comparison of initial high versus low dose l-thyroxine (lt4) for congenital hypothyroidism (ch)...
TRANSCRIPT
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]
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.