congenital hypothyroidism: what on earth is it? a more ‘progressive’ approach
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Congenital hypothyroidism: what on earth is it? A more ‘progressive’ approach. John Gregory Professor in Paediatric Endocrinology Cardiff University. Congenital hypothyroidism: what on earth is it? A more ‘progressive’ approach. Challenges in screening Changing incidence - PowerPoint PPT PresentationTRANSCRIPT
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Congenital hypothyroidism:
what on earth is it?A more ‘progressive’
approach.
John Gregory
Professor in Paediatric Endocrinology
Cardiff University
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Congenital hypothyroidism:what on earth is it?
A more ‘progressive’ approach.
• Challenges in screening
• Changing incidence
• Consequences of ‘gland in situ’
• Biochemical consequencies of TSH <20mU/L
• Pros & cons of changing the ‘cut-off’
• Conclusions
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Challenges in management of congenital hypothyroidism• Different aetiologies of congenital
hypothyroidism
• Guidelines for premature or low birth weight babies
• Biochemical: lack of agreement on cut-offs to detect congenital hypothyroidism
• Is there a correlation between neonatal fT4 or TSH & later neurodevelopment?
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Changing incidence of congenital hypothyroidism?• Over last 2 decades
– New York 1:3378 (1978) → 1:1414 (2005)– USA 1:4098 (1987) → 1:2370 (2002)
• Changes in clinical evaluation & therapy• Transient hypothyroidism• Epidemiology
– prematurity– genetic factors, sex, race & ethnicity– prenatal iodine intake– Autoimmunity
• Changes in lab method & screening paradigms
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Is the incidence of congenital hypothyroidism really increasing?
1. All cases in Quebec
2. Thyroid dysgenesis
3. Goitre
5. Unknown4. Normal gland in situ
Deladoey et al, 2011
TSH cut-off decreased from 15 to 5mU/L
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Comparison of yearly incidences of congenital hypothyroidisma = 1990-2000: TSH <15mU/L cut-off
b = 2001-2009: TSH <5mU/L cut-off (all cases)
c = 2001-2009: TSH <5mU/L cut-off (without additional cases)
Deladoey et al, 2011
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Congenital hypothyroidism in Wales (2003-5)
• Perkin Elmer autoDELFIA neonatal hTSH assay introduced– compared to ACS 180 Bayer ACS TSH method (Bayer) results
approximately 50% lower– cut-off of <5mU/L therefore audited
• 41 infants with blood spot TSH >5mU/L– 23 had TSH >20mU/L– 8 had TSH 10-20mU/L
• 10 had TSH 5-10mU/L– 9 had ↑ neonatal plasma TSH (mean TSH 20.6, range 6–30.1mU/L)– 6 normalised TSH between 4 weeks and 3 months
• 3 infants given thyroxine– 1 stopped therapy aged 2.5yrs (neonatal TSH 30.14mU/L)– 2 infants remain on treatment– 1 has Down syndrome (neonatal TSH 80mU/L)– 1 required ↑ doses of thyroxine due to persistently raised TSH
concentration (neonatal TSH 14.5mU/L)
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Reaudit of newborn screening in Wales
• April ‘07 - March 2010
• 105,295 babies screened
• 49 babies had a TSH >20mU/L
• 364 babies had a TSH 5 – 19mU/L– 37 had persistently raised TSH &
referred to designated Paediatrician
– 6 started on thyroxine
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Relationship of newborn bloodspot TSH and pre-therapy fT4 in 310 Scottish infants (excluding sick babies)
Proportion of non-sick cases with sub-normal, low normal or adequate fT4 on pre-treatment venous blood sample
0
10
20
30
40
50
60
70
80
90
100
>100 75-100 50-74.9 40-49.9 30-39.9 20-29.9 <20
Screening TSH
%
% fT4<9
% fT4 9-14.9
% fT4 >=15
Courtesy of Malcolm Donaldson
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Cause of congenital hypothyroidism & initial biochemistry
• Dysgenesis associated with most severe hypothyroidism
• Majority of gland in situ cases have FT4 levels below normal
Corbetta et al, 2009
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Effect of lowering TSH cut-off on causes of congenital hypothyroidism
• 629,042 newborns in Italy
• TSH cut-off changed in 1999 (12mU/L) & 2003 (10mU/L)
• Using 20mU/L cut-off
– misses 45% cases
– misses 12/141 dysgenesis
• 78% of gland in situ show persistent thyroid dysfunction at 3-5yrs
Corbetta et al, 2009
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Why treat ‘subclinical’ neonatal congenital hypothyroidism?
• Evidence limited
• Persistent or worsening biochemistry
• Neurodevelopment
• Growth
• Lipid metabolism
• Heart function
• Pregnancy
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Repeat testing of 67 term infants with initial TSH >6 & <10mU/L in North of England
Proportion of specialists opting to treat
44.7 17/17
24.3 16/17
21.4 10/178.7 0/17
Korada et al, 2010
Serum TSH (mU/L)
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TSH values at reevaluation aged 3yrs
Neonatal TSH 10-20mU/L
Neonatal TSH >20mU/L
Prem Term Prem Term
Mengreli et al, 2010
• 311,390 infants screened in Greece
• 200 diagnosed CH
• 28% TSH 10-20mU/L
• 85.1% permanent CH on reevaluation
• 20% structural defect
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TSH levels through childhood in transient neonatal hyperthyrotropinaemia
• Group 1 normal TSH aged 2-3yrs
• Group 2 TSH 4-10.1mU/L aged 2-3yrs
• At 8yrs subclinical hypothyroidism persists in 31.8%
• 13/44 hypoplasia of one lobe
Leonardi et al, 2008
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Adverse effect of transient neonatal hyperthyrotropinaemia (1)
• Iranian study• Iodine deficiency common• No difference in TFTs or iodine status aged 9yrs• No difference in growth or psychomotor performance
aged 9yrs• No correlation between neonatal TSH & IQ aged 9yrs
↑ neonatal TSH
(n=18)
Normal TSH
(n=19)
p value
Neonatal TSH (mU/L)
23.4
+/-8.3
3.6
+/-1.0
<0.001
IQ aged 9yrs 98
+/-11
106
+/-8
<0.01
Azizi et al, 2001
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Adverse effect of transient neonatal hyperthyrotropinaemia (2)
• Italian study in area of endemic goitre• No difference in TFTs at assessment aged 7-8yrs• No difference in height or bone age aged 7-8yrs
↑ neonatal TSH
(n=9)
Normal TSH
(n=9)
p value
Global IQ 78.3
+/-11.1
90.9
+/-14.2
<0.05
Verbal IQ 84.4
+/-15.4
96.2
+/-14.8
NS
Performance IQ 75.0
+/-8.5
89.2
+/-12.5
<0.01
Calaciura et al, 1995
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Effect of compensated hyperthyrotropinaemia on metabolic rate
• Basal metabolic rate studies in 10 infants <2months old with normal serum T4
• 6 infants normal BMR (49.6+/-1.9kcal/kg/d)– TSH<6mU/L
• 4 infants low BMR (38.1+/-4.1kcal/kg/d)– TSH>7mU/L– thyroxine therapy normalised TSH & BMR (48.7+/-
1.0kcal/kg/d) within 3 weeks
• Japanese study of 16 infants with hyperthyrotropinaemia showed normal BMR
Alemzadeh et al, 1992 & Miki et al, 1989
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Implications for screening programmes of changing TSH cut-offs
TSH cut-off (mU/L whole
blood)
Newborns recalled
(n)
Recall rate (%)
Infants diagnosed
with CH
30 173 0.05 114
20 376 0.12 144
10 3784 1.20* 200
Mengreli et al, 2010
• 311,390 infants screened in Greece• prospective study, Jan 2000 – Dec 2002• * additional costs = 1.8% of screening budget
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Management of a child with ‘borderline’ TSH values
• clinical evaluation
• venous fT4 & TSH & maternal TSHr Ab
• thyroid ultrasound +/- isotope scan
• thyroxine to normalise fT4 within 24hrs & TSH within 1 week
• trial of discontinuation aged 3yrs if TSH never elevated
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If we don’t treat, can we subsequently diagnose untreated hypothyroidism?
• Neurodevelopmental delay– most will still be within the
normal range
• Growth failure– screening programmes poor
at identifying abnormal growth
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Conclusions
↓ TSH cut-off below 20mU/L• ↑ incidence of congenital hypothyroidism
– mostly gland in situ & hyperthyrotropinaemia– potential risk of adverse neurodevelopment
• may identify iodine deficiency• potential new genetic causes?• therapy may prevent adverse consequencies• until further trials have established benefit,
cut-off should be lowered from 20mU/L