| Schütz et al., Berlin, Germany, report further on a new syndrome of congenital hypothyroidism, pulmonary defects, choreoathetotic movement disorder and mental retardation due to haploinsufficiency of the NKX2-1 gene. This gene, originally named thyroid transcription factor 1 (TTF-1), plays an essential role in the development of different organs including the thyroid. They now describe two patients, one with a heterozygous GG insertion at nucleotide position 2595 in exon 3 of this gene and another patient with a heterozygous C->T transition at position 2517. (Comment: Still more causes of congenital hypothyroidism are being characterized since cloning of essential genes, playing a role in either thyroid development or function, are being performed. Newly identified causes are inactivating mutations in the genes of TSH, the TSH receptor, TPO, thyroglobulin, NIS, Pendrin, Pax-8 and the here reported one). Olivieri et al., Rome, Italy, investigated the risk of congenital hypothyroidism (CH) in twin (multiple) pregnancies versus single pregnancies in Italy between 1987 and 2000. The incidence of overall CH was 1:3130 live births. The prevalence of twin (multiple) pregnancies among CH twins was 3% being about 3-fold higher than the frequency of twin (multiple) pregnancies in the normal population. The proportion of affected pairs concordant for CH was 7.1% (pairwise concordance rate) while the probability of having an affected twin, given that his/her co-twin is affected, was 15.7% (probandwise concordance rate). They also found a higher prevalence of eutopic gland in twin- versus singletons CH (51% vs 26%), while, after re-evaluation at 2-3 years of age, the prevalence of twins with permanent CH was 1.7% and with transient CH was 10.5%. The authors concluded that twin pregnancies result in a higher risk of CH and that transient hypothyroidism was more prevalent in twins than in singletons. (Comment: It would be interesting to know what factors would be responsible for the transient hypothyroidism in twins, such as circulating thyroid antibodies and if mothers of twins had a higher prevalence of these antibodies than mothers of single pregnancies). Persani et al., Milan, Italy, analyzed TSH receptor gene mutations in 10 young (one month - 25 years) unrelated patients with non-autoimmune subclinical hypothyroidism i.e. slight (6,6-14,9 mU/l; n = 7) to moderate (24-46 mU/l; n = 3) elevation of TSH associated with normal free T4 and free T3 serum levels. They found in 4/10 familial settings germline loss-of-function mutations of the TSH receptor gene. The authors conclude that this type of subclinical hypothyroidism is probably less rare than thought so far. Perri et al., Pisa, Italy, sequenced genomic DNA for mutations in the TSH receptor gene and the Gsa gene in 8 patients with subclinical hypothyroidism without the presence of autoimmunity. In 6 sporadic cases no genetic alterations were found in both genes. However, in 2 patients being mother and son, a mutation was found in the TSH receptor gene for which the mother was homozygous and the son heterozygous. (Comment: so far it is understood that subclinical hypothyroidism is a condition secondary to thyroid disease, mostly based on thyroid autoimmunity. However these previous 2 reports show that other causes may be operative as well. It would be important to know if in these cases there is indeed subclinical- or mild hypothyroidism present, like in the cases secondary to thyroid disease, or that full compensation of thyroid function is reached. If the latter is not the case, T4 treatment is maybe an option as well in these patients). Dedecjus et al., Lódz, Poland, and Dijon, France, measured cholesteryl ester transfer protein (CETP) concentrations in patients during hypothyroidism and after replacement therapy and compared levels with controls. CETP is considered to be a key protein in reverse cholesterol transport, a protective system against atherosclerosis and its deficiency leads to an increased risk for coronary sclerosis. The authors found low levels of CETP during hypothyroidism that normalized after T4 replacement therapy. Furthermore CETP mass and activity levels correlated positively with free concentrations of serum T3 and T4 and negatively with serum TSH. Dagre et al., Athens, Greece, who previously showed that flow mediated vasodilatation of the brachial artery is impaired in hypothyroidism, evaluated the duration and degree of reactive hyperemia in patients with hypothyroidism of different severity: 29 patients had low-normal TSH 0,3-2,0 mµ/ml, group 0; 26 had TSH 2,1-4, 0, group 1; 19 had TSH 4,1-10, 0 and normal T4 levels, group 2; and 24 patients with overt hypothyroidism TSH >10 mU/ml, group 3. Baseline forearm blood flow (FBF) was similar in all groups. However, the duration of reactive hyperemia (after release of an occluding cuff) was shorter in groups 2 and 3 as compared to the other two groups. Thus, not only in overt hypothyroidism but also in subclinical hypothyroidism endothelial function is impaired in the microvasculature. Caraccio et al., Pisa, Italy, measured the lipoprotein profile in stable subclinical hypothyroidism in 53 patients (6 men) before and after treatment with T4 or placebo. At baseline, triglycerides, LDL cholesterol, Apo B and LP(a) were significantly higher than in controls and were significantly positively related to serum TSH. After 6 months of treatment, T4 patients showed a decrease in triglycerides and LDL cholesterol without a change in Apo B and LP. No changes occurred during placebo treatment. The findings of this study are that subclinical hypothyrodism results in an atherogenic lipoprotein profile that is reversible by T4 treatment. It appeared furthermore that the LP(a) levels that were elevated, were significantly correlated with a familiar disposition for diabetes mellitus and/or coronary heart disease. (Comment: more and more investigations show that even in subclinical hypothyroidism secondary to thyroid disease (see above), different parameters point to an increased risk of developing atherosclerosis. However, the clinical relevance of these associations has not been shown so far. Despite this, my personal opinion is that replacement therapy with T4 is certainly an option in such patients, for instance when there are other risk factors present for cardio-vascular disease or when patients have complaints compatible with hypothyroidism, but should be decided on an individual basis). Calvo et al., Madrid, Spain, London, UK, and Brussels, Belgium, measured thyroid function parameters in coelomic- and amniotic fluids (CF and AF) and fetal serum (FS) from 27 normal women/fetuses undergoing termination of pregnancy. CF between 5.8 and 17 wks. of gestational age, FS from 12 to 17 wks., AF from 5.8 to 17 wks. Maternal serum was also obtained. Overall results were that a decrease in maternal T4, even within the euthyroid range, would lead to a decrease of FT4 in CF and FS, being the source of T4 for the ontogenically-regulated intracellular generation of T3 and nuclear receptor T3 occupancy. The authors suggest that the end result of such a situation could be theloss of opportunity for an orderly cerebral development in the fetus. For the latter they foundevidence, as reported in another communication at this meeting by Lavado et al., Madrid and Alicante, Spain, in developing rat fetuses made hypothyroxinemic whenever there was an inadequate supply of maternal T4, even when serum T3 was normal. From both these studies the authors conclude that the results support the convenience that maternal hypothyroxinemia in human pregnancy should be prevented. |
