Thrombosis in Thyroid Cancer.

BACKGROUND: The number of studies on venous thromboembolism (VTE) and thyroid cancer is very scarce and existing data are contradictory. This paper reviews VTE in thyroid cancer. METHODS: The following words were used for a comprehensive literature review using MEDLINE database: Blood coagulation factors; thyroid hormones; blood coagulation tests; venous thromboembolism; receptors thyroid hormone; hemostasis; fibrinolysis; bleeding; blood coagulation disorders; thyroid neoplasms; Thyroid cancer, papillary; Thyroid cancer, follicular; Thyroid carcinoma, anaplastic; Thyroid cancer, Hurthle cell; Familial medullary thyroid carcinoma; venous thrombosis; Pulmonary embolism; Blood coagulation factors. The studies, which include any changes in hemostasis and thyroid cancer were included and reviewed. RESULTS: Although few studies have shown a possible increase in VTE occurrence in thyroid cancer in patients ≥ 60 years old and in proximity to cancer diagnosis, other studies could not find any difference compared to general population. New thyroid cancer classification excluding common subtype(s) with benign nature, may affect the results of the future studies on association of VTE and thyroid cancer. CONCLUSIONS: Prospective studies on the occurrence of VTE in various types and severities of thyroid cancer and in different age groups are warranted, as the results would affect clinical practice on the necessity of usage of anticoagulants in some thyroid cancer groups.

Hemostasis in Overt and Subclinical Hyperthyroidism.

CONTEXT: There are contradictory results on the effect of hyperthyroidism on hemostasis. Inadequate population-based studies limited their clinical implications, mainly on the risk of venous thromboembolism (VTE). The present review focuses on hemostatic changes in overt and subclinical hyperthyroidism. METHODS: A systematic literature search was conducted employing MEDLINE database. The following words were used for the search: Hyperthyroidism; thyrotoxicosis; Graves disease; goiter, nodular; hemostasis; blood coagulation factors; blood coagulation disorders; venous thromboembolism; bleeding; fibrinolysis. The articles that were related to hyperthyroidism and hemostasis are used in this manuscript. RESULTS: Hyperthyroidism, either overt or subclinical, renders a hypercoagulable state, although there are several studies with contradictory findings in the literature. Hypercoagulability may be caused by an increase in the level of various coagulation factors such as factor (F) VIII, FX, FIX, von Willebrand F (vWF), and fibrinogen, while hypofibrinolysis by changes in coagulation parameters such as a decrease in plasmin and plasmin activator or an increase in α2-antiplasmin, plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor. CONCLUSIONS: Although many reports are in favor of a hypercoagulable state in overt hyperthyroidism but this finding at the biochemical level and its clinical implication, on the occurrence of VTE, has yet to be confirmed.

Hemostasis in Hypothyroidism and Autoimmune Thyroid Disorders.

CONTEXT: There are contradictory results on the effect of hypothyroidism on the changes in hemostasis. Inadequate population-based studies limited their clinical implications, mainly on the risk of venous thromboembolism (VTE). This paper reviews the studies on laboratory and population-based findings regarding hemostatic changes and risk of VTE in hypothyroidism and autoimmune thyroid disorders. EVIDENCE ACQUISITION: A comprehensive literature search was conducted employing MEDLINE database. The following words were used for the search: Hypothyroidism; thyroiditis, autoimmune; blood coagulation factors; blood coagulation tests; hemostasis, blood coagulation disorders; thyroid hormones; myxedema; venous thromboembolism; fibrinolysis, receptors thyroid hormone. The papers that were related to hypothyroidism and autoimmune thyroid disorder and hemostasis are used in this review. RESULTS: Overt hypothyroidism is more associated with a hypocoagulable state. Decreased platelet count, aggregation and agglutination, von Willebrand factor antigen and activity, several coagulation factors such as factor VIII, IX, XI, VII, and plasminogen activator-1 are detected in overt hypothyrodism. Increased fibrinogen has been detected in subclinical hypothyroidism and autoimmune thyroid disease rendering a tendency towards a hypercoagulability state. Increased factor VII and its activity, and plasminogen activator inhibitor-1 are among several findings contributing to a prothrombotic state in subclinical hypothyroidism. CONCLUSIONS: Overt hypothyroidism is associated with a hypocoagulable state and subclinical hypothyroidism and autoimmune thyroid disorders may induce a prothrombotic state. However, there are contradictory findings for the abovementioned thyroid disorders. Prospective studies on the risk of VTE in various levels of hypofunctioning of the thyroid and autoimmune thyroid disorders are warranted.

Emphysema lung lobe volume reduction: effects on the ipsilateral and contralateral lobes.

OBJECTIVES: To investigate volumetric and density changes in the ipsilateral and contralateral lobes following volume reduction of an emphysematous target lobe. METHODS: The study included 289 subjects with heterogeneous emphysema, who underwent bronchoscopic volume reduction of the most diseased lobe with endobronchial valves and 132 untreated controls. Lobar volume and low-attenuation relative area (RA) changes post-procedure were measured from computed tomography images. Regression analysis (Spearman's rho) was performed to test the association between change in the target lobe volume and changes in volume and density variables in the other lobes. RESULTS: The target lobe volume at full inspiration in the treatment group had a mean reduction of -0.45 L (SE = 0.034, P < 0.0001), and was associated with volume increases in the ipsilateral lobe (rho = -0.68, P < 0.0001) and contralateral lung (rho = -0.16, P = 0.006), and overall reductions in expiratory RA (rho = 0.31, P < 0.0001) and residual volume (RV)/total lung capacity (TLC) (rho = 0.13, P = 0.03). CONCLUSIONS: When the volume of an emphysematous target lobe is reduced, the volume is redistributed primarily to the ipsilateral lobe, with an overall reduction. Image-based changes in lobar volumes and densities indicate that target lobe volume reduction is associated with statistically significant overall reductions in air trapping, consistent with expansion of the healthier lung. KEY POINTS: Computed tomography allows assessment of the treatment of emphysema with endobronchial valves. • Endobronchial valves can reduce the volume of an emphysematous lung lobe. • Compensatory expansion is greater in ipsilateral lobes than in the contralateral lung. • Reduced air trapping is measurable by RV/TLC and smaller low attenuation area.

Seasonal variation of neonatal transient hyperthyrotropinemia in Tehran province, 1998-2005.

Seasonal aggregation and the monthly rate of neonatal transient hyperthyrotropinemia (THT) were assessed. From November 1998 to April 2005, neonates of gestational age ≥37 wks, birth weight 2500-4000 g, birth length 45-55 cm, and 1st min Apgar score >3, who had thyrotropin (TSH) ≥20 mU/L in their cord dried-blood specimen, but without congenital hypothyroidism, were enrolled in the study. The recall rate equals the rate of THT occurrence in this study. Of 47,945 neonates, 555 had THT (recall rate: 1.2%). The aggregated seasonal recall rate (recall for further assessment to rule out congenital hypothyroidism) was significantly higher in winter (January, February, and March) than the other seasons (p < .0001). Winter had higher recall rate in each year as compared to other seasons, but the overall rate of recalls decreased in 2001 and 2002. Excluding the first 6 months (due to erratic variations), the remaining 72 months revealed a relatively sinusoidal pattern in monthly recall rates; indeed, there was an initial 11-month high recall rates (1.7%), followed by a 33-month decrease (0.7%), a 19-month increase (1.9%), and a final 9-month decrease (0.8%). The recall rate of each of these time intervals was significantly different from that of the next time interval (p < .0001). The monthly recall rates were best fitted to cubic curve estimation and then autoregressive integrated moving average (ARIMA) (0, 1, 1) models. THT occurs significantly more in winter than in other seasons, and this suggests a possible role for time-varying factor(s) contributing to its seasonal preponderance.

Detection of circulating autoantibodies against thyroid hormones in an infant with permanent congenital hypothyroidism and her twin with transient congenital hypothyroidism: possible contribution of thyroid hormone autoantibodies to neonatal and infant hypothyroidism.

Premature, very-low-birth-weight female twins were diagnosed with congenital hypothyroidism (CH). Thyroid hormone antibodies (THAb) directed against triiodothyronine (T3) and thyroxine (T4) of both the IgM and IgG class were detected in both twins. At age 10 months, a rise in thyroid stimulating hormone (TSH) occurred in both infants and measurement of THAb at the same time revealed the appearance of IgM-T4 and IgG-T4 and an increase in IgG-T3 levels in twin 1 (permanent CH), and with a slight increase of IgM-T4 and IgG-T4 levels and appearance of IgM-T3 in twin 2 (transient CH). THAb may contribute to the induction of hypothyroidism in neonates and infants, especially those with underlying autoimmune thyroid disease.

The effect of type of delivery and povidone-iodine application at delivery on cord dried-blood-specimen thyrotropin level and the rate of hyperthyrotropinemia in mature and normal-birth-weight neonates residing in an iodine-replete area: report of Tehran Province, 1998-2005.

OBJECTIVE: To evaluate the effects of delivery type and of povidone-iodine disinfection at delivery on cord dried-blood-specimen (DBS) thyrotropin (TSH) concentrations. METHODS: From 1998 to 2005, cord DBSs were collected from live deliveries in Tehran and Damavand, and TSH was assayed by a two-site immunoradiometric assay. Hyperthyrotropinemia was defined as TSH > or =20 mU/L. Vaginal deliveries prepared with povidone-iodine (VGL-PVP-I) or chlorhexidine (VGL-CHL), and cesarean sections prepared with povidone-iodine (CS-PVP-I) disinfection were assessed. Full-term, normal-size newborns were included. Iodine concentrations were measured in urine samples collected from 132 pregnant women immediately prior to delivery. RESULTS: Median (range) TSH was 5.3 (1.0 to >100) mU/L in VGL-PVP-I (n = 23,432), 5.3 (1.0 to >100) mU/L in VGL-CHL (n = 5658), and 5.0 (1.0 to >100) mU/L in CS-PVP-I (n = 19,016) (p < 0.0001). Median TSH was higher in VGL-PVP-I versus CS-PVP-I (p < 0.0001) and in VGL-CHL versus CS-PVP-I (p < 0.0001). Hyperthyrotropinemia was present in 1.4%, 1.2%, and 0.8% of VGL-PVP-I, VGL-CHL, and CS-PVP-I deliveries, respectively, and was significantly higher in VGL-PVP-I versus CS-PVP-I (p < 0.0001) and in VGL-CHL versus CS-PVP-I (p = 0.005). Median (range) urinary iodine concentration of pregnant women was 176 (20-4600) microg/L. CONCLUSION: Cord DBS TSH and rates of hyperthyrotropinemia are lower in cesarean section than in vaginal deliveries. Povidone-iodine disinfection at delivery has an effect neither on DBS TSH concentrations nor on the rate of hyperthyrotropinemia in the iodine-replete area of Iran.

Assessment of intertrimester and seasonal variations of urinary iodine concentration during pregnancy in an iodine-replete area.

OBJECTIVE: To assess intertrimester and seasonal variations in urinary iodine concentration (UIC) among pregnant women. PATIENTS AND MEASUREMENTS: Pregnant Tehranian women, with no history of thyroid ablation or consumption of thyroid-affecting medication were selected consecutively from November 2004 to November 2006. Morning spot urine samples were collected from each participant during the first, second and third trimesters of pregnancy. Of 466 participants, 298 completed the study in all three trimesters of pregnancy. UIC < 150, 150-250, and > 250 microg/l indicated low, adequate, and high levels, respectively. UIC was measured using a modified Sandell-Kolthoff digestion method. RESULTS: The pregnant women were aged 25.0 +/- 5.0 (range 16-48) years. Median UIC did not show seasonal fluctuations during pregnancy. However, median (range) UIC was 193 (19-840), 159 (16-640), and 141 (16-400) microg/l in the first, second and third trimesters of pregnancy, respectively (P < 0.0001). Frequency distributions of low, adequate and excessive UIC were 33.2, 31.2 and 35.6% in the first trimester, 46.0, 28.9 and 25.2% in the second trimester, and 53.4, 30.9 and 15.8% in the third trimester of pregnancy, respectively (P < 0.0001). Women with UIC < 150 were more frequently represented in the second vs. the first (P = 0.043; odds ratio 1.49, 95% confidence interval 1.012-2.213) and in the third vs. the first (P = 0.013; odds ratio 1.62, 95% confidence interval 1.108-2.379) trimesters of pregnancy than the 150-250 microg/l group were. UIC decreased throughout pregnancy in all seasons. CONCLUSIONS: Iranian national salt iodization may prevent seasonal fluctuations of UIC but does not maintain median UIC within adequate and recommended ranges throughout pregnancy. Extra iodine supplementation during pregnancy is recommended.

Rapid acid digestion and simple microplate method for milk iodine determination.

Iodine deficiency leads to deficiency of thyroid hormones, which causes mental retardation in infant. Laboratory confirmation is important in its diagnosis. The major problems associated with the existing methods for iodine determination in milk samples are: 1) nonsafe alkaline solution; 2) harsh thermal condition; and 3) extra time required to complete various steps. In this study, a simple and rapid colorimetric method was investigated, which used acid digestion in combination with a rapid microplate reading format method to determine the total iodine content in milk. Sample digestion was done on 50 microL milk in metavanadate/perchloric, at 230 degrees C for 10 min. After digestion, iodine determination was based on the Sandell-Kolthoff reaction. The reaction results were read in 96-well microplates by an enzyme-linked immunosorbent assay (ELISA) reader. The determination range of the assay was between 2 and 40 microg/dL. The within-run coefficient of variation percent in three levels (3, 12, and 36 microg/dL) ranged from 6.7 to 9.3 and between-run coefficients of variation ranged from 8.6 to 12.3%. The results obtained (n=70) by the optimized method have good correlation with the results of alkaline incineration as a reference method (n=70; r2=0.907; y=0.952x+1.77). Recovery tests for accuracy assessment in six levels from 6.2 to 34.2 microg/dL) were between 91.3 and 113%. This method has enabled us to achieve 0.12 microg/dL sensitivity. The results of this study show that a quick acid digestion combined with mild thermal and low sample volume with a quick reading of assay results were the main advantages of the acid digestion and microplate reading format.

Assessment of thyroid function and urinary and breast milk iodine concentrations in healthy newborns and their mothers in Tehran.

OBJECTIVE: To measure breast milk iodine (MI) and urinary iodine (UI) concentrations in healthy newborns and their nursing mothers from an iodine-sufficient region to determine adequacy and to relate these parameters to thyroid function tests in mothers and infants. DESIGN: Cross-sectional. PATIENTS: Forty-eight healthy neonates of 37 to 42 weeks' gestation with normal cord blood TSH values and their mothers were recruited in Tehran, Iran. MEASUREMENTS: Serum thyroid function tests were performed, and maternal and infant urinary iodine excretion, and maternal MI concentration were measured. RESULTS: Neonatal age was 12.9 +/- 3.9 (mean +/- SD; range 7-30) days and maternal age was 25.8 +/- 5 years. Median (range) UI in neonates was 271 microg/l (57-800) and in mothers was 107 microg/l (20-710). Median (range) MI was 148 microg/l (45-750). Neonatal and maternal UI did not correlate with serum thyroid function tests. UI < 150, 150-230, and > 230 microg/l was found in 20, 12.5, and 67.5% of neonates and 79.1, 14, and 7% of mothers, respectively. MI was < 150, 150-180, and > 180 microg/l in 52.4, 11.9, and 35.7% of mothers, respectively. CONCLUSIONS: Among euthyroid neonates, UI was adequate despite low median maternal UI and MI concentrations. There were no significant correlations between UI or MI and thyroid function tests in the mothers and infants.

Genetic analysis of the PAX8 gene in children with congenital hypothyroidism and dysgenetic or eutopic thyroid glands: identification of a novel sequence variant.

OBJECTIVE: To analyse the coding region of PAX8 in individuals with congenital (CH) or post neonatal hypothyroidism due to dysgenetic (TD) or eutopic thyroid glands. DESIGN AND PATIENTS: Forty-three children with CH and TD (13 agenesis, 23 ectopia, and seven hypoplasia), one subject with post neonatal onset of hypothyroidism and thyroid ectopia, 15 children with CH and eutopic thyroid glands and six euthyroid adults with thyroid hemiagenesis were enrolled as cases, along with 120 healthy individuals as controls. MEASUREMENTS: Exons 2-8 of the PAX8 were directly sequenced. HeLa and HEK293 cells were transfected with PAX8 wild-type (PAX8-WT), mutant PAX8, p300, thyroid transcription factor 1 (TTF-1) and thyroglobulin promoter pGL3 (TG prom-pGL3). Synergism of TTF-1 with PAX8-WT vs. mutant and activity of PAX8-WT vs. mutant in accompaniment with p300 on TG prom-pGL3 were also assessed. The luminescence produced by PAX8-WT and mutant PAX8 was measured. RESULTS: Among patients and controls only a 15-year-old girl with thyroid ectopia showed a heterozygous transition of cytosine to thymine at position 674 in exon 6, which changed a conserved threonine at position 225 to methionine (PAX8-T225M). Her father and sister harboured PAX8-T225M without abnormal thyroid phenotypes. PAX8-T225M and PAX8-WT similarly increased luciferase activity and had a similar synergistic effect with TTF-1. At 500 ng p300, however, PAX8-T225M could not significantly increase TG promoter activity when compared to PAX8-T225M alone, while PAX8-WT +500 ng p300 induction was significantly higher than PAX8-WT alone (P < 0.001). Cotransfection of TTF-1 together with PAX8-T225M resulted in rescuing of the lack of synergism with p300. CONCLUSIONS: PAX8 mutations in congenital hypothyroidism due to dysgenetic or orthotopic thyroid glands are rare. PAX8-T225M is probably a rare variant.

Transient neonatal hypothyroidism is associated with elevated serum anti-thyroglobulin antibody levels in newborns and their mothers.

Transient congenital hypothyroidism (TCH) was detected in 6 of 35,067 newborns (1:5845 births) screened in Iran. Antithyroglobulin antibodies positivity was present in 4 of 6 (66.7%) of those with TCH and in 6 of 106 (5.7%) of those with "transient hyperthyrotropinemia and normal" diagnoses (P = .0005), but positivity was similar in newborns with transient hyperthyrotropinemia versus normal neonates (P = .397).

An assessment of urinary and breast milk iodine concentrations in lactating mothers from Gorgan, Iran, 2003.

Dietary iodine is essential for the production of thyroid hormones. Breast-fed infants are reliant on maternal iodine intake. The aim of this study was to evaluate iodine sufficiency in lactating women in Iran. The sample consisted of 100 lactating mothers referred to the Taleghani Hospital of Gorgan, Iran. Goiter was graded according to World Health Organization (WHO) classification. Spot urine and breast-milk samples were collected for the measurement of iodine concentrations. Urine iodine concentrations (UIC) less than 100 and breast-milk iodine concentrations (MIC) less than 50 microg/L were considered consistent with iodine deficiency. Forty-three percent of women had grade 1 and 2 goiters, respectively. The median UIC was 259 microg/L. UIC was less than 100 in 16%. Grade 1 and 2 goiters were each present in 8% of mothers with UIC less than 100 microg/L. The median MIC was 93.5 microg /L. MIC was less than 50 microg /L in 19%. Grade 1 and 2 goiters were present in 11% and 8%, respectively, of women with MIC <50 mg/L. MIC and UIC levels were significantly correlated (r = 0.44, p < 0.0001). Iodine deficiency and goiter were associated (p < 0.0001). UIC and MIC concentrations are sufficient in Gorgan, Iran. However, individual infants remain at risk for low iodine intake via breast milk.

Intrauterine diagnosis and management of fetal goitrous hypothyroidism: a report of an Iranian family with three consecutive pregnancies complicated by fetal goiter.

The diagnosis and treatment of hypothyroidism during the fetal period may decrease perinatal morbidity and are believed to be important to optimize growth and intellectual development. Herewith a case report of fetal goitrous hypothyroidism is presented in a euthyroid mother, detected at 34 weeks' gestation by ultrasonography, and treated with intra-amniotic levothyroxine injections. The mother had two previous consecutive pregnancies (13 and 8 years ago), also complicated by the occurrence of fetal goiter, resulting in tracheal compression, asphyxia, and early neonatal death in the first and in an emergency cesarean section delivery, because of fetal malpresentation, in the second neonate affected by congenital hypothyroidism (CH). The present male newborn, although born without observable goiter, had a large thyroid on ultrasonography and an early rise of his peripheral venous blood thyrotropin confirmed the diagnosis of CH. Low serum thyroglobulin in the proband and his older brother and parental consanguinity was mostly compatible with a thyroglobulin defective synthesis and secretion as the cause of CH and fetal goiter. Despite apparently sufficient dose of intraamniotic levothyroxine injections repeated weekly from 34-37 weeks' gestation (i.e., four injections of 500 microg levothyroxine), neonatal bone age on the second day of life showed delayed skeletal maturation.

A high prevalence of consanguineous and severe congenital hypothyroidism in an Iranian population.

To determine the incidence of permanent congenital hypothyroidism (CH) in Tehran and Damavand, cord blood spots were collected from February 1998-August 2002 and infants with TSH > or =20 mU/l were recalled. CH was confirmed in neonates (aged > or =7 days) with serum TSH >10 mU/l and T4 <84 nmol/l. Cases were followed up until September 2003. Dysgenesis was detected by thyroid imaging. In eutopic cases, serum TSH and T4 measurements following levothyroxine discontinuation (2-3 years of age) confirmed dyshormonogenesis and transient CH. Of 35,067 neonates, 373 (1.06%) were recalled and 25 (1:1,403 births) had permanent CH (six had transient CH and four remain unknown). Dysgenesis was detected in 18 (1:1,948 births) and dyshormonogenesis in seven (1:5,010 births) infants. Parental consanguinity was present in 10 (55.6%) dysgenetic, three (42.9%) dyshormonogenetic, and overall 6,648 (28.6%) of 23,227 screened infants. Odds ratio (95%CI(OR)) of consanguinity in permanent CH and dysgenesis was 2.75 (1.17-6.47) and 3.74 (1.33-10.52), respectively. The high prevalence of parental consanguinity in infants with permanent CH warrants genetic assessment.

Congenital hypothyroidism in Iran.

OBJECTIVE: Following elimination of iodine deficiency in Iran, the program of screening for congenital hypothyroidism (CH) was established in 1998. The descriptive findings of the study are reported here. METHODS: From February 1998 to June 2001, cord blood spot samples from 8 hospitals and a rural birth center in Tehran and Damavand were collected and tested for TSH measurement using a two-site IRMA method. TSH values > or = 20 microU/mL were recalled. The diagnosis of CH was confirmed using age adjusted reference values for serum TSH and T4 levels. RESULTS: Of 20107 screened neonates, 256 had cord TSH values > or = 20 microU/mL (recall rate: 1.3%) and 22 showed hypothyroidism (1:914 live births). History of maternal ingestion of drugs and dietary goitrogens were negative and minimal, respectively. 15 out of 21 CH neonates had parental consanguinity. The odds ratio of CH occurrence in blood-related to non-related marriages was 6.9 (CI=1.82-25.87). Thyroid dysgenesis occurred in 10 neonates; 1:2011 births. Urinary iodine excretion was between 12-22 (n=3) and 40-42.5 (n=5) microg/dL in 10 eutopic neonates (2 not assessed). CONCLUSION: Parental consanguinity and iodine excess could be the causative factors for the high incidence of CH.