagari B, Nagender J, Neelaveni K, Sahay R, Jayanthy R. Evaluation of etiology, clinical profile and management outcomes in juvenile hypo and hyperthyroidism: A single centre experience. Thyroid Res Pract 2015;12:14-22
|How to cite this URL:|
Venkateswarlu J, Hanmayyagari B, Nagender J, Neelaveni K, Sahay R, Jayanthy R. Evaluation of etiology, clinical profile and management outcomes in juvenile hypo and hyperthyroidism: A single centre experience. Thyroid Res Pract [serial online] 2015 [cited 2022 Jan 21];12:14-22. Available from: https://www.thetrp.net/text.asp?2015/12/1/14/147280
| Introduction|| |
Disorders affecting the thyroid gland represent the most common endocrinopathies in childhood. Thyroid dysfunction in infancy and childhood affects growth maturation, and puberty along with metabolic abnormalities. Symptoms and signs of thyroid disorders in children and adolescents though similar to those in adults, poor scholastic performance, decreased memory, cognitive, and growth disturbances may affect the overall development of the child when untreated.
Reduced production of thyroid hormone (TH) is the central feature of the clinical state termed hypothyroidism. Hypothyroidism is the most common disturbance of thyroid function in children. As in adults, acquired hypothyroidism can be caused by both thyroid disease (primary hypothyroidism) and hypothalamic pituitary disease (central hypothyroidism). Primary hypothyroidism is the etiology in approximately 95-99% of cases of hypothyroidism, with less than 1-5% being due to thyroid-stimulating hormone (TSH) deficiency or other causes.
Increased production of TH occurs in hyperthyroidism, it is less common than hypothyroidism in children and adolescents. Its incidence increases after 5 years of age with peak incidence during adolescence (11-15 yrs).  Ninety-five percent of hyperthyroidism in children is caused by Graves Disease, whereas toxic nodule and toxic multinodular goiter are rare. Hyperthyroidism in children and adolescents has effects on growth and development. Nearly all children with Graves' disease have a diffuse goiter; Graves' ophthalmopathy also may be present, but is less severe than in adults.
This study was undertaken to know the causes, clinical presentation and response to treatment in physical, sexual and intellectual ability in children and adolescents with hypothyroidism or hyperthyroidism.
Objective of the study
To study the etiology and clinical presentation of hypothyroidism and hyperthyroidism in juvenile age group and treatment outcome in physical, sexual and psychological aspects.
| Materials and Methods|| |
This study was conducted at Department of Endocrinology between September 2011 to January 2013. Biochemically proven, new onset cases with hypothyroidism (with TSH > 15 μIU/ml and thyroxine, T4 < 5.5 μg/dl) and hyperthyroidism (with TSH < 0.1 μIU/ml and T4 > 12 μg/dl) in juvenile age-group (8-16 years) were studied after taking detailed history, clinical examination and required investigations. General mental ability was assessed with the help of Binet Kamat test to know the mental age and cognitive function.
Patients with subclinical hypo and hyperthyroidism or those who already on treatment were excluded from the study as well as patients with known chronic systemic illness (anemia, heart, kidney, liver, respiratory, and neurological diseases like cerebral palsy). As these conditions can adversely affect physical and mental parameters of our study.
Treatment with T4 and carbimazole was started in standard doses and these patients were periodically assessed for the compliance of treatment, adjustments in the dosages were made as needed. Physical, sexual maturity rating (SMR), and IQ assessment done before the initiation of treatment and after 1 year of follow-up. Informed consent was taken from all patients and this study was approved by ethical committee.
Statistics were done using Windostat Version 9.2. Differences between patient groups were assessed for statistical significance using the Student's t-test for independent variables among the groups. Analysis of variance (ANOVA) was used for comparisons of different variables in same group. Differences within the groups before and after treatment were compared using paired samples t-test. All results were expressed as means ± standard deviation (SD) and Statistical significance was considered when a P ≤ 0.05.
| Results|| |
A total 68 patients were studied, of which 63 were hypothyroid and five were hyperthyroid. Among 63 hypothyroid patients, 45 (71.4%) were females and 18 (28.6%) were males, ratio being 2.5:1. 38 were in 8-11 years group and 25 were in >11 years group. Female to male ratio in school children was 1.9:1 (25/13) and in adolescents it was 4:1 (20/5) [Table 1].
|Table 1: Characteristics of the patients at base line and after treatment in both groups|
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| Discussion|| |
There is a paucity of observational data on growth and development in Indian children with juvenile hypothyroidism and hyperthyroidism. Hence this study was undertaken to know the effects of hypothyroidism and hyperthyroidism in juvenile age-group and the response to treatment. Our study focused on newly diagnosed patients in the age group of 8-16 years [Figure 1] who were followed up for a period of at least 1 year while on treatment. In our study female to male ratio was 2.5:1 which was similar to 2.8: 1 in a study by Hunter et al.  [Figure 2] and [Figure 3].
Out of 63 children in our study with hypothyroidism, 63.4% had autoimmune etiology, 3.1% [Figure 4] (2 out of 63) patients had secondary hypothyroidism (both due to hypopitutarism) and 1.5% patients had ectopic thyroid. None of them had any evidence of other autoimmune disorders like type-I diabetes mellitus (T1DM), Juvenile rheumatoid arthritis, and adrenal insufficiency. Hunter I et al.,  reported autoimmune thyroid disease in 66% and idiopathic hypothyroidism in 25% in which 3.5% had T1DM, 2% had juvenile rheumatoid arthritis and 1.5% had Down's syndrome. Family history of thyroid disorders were positive in 15 (23.8%) of our patients [Figure 5].
|Figure 4: TPO antibodies, Anti TPO antibodies were positive in 40 (63.5%)|
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The most common physical findings at presentation in our patients with hypothyroidism were goiter in 46%, short stature in 50.7%, decreased appetite in 41.2% and dry skin in 34.9%, [Figure 6] where as Ozer et al., reported presence of goiter in 39.5 percent of children with autoimmune thyroiditis. 
In our study, initial mean height standard deviation score (HSDS) was- 2.42 ± 1.83 in all subjects with hypothyroidism [Figure 7]. The initial height deficit in our patients was comparably less when compared to the data reported by Rivkees SA et al.,  in juvenile hypothyroidism, where initial heights were 4.04 ± 0.5 and 3.15 ± 0.4 SD below the mean heights for age of normal girls and boys, respectively.
Ozer G et al.,  in their study found that 80% of hypothyroid children in 5 to 12 years age-group at diagnosis were below the fifth percentile for heights. However in our study, on comparing the initial HSDS of children (8-11 yrs) 2.14 ± 1.76 and adolescents (11-16 yrs) 2.86 ± 1.87, no statistically significant difference was found (P = 0.09). This indicates that the age at onset of hypothyroidism has no influence on initial height.
Mean initial T4 in total number of subjects was 2.08 ± 1.43 μg/dl. Mean initial T4 in children was 2.17 ± 1.33 μg/dl and in adolescence it was 1.93 ± 1.58 μg/dl (P = 0.51). There was no significant difference in T4 levels in children and adolescents. In a study done by Rivkees SA et al.,  serum T4 level at diagnosis in juvenile acquired hypothyroidism was 1.1 ± 0.3 μg/dl.
Thyroid peroxidase (TPO) antibodies was associated with low T4 levels (P < 0.05). Mean initial T4 in patients with positive TPO antibodies was 1.73 ± 1.26 μg/dl when compared to 2.68 ± 1.53 μg/dl in patients with negative antibodies [Figure 8]. This indicates that autoimmune etiology was associated with severe hypothyroidism.
|Figure 8: Correlation of initial T4 with TPO antibodies, Positive TPO antibodies was associated with low T4 levels (P < 0.05)|
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Initial TSH in primary hypothyroidism ranges from 15.6 to >150 μIU/ml. TSH was 15 to <50 μIU/ml in 28.5%, 50 to <150 in 42.8% and ≥150 in 28.5%. TSH in two secondary hypothyroidism patients were 1.3 and 2.6. This indicates TSH is high (≥50) in 71% of patients [Figure 9].
In our study mean dose of thyroxine required to restore euthyroidism was 2.97 ± 0.24 μg/kg/day. Mean dose of thyroxine required in children of 8-11 years age was 3.22 ± 0.95 μg/kg/day and in adolescents of 11-16 years age was 2.58 ± 0.93 μg/kg/day [Figure 10]. T4 requirement is more in children than in adolescents as expected
|Figure 10: Thyroxine dose required to restore euthyroidism, T4 requirement in most patients is in the range of 2-4 μg/kg/day and requirement decrease as age advances|
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because T4 dose requirement decreases as age advances in children and arbitrary T4 requirement in 3-10 years age was 3-5 μg/kg/day and in 10-16 years age it is 2-4 μg/kg/day. In a study done by Rivkees SA et al.,  the dose of levo-thyroxine required to maintain normal thyroid function was 3.4 ± 0.3 μg/kg/day. The T4 dose required in a study by Ellerbroek V et al., to restore euthyroidism in 75 children and adolescents was 1.5 ± 0.5 μg/kg per day.  The requirement was less in study by Ellerbroek et al., because most patients were >10 years of age. Mean time required for normalization of TSH was 3.8 months [Figure 11].
|Figure 11: Time required for TSH normalization, Average time required for TSH normalization was 3.8 months|
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In our patients mean dose of thyroxine required to restore euthyroidism was more in those with autoimmune etiology (mean dose of 3.09 ± 1.07 μg/kg/day) compared to non autoimmune etiology (mean dose of 2.76 ± 0.79 μg/kg/day) though statistically not significant (P = 0.19).
Basal metabolic index (BMI) of patients ranges from 10.4-27.1 with an average of 17.99. Decreased intake of calories and proteins due to low socioeconomic status in most of our patients will explain the lower normal BMI levels.
Usually bone age is delayed compared to chronological age. In our study average bone age delay was 2.4 years compared to chronological age. In a study by Pantsiouou et al.,  there was bone age delay of 3.4 years in girls and 3.2 years in boys with juvenile primary hypothyroidism. More delay in bone age in study by Pantsiouou S et al., may be due to small sample size and low mean age (8.8 in girls and 9.5 in boys) than in our study.
Height improvement with treatment
Standard deviation score (SDS) for height improved ranging from - 1.55-1.6 with a mean of 0.31 ± 0.61 and reached a final SDS with a mean of -2.10 ± 1.67 [Table 2]. This clearly shows there was improvement in height SDS with treatment [Figure 12].
|Table 2: Height standard deviation scores before and after treatment in hypothyroid group|
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|Figure 12: Paired t-test was done to compare initial and post treatment HSDS|
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In a study by Pantsisou et al.,  initial mean HSDS for bone age before treatment in the girls was +0.59 and after 11 years of treatment fell to -0.55 Mean HSDs for bone age in the boys decreased from +1.6-−0.87 during treatment. In the girls the onset of puberty was 1.2 years later than the normal population but the duration of puberty was reduced.
We evaluated the difference in treatment response in autoimmune and non autoimmune etiology by comparing height standard deviation scores. Initial heights were 2.69 ± 0.29 and 1.96 ± 0.36 SD below the mean heights for age in patients with positive and negative TPO antibodies respectively and final heights were 2.43 ± 1.69 and 1.53 ± 1.50 SD below the mean heights for age in patients with positive and negative TPO antibodies respectively (P = 0.039). This indicates that initial heights were not significantly different in autoimmune and non autoimmune etiology but height gain due to treatment was less in patients with autoimmune patients as seen in final height standard deviation scores. In our study delayed puberty was present in 4 (36.3%) patients out of 11 subjects in pubertal age group [Figure 13]. There was no history suggestive of precocity. After 1 year of treatment, three out of four subjects with pubertal delay entered puberty.
After 3 years of age, hypothyroidism usually has no permanent influence on cognitive or neurological development. There were many studies on effect of congenital hypothyroidism on cognitive function but lack of studies in juvenile hypothyroidism. So we had done this study to know the effect of hypothyroidism on cognitive function by IQ assessment using Binet Kamat test. Initially IQ was borderline impaired in 3.1% and low average in 28.5% patients with no patient was having mildly or moderate impairment according to Binet classification. IQ after 1 year of treatment was borderline impaired in one (1.5%), low average in 23.8%, average in 65% and above average in 9.5% patients indicating that there was no significant change with treatment [Figure 14] and [Figure 15]. More comprehensive neurocognitive evaluations are essential to better determine the patterns of cognitive strengths and weaknesses associated with hypothyroidism.
A rapid return to the euthyroid state in adolescents rarely can cause psychosis  or benign intracranial hypertension.  In our patient there was no history suggestive of either psychosis or benign intracranial hypertension.
Hyperthyroidism in children is usually caused by Graves disease, other causes being rare. All five patients in our study were having features of Graves disease. Mean age in our study was 10.85 ± 2.16 years [Figure 16]. Which is less than those in other studies in which peak incidence was during 11-15 years. , In a report of 143 children with Graves' disease, 38 percent were prepubertal at diagnosis.  Grave's disease is more common in girls than in boys, with a female: male ratio of 5:1, which was similar to our study (4:1) [Figure 17].
Signs and symptoms of hyperthyroidism in our study were [Figure 18] goitre (100%), nervousness (100%), tachycardia (100%), increased pulse pressure (80%), tremulousness (80%), Increased appetite (60%), weight loss (60%), thyroid bruit (40%), excess sweating, palpitations and heat intolerance (40% each), prominent eyes (60%), headache and diarrhea (20%). The frequency of the symptoms were comparable to most other studies. ,,, The main clinical features of thyrotoxicosis in children and adolescents are similar to those in adults. ,,,
Staring look and wide palpebral fissures, which are signs of thyrotoxicosis were present in three patients in our study with no features of ophthalmopathy (CAS-0/7 in all patients). This was expected as exophthalmos is rarely the presenting complaint in children. 
In our study all hyperthyroid patients were shorter than mean height for age. Initial SDS for height ranges from −0.94-−1.69 with a mean of −1.244 ± 0.327 (P = 0.688) [Figure 19]. This was in contrast to the normally expected acceleration of growth  and this can be explained by low calorie intake due to poor socioeconomic status in most of our patients which was also indicated by low normal BMI (13.34) (range 10.4-14.9) SDS for height improved in all patients to final SDS in range of −1.2-−0.18 with a mean of - 0.756 ± 0.392 (P = 0.68). This indicates that height gain was slightly improved with treatment [Table 3], [Figure 20] and [Figure 21].
|Table 3: Height standard deviation scores before and after treatment in hyperthyroid group|
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Bone age was advanced by 1 year in 2 patients and appropriate for chronological age in three patients. After 1 year of treatment bone age was advanced by 6 months in those 2 patients with initial advanced bone age. Normally in children with Graves' disease bone age will be advanced at presentation and with antithyroid drug treatment, growth velocity and bone age approach a more normal pattern. 
In our study pubertal development was appropriate for age in all patients. Attainments of pubertal stages do not appear to be altered by hyperthyroidism.  IQ levels as well not altered with hyperthyroidism. [Mean initial IQ was 94.4 ± 7.63 and mean final IQ (after 1 year) was 92.8 ± 2.94] [Figure 22].
Initial T4 ranges from 18 to > 30 μg/dl with 3 patients having T4 > 30 μg/dl [Figure 23] TSH was ≤ 0.01 μIU/ml indicating severe thyrotoxicosis [Figure 24]. Anti TPO antibodies were positive in all patients in our study which can be compared to a study by Lavard L et al., in which more than 75% of children with Graves' thyrotoxicosis have high serum concentrations of antithyroid peroxidase and antithyroglobulin antibodies. 
The treatment for Graves' disease in children are medical therapy, radioactive iodine or surgery We preferred antithyroid drug (carbimazole) treatment to radioactive iodine or surgery in all patients in the hope that a remission of the Graves' disease will occur and also as most of children in our study were young.
In our study all patients were started on carbimazole 0.5-1.0 mg/kg/day and the mean dose required to restore euthyroidism was 0.76 ± 0.14 mg/kg/d (0.55-0.93 mg/kg/d) [Figure 25]. Mean duration of follow-up was 14.15 ± 2.23 months (12-15 months).
There was no remission in all cases as expected, as the median time to remission is 8 years in prepubertal children, compared to 4 years in pubertal children.  25% had remission at 2 years and the 5-year remission rate was 50%.  In a study by Bergman P et al., fewer than 20% of children experienced successful sustained remission at median follow-up of 3.2 years. 
| Conclusion|| |
In juvenile age group, most common cause for hypothyroidism was Hashimoto's thyroiditis and for hyperthyroidism was Grave's disease. The common modes of presentation were goitre and growth retardation in hypothyroidism and goitre and nervousness in hyperthyroidism. Autoimmune etiology was associated with severe hypothyroidism and requires high mean dose of thyroxine requirement. Height velocity and sexual maturity can be affected and improve with treatment in hypothyroidism. Height velocity can be affected and improve with treatment in hyperthyroidism. In our study mental ability was not significantly affected with hypo or hyperthyroidism.
Limitations of the study
We have not measured urinary iodine levels, molecular diagnostic tests, and specialized tests for the diagnosis of dyshormonogenesis were not done in our study population. We diagnosed hyperthyroidism mostly based on clinical presentation; thyroid uptake scan was not done to confirm the diagnosis of hyperthyroidism, largely because these tests were not available at our center.
| References|| |
Barnes HV, Blizzard RM. Antithyroid drug therapy for toxic diffuse goiter (Graves disease): Thirty years experience in children and adolescents. J Pediatr 1977;91:313-20.
Hunter I, Greene SA, MacDonald TM, Morris AD. Prevalence and aetiology of hypothyroidism in the young. Arch Dis Child 2000;83:207-10.
Ozer G, Yüksel B, Kozanoðlu M, Serbest M, Turgut C. Growth and development of 280 hypothyroidic patients at diagnosis. Acta Paediatr Jpn 1995;37:145-9.
Rivkees SA, Bode HH, Crawford JD. Long-term growth in juvenile acquired hypothyroidism: The failure to achieve normal adult stature. N Engl J Med 1988;318:599-602.
Ellerbroek V, Warncke K, Köhle J, Bonfig W. A levothyroxine dose recommendation for the treatment of children and adolescents with autoimmune thyroiditis induced hypothyroidism. J Pediatr Endocrinol Metab 2013;26:1023-8.
Pantsiouou S, Stanhope R, Uruena M, Preece MA, Grant DB. Growth prognosis and growth after menarche in primary hypothyroidism. Arch Dis Child 1991;66:838-40.
Rovet JF, Daneman D, Bailey JD. Psychologic and psychoeducational consequences of thyroxine therapy for juvenile acquired hypothyroidism. J Pediatr 1993;122:543-9.
Van Dop C, Conte FA, Koch TK, Clark SJ, Wilson-Davis SL, Grumbach MM. Pseudotumor cerebri associated with initiation of levothyroxine therapy for juvenile hypothyroidism. N Engl J Med 1983;308:1076-80.
Saxena KM, Crawford JD, Talbot NB. Childhood thyrotoxicosis: A long-term perspective. Br Med J 1964;2:1153-8.
Purandare A, Co Ng L, Godil M, Ahnn SH, Wilson TA. Effect of hypothyroidism and its treatment on the IGF system in infants and children. J Pediatr Endocrinol Metab 2003;16:35-42.
Vaidya VA, Bongiovanni AM, Parks JS, Tenore A, Kirkland RT. Twenty-two years experience in the medical management of juvenile thyrotoxicosis. Pediatrics 1974;54:565-70.
Kogut MD, Kaplan SA, Collip PJ, Collipp PJ, Tiamsic T, Boyle D. Treatment of hyperthyroidism in children Analysis of Forty-Five patients. N Engl J Med 1965;272:217-21.
Gorman CA. Temporal relationship between the onset of Graves' ophthalmopathy and the diagnosis of thyrotoxicosis. Mayo Clin Proc 1983;58:515-9.
Cassio A, Corrias A, Gualandi S, Tato' L, Cesaretti G, Volta C, et al
. Influence of gender and pubertal stage at diagnosis on growth outcome in childhood thyrotoxicosis: Results of a collaborative study. Clin Endocrinol (Oxf) 2006;64:53-7.
Lavard L, Perrild H, Jacobsen BB, Høier-Madsen M, Bendinelli G, Vitti P. Prevalence of thyroid peroxidase, thyroglobulin and thyrotropin receptor antibodies in a long-term follow-up of juvenile Graves' disease. Autoimmunity 2000;32:167-72.
Shulman D, Muhar I, Jorgensen V, Diamond FB, Bercu BB, Root AW. Autoimmune hyperthyroidism in prepubertal children and adolescents: Comparison of clinical and biochemical features at diagnosis and responses to medical therapy. Thyroid 1997;7:755-60.
Lippe BM, Landau EM, Kaplan SA. Hyperthyroidism in children treated with long term medical therapy: Twenty-five percent remission every two years. J Clin Endocrinol Metab 1987;64:1241-5.
Bergman P, Auldist AW, Cameron F. Review of the outcome of management of Graves' disease in children and adolescents. J Paediatr Child Health 2001;37:176-82.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20], [Figure 21], [Figure 22], [Figure 23], [Figure 24], [Figure 25]
[Table 1], [Table 2], [Table 3]