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

• 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

– prematurity– genetic factors, sex, race & ethnicity– prenatal iodine intake– Autoimmunity

• Changes in lab method & screening paradigms

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

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

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)

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

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

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?

• 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

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)

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

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

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

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

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 (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

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

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

• 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