Initial Dose Of Levothyroxine Research Articles

Should the levothyroxine starting dose be tailored to disease severity in neonates with congenital hypothyroidism?

Early levothyroxine treatment is crucial to minimize neurocognitive impairment associated with congenital hypothyroidism. In this Practice Point commentary, I discuss the findings, implications, and limitations of the study of Mathai et al. in which neonates with congenital hypothyroidism were treated with variable initial doses of levothyroxine. A high initial levothyroxine dose was used for newborn babies with athyreosis, an intermediate dose for those with ectopic glands, and a low dose for those with dyshormonogenesis. Serum free T(4) levels normalized within 2 weeks, but serum TSH levels within up to 4 weeks. A dose adjustment (mostly a dose reduction) was required in about half of the neonates in the first 2 weeks of life. As Mathai et al. carried out no neuropsychological tests, we do not know if their approach has a more beneficial effect on neurocognitive outcomes than other treatment strategies. Nevertheless, as tailoring the levothyroxine dose to severity rapidly normalized serum free T(4) levels, one would predict a beneficial effect of this approach on neurocognitive outcome.

Biochemical severity of thyroid ectopia in congenital hypothyroidism demonstrates sexual dimorphism

A recent study suggested that sexual dimorphism affects initial thyroid function in congenital hypothyroidism (CH) but differs according to aetiology of CH. To determine if sexual dimorphism was associated with biochemical severity of CH and its aetiology in our large British population. We examined retrospectively the initial thyroid function tests of 140 infants diagnosed with CH from screening. All infants underwent Tc-pertechnetate radionuclide scans at diagnosis to establish the aetiology of CH prior to commencement of treatment. Patients were classified into athyreosis, ectopia and presumed dyshormonogenesis on the basis of thyroid scans. A comparison of males and females were made within the three aetiological groups for gestational age, birth weight, initial dose of levothyroxine (LT4), screening TSH, confirmatory plasma thyroxine (T4), confirmatory plasma TSH and age of TSH suppression. There was no significant difference between sexes for gestation, birth weight and initial treatment dose in all aetiological subgroups. In thyroid ectopia, screening TSH and confirmatory plasma TSH were significantly higher in females compared with males (P < 0.01), while confirmatory plasma T4 were significantly lower in females (P < 0.05). No difference was detected between males and females in athyreosis and dyshormonogenesis subgroups for screening TSH, confirmatory plasma TSH and total T4. Sexual dimorphism influenced the biochemical severity of thyroid ectopia in congenital hypothyroidism in our British population. However, this effect was not apparent in patients with athyreosis or dyshormonogenesis. Further advances in the molecular genetics of CH are essential to evaluate this phenomenon further.

Effects of Early High-Dose Levothyroxine Treatment on Auditory Brain Event-Related Potentials at School Entry in Children with Congenital Hypothyroidism

Aims: We tested whether brain event-related potentials (ERPs) are normal in children with congenital hypothyroidism (CH) after early high-dose levothyroxine treatment. Methods: Auditory ERPs were recorded in 33 normal controls and in 15 children with CH at 5 years 9/12. Based on bone maturation at diagnosis, the CH group was divided into severe (n = 8) and moderate (n = 7) subgroups. CH patients were treated at a median age of 14 days with a mean initial dose of levothyroxine of 11.6 µg/kg·day. Two ERP components (N100 and N200) were measured and clinical follow-up variables collected. Results: The functional anatomical and cognitive organisation of the auditory system, as revealed by the analyses of ERP measures, did not differ between CH and controls, or between severe and moderate CH subjects. However, N200 latency was globally longer in the CH than in the control group (p = 0.01) and was positively correlated with the over-treatment index (r = 0.61; p < 0.05) and verbal IQ. N200 amplitude was negatively correlated with initial dose (r = –0.74; p < 0.005). Conclusion: These data suggest that sensitive tools such as ERPs can reveal differences between CH and controls and relate these differences to the adequacy of treatment of CH.

Low initial dose of levothyroxine for treatment of congenital hypothyroidism

To evaluate the results of treatment of infants with congenital hypothyroidism (CH) with a low initial dosage of levothyroxine. 138 newborns with primary CH detected by neonatal screening were divided into 3 groups according to levels of serum TSH, TT(3) and TT(4): sub-clinical CH (TSH >50 mU/L), mild CH (TT(4) <54 nmol/L), severe CH (TT(4)<54 nmol/L and TT(3)<1.2 nmol/L). The initial dose of levothyroxine was (3.5 +/-1.0) microg/(kg.d) for sub-clinical CH group, (4.3 +/-0.7)microg/(kg.d) for mild CH group and (4.7 +/- 0.6)microg/(kg.d) for severe CH group. Follow-up evaluation was carried out at 1, 2 and 3 months of age by measuring serum levels of TT(3), TT(4) and TSH. The time, when clinical signs and symptoms were eliminated and serum levels of TT(3), TT(4) and TSH normalized, was recorded. Development Quotient (DQ) testing was performed when CH cases were about 2 years old. The mean initial dose of levothyroxine in 138 cases was (4.3 +/-0.9)microg/(kg.d). In one month the serum TT(3) and TT(4) levels returned to normal, while for TSH levels 67.4 % cases reached normal range in 2 months and 84.1 % in 3 months. Two months after therapy, the levels of TT(3) and TT(4) reached to the upper half of normal range and there were no signs or symptoms of hypothyroidism. The time for all cases in 3 groups to reach the normal clinical and biochemical indicators was similar (P=0.925). The dosage for cases with low circulating thyroxine before treatment was higher than that of the other groups (P<0.01). The average DQ score of 18 cases after treatment was 116.7 +/- 17.0. he levothyroxine dosage of (4.3 +/- 0.9)microg/(kg.d) is appropriate for the initial treatment of the majority of infants with CH. However it is better to individualize the dosage for each case.

The importance of early management in optimizing IQ in infants with congenital hypothyroidism

The importance of early management in optimizing IQ in infants with congenital hypothyroidism

Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism

Objectives: To test whether early treatment with a high initial dose of levothyroxine can prevent suboptimal mental development in all neonates with congenital hypothyroidism (CH). Study design: Sixty-one patients, 27 with severe CH and 34 with mild CH, were treated either early (<13 days) or late (≥13 days) with either a high initial dose of levothyroxine (≥9.5 μg/kg/d) or a low initial dose (<9.5 μg/kg/d). With these criteria, 4 treatment groups were formed. The results of the Bayley test, performed at the age of 10 to 30 months and expressed as mental developmental index (MDI) and psychomotor developmental index (PDI), were related to socioeconomic status, treatment group, initial free thyroxine (FT4) concentration, and mean FT4 concentration during the first 3 months of treatment (FT4-A) and the ensuing 9 months (FT4-B). Results: Mean (± SD) MDI was 113 ± 14, and mean PDI was 114 ± 12. In the severe CH group, only the patients treated early with a high initial dose had normal MDI scores (124 ± 16), whereas the scores of the other groups ranged from 97 to 103. In contrast, all patients in the mild CH group had normal scores (range, 122-125), except those in the group treated late with a low initial dose, whose score was 110 ± 10. Forty-three percent of the variance in MDI and PDI scores was explained by treatment factors, such as the treatment group, initial FT4 concentration, FT4-A, and FT4-B. Conclusions: Our data suggest that optimal treatment includes achievement of euthyroidism before the third week of life by initiation of therapy before 13 days with a levothyroxine dose above 9.5 μg/kg/d and maintenance of FT4 concentrations in the upper normal range during the first year. Thus treated, patients with CH can achieve normal psychomotor development at 10 to 30 months, irrespective of the severity of the disease. (J Pediatr 2000;136:292-7)

Neonatal hypothyroidism: treatment and outcome.

Systematic neonatal screening for congenital hypothyroidism (CH), which was progressively implemented in industrialized countries over the past 15 to 25 years, has been extremely successful in eradicating severe mental deficiency resulting from CH. However, in the first generation of children diagnosed by screening, the concept that CH has a threshold effect on intelligence was confirmed. In spite of earlier diagnosis through screening, children with severe CH (i.e., those with a marked retardation of bone age and/or a low circulating thyroxine [T4] before treatment) still had clinically significant intellectual sequelae, amounting to a loss of 6 to 19 IQ points. Recent studies suggest that this developmental gap may be closed by treating more rapidly after birth (2 weeks instead of 4-5 weeks in the early years of the screening era) and by using a higher initial dose of levothyroxine (10-15 instead of 5-8 microg/kg per day). This regimen induces transient hyperthyroxinemia, but no clinical signs or symptoms of hyperthyroidism. Longer term follow-up of larger numbers of patients remains necessary to confirm the normalization of intellectual development and the absence of untowards effects of the treatment regimen in children with severe CH.

Frequency and necessity of thyroid function tests in neonates and infants with congenital hypothyroidism.

The American Academy of Pediatrics recommends frequent thyroid function tests in infants and children with congenital hypothyroidism (CH). Data supporting the recommended frequency are lacking. This review was conducted to assess the validity of these recommendations. The thyroxine (T4) and thyroid-stimulating hormone (TSH) levels of 50 neonates diagnosed between 1988 to 1993 were reviewed to assess the length of time on a specific dose of levothyroxine. 1) Changes in the dose of levothyroxine occurred 35 times during the first year of life for the 39 children treated with .025 mg/day, five times during the first year of life for the 9 children treated with .0375 mg/day, and three times during the first year of life for the 2 children treated with .050 mg/day. 2) These dose changes occurred at varying time intervals. 3) The T4 and TSH levels obtained at visits requiring dose changes were statistically different from the T4 and TSH levels obtained at the previous two visits. The T4 and TSH levels at the two visits before the change in dosage did not differ statistically. 1) An initial levothyroxine dose of .0375 mg/day requires fewer dose changes than a dose of .025 mg/day. 2) A lack of statistical change in T4 or TSH levels obtained at visits before the change-in-dose visit and the variable time span between dose changes necessitate frequent monitoring regardless of the dose of levothyroxine, the previous T4 or TSH levels, or the length of time at a specific dose. 3) These data support the recommendations of the American Academy of Pediatrics regarding the frequency of thyroid function studies during the first 2 years of life.

Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment.

We have previously reported that despite neonatal screening, children with severe congenital hypothyroidism treated at 5 weeks of age with 6 micrograms/kg.day levothyroxine have clinically significant intellectual impairment, whereas those with the moderate form of the disease are indistinguishable from controls. The developmental outcome of children with severe congenital hypothyroidism treated earlier with higher initial doses of levothyroxine remained to be determined. In the present study, 45 infants with permanent congenital hypothyroidism detected by neonatal screening are described. For the group, the median age at starting treatment was 14 days, and the median initial dose of levothyroxine was 11.6 micrograms/kg.day. Based on the area of their knee epiphyses at diagnosis, the patients were divided into 2 subgroups: severe (< 0.05 cm2; n = 10) and moderate (> or = 0.05 cm2; n = 35). The psychomotor development of 8 patients in each subgroup, matched for the socioeducational level of their families, was assessed at 18 months. Mean plasma free T4 levels were supraphysiological during the first few months of life, but mean plasma T3 levels remained within the normal range, and there were no signs or symptoms of hyperthyroidism. The mean plasma TSH concentration was less than 4.5 mIU/L 4 weeks after starting treatment. Bone maturation remained delayed at 12 months in the severe cases and was not unduly advanced in the moderate cases. The mean (+/- SD) developmental quotients at 18 months were similar in severe and moderate cases (107 +/- 10 and 110 +/- 5, respectively). We conclude that with earlier treatment and a higher initial dose of levothyroxine, the early developmental outcome of infants with severe congenital hypothyroidism is now indistinguishable from that of infants with the moderate form of the disease who were used as controls.

Optimal Daily Levothyroxine Dose in Primary Hypothyroidism

Several studies have described the mean optimal replacement daily dose of levothyroxine sodium in subjects with primary hypothyroidism. Furthermore, a cautious approach in replacement therapy of the elderly population is well established. However, the initial dose of levothyroxine has remained variable, especially in young subjects, since the guidelines for the prediction of the final replacement dose are scarce. This study assessed the efficacy of pretreatment thyroid hormone indexes in determination of the final maintenance levothyroxine dose in 156 subjects with primary hypothyroidism. The optimal daily levothyroxine dose as defined by normalization of serum thyroxine and basal thyroid-stimulating hormone levels, as well as thyroid-stimulating hormone response to the intravenous administration of thyrotropin-releasing hormone, varied between 50 micrograms and 200 micrograms and, hence, the subjects were grouped according to the final levothyroxine dose. Significant correlations were noted between the levothyroxine dose for individual groups and pretreatment serum triiodothyronine, thyroxine, and thyroid-stimulating hormone concentrations. However, the serum thyroid-stimulating hormone concentration demonstrated a markedly closer relationship with the levothyroxine dose than did either triiodothyronine or thyroxine for both comparisons. Furthermore, when assessed for all subjects, the correlation between levothyroxine dose and thyroid-stimulating hormone level, alone, remained significant. This study demonstrates that obtaining routine thyroid hormone indexes prior to initiation of replacement levothyroxine therapy may be reliable predictors of the final levothyroxine dose; serum thyroid-stimulating hormone concentration being the best index. Thus, the levothyroxine dose may be reliably predicted depending on a specific range of thyroid-stimulating hormone levels. Therefore, in an individual subject, aiming for the predicted dose rather than the mean dose, a procedure described in the medical literature, may be more helpful in arriving at an optimal levothyroxine dose.