REVIEW URRENT C OPINION
Congenital hypothyroidism: recent advances Ari J. Wassner and Rosalind S. Brown
Purpose of review This review summarizes significant recent advances in the epidemiology, pathophysiology, and treatment of congenital hypothyroidism. Recent findings The apparent incidence of congenital hypothyroidism has more than doubled in recent years because of several factors, including more inclusive diagnostic criteria, shifting demographics, and increasing survival of preterm infants. The greatest increase has occurred in mildly affected patients, many of whom have a eutopic thyroid gland. Congenital hypothyroidism may be transient or persistent, but the natural history cannot be predicted by severity at diagnosis. In premature infants, who are especially vulnerable to hypothyroidism, the rise in thyroid-stimulating hormone may be delayed and therefore detected only by routine follow-up screening. Recent studies of defects in thyroid hormone synthesis have focused on the role of mutations in the dual oxidase system and of a novel apical iodide transporter, anoctamin 1. Finally, emerging data suggest that exposure to excess thyroid hormone may be as harmful as hypothyroidism to long-term cognitive development. Summary Although newborn screening has virtually eradicated mental retardation due to congenital hypothyroidism in parts of the world, new information continues to accumulate and new questions to arise about the diagnosis, physiology, and optimal management of this disorder. Keywords congenital hypothyroidism, eutopic, prematurity, preterm, thyroid
INTRODUCTION Thyroid hormone is critical for normal growth and brain development, and hypothyroidism in infancy is the leading cause of intellectual impairment worldwide. This update will discuss significant new contributions in the area of congenital hypothyroidism since the topic was last reviewed in June 2013 [1]. Particular attention will be given to the emerging understanding of congenital hypothyroidism in patients with a normally located (eutopic) thyroid gland.
INCIDENCE OF CONGENITAL HYPOTHYROIDISM Over the last several years, reports from newborn screening programs around the world have described an increase in the incidence of congenital hypothyroidism. Compared with the rate of 1 : 3000–1 : 4000 when screening was introduced [2], rates ranging from 1 : 1400 to 1 : 2800 have been reported recently by screening programs in many countries including the USA [3], Canada [4], Greece [5], Italy [6], and New Zealand [7]. One factor contributing to this change
may be increased screening of patients at higher risk of congenital hypothyroidism, including premature infants [3] and particular ethnic populations such as Hispanics and Asians [7,8]. Methodological changes in newborn screening appear to be another major factor in the rising incidence of congenital hypothyroidism, specifically the widespread lowering of thyroid-stimulating hormone (TSH) screening cutoffs that leads to detection of milder cases [4,6]. In a comprehensive review of newborn screening strategies for congenital hypothyroidism around the world, Ford and LaFranchi [9 ] found that lowering the TSH cut-off from greater than 20–25 mIU/l to greater than 6–10 mIU/l in six national newborn screening programs resulted in a 2.2-fold increase &
Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA Correspondence to Rosalind S. Brown, Division of Endocrinology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. Tel: +1 617 355 7476; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2015, 22:407–412 DOI:10.1097/MED.0000000000000181
1752-296X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-endocrinology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Thyroid
408
www.co-endocrinology.com
1:3900
1:3900
1:4100
1:3800 Thyroid dysgenesis
1:3900
5000
Eutopic thyroid
9000
1:5900
1:6400
1:9800
1:11500
13000 17000 1:17000
-2 00 8 07 20
03 20
-2 00 2 99
-2 00 6
21000
19
&&
1000
-1 99 8
&&
95
&
19
in the average incidence of congenital hypothyroidism (from 1 : 3264 to 1 : 1464) (values recalculated from original data in [9 ]). Two recent studies have characterized in more detail the factors contributing to the rising incidence of congenital hypothyroidism. In a study of the Argentine newborn screening program over 14 years (1997–2010), the incidence of congenital hypothyroidism increased by 31% (from 1 : 2619 to 1 : 1997), with 42% of the increment attributable directly to a decrease in the screening TSH cut-off from greater than 15 mIU/l to greater than 10 mIU/l [10]. Olivieri et al. [11 ] similarly analyzed data from the Italian network of regional newborn screening programs over a 22-year period (1987–2008) during which TSH cut-offs decreased from greater than 20 mIU/l to greater than 7–15 mIU/l. During the study period they observed a 54% increase in the incidence of congenital hypothyroidism (from 1 : 3000 to 1 : 1940), with the change in TSH cutoff accounting for 78% of additional cases detected. Thyroid scintigraphy – performed in both studies in most cases of permanent congenital hypothyroidism – demonstrated that the rising incidence of congenital hypothyroidism was mostly attributable to cases with a eutopic thyroid gland, whereas the incidence of thyroid dysgenesis did not change significantly (Fig. 1) [10,11 ]. These studies confirm initial reports that the observed increase in congenital hypothyroidism incidence is driven largely, though not entirely, by the detection of milder cases of congenital hypothyroidism, often with a eutopic thyroid gland [4–6]. As more cases of congenital hypothyroidism with a eutopic thyroid are diagnosed, an important clinical question is whether these cases are likely to
-1 99 4
High levels of circulating thyroid hormone, like low levels, may be detrimental to neurodevelopment in both preterm infants and children treated for congenital hypothyroidism, but more long-term data are needed.
91
Cases of congenital hypothyroidism with a eutopic thyroid gland are increasingly common, but whether such cases will be transient or permanent cannot be distinguished reliably at diagnosis, and a trial off therapy should be strongly considered at age 2–3 years.
19
The incidence of congenital hypothyroidism has risen over the last few decades, largely because of changes in newborn screening strategies, shifting demographics, and the increasing survival of preterm infants at high risk of congenital hypothyroidism.
be transient or permanent. Two recent studies provide insight into the natural history of congenital hypothyroidism with a eutopic thyroid gland. In both studies, patients treated for congenital hypothyroidism received a trial off levothyroxine (LT4) at 2–3 years of age. In 43 Korean congenital hypothyroidism patients with a eutopic thyroid gland, LT4 withdrawal demonstrated that 28% had transient congenital hypothyroidism, 51% had permanent congenital hypothyroidism, and the remaining 21% had persistent subclinical hypothyroidism (TSH 5–10 mIU/l) [12]. In a similar French cohort of 32 congenital hypothyroidism patients with a eutopic thyroid gland, Castanet et al. [13] identified transient congenital hypothyroidism in 38%, permanent congenital hypothyroidism in 38%, and persistent subclinical hypothyroidism in 25%. Of note, Castanet et al. included only patients with ‘unexplained’ congenital hypothyroidism, excluding those with defects of iodine organification documented by a perchlorate discharge test. In addition, both studies excluded children born preterm, so these data may not apply to this important population of congenital hypothyroidism patients. Combining these new data with a prior similar study [14] suggests that among congenital hypothyroidism patients with a eutopic thyroid, roughly equal proportions have transient (35%) or permanent (40%) disease (Table 1). The remaining 25% have persistent hyperthyrotropinemia without overt hypothyroidism, and whether ongoing treatment is necessary in this group remains controversial [15]. Of interest, across all three studies, clinical characteristics – including TSH and free T4 at diagnosis – did not differ between transient and
Incidence: 1/X live births
KEY POINTS
Years
FIGURE 1. The increasing incidence of congenital hypothyroidism is primarily due to a rise in cases with a eutopic thyroid gland, with little change in the rate of thyroid dysgenesis. Data from [4] and [11 ]. &&
Volume 22 Number 5 October 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Congenital hypothyroidism Wassner and Brown Table 1. Natural history of congenital hypothyroidism with a eutopic thyroid gland n
Permanent congenital hypothyroidism
Subclinical hypothyroidism
Transient congenital hypothyroidism
Rabbiosi et al. [14]
84
29 (35%)
23 (27%)
32 (38%)
Jin et al. [12]
43
22 (51%)
9 (21%)
12 (28%)
Castanet et al. [13]
32
12 (38%)
8 (25%)
12 (38%)
159
63 (40%)
40 (25%)
56 (35%)
Total
permanent cases of congenital hypothyroidism, and Rabbiosi et al. demonstrated that outcome was independent of whether congenital hypothyroidism at diagnosis was mild (TSH
Congenital hypothyroidism: recent advances Ari J. Wassner and Rosalind S. Brown
Purpose of review This review summarizes significant recent advances in the epidemiology, pathophysiology, and treatment of congenital hypothyroidism. Recent findings The apparent incidence of congenital hypothyroidism has more than doubled in recent years because of several factors, including more inclusive diagnostic criteria, shifting demographics, and increasing survival of preterm infants. The greatest increase has occurred in mildly affected patients, many of whom have a eutopic thyroid gland. Congenital hypothyroidism may be transient or persistent, but the natural history cannot be predicted by severity at diagnosis. In premature infants, who are especially vulnerable to hypothyroidism, the rise in thyroid-stimulating hormone may be delayed and therefore detected only by routine follow-up screening. Recent studies of defects in thyroid hormone synthesis have focused on the role of mutations in the dual oxidase system and of a novel apical iodide transporter, anoctamin 1. Finally, emerging data suggest that exposure to excess thyroid hormone may be as harmful as hypothyroidism to long-term cognitive development. Summary Although newborn screening has virtually eradicated mental retardation due to congenital hypothyroidism in parts of the world, new information continues to accumulate and new questions to arise about the diagnosis, physiology, and optimal management of this disorder. Keywords congenital hypothyroidism, eutopic, prematurity, preterm, thyroid
INTRODUCTION Thyroid hormone is critical for normal growth and brain development, and hypothyroidism in infancy is the leading cause of intellectual impairment worldwide. This update will discuss significant new contributions in the area of congenital hypothyroidism since the topic was last reviewed in June 2013 [1]. Particular attention will be given to the emerging understanding of congenital hypothyroidism in patients with a normally located (eutopic) thyroid gland.
INCIDENCE OF CONGENITAL HYPOTHYROIDISM Over the last several years, reports from newborn screening programs around the world have described an increase in the incidence of congenital hypothyroidism. Compared with the rate of 1 : 3000–1 : 4000 when screening was introduced [2], rates ranging from 1 : 1400 to 1 : 2800 have been reported recently by screening programs in many countries including the USA [3], Canada [4], Greece [5], Italy [6], and New Zealand [7]. One factor contributing to this change
may be increased screening of patients at higher risk of congenital hypothyroidism, including premature infants [3] and particular ethnic populations such as Hispanics and Asians [7,8]. Methodological changes in newborn screening appear to be another major factor in the rising incidence of congenital hypothyroidism, specifically the widespread lowering of thyroid-stimulating hormone (TSH) screening cutoffs that leads to detection of milder cases [4,6]. In a comprehensive review of newborn screening strategies for congenital hypothyroidism around the world, Ford and LaFranchi [9 ] found that lowering the TSH cut-off from greater than 20–25 mIU/l to greater than 6–10 mIU/l in six national newborn screening programs resulted in a 2.2-fold increase &
Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA Correspondence to Rosalind S. Brown, Division of Endocrinology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. Tel: +1 617 355 7476; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2015, 22:407–412 DOI:10.1097/MED.0000000000000181
1752-296X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-endocrinology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Thyroid
408
www.co-endocrinology.com
1:3900
1:3900
1:4100
1:3800 Thyroid dysgenesis
1:3900
5000
Eutopic thyroid
9000
1:5900
1:6400
1:9800
1:11500
13000 17000 1:17000
-2 00 8 07 20
03 20
-2 00 2 99
-2 00 6
21000
19
&&
1000
-1 99 8
&&
95
&
19
in the average incidence of congenital hypothyroidism (from 1 : 3264 to 1 : 1464) (values recalculated from original data in [9 ]). Two recent studies have characterized in more detail the factors contributing to the rising incidence of congenital hypothyroidism. In a study of the Argentine newborn screening program over 14 years (1997–2010), the incidence of congenital hypothyroidism increased by 31% (from 1 : 2619 to 1 : 1997), with 42% of the increment attributable directly to a decrease in the screening TSH cut-off from greater than 15 mIU/l to greater than 10 mIU/l [10]. Olivieri et al. [11 ] similarly analyzed data from the Italian network of regional newborn screening programs over a 22-year period (1987–2008) during which TSH cut-offs decreased from greater than 20 mIU/l to greater than 7–15 mIU/l. During the study period they observed a 54% increase in the incidence of congenital hypothyroidism (from 1 : 3000 to 1 : 1940), with the change in TSH cutoff accounting for 78% of additional cases detected. Thyroid scintigraphy – performed in both studies in most cases of permanent congenital hypothyroidism – demonstrated that the rising incidence of congenital hypothyroidism was mostly attributable to cases with a eutopic thyroid gland, whereas the incidence of thyroid dysgenesis did not change significantly (Fig. 1) [10,11 ]. These studies confirm initial reports that the observed increase in congenital hypothyroidism incidence is driven largely, though not entirely, by the detection of milder cases of congenital hypothyroidism, often with a eutopic thyroid gland [4–6]. As more cases of congenital hypothyroidism with a eutopic thyroid are diagnosed, an important clinical question is whether these cases are likely to
-1 99 4
High levels of circulating thyroid hormone, like low levels, may be detrimental to neurodevelopment in both preterm infants and children treated for congenital hypothyroidism, but more long-term data are needed.
91
Cases of congenital hypothyroidism with a eutopic thyroid gland are increasingly common, but whether such cases will be transient or permanent cannot be distinguished reliably at diagnosis, and a trial off therapy should be strongly considered at age 2–3 years.
19
The incidence of congenital hypothyroidism has risen over the last few decades, largely because of changes in newborn screening strategies, shifting demographics, and the increasing survival of preterm infants at high risk of congenital hypothyroidism.
be transient or permanent. Two recent studies provide insight into the natural history of congenital hypothyroidism with a eutopic thyroid gland. In both studies, patients treated for congenital hypothyroidism received a trial off levothyroxine (LT4) at 2–3 years of age. In 43 Korean congenital hypothyroidism patients with a eutopic thyroid gland, LT4 withdrawal demonstrated that 28% had transient congenital hypothyroidism, 51% had permanent congenital hypothyroidism, and the remaining 21% had persistent subclinical hypothyroidism (TSH 5–10 mIU/l) [12]. In a similar French cohort of 32 congenital hypothyroidism patients with a eutopic thyroid gland, Castanet et al. [13] identified transient congenital hypothyroidism in 38%, permanent congenital hypothyroidism in 38%, and persistent subclinical hypothyroidism in 25%. Of note, Castanet et al. included only patients with ‘unexplained’ congenital hypothyroidism, excluding those with defects of iodine organification documented by a perchlorate discharge test. In addition, both studies excluded children born preterm, so these data may not apply to this important population of congenital hypothyroidism patients. Combining these new data with a prior similar study [14] suggests that among congenital hypothyroidism patients with a eutopic thyroid, roughly equal proportions have transient (35%) or permanent (40%) disease (Table 1). The remaining 25% have persistent hyperthyrotropinemia without overt hypothyroidism, and whether ongoing treatment is necessary in this group remains controversial [15]. Of interest, across all three studies, clinical characteristics – including TSH and free T4 at diagnosis – did not differ between transient and
Incidence: 1/X live births
KEY POINTS
Years
FIGURE 1. The increasing incidence of congenital hypothyroidism is primarily due to a rise in cases with a eutopic thyroid gland, with little change in the rate of thyroid dysgenesis. Data from [4] and [11 ]. &&
Volume 22 Number 5 October 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Congenital hypothyroidism Wassner and Brown Table 1. Natural history of congenital hypothyroidism with a eutopic thyroid gland n
Permanent congenital hypothyroidism
Subclinical hypothyroidism
Transient congenital hypothyroidism
Rabbiosi et al. [14]
84
29 (35%)
23 (27%)
32 (38%)
Jin et al. [12]
43
22 (51%)
9 (21%)
12 (28%)
Castanet et al. [13]
32
12 (38%)
8 (25%)
12 (38%)
159
63 (40%)
40 (25%)
56 (35%)
Total
permanent cases of congenital hypothyroidism, and Rabbiosi et al. demonstrated that outcome was independent of whether congenital hypothyroidism at diagnosis was mild (TSH
