Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies.

Autoimmune thyroid disease is a generic term that includes Graves' disease and Hashimoto's thyroiditis. In the former, there is overactivity of the thyroid due to the action of a thyroid-stimulating antibody (TSAb). Pathogenesis of Hashimoto's thyroiditis is largely cell-mediated immune destruction of the thyroid. Nonetheless, there may be either a goiter or an atrophic gland. There is evidence that in some patients the lack of goiter is associated with the presence in the blood of an antibody that inhibits the binding of TSH to its receptor. This TSH-binding inhibiting antibody (TBIAb), therefore, prevents TSH from stimulating the thyroid and constitutes an acceptable explanation for an agoitrous state. Collectively, TSAb and TBIAb, both of which are IgG, are known as TSH receptor antibodies (TRAb).     

Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations

Three syndromes affecting the thyroid gland are described in the literature separately: familial nonautoimmune hyperthyroidism, sporadic congenital nonautoimmune hyperthyroidism, and autonomous adenomas. Recent studies have shown that these three syndromes are caused by similar activating mutations of the TSH receptor gene (TSHR), and that the consequences of these mutations on the physiology and gene expression of the thyroid are qualitatively, but not quantitatively, similar. The three syndromes and two suggested unrecognized variants are in fact facets of the same disease, genetic hyperthyroidism due to TSHR mutations, the expression of which depends on the intensity of activation, its timing, and on the number of affected cells.     

Central hypothyroidism due to isolated TRH deficiency in a depressive man

A depressive man was evaluated for developing chronic fatigue and cold intolerance, in whom laboratory findings showed decreased thyroid hormone levels (T4, 2.7 micrograms dl-1; T3, 0.76 ng ml-1) with normal blood levels of TSH. A single bolus injection of TRH (500 micrograms) significantly stimulated prolactin secretion, but did not cause an increase in blood TSH levels (basal level, 1.2 microU ml-1 vs. 1.3 microU ml-1 30 min after injection). By contrast, TRH-induced TSH stimulation occurred after repeated injection of TRH for 4 consecutive days (basal level, 1.5 microU ml-1 vs. 5.6 microU ml-1 30 min after injection). Blood thyroid hormone concentrations were restored to normal levels after long-term administration of TRH. Other pituitary functions remained unchanged. A diagnosis of central hypothyroidism due to isolated TRH deficiency was made in this case, and the data presented here indicate that partial resistance of pituitary thyrotrophs to TRH may be associated with depression.     

Neonatal detection of congenital hypothyroidism of central origin

Due to the high frequency of concurrent pituitary hormone deficiencies, congenital hypothyroidism (CH) of central origin (CH-C) is a life-threatening disorder. Yet only a minority of these patients are detected by neonatal CH screening programs worldwide. We conducted a prospective multicenter study involving a 2-yr cohort of neonatally diagnosed CH-C patients to determine whether a T(4)-TSH-based neonatal CH screening protocol extended with T(4) binding globulin determinations improves early detection of CH-C and to assess the extent of pituitary hormone deficiency among the identified CH-C patients. In all infants with screening results indicative of CH-C, the functional integrity of the hypothalamo-hypophyseal system was investigated by dynamic tests; the anatomical integrity was investigated by magnetic resonance imaging. Initial test results were evaluated after 5 yr of follow-up. Among 385,000 infants screened over the 2-yr period, 19 cases of permanent CH-C were detected (prevalence, 1:20,263; 95% confidence interval, 1:12,976 to 1:33,654), representing 13.5% of all detected cases of permanent CH. The majority (78%) had multiple pituitary hormone deficiency, whereas 53% had pituitary malformations on magnetic resonance imaging. We conclude that infants with CH-C can very well be detected by neonatal screening. The estimated prevalence and the severity of pituitary dysfunction of this treatable disorder call for explicit attention for this entity of CH in neonatal screening programs worldwide.     

Subclinical thyroid disease: subclinical hypothyroidism and hyperthyroidism

Subclinical hypothyroidism (SHT) and subclinical hyperthyroidism (SCH) are defined as normal serum free T4 and T3 levels associated with elevated (SHT) or subnormal (SCH) serum TSH levels, respectively. Symptoms and signs of thyroid dysfunction are scarce. The prevalence is low. In SHT, total cholesterol and LDL-C are modestly elevated and levothyroxine may influence the lipids levels. There is decreased cardiac contractility and increased peripheral vascular resistance that improve with treatment. SCH is associated with atrial fibrillation, increased cardiac contractility and left ventricular mass, diastolic and systolic dysfunction that can be reversed with beta-adrenergic antagonists. Bone density is reduced in SCH. Depression, panic disorders and alterations in cognitive testing are frequent in SHT. Treatment of SHT is recommended for serum TSH levels greater than 8 mU/L and presence of thyroid antibodies. Endogenous SCH should be treated for serum TSH levels less than 0.1 mU/L, in the presence of symptoms and in elderly patents.     

Sex-specific impact of congenital hypothyroidism due to thyroid dysgenesis on skeletal maturation in term newborns

Newborns with severe congenital hypothyroidism (often defined by the absence of knee epiphyses at diagnosis) are still at risk of loss of intellectual potential despite early treatment. Although there is no significant sexual dimorphism in the age at appearance and size of the knee epiphyses in normal newborns, it was our clinical impression that these epiphyses were more often absent in hypothyroid newborn males than in affected females. Using the large French database of congenital hypothyroidism, we studied the presence or absence of knee epiphyses at diagnosis, as well as the length of gestation and the birth weight of 1827 term newborns with athyreosis or ectopic thyroid. Boys were twice as likely as girls to have absent epiphyses [odds ratio, 2.1 (95% confidence interval, 1.6-2.7), P < 0.001, after adjustment for etiology, plasma free T(4) concentration, and presence or absence of clinical signs at diagnosis, gestational age and birth weight]. Compared with the general population of French newborns, those with congenital hypothyroidism were more often born after a prolonged gestation (> or =42 wk) and with a high birth weight (9% were above the 95th centile, as opposed to the expected 5%), regardless of sex. We conclude that the impact of congenital hypothyroidism on fetal skeletal maturation is sexually dimorphic. This may result from less efficient conversion of T(4) to T(3) by growth plate chondrocytes in males.     

Children with congenital hypothyroidism are at risk of adult obesity due to early adiposity rebound

OBJECTIVE: There is some evidence that children with congenital hypothyroidism (CH) are heavier than their reference population. There are few data on adults with CH. The timing of adiposity rebound (AR) in childhood has been shown to have strong correlations with adult obesity. Our aims were to study the timing of AR and factors affecting AR in children with CH. PATIENTS AND METHODS: The timing of AR was examined in a retrospective study of children with CH with growth data at least up to 5 years of age. The proportion of children with CH who reached AR by 37 months and by 49 months of age were compared with healthy children and children with acute lymphoblastic leukaemia (ALL) described in the literature. Correlation of timing of AR with body mass index (BMI) standard deviation score (SDS) at 10 years, initial severity of hypothyroidism and age at normalization of TSH were examined. Multiple logistic regression was used to identify independent factors associated with BMI > or = 20 (overweight) at 10 years of age. RESULTS: The study included 53 children (34 females and 19 males). AR had occurred by 37 months in 37.7% children with CH, in 42.7% children treated for ALL (CH vs. ALL, P = 0.58) and in 4.5% healthy British children (CH vs. normal, P < 0.0001). We found that 54.7% children with CH had reached AR compared with 21.4% of normal children (CH vs. normal, P < 0.0001) by the age of 49 months. Timing of AR showed significant negative correlation with BMI SDS at 10 years (r = -0.487, P = 0.01). There were no significant relationships between timing of AR and initial thyroid function or age at normalization of TSH. Multiple logistic regression analysis identified age at AR as an independent factor associated with BMI > or = 20 at 10 years of age (P = 0.04). CONCLUSIONS: Children with CH showed significantly earlier AR compared to normal British children. This showed significant negative correlation with BMI SDS at 10 years. AR in CH does not appear to be directly related to the initial severity of hypothyroidism or to treatment factors.     

Hyponatremia due to hypothyroidism: a pure renal mechanism

Hyponatremia is a common disorder. When hyponatremia is the result of hypothyroidism it can be successfully treated with thyroid hormone substitution. We followed cumulative sodium- and fluid balances of a patient with hyponatremia, resulting from hypothyroidism. We concluded that hyponatremia in hypothyroidism is due to a pure renal mechanism, and cannot be ascribed to inappropriate secretion of antidiuretic hormone.     

Comparative response to parathyroid hormone in hyperthyroidism and hypothyroidism.

The effects of exogenous parathyroid hormone, administered for 3 days, were compared in six hyperthyroid and six hypothyroid subjects. Maximum increments were much greater in hyperthyroid than in hypothyroid subjects for serum calcium (3.5 mg/100 ml versus 1.6 mg/100 ml), urine calcium (476 mg versus 79 mg), urine hydroxyproline (56 mg versus 11 mg), and urine phosphorus (671 mg versus 192 mg). Maximum decrease in serum phosphorus (minus0.9 mg/100 ml versus minus 0.1 mg/100 ml) was also greater in hyperthyroid subjects. Serum parathyroid hormone immunoreactivity was significantly higher in hypothyroid subjects (0.48 ng/ml) that either normals (0.21 ng/ml) or hyperthyroid subjects (0.19 ng/ml). The data support the concept that excess thyroid hormone sensitizes and deficient thyroid hormone blunts the responsiveness of bone to parathyroid hormone. This may lead to a state of hypoparathyroidism in hyperthyroidism and hyperparathyroidism in hypothyroidism.     

Development of hyperthyroidism following primary hypothyroidism: a case report

Development of hyperthyroidism following primary hypothyroidism is uncommon, and only a few documented cases have been reported. Alterations in thyroid-stimulating hormone receptor antibodies in serum are currently considered to play the main role in the pathophysiology, but the exact mechanism is still unknown. Here, we report the case of a 60-year-old man with disturbed consciousness due to hyponatremia. Thyroid function tests showed primary hypothyroidism with a high anti-microsomal antibody titer (1:6,400). The patient experienced weight loss and exophthalmos 6 years later. Serum thyroid hormone levels were increased and thyroxine treatment was discontinued, but the patient remained thyrotoxic 2 months later. 131I thyroid uptake was 40.9% at 24 hours, and bilateral thyroid lobes were not enlarged with diffuse radioactivity. Six months later, the patient was still thyrotoxic and therapy with methimazole 10 mg/day was started. He is now taking methimazole and is euthyroid.     

Frequent failed early HIV detection in a high prevalence area: implications for prevention

To identify the frequency of and factors associated with early detection of HIV infection in Los Angeles County, data were evaluated from interviews of a population-based sample of adult persons with AIDS. Early detection was defined as greater than 5 years between the first reported positive HIV test and an AIDS diagnosis. The associations between early detection and sociodemographic and behavioral factors were assessed for the period January 1997 through June 2002. Over the study period, only 20% (253/1268) of persons interviewed met the criterion for early detection. Early HIV detection was less likely for women (adjusted odds ratio [AOR] = 0.6, 95% confidence interval [CI]: 0.4, 0.9), blacks (AOR = 0.5, 95% CI: 0.4, 0.8), foreign-born Latinos (AOR = 0.2, 95% CI: 0.1, 0.3), U.S.-born Latinos (AOR = 0.3, 95% CI: 0.2, 0.6, and heterosexuals (AOR = 0.5, 95% CI: 0.3, 0.7). Trends of increasing early detection with older age groups (p < 0.001) and higher educational levels (p < 0.001) were also observed. Our findings indicate an overall low level of early HIV detection and suggest that major sociodemographic and risk group disparities exist in the likelihood of early detection among HIV-infected persons in Los Angeles. These differences have important implications for reducing the level of community HIV transmission and for improving individual health outcomes among people with HIV. Aggressive efforts are needed to expand HIV testing and early detection for women, minorities, heterosexuals, younger age groups, and persons of lower education. Links to treatment and behavioral intervention programs should accompany such expanded testing efforts.     

Relationship of etiology to treatment in congenital hypothyroidism

We examined the patterns of TSH, T(4), and treatment schedules from diagnosis to 4 yr of age in 125 children (50 males anf 75 females) with congenital hypothyroidism (CH). Subjects were divided into 3 groups based on their thyroid scans: 1) athyreosis (n = 31), 2) dysgenesis (n = 54; 49 lingual and 5 hypoplastic), and 3) dyshormonogenesis (n = 40). Follow-up evaluation was carried out at 2-4 wk and 3, 6, 9, 12, 24, 36, and 48 months of age. Median gestational age, age at onset of therapy, and starting L-T(4) dose were similar in the three groups. In infants with athyreosis median screening TSH levels were higher (P < 0.02) and confirmatory T(4) levels were lower than in the other two groups (P < 0.01 vs. dysgenetic; P < 0.05 vs. dyshormonogenetic CH). During the first 6 months of therapy, mean TSH levels were highest in the athyrotic group, intermediate in the dysgenetic group, and lowest in the dyshormonogenetic group. In children with athyreosis, TSH levels normalized by 12 months of age. At 12 months dysgenetic patients had the highest TSH levels (P < 0.05). During the entire study period, TSH levels were lowest in patients with dyshormonogenesis (except at 48 months) and normalized earlier. Mean T(4) levels normalized by 2-4 weeks in all groups. At 3 and 6 months, the percentage of patients who required dose changes was highest in the athyrotic group, and at 12 months it was highest in the dysgenetic group. The athyrotic group received the highest dose of L-T(4), and dyshormonogenetic group received the lowest dose. We conclude that treatment and follow-up schedules for CH may differ in the three etiological categories based on the different hormonal patterns and responses to therapy. Children with athyreosis need close monitoring particularly early in life, whereas those with dysgenesis and dyshormonogenesis require more attention later in life.     

Structural analysis of the thyrotropin receptor in four patients with congenital hypothyroidism due to thyroid hypoplasia.

Sporadic congenital hypothyroidism is most commonly caused by developmental abnormalities of the thyroid gland. More rarely, it is due to defects in gene products involved in the regulation of the hypothalamic-pituitary-thyroid axis or thyroid hormone synthesis. Loss of function mutations in the thyrotropin (TSH) receptor have been shown to result in resistance to biologically active TSH. In complete resistance to TSH, the thyroid gland is hypoplastic and unable to synthesize and secrete sufficient amounts of thyroid hormones. In partial resistance, referred to as euthyroid hyperthyrotropinemia, the size of the gland and the thyroid hormone levels are normal at the expense of an elevated TSH. Four patients with sporadic congenital hypothyroidism and properly located hypoplastic thyroid glands were included in this study. Serum TSH concentrations were 150 mU/L or higher, serum thyroglobulin levels were within normal limits (6.1 to 8.2 ng/mL; normal range: 2.1 to 32 ng/mL), and thyroid autoantibodies were absent. The coding region of the TSHbeta subunit gene, the TSH receptor gene, and exons 8 and 9 of Gsalpha were analyzed by direct sequencing and found to be normal in all patients. One patient was heterozygous for a G to A transition in the TSHbeta gene resulting in a substitution of alanine by threonine at position -7 of the signal peptide. This substitution was also found in her euthyroid father. In addition, Southern analysis of the TSH receptor gene excluded major structural alterations. These findings support previous reports that indicate that TSH resistance is genetically heterogeneous. In addition to mutations in the TSH receptor or the Gsalpha genes, other genetic defects can lead to an identical phenotype. These observations also suggest that TSH receptor mutations might be a relatively rare cause of congenital thyroid hypoplasia.     

A novel therapeutic paradigm to treat congenital hypothyroidism

Objective To determine the effectiveness of a novel therapeutic paradigm to treat congenital hypothyroidism (CH) incorporating variable initial doses of L‐T4 based on the underlying aetiology and frequent monitoring, up to 2 years of age. Design Retrospective cohort study. Patients Infants with primary CH diagnosed by newborn screening. Measurements Treatment with L‐T4 suspension initiated at 10, 12 and 15 µg/kg/day for dyshormonogenesis, ectopia and athyreosis, respectively. Serum TSH and free T4 (FT4) levels monitored weekly during the first 4 weeks, at 6 weeks, thereafter monthly during the first 2 years. Dose changes were made to keep FT4 level in upper half of the normal range. Results Sixty‐nine infants; 17 had dyshormonogenesis, 35 ectopia and 17 athyreosis. Seventy‐eight percent of subjects normalized FT4 levels within 7 days of treatment and 100% within 14 days. TSH levels normalized in 26% of infants within 7 days and in 92% by 21 days. Supraphysiological levels of FT4 were noted in 28% of infants, for a maximum of 2 weeks. 48% infants needed one dose adjustment and 30% needed at least two in the first month. In 52 infants over the first 2 years, mean FT4 levels were consistently in the upper half of the normal range. Two or more dose adjustments every 3 months were made 57 times in the first year as compared to 19 times in the second year. Conclusions A variable initial dose paradigm based on aetiology with frequent testing and using T4 suspension rapidly normalizes FT4 levels without producing persistent hyperthyroxinaemia.     

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