Urinary iodine excretion and serum thyroid function in adults after iodinated contrast administration.

BACKGROUND: Iodinated contrast media (ICM) is a source of excess iodine that may induce thyroid dysfunction. A prospective cohort study was conducted to assess the effects of ICM on urinary iodine clearance and serum thyroid function tests (TFTs) in adults. METHODS: In this prospective cohort study of 54 adults undergoing elective computed tomography (CT) scans at an academic medical center, serial urinary iodine concentrations (UIC) and serum TFTs were obtained until UIC normalized following ICM administration. Thyroid volume/nodularity were assessed by ultrasound. Associations between covariates and peak UIC, duration for UIC to peak and normalize, and thyroid dysfunction risk were assessed. RESULTS: The mean±standard deviation (SD) iodine administered was 34.6±6.0 g. Baseline median (range) UIC was 105.1 (17.0-866.1) µg/L, and serum thyrotropin (TSH) concentration was 1.26 (0.5-11.2) mIU/L. The mean±SD times to achieve peak UIC (median [range]: 3519 [233-157,500] µg/L] and normalized UIC were 1.1±0.5 and 5.2±4.0 weeks, respectively. Four subjects had elevated baseline TSH, and one had missing baseline TSH values. Of the remaining 49 subjects, 11 (22%) developed an abnormal TSH within one to four weeks (six elevated and five decreased). Administered iodine amount correlated with peak UIC following ICM administration (p<0.001). Increasing age and administered iodine amount predicted peak UIC (p=0.024 and p<0.001, respectively). Age, sex, race/ethnicity, smoking status, family history of thyroid disease, personal or family history of thyroid autoimmunity, thyroid volume, presence of thyroid nodules ≥1 cm, iodine dose, baseline UIC, and baseline TFTs were not predictive of durations to achieve peak or normalized UIC. CONCLUSION: Peak UIC occurred at 1.1 weeks and normalized by 5.2 weeks following ICM administration for outpatient CT scans. Because thyroid dysfunction developed in 22% of individuals following a single ICM dose, monitoring of thyroid function should be considered in at-risk patients.

Screening for maternal thyroid dysfunction in pregnancy: a review of the clinical evidence and current guidelines.

Observational studies have demonstrated that maternal thyroid dysfunction and thyroid autoimmunity in pregnancy may be associated with adverse obstetric and fetal outcomes. Treatment of overt maternal hyperthyroidism and overt hypothyroidism clearly improves outcomes. To date there is limited evidence that levothyroxine treatment of pregnant women with subclinical hypothyroidism, isolated hypothyroxinemia, or thyroid autoimmunity is beneficial. Therefore, there is ongoing debate regarding the need for universal screening for thyroid dysfunction during pregnancy. Current guidelines differ; some recommend an aggressive case-finding approach, whereas others advocate testing only symptomatic women or those with a personal history of thyroid disease or other associated medical conditions.

Thyroid testing during pregnancy at an academic Boston Area Medical Center.

CONTEXT: Gestational hypothyroidism leads to adverse obstetric outcomes and intellectual impairment in offspring. Pregnancy thyroid screening is controversial. OBJECTIVE: Our objective was to determine thyroid function testing and thyroid dysfunction rates in pregnant women at Boston Medical Center (BMC). METHODS: We retrospectively enrolled 1000 pregnant women aged 18-46 yr seen in BMC's Obstetrics/Gynecology (OB/GYN) or Family Medicine (FM) Clinics for their initial prenatal visit during 2008. Age, race, insurance, gestational age (GA), medical history (thyroid or other autoimmune disorders), obstetric history, and thyroid function tests were ascertained. RESULTS: A total of 983 women were included (17 excluded for coding error). Median maternal age was 28 yr and GA 9.4 wk. Thyroid testing rates were similar in the 918 (93%) followed by OB/GYN and 65 (7%) followed by FM (84 vs. 86%). Thirty-nine women had previous thyroid disease, of whom 19 took thyroid medications. Four had type 1 diabetes, and nine had other autoimmune diseases. Serum TSH was obtained in 832 women (84.6%) at median GA 9.7 wk (range, 0.1-39.7). The majority were tested during their first trimester (65.5%). Of the 832 tested, 56 (6.7%) had trimester-specific elevated TSH, of whom nine had a previous history of thyroid disease, two had type 1 diabetes, and one had dyschromia. Based on current case-finding guidelines, 45 of 56 women (80.4%) with an elevated TSH in pregnancy might not have been tested. CONCLUSION: BMC has a high rate of thyroid function testing in pregnancy. Targeted thyroid testing in only high-risk patients would have missed 80.4% of pregnant women with hypothyroidism.

MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein.

Inactivation of retinoblastoma protein (Rb) plays a critical role in the development of human malignancies. It has been shown that Rb is degraded through a proteasome-dependent pathway, yet the mechanism is largely unclear. MDM2 is frequently found amplified and overexpressed in a variety of human tumors. In this study, we find that MDM2 promotes Rb degradation in a proteasome-dependent and ubiquitin-independent manner. We show that Rb, MDM2, and the C8 subunit of the 20S proteasome interact in vitro and in vivo and that MDM2 promotes Rb-C8 interaction. Expression of wild-type MDM2, but not the mutant MDM2 defective either in Rb interaction or in RING finger domain, promotes cell cycle S phase entry independent of p53. Furthermore, MDM2 ablation results in Rb accumulation and inhibition of DNA synthesis. Taken together, these findings demonstrate that MDM2 is a critical negative regulator for Rb and suggest that MDM2 overexpression contributes to cancer development by destabilizing Rb.

Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors.

Only about 5% of human breast cancers can be attributed to inheritance of breast cancer susceptibility genes, while the balance are considered to be sporadic in origin. Breast cancer incidence varies with diet and other environmental influences, including carcinogen exposure. However, the effects of environmental carcinogens on cell growth control pathways are poorly understood. Here we have examined oncogenic signaling pathways that are activated in mammary tumors in mice treated with the prototypical polycyclic aromatic hydrocarbon (PAH) 7,12-dimethylbenz[a]anthracene (DMBA). In female FVB mice given 6 doses of 1 mg of DMBA by weekly gavage beginning at 5 weeks of age, all of the mice developed tumors by 34 weeks of age (median 20 weeks after beginning DMBA); 75% of the mice had mammary tumors. DMBA-induced mammary tumors exhibited elevated expression of the aryl hydrocarbon receptor (AhR), c-myc, cyclin D1, and hyperphosphorylated retinoblastoma (Rb) protein. Because of this, the activation of upstream regulatory pathways was assessed, and elements of the Wnt signaling pathway, the NF-kappa B pathway, and the prolyl isomerase Pin-1 were found to be frequently up-regulated in the tumors when compared to normal mammary gland controls. These data suggest that environmental carcinogens can produce long-lasting alterations in growth and anti-apoptotic pathways, leading to mammary tumorigenesis.

DNA-binding and transactivation activities are essential for TAp63 protein degradation.

The p53-related p63 gene encodes six isoforms with differing N and C termini. TAp63 isoforms possess a transactivation domain at the N terminus and are able to transactivate a set of genes, including some targets downstream of p53. Accumulating evidence indicates that TAp63 plays an important role in regulation of cell proliferation, differentiation, and apoptosis, whereas transactivation-inert deltaNp63 functions to inhibit p63 and other p53 family members. Mutations in the p63 gene that abolish p63 DNA-binding and transactivation activities cause human diseases, including ectrodactyly ectodermal dysplasia and facial clefting (EEC) syndrome. In this study, we show that mutant p63 proteins with a single amino acid substitution found in EEC syndrome are DNA binding deficient, transactivation inert, and highly stable. We demonstrate that TAp63 protein expression is tightly controlled by its specific DNA-binding and transactivation activities and that p63 is degraded in a proteasome-dependent, MDM2-independent pathway. In addition, the N-terminal transactivation domain of p63 is indispensable for its protein degradation. Furthermore, the wild-type TAp63gamma can act in trans to promote degradation of mutant TAp63gamma defective in DNA binding, and the TA domain deletion mutant of TAp63gamma inhibits transactivation activity and stabilizes the wild-type TAp63 protein. Taken together, these data suggest a feedback loop for p63 regulation, analogous to the p53-MDM2 feedback loop.