Comparison of initial high versus low dose L-thyroxine

(LT4) for congenital hypothyroidism (CH)

BALÁZS GELLÉN MD PhDDepartment of Paediatrics, University of

Szeged, Hungary

• In Hungary:- Incidency of CH: 1:3000

- Screening program from 1984: Guthrie-test

(+ PKU, galactosaemia, biotinidase def. - MTS)- measurement of TSH must be on the 2nd or 3rd day of life – DRIED BLOOD SPOT

If TSH > 30 μU/ml

the infant must be transported to the regional pediatric

endocrinology and screening center to confirm the

diagnosis and initiate treatment

If TSH = 20-29 μU/ml – test must be repeated

Congenital hypothyreodism (CH)

ETIOLOGY of CH • 85% thyreoid gland dysgenesis organification

def.agenesia, hypoplasia, ectopia

• 10% dyshormongenesis - defects of thyroxine or triiodothyronine synthesis within a structurally normal gland - nongoitrous CHTRH,TSH ,TSHR def.,TSH resistance, iodine trapping and transport def., thyroglobulin def., deiodinase, peroxydase def., G-protein def.

• 2% transcription factor gene mutationTTF1, TTF2, PAX8

• 3% others – maternal radio-iodine therapy during pregnancy etc.

Classic signs: excessive sleeping, reduced interest in nursing, bad appetite, poor

muscle tone, low or hoarse cry, infrequent bowel movements, constipation, exaggerated

jaundice, low body temperature, dry skin, larger

anterior fontanel, persistence of a posterior fontanel, umbilical hernia, large tongue lethargia,

wide nasal sella, oedema, bradycardia and

sometimes- goiter .

Introduction

• The optimal dose of LT4 during infancy is controversial

• Advocates of high doses claim that intellectual outcome is improved

• Others consider that high dose LT4 in infancy may cause behaviour and concentration difficulties in later childhood

Hypothesis

Initial high dose (50 µg/day) of LT4 normalises thyroid function more quickly than low dose (25 µg/day), with no evidence of somatic overgrowth – a surrogate index of overtreatment - between birth and 3 years of age.

Background• From 1979, when the Scottish newborn

screening programme for CH began, thestandard initial dose of LT4 in most centres was 25 µg daily

• From 1997 a high dose LT4 regime has been increasingly used in the West of Scotland: 50 µg daily for the first 10 days followed by 37.5 µg daily thereafter, titrating subsequent doses according to thyroid biochemistry

Patients and Methods 1 A retrospective study of patients

referred between 1979 and 2005 in Scotland.

Patients divided into 3 groups according to initial daily LT4 dose (µg)

• 25 (Group 1)• 30-40 (Group 2)• 50 (Group 3)

Patients and Methods 2

Patients were excluded from the study if:

• they did not conform to one of the three initial LT4 treatment groups

• the diagnosis was either transient elevated TSH or uncertain

• there were less than two useable data points after birth

Patients and Methods 3Differences in thyroid biochemistry (serum fT4 and TSH) between the 3 groups were compared at:

• diagnosis • 7-21 days after the start of treatment

(7-21dT4)• 3, 6, 12, 18, 24 and 36 months of age

Differences in somatic growth - length, weight and head circumference - were examined at 3, 6, 12, 18, 24 and 36 months of age

SD scores were calculated vs. Cole, Freeman & Preece (Stat Med 1998, 17; 407-09)

Results 1N = 274 children with CH

• Group1 (25 µg/day) n=124 • Group2 (30-40 µg/day) n=67 • Group3 (50 µg/day) n=83

0

10

20

30

40

50

60

70

Group 1 Group 2 Group 3

% c

on

trib

uti

on

Unknown Ectopic Absent Hypoplasia DHG Other

Aetiology of CH in the three dosage groups

Median mcg/kg/day LT4 for each dosage group

4

6

8

10

12

7-21dLT4 3m 6m 12m

Time point

mcg

/kg

/day

Group 1

Group 2

Group 3

Comparison of LT4 dose (μg/kg/day) in the 3 groups from 7-21 days after the start of LT4 to 12 months of age

Results 2

No statistical difference for any of the following parameters was found between the 3 groups:

• Biochemistry – capillary TSH, venous TSH and fT4• Auxology – birth weight

Results 3 - comparison of data at diagnosis

TSH values 5 mU/L are highlighted for comparison

Results 4 – median TSH values

TIME OF VISIT

TSH median [IQR] in mU/L (number of patients)

Group1 (25 μg)Group2 (30-40 μg)

Group3 (50 μg)

At diagnosis150 [89.2-324]

(152)108 [65.9-375]

(63)150 [75-196] (99)

7-21 days after the start of LT4 58 [21-100] 29 [11-56] 4.1 [1.3-9.5]

3 months of age 10 [2.7-25.3] 8 [2.8-16] 1.5 [0.6-4.6]

6 months of age 5.2 [1-16.4] 7.8 [0.9-20] 2.7 [0.5-7.6]

12 months of age 3.5 [1.1-8.4] 6.3 [1.2-15.6] 4.3 [1-10.4]

18 months of age 2.5 [0.6-8.9] 2.3 [1.4-13.1] 2.4 [0.5-8.3]

24 months of age 3.3 [1-5.6] 4.7 [1.5-10.2] 1.0 [0.3-6.1]

36 months of age 2.4 [0.4-5.6] 3.3 [1.6-14.3] 4.5 [1.4-7.4]

Free T4 values outside reference range (9.0 – 26.0 pmol/L)

are highlighted

Results 5 – median fT4 values

TIME OF VISIT

Median fT4 [IQR] in pmol/l (number of patients)Group1 (25 μg) Group2 (30-40 μg) Group3 (50 μg)

At diagnosis 5.1[5.0-8.95] (152) 5.4 [5.0-8.8] (63) 5.0 [5.0-9.0] (99)

7-21 days after the start of LT4 20.1 [15.5-23.8] 19.7 [15.7-27.1] 29.1 [22.8-35.5]

3 months of age 21.6 [18.3-26] 23 [18.1-26.2] 23.1 [19.8-28]

6 months of age 20.5 [18.4-24.6] 21.0 [17.0-25.2] 20.1 [16.0-26.3]

12 months of age 19.6 [17.0-23.0] 19.8 [17.1-23.4] 20.4 [16.2-24.0]

18 months of age 21.0 [19.4-24.2] 22.8 [18.6-27.7] 21.6 [18.0-24.2]

24 months of age 21.1 [18.3-24.0] 21.2 [19.0-25.7] 21.0 [17.8-25.7]

36 months of age 21.8 [18.9-24.7] 20.8 [18.0-23.0] 21.2 [17.8-23.6]

median TSH, fT4 values

serum TSH < 10 mU/l after 7-21 days LT4 treatment:

Group 1 (25 µg/day) 17% Group 2 (30-40 µg/day) 19%Group 3 (50 µg/day) 79%

serum fT4 < 9 pmol/l after 7-21 days LT4 treatment:

Group 1 (25 µg/day) 7,4%Group 2 (30-40 µg/day) 5,1%Group 3 (50 µg/day) 0%

No significant differences between height and weight and head circumference were found in the three groups at any time point

Results 6 – comparison of growth data between 3 groups

Table 4

Conclusion

• An initial LT4 of 50µg daily normalises thyroid function several months earlier than lower dose regimes, with no evidence of significant somatic overgrowth between birth and 3 years

• At this critical time for neurodevelopment low dose LT4 should no longer be used in the early treatment of CH

Effect of high versus low initial doses of L-thyroxine for congenital hypothyroidism on thyroid function and somatic growth.Jones JH, Gellén B, Paterson WF, Beaton S, Donaldson MD.Arch Dis Child. 2008 Nov;93(11):940-4.

Treatment guideline:

Dosage: 12-15 μg/kg/day LT4≈ 50μg = 1tbl/day LT4(Letrox, Euthyrox, L-Thyroxin)to maintain the right dose of LT4 based on clinical signs and

regular checked lab results of

serumTSH, freeT4 (and dried blood

spotTSH)

Timepoint of regular checking:

1-3 months of age - monthly3-12 months of age – 2-3 monthly1-2 years of age – 4 monthly2-3 years of age – 6 monthlyFrom 3 years of age - 6-12

monthly

Prognosis

• Most children born with congenital hypothyroidism and correctly treated with thyroxine grow and develop normally in all respects.

• Congenital hypothyroidism is the most common preventable cause of mental retardation.

• Few treatments in the practice of medicine provide as large a benefit for as small an effort.