Transcript The interface between paediatric endocrinology and

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.
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Challenges in screening
Changing incidence
Consequences of ‘gland in situ’
Biochemical consequencies of TSH <20mU/L
Pros & cons of changing the ‘cut-off’
Conclusions
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?
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
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prematurity
genetic factors, sex, race & ethnicity
prenatal iodine intake
Autoimmunity
• Changes in lab method & screening paradigms
Is the incidence of congenital
hypothyroidism really increasing?
TSH cut-off decreased
from 15 to 5mU/L
1. All cases in Quebec
2. Thyroid dysgenesis
4. Normal gland in situ
5. Unknown
3. Goitre
Deladoey et al, 2011
Comparison of yearly incidences of
congenital hypothyroidism
a = 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
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
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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)
Reaudit of newborn screening in Wales
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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
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
100
90
80
70
60
% fT4<9
% 50
% fT4 9-14.9
% fT4 >=15
40
30
20
10
0
>100
75-100
50-74.9
40-49.9
30-39.9
20-29.9
<20
Screening TSH
Courtesy of Malcolm Donaldson
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
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
Why treat ‘subclinical’ neonatal
congenital hypothyroidism?
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Evidence limited
Persistent or worsening biochemistry
Neurodevelopment
Growth
Lipid metabolism
Heart function
Pregnancy
Repeat testing of 67 term infants with initial
TSH >6 & <10mU/L in North of England
Serum TSH
(mU/L)
44.7
17/17
24.3
16/17
21.4
8.7
10/17
0/17
Proportion of
specialists
opting to
treat
Korada et al, 2010
TSH values at reevaluation aged 3yrs
Neonatal TSH
10-20mU/L
Neonatal TSH
>20mU/L
• 311,390 infants
screened in Greece
• 200 diagnosed CH
• 28% TSH 1020mU/L
• 85.1% permanent
CH on reevaluation
• 20% structural
defect
Prem
Term
Prem
Term
Mengreli et al, 2010
TSH levels through childhood in transient
neonatal hyperthyrotropinaemia
• Group 1 normal
TSH aged 23yrs
• Group 2 TSH 410.1mU/L aged
2-3yrs
• At 8yrs
subclinical
hypothyroidism
persists in
31.8%
• 13/44
hypoplasia of
one lobe
Leonardi et al, 2008
Adverse effect of transient neonatal
hyperthyrotropinaemia (1)
↑ neonatal TSH Normal TSH
(n=18)
(n=19)
Neonatal TSH
(mU/L)
IQ aged 9yrs
23.4
+/-8.3
98
+/-11
3.6
+/-1.0
106
+/-8
p value
<0.001
<0.01
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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
Azizi et al, 2001
Adverse effect of transient neonatal
hyperthyrotropinaemia (2)
Global IQ
Verbal IQ
Performance IQ
↑ neonatal TSH Normal TSH
(n=9)
(n=9)
78.3
90.9
+/-11.1
+/-14.2
84.4
+/-15.4
75.0
+/-8.5
96.2
+/-14.8
89.2
+/-12.5
p value
<0.05
NS
<0.01
• 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
Calaciura et al, 1995
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
Implications for screening programmes
of changing TSH cut-offs
TSH cut-off Newborns Recall rate
(mU/L whole recalled
(%)
blood)
(n)
30
173
0.05
20
376
0.12
10
3784
1.20*
• 311,390 infants screened in Greece
• prospective study, Jan 2000 – Dec 2002
• * additional costs = 1.8% of screening budget
Infants
diagnosed
with CH
114
144
200
Mengreli et al, 2010
Management of a child with
‘borderline’ TSH values
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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
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
Conclusions
↓ TSH cut-off below 20mU/L
• ↑ incidence of congenital hypothyroidism
– mostly gland in situ & hyperthyrotropinaemia
– potential risk of adverse neurodevelopment
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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