Thyroid associated ophthalmopathy (TAO)
Williams, Cambridge, UK, reported on the pathological and molecular biological findings in thyroid cancers, reported in children exposed to fallout from the Chernobyl nuclear accident. Between 1990 and 1994, 298 cases of thyroid carcinoma in children, aged under 15 at the time of operation, were diagnosed. The histological diagnosis was virtually in all cases papillary carcinomas, many showing local invasion and many were of an unusual solid/follicular subtype. With regard to the molecular biological findings no activation was found of ras oncogene, while activation of ret oncogene by intrachromosomal rearrangement was found in 26% of cases, which findings are compatible with the known high frequency of double stranded breaks that occur after exposure to radiation. In a further report the same group, in combination with thyroidologists from Kiev, Ukraine and Minsk, Belarus, analyses 101 cases of papillary carcinoma, of which 58 were from areas exposed to fallout from the Chernobyl accident and 43 from an unexposed area. They analyse three rearrangements of the ret protooncogene that were present in 35% of the whole group. It appeared that ret activationwas not different in tumors from exposed and unexposed areas and there were no significant differences between adults and children. (Comment: It has recently emerged that intrachromosomal rearrangement of the ret proto-oncogene is associated with papillary carcinoma, whereas point mutations, that activate ret proto-oncogene, are associated with medullary carcinoma, either sporadic or as a component of multiple endocrine neoplasia IIa and IIb.)
Santoro et al., Naples, Italy, and New Haven, Connecticut, USA, report an analysis of 300 human tumors for ret activation and demonstrated that in about 35% of papillary carcinoma ret activation occurs. Ret activation was not present in poorly differentiated and undifferentiated carcinomas. In the papillary carcinomas, microcarcinomas showed an especially high frequency of ret rearrangement (59%).
Mayr et al., Hannover, Düsseldorf, Regensburg, Halle-Wittenberg, Germany, assessed the relevance of ret activation by rearrangement in 101 papillary thyroid carcinoma tumor specimens. They found in 8% ret activation and their analysis revealed that positivity for ret activation did not lead to increased risk of metastatic spread.
Romei et al., Pisa, Italy, studied ret proto-oncogene activation by mutations in sporadic medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and primary parathyroid adenomas (PTA). They studied 25 tumor specimens MTC, 6 PTA and 15 PHEO. Ret mutations were analyzed in exon 1, 10, 11, 15, and 16. In 25 MTC patients, 1 patient had a germline mutation (thus appeared to suffer from a hereditary form), but in the other 24 MTC patients somatic mutations were found in 10 cases (41.6%). In 2 out of 15 PHEO patients a somatic mutation was found, but no mutation was present in 6 PTA patients. It is concluded that somatic ret mutations, but also sometimes deletions (1 patient) are frequently found in sporadic MTC, and further analysis showed that these patients are at high risk of tumor recurrence and metastases. Ret mutations are rarely found in sporadic PHEO and not in PTA.
Husmark et al., Göteborg, Sweden, studied expression of E-cadherin (E-CAD) and of catenins (CATs) in one Hürthle cell adenoma, one Hürthle cell carcinoma, and one poorly differentiated/anaplastic thyroid carcinoma with metastatic spread. E-CADs are transmembrane adhesion molecules that play a role in formation of cell-adherence junctions and catenins are intracellular proteins that link E-CAD to the cytoskeleton and thus play also a role in cell to cell linking. It was already reported that thyroid carcinomas often show a reduced expression of E-CAD. Less is known about the catenins (alpha-, beta-, and gamma-catenins). In this study it was found that E-CAD expression was reduced to 10% in both Hürthle cell tumors and expression of catenins was unchanged. However, in the poorly differentiated/anaplastic thyroid carcinoma E-CAD expression was reduced, but also that of alpha-CAT and gamma-CAT. This preliminary study suggests that a highly malignant phenotype may be associated with specific alterations, not only of E-CAD, but also of catenins. (Comment: This is indeed a prelimi-nary study, and it should be extended to more cases. If the results with regard to catenins are confirmed in these further studies, determination of its expression may be used to determine the prognosis of the patient.)
Dahlman et al., Uppsala, Sweden, studied the expression of integrins in cryosections of 58 normal and pathological thyroid specimens and of 3 lymphnode metastases from papillary carcinoma. Integrins (several alpha- and beta-forms) specifically play a role in interactions of cells with their extracellular matrix. Also E-CAD expression was studied. It was found that there was a gain of integrin expression a2 and a6, and a loss of E-CAD expression in anaplastic carcinoma, but not in follicular or papillary carcinoma.
Smit et al., Leiden, The Netherlands, studied the function of b1 integrin in in vitro adhesion of 2 metastatic follicular thyroid carcinoma cell lines in culture. They found that both cell lines attached rapidly to calcified vertebrae and expressed b1 integrin. However, addition of antibody against b1 integrin prevented adhesion almost completely, indicating that b1 integrin may play a role in the metastatic tendency of these tumor cell lines.
Belfiore et al., Catania, Italy, studied expression of the hepatocyte growth factor receptor (HGF-R) encoded by the proto-oncogene C-Met in 120 papillary carcinomas. They found that absent or low expression of HGF-R was associated with vascular invasion, which was present in 18.0% in HGF-R negative patients versus 4.3% in HGF-R positive patients. Its absence or low expression was also related to distant metastases (28.0% versus 2.9% respectively). (Comment: This observation also points to the possibility of determining the prognosis of a patient with papillary carcinoma by measuring HGF-R expression in tumor specimens.)
Antonelli et al., Pisa, Italy, studied the epidemiology of thyroid carcinoma in children from the Gomel region in Belarus after the nuclear accident of Chernobyl in April 1986. Before the accident between 1981 and 1985 only 1 case of childhood thyroid cancer was reported from that area (rate = 0.5: annual average per one million children under 15 years). After the Chernobyl accident between 1986 and 1990, 21 cases (rate = 10.5) and between 1951 and 1955 another 143 cases (rate = 97) were detected, while in the first 7 months of 1995, 33 more cases were observed. Sixty-four children were studied. The female to male ratio was 1.4 : 1. The mean age at diagnosis was 9.5 ± 2.8 years and at the time of the accident 3.8 ± 2.4. The mean period of latency between the accident and the diagnosis was 5.6 ± 1.5 years. Over 90% of patients were less than 6 years of age at the time of the accident, and 3 were still in utero. There was no correlation between the age of the patients and the aggressiveness of the tumor.
Pacini et al., Pisa, Italy, and Villejuif, France, reported on the epidemiology of thyroid carcinoma after the Chernobyl fallout from the whole area of Belarus, comprising 427 patients: 334 children (< 15 years) and 93 adolescents (15-21 years), and compared the results with 346 unexposed children and adolescents: 219 from Pisa and Rome, Italy and 127 from Villejuif, France. In Belarus children the mean age at the time of the accident was 3.3 ± 2.4 years and at diagnosis 10.0 ± 2.3 years in the adolescents 9.9 ± 2.7 years and 16.1 ± 1.1 years respectively. Time between exposure and diagnosis was similar in the two age groups. The overall female to male ratio was significantly higher in Italy and France (2.5 : 1) than in Belarus (1.6 : 1). In Belarus 94.6% tumors were papillary thyroid carcinoma (PTC), 4.7% follicular thyroid carcinoma (FTC) and 0.5% were medullary carcinoma (MTC). In the Italy-France series these figures were 82.0% PTC, 15.6% FTC, and 2.3% were unclassified. Extrathyroidal extension and lymphnode metastases were significantly more frequent in Belarus. In Belarus children the mean age at exposure was inversely related to aggressiveness of tumor at presentation. No such correlation was found in the children from Italy and France. Thyroperoxidase (TPO) antibodies were significantly more found in Belarus.
Goslings et al., Leiden, The Netherlands, reported embolization of spinal metastases from follicular thyroid carcinoma in combination with 131I therapy in 6 patients. Embolization was effected by injection of Ivalon®. In 2 patients symptoms of paralysis disappeared completely and in 3 patients decreased substantially. In 1 patient no effect was seen.
Cascone et al., Naples, Italy, studied the effect of octreotide injection (150 µg daily for 6 months and subsequently 300 µg daily for the next 6 months) in combination with recombinant interferon alpha 2b (3 times a week 5.000.000 IU intramuscularly for 12 months) in 8 patients with advanced medullary carcinoma. After 3 weeks, 2 patients were taken off the study because of aggravation of pre-existing diarrhoea and servere toxicity of interferon. In the other patients a maximal decrease in serum calcitonin was observed ranging between 88 and 34% of basal value and between 32 and 47% of basal value of CEA levels. Symptoms of diarrhoea and flushing disappeared in 4 and 1 patient respectively. (Comment: Although tumor markers decreased, no information was reported on any possible change of tumor mass. Symptomatic improvement, however, was present in several patients.)
Tielens et al., Rotterdam, The Netherlands, studied cardiovascular status, using multi-gated equilibrium radionuclide ventriculography, in 11 patients with primary hypothyroidism at diagnosis and during substitution when euthyroidism was reached and in 12 patients with hyperthyroidism at diagnosis and at euthyroidism after treatment. The following results were obtained; In hypothyroidism: impaired diastolic function, a decreased afterload independent contractility and maintenance of cardiac output by a compensatory increase in end-diastolic volume. In hyperthyroidism: a markedly increased diastolic function, an augmented systolic cardiac performance and an increased cardiac output due to an increased heart rate. All abnormalities disappeared at the time of euthyroidism.
Verhoeven et al., Rotterdam, The Netherlands, studied the effects of calcium channel blockers on T3 uptake in cardiac myocytes of neonatal rats. They found that in the order of Nifedipine > Verapamil > Diltiazem inhibition of both calcium entry and T3 transport in cardiac myocytes was observed. It was concluded that the inhibition of thyroid hormone transport into cardiac myocytes, effected by calcium channel blockers, may thus contribute to the decrease in cardiac output being beneficial in angina pectoris.
Holzapfel et al., Leipzig and Freiburg, Germany, report on congenital non-autoimmune hyperthyroidism, caused by a sporadic germline mutation in the TSH-R in a boy at the age of 5 months. This boy was first treated with antithyroid drugs, but finally operated at the age of 26 months and subsequently put on thyroxine substitution.
Esapa et al., Southampton and Newcastle upon Tyne, UK, had a similar report with regard to a female infant in whom the diagnosis was made at the age of 9 months.
Finally Biebermann, Berlin, Germany, studied a 6 year old girl, who developed symptoms of hyperthyroidism at the age of 2 months and despite PTU treatment required thyroidectomy 6 years later. In this report the family was screened for the mutation and evidence was found for autosomal dominancy of the trait. Both the paternal grandmother and a paternal aunt had suffered from severe hyperthyroidism in the past in childhood, requiring also thyroidectomy. The father of the patient, who is carrying the mutation also, has still no symptoms of hyperthyroidism.
In these 3 reported cases a diffuse goiter is present and the patients do not suffer from eyesigns and there are no signs of thyroid autoimmunity. The disease is caused by a mutation in the TSH-R (3 different mutations were found in these 3 patients), that leads to constitutive activation of the cyclic AMP pathway thereby rendering the thyroid overactive. Apparently other factors than the mutation only play a role in the development of hyperthyroidism, because of the fact that the father of the last patient, despite having the mutation, has not developed, so far, signs of hyperthyroidism. Another type of "TSH-R mutation disease" is when a mutation causes impossibility of TSH to normally stimulate the TSH receptor to elicit an intracellular response.
Thus, Asteria et al., Naples, Italy, reported on a 25 year old man, who had elevated serum TSH (31.5 mU/l), but normal free T3 and free T4 levels. Normal bioactivity of TSH was found, but a mutation was present in the TSH-R causing this hyposensitivity to TSH. Pituitary-thyroid function was found to be normal in all relatives, but the same mutation was found also in the mother and a brother of the propositus, but evidently without clinical expression of the disease.
A similar case was reported by Clifton-Bligh et al., Cambridge, UK. They describe a boy, who already at birth had elevated serum TSH levels. At the age of 2 years serum TSH was > 100 mU/l, but free T4 was normal. Two mutations were detected in the TSH-R gene, one coming from the mother, and one from the father, both having normal thyroid function. (Comment: In the first case, a mutation was found only in 1 allele and the authors suggest that another mutation should probably exist also, which they have not detected yet because normally, heterozygosity of both parents is commonly required for the disease to manifest itself. In the second patient, this is indeed the case. In these two patients no signs of autoimmunity were present and TSH bioactivity was found to be normal. The three mutations (one in the first patient and two in the second patient) were all at a different position.) Both congenital non-autoimmune hyperthyroidism and congenital TSH unresponsiveness are thus caused by germline mutations in the TSH-R gene. Somatic mutations (acquired during life) are also known to cause thyroid disease.
Thus, Paschke et al., Leipzig, Germany, show somatic mutations in the TSH-R gene in 2 patients, each with two hyperfunctioning adenomas in a toxic multinodular goiter. In 1 patient two different mutations were identified in the two hyperfunctioning thyroid adenomas, but in the other patient the mutations in the two adenomas were the same. The mutations in the first patient have been previously reported to cause toxic adenoma, but in the second patient the found mutation was newly detected.
Duprez et al., Brussels and Haine-St-Paul, Belgium, analyzed 24 toxic adenomas from 23 patients for somatic mutations in the TSH receptor gene and found mutations to be present in 75% of the adenomas. They also found in 4% mutations in the Gs-alpha coupled protein. They also found that multiple adenomas can harbour different mutations and the mutations detected were at different locations. (Comment: Although in the report of Paschke et al. the patients had toxic multinodular goiter, it is not proven that these mutations are the cause of the multinodular goiter, because somatic mutations may also occur in multinodular goiter, leading to the development of a toxic adenoma. On the other hand, it is not excluded that TSH-R gene mutations not only play a role in solitary adenomas, but also in the etiopathology of toxic multinodular goiter.)
Gerding et al., Amsterdam, The Netherlands, tested the reproducibility and the clinical usefulness of octreotide scintigraphy (OCS) in patients with TAO. To establish reproducibility, OCS was done twice in 18 patients. Reproducibility was increased when occipital uptake was used for background measurement. Subsequently 22 patients with moderately severe TAO were investigated before and 6 months after retrobulbar irradiation. Twelve patients, who responded to therapy, had a higher initial OCS than non-responders. OCS scanning had a positive predictive value for response of 75%, a negative predictive value of 70%, a sensitivity of 75%, and a specificity of 70%. It is concluded that OCS scanning is promising in predicting therapeutic outcome of immunosuppressive treatment in TAO.
Schuppert et al., Hannover, Germany and Bethesda, MD, USA, investigated the effect of pretreatment with iodide of patients with untreated Graves' disease on the expression of the major histocompatibility complex (MHC) class I and class II, as it has been previously suggested that increased expression of MHC I and II may play a role in the expression and perpetuation of autoimmune thyroid disease. They found that expression of MHC class I and II was lower in patients pretreated with iodide as to no-iodide pretreatment. The authors conclude that the therapeutical action of iodide may also be related to lowering of MHC gene expression in thyroid autoimmune disease. (Comment: The "classical" effect of iodide in Graves' disease has been attributed to its inhibitory action on thyroid hormone synthesis and release (Wolff-Chaikoff effect). However, after about 10 days, the thyroid escapes from this effect and thyroid hormone synthesis and release may be stimulated at an increased rate. The results of these authors are of interest, but at this moment it is not advocated to routinely use iodide as pretreatment in the routine medical approach of Graves' disease).
Rippegather et al., Frankfurt, Germany, studied the role of intrathyroidal lymphocytes (ITL) on the pathogenesis of human autoimmune thyroid disease by injecting ITL from 9 patients with Graves' disease (GD) and 9 patients with non-toxic nodular goiter (NTG) into nude (athymic) mice which were 8 weeks previously grafted with normal human thyroid tissue. After injection of ITL a significantly higher number of CD3+ human lymphocytes was found in the transplant of GD-lymphocytes injected mice as compared to NTG-lymphocytes injected mice. In addition, a significant increase of HLA-class II, intracellular adhesion molecule-I (ICAM-I), vascular cell adhesion molecule-I (VCAM-I), and CD58-expression was seen, as well as a number of IgG presenting plasma cells only after injection of Graves' disease-lymphocytes. The authors conclude that in the nude mouse model, grafted GD-lymphocytes selectively migrate into human thyroid transplants and induce significant functional as well as histological changes, like in autoimmune human thyroid disease. The results suggest an important role of ITL in the etiopathology and clinical course of Graves' disease.
Mühlberg et al., München and Leipzig, Germany, studied the effects of dexamethasone and UV-irradiation on cultured retroorbital fibroblasts of 3 patients with TAO on the induction of interleukin-1 (IL-1) and its antagonist IL-1 receptor antagonist (IL-1RA). They found that with increasing concentrations of dexamethasone IL-1RA gene expression was inhibited in a dose dependent manner. By contrast UV irradiation dose dependently upregulated IL-1RA expression and the authors conclude that induction of this antagonist to IL-1 may represent an important mechanism, by which orbital radiotherapy exerts its beneficial therapeutic actions in patients with active GO, because it is known that IL-1 plays a prominent role in the evolution of TAO by its capacity to stimulate cell proliferation, glycosaminoglycan synthesis and prostaglandin production. (Comment: corticosteroids, like dexamethasone, also have beneficial effects on development of TAO, apparently by a different mechanism than through its effects on IL-1RA.)
Pop et al., Eindhoven, The Netherlands, examined the question if women, who are thyroperoxidase-antibody (TPO-Ab) positive, are at risk for mental depression. They investigated 2779 women, who were at random chosen from a cohort of 6293 women, being 79% of women between 47 and 53 years of age from the city of Eindhoven, who were invited to participate in a screening program for osteoporosis. In these 2779 women FT4, TSH, and TPO-Ab were assessed and depression was evaluated by means of the Edinburgh Postnatal Depression Scale. From this group 1124 women were at random chosen, who completed also other questionnaires (Beck Depression Scale and other determi-nants on stressful life events). In the regression analysis, the occurence of stress-ful life events, a previous episode of depression and TPO-Ab were significantly associated with depression at the moment of investigation. Moreover, women with depression had an 2.5 times increased risk for positivity of TPO-Ab. It is concluded that an association may be present between depression and autoimmune thyroid disease as reflected by high titers of TPO-Ab. (Comment: Serum TSH levels and FT4 levels were not reported. Thus, it is not known if the patients, who were depressed, had abnormal thyroid function and/or if the mean values of these parameters differed from those without depression.)
Muller et al., Rotterdam, The Netherlands, did a prospective study in 173 women out of 467 women, undergoing in vitro fertilisation, to analyze whether spontaneous abortion was related to the presence of TPO-Ab and/or anticardiolipin antibodies (ACL-Ab). Fifty-five women became pregnant, of whom 45 had ongoing pregnancies and 10 miscarried. The prevalence of TPO-Ab in aborters was 4/10 (40%) and in ongoing pregnancies 7/42 (17%) (not signifi-cant). However, the prevalence of TPO-Ab in aborters was different compared to normal non-pregnant females, 78/692 (11%). ACL-Ab in aborters and ongoing pregnancies and in control females were not significantly different. The authors conclude that thyroid autoimmunity before pregnancy is significantly more prevalent in future aborters versus normal female non-pregnant controls. (Comment: So far, maybe to limited number of subjects, the authors have not shown that in pregnancy, due to IVF, abortion is more prevalent in TPO positive subjects. It would be of interest to see a similar study in a larger group of subjects.)
Premawardhana et al., Cardiff, UK, studied abnormalities of thyroid function and morphology, as reflected by ultrasound in 134 women, 7 to 10 years following recruitment to a postpartum thyroid dysfunction (PPTD) study. Twenty-nine TPO-Ab negative women formed the control group (21.6%). Of the 105 TPO positive women 57 had no previous evidence of PPTD, and 48 had PPTD in the past. At follow-up, all TPO-Ab negative subjects had normal thyroid function. Of the TPO-Ab positive subjects 23.8% had thyroid dysfunction, predominantly hypothyroidism. Hypothyroidism was much more common (43.7%) in TPO positive women, who previously had PPTD than in those (7.1%) who had not. Thyroid echography was abnormal in 55% of TPO positive women and was even more prevalent in those who had PPTD than in those who had not. There was no correlation between morphological abnormalities and thyroid dysfunction. It is concluded that in TPO positive women, who developed transient PPTD in the past, significant thyroid dysfunction continues to occur 7 to 10 years postpartum. From this study it appeared also that most women, who were hypothyroid, required T4 substitution permanently.
Barbesino et al., Pisa and Cagliari, Italy, studied the prevalence of anti-cardiolipin antibodies (aCL) in 35 patients with Graves' disease and in 36 patients with Hashimoto thyroiditis. They found positive aCL in 11/35 (= 31.4%) of Graves' disease patients, and in 2 (5.5%) patients with Hashimoto thyroiditis. The history of spontaneous abortions was not different in aCL positive and aCL negative patients. Treatment of Graves' disease patients with methimazo-le or radioactive iodine effected a decrease in aCL levels. The presence of aCL antibodies was not associated with clinical manifestations of the aCL syndrome. (Comment: this study shows that the prevalence of aCL antibody is rather an epiphenomenon of autoimmune disease than a marker of clinical manifestation of the aCL syndrome.)
Szabolcs et al., Budapest, Hungary, and Düsseldorf, Germany studied thyroid function, the presence of thyroid antibodies and thyroid echography in nursing home residents from three regions with different iodine intake. A: mean iodine excretion 70 µg/g creatinin (n = 119), B: 108 mg/g creatinin (n = 119), C: 512 µg/g creatinin (n = 92). Clinical hypothyroidism was present in 0.8, 1.7, and 7.5% respectively. Subclinical hypothyroidism occurred in 4.2, 11.8, and 23.9%. Antibody prevalence was not significantly different (19.3, 22.7, and 22.8%). Goiter rate was 38.5, 17.9, and 12.2% respectively. Eighty-three percent of patients with poor echography texture in region C were antibody positive or had elevated TSH, whereas this was 52% in region A. It is concluded that a high iodine intake is correlated with development of hypothyroidism, and that in these patients echography of the thyroid is predictive for development of hypothyroidism.
Salvi et al., Parma, Italy, and Worcester, MA, USA, evaluated thyroid function in 60 euthyroid subjects, previously treated with recombinant interferon-a (rIFNa) for hepatitis C, of which 8 subjects did not develop any thyroid dysfunction (group A), and 8 patients did (group B). rIFNa therapy was withdrawn 12 and 14 months previously respectively. Before and after administration of 10 drops of saturated solution of KI (SSKI) for 60 days, thyroid function was measured. No patient from group A, but 4 of group B developed abnormal thyroid function, mainly iodine-induced subclinical hypothyroidism. It is concluded that subjects with previous thyroid dysfunction induced by rIFNa are at risk to develop iodine induced thyroid dysfunction.
Ares et al., Madrid, Spain, measured iodine excretion in 69 preterm (P) and 28 fullterm (N) newborns up to 6-8 postnatal weeks. The amount of iodine ingested was also determined as well as serum levels of T4, FT4, T3, TSH, and thyroglobulin (Tg). In the very premature infants as well as in the very sick ones there was negative iodine balance in the first week after birth, but then it became positive in this group as well as in the other P infants and in the N infants. Apparently iodine was accumulated by the thyroid. From these data and measurements of thyroid function the authors concluded that urinary iodine excretion is not equivalent to iodine intake in newborns in the first week of birth, whether P or N. Care should be taken that in P infants iodine supplementation is given, because the lower intake affects serum parameters of thyroid function negatively. However, they also calculated that, even when iodine intake is adequate, P newborns remain hypothyroxinemic as compared to N babies. It is suggested that temporary treatment with T4 may be necessary during this important period of brain development (see also below, section miscellaneous, the report of Van Wassenaer et al.).
Loviselli et al., Cagliari and Pisa, Italy, report thyroid antibody (TA) prevalence and islet cell antibody (ICA) in relation to endemic goiter and urinary iodine excretion in 8088 school children (age 6-14 years), living in 29 communities from areas with mild to moderate iodine deficiency in Italy. Highly variable TA and ICA prevalences with individual geographical "hot spots" were detected without apparent correlation. Both antibodies were also unrelated to goiter and to iodine excretion. The results suggest the involvement of genetic and/or environmental factors independent from iodine deficiency in triggering thyroid and/or islet autoimmunity.
Rolleman et al., Rotterdam, The Netherlands, studied renal handling of T3 and T4 in 4 healthy subjects prior to and on the third day of fasting. During fasting daily T3 as well T4 urinary excretion decreased by 46 and 37% respectively. Also serum T3 decreased, but not serum T4. To exclude effects of changes of serum thyroid hormone concentrations on urinary T3 and T4 excretion, renal clearances of the free hormone fractions (F) were determined. Both FT3 and FT4 renal clearances decreased significantly (38% and 46% respectively) during fasting. Before fasting FT4 clearance was lower, but FT3 clearance was higher than creatinin clearance. It is concluded that in the fed state there is net excretion of T3 into the urine and net T4 absorption. The decreased renal clearances during fasting are possibly caused by decreased basolate-ral uptake of T4 and T3 induced by the reduced energy state in the proximal tubule cell effected by fasting.
Van Tijn et al., Amsterdam and Leiden, The Netherlands, report further on newborns having TSH-deficiency as detected by "the Dutch method" (low T4 and TSH with normal TBG). They performed MRI studies in 8 subjects with TSH deficiency, 5 having isolated TSH deficiency, and 3 having multiple pituitary deficiences. All these 3 latter patients, and 1 with isolated TSH deficiency, showed posterior pituitary ectopia. The same 3 patients and 2 of the patients with isolated TSH deficiency showed additio-nal cerebral developmental abnormalities, such as corpus callosum dysgenesis and gray matter heterotopia. It is concluded that posterior pituitary ectopia is a frequent and early feature of congenital hypothalamic/pituitary disorders, as found by neonatal screening.
Köhler et al., Berlin, Germany, and Amsterdam, The Netherlands, investigated the thyroperoxidase (TPO) gene in 14 children with CH, who had a thyroid gland in the normal position, thus no thyroid dysgenesis. In 3 of 14 patients defects in the TPO gene were found. The authors conclude that future mutation screening of the TPO gene may become an important tool for genetic counselling of patients with early detected and treated CH and a thyroid in the normal position.
Martino et al., Pisa, Italy, performed color flow doppler sonography (CFDS) in 5 non-goitrous thyrotoxic women with elevated FT4 and FT3, undetectable TSH, absent thyroid antibodies and TSH receptor antibodies, and undetectable serum TG levels, all suspected of suffering from thyrotoxicosis factitia (due to surreptitious ingestion of excess thyroid hormone), and compa-red the results of CFDS in untreated Graves' disease patients. All patients with Graves' disease showed a pattern of hypervascularity and increased peak systolic velocity (PSV), but the patients with suspected thyrotoxicosis factitia showed absent hypervas-cularity and significantly lower PSV as compared to Graves' disease and at the lower normal level of PSV in euthyroid normal subjects. (Comment: Although the first line of approach, when thyrotoxicosis factitia is suspected, is to detect serum TG as it is low or absent in these cases, its estimation is difficult, if not impossible, when TG antibodies are present. In that case CFDS may be an important tool for establishing the diagnosis.)
Van Wassenaar et al. evaluated neurodevelopmental outcome in infants < 30 weeks of gestation, when supplemented with T4, as transient hypothyroxinemia of very preterm infants may cause developmental delay and neurological dysfunction. The study was done in 200 infants < 30 weeks'gestational age in a randomized double-blind placebo-controlled trial. Daily administration of 8 µg T4 per kilogram of birth weight or placebo was started 12-24 hours after birth and discontinued 6 weeks later. Ultimately 82 children remained in the T4 group and 75 in the placebo group. At 24 months of age abnormal neurological outcome was reduced in the T4 group as a whole compared to the placebo group. In infants < 27 weeks however, mental development was significantly better in the T4 treated group versus placebo, but the reverse was true in infants > 27 weeks i.e. a better result in the placebo group. The authors conclude that T4 supplementation to infants < 30 weeks gestation cannot be advised on the basis of these results. They suggest that a new trial, including only infants < 27 weeks gestation, should be performed for confirmation of their results.