A minimum of two years of undertreated primary hypothyroidism, as a result of drug-induced malabsorption of l-thyroxine, may have metabolic and cardiovascular consequences.

OBJECTIVE: Cross-sectional studies have reported that TSH above or close to the upper normal limit correlates with unfavorable metabolic and cardiovascular outcomes. Certain medications impair intestinal absorption of levothyroxine (L-T4), resulting in undertreated hypothyroidism (viz. failure of serum TSH to reach target levels, if hypothyroidism is primary).Further to evaluating the magnitude of sub-optimally treated primary hypothyroidism as a result of co-ingestion of those medications, we wished to ascertain whether the above complications would occur during a low number of years under polypharmacy. METHOD: In this retrospective study in collaboration with 8 family physicians, we enrolled adults with primary hypothyroidism under L-T4 therapy that, for 2 years minimum, was not associated with those medications (non-exposure, baseline) and that, for another 2 years minimum, it was (exposure). Outcomes were serum levels and proportions of serum TSH levels >4.12 mU/L, and proportions of complications. Complications were aggravation of pre-existing or de novo onset of any of metabolic syndrome, impaired fasting glycemia (IFG), diabetes mellitus, dyslipidemia, hypertension, coronary heart disease (CHD), cerebrovascular disease (CVD). RESULT: A total of 114 patients were enrolled. Duration of exposure to the interfering medication was 32.1 ±â€¯6.9 months (median 31; range 24-55). Compared with non-exposure, the exposure period resulted in greater TSH levels (2.81 ±â€¯3.62 [median 1.79] vs 1.27 ±â€¯1.34 [median 0.93], P = 2.2 × 10-20) and proportions of values >4.12 mU/L (18.5% vs 4.7%, P = 1.2 × 10-7). Seventy-six patients (67%) had complications, whose rates of TSH >4.12 mU/L were greater than in the 36 complication-free patients (22% vs 11%, P = 0.018). CONCLUSION: During a median period of 31 months, there are relevant consequences for L-T4 treated adult hypothyroid patients resulting from hyperthyrotropinemia caused by medications impairing L-T4 absorption. This should be taken into account by future guidelines on hypothyroidism management.

Switching levothyroxine from the tablet to the oral solution formulation corrects the impaired absorption of levothyroxine induced by proton-pump inhibitors.

CONTEXT: Proton-pump inhibitors (PPIs) impair tablet levothyroxine (LT4) intestinal absorption by increasing the gastric pH and decreasing LT4 dissolution in the stomach. OBJECTIVE: The purpose of this study was to verify whether a liquid formulation of LT4 would correct LT4 malabsorption induced by PPIs. DESIGN: This was a prospective observational cohort study. The study was conducted from 2012 to 2013, and the mean duration of the follow-up was 23.7 ± 11.9 weeks. SETTING: The study was conducted in a tertiary university hospital outpatients clinic. PATIENTS: Upon informed consent, we recruited 24 consecutive adult patients (18 women and 6 men), who took LT4 for replacement (n = 14) or suppressive purposes (n = 10) and who had absorption of tablet LT4 impaired by PPIs. INTERVENTION: The 24 patients were switched from the tablet to the oral solution LT4 at the same daily dose. MAIN OUTCOME MEASURES: Significantly lower mean TSH levels were seen with the oral solution than with the tablet as were significantly greater rates of serum TSH less than or equal to the specified cutoff values (replacement [REP] group) or ≤ 0.10 mU/L (suppressive [SUP] group) with the oral solution than with the tablet. RESULTS: Serum TSH was lower with the oral solution than with the tablet formulation (REP group, 1.7 ± 1.0 mU/L vs 5.4 ± 4.3, P < .0001; SUP group, 0.1 ± 0.3 mU/L vs 2.1 ± 2.7, P < .0001). In the REP group, the rate of TSH values of ≤ 4.12 or ≤ 2.5 mU/L was 29 of 30 (96.7%) or 24 of 30 (80.0%) postswitch but only 17 of 36 (47.2%) or 9 of 36 (25.0%) preswitch (P < .0001). In the SUP group, the rate of serum TSH values of ≤ 0.10 mU/L was 26 of 35 (74.3%) postswitch but 0 of 22 (0%) preswitch (P < .0001). CONCLUSIONS: These data demonstrate the continued absorption of liquid LT4 despite the increased gastric pH due to PPI therapy.

Intranuclear cytoplasmic inclusions in cytologically suspicious or malignant thyroid nodules: identification and correlation with echogenicity and size of the nodules.

Intranuclear inclusions (ICI) represent one cytological feature suggestive of malignancy. The aims of this study are (1) to correlate ICI with size and echogenicity of the thyroid nodules that, at fine-needle aspiration cytology (FNAC), are suspiciously malignant (THY4) or malignant (THY5); and (2) to ascertain whether ICI alone or combined with some ultrasonography (US) characteristics would help in predicting malignancy. We studied 90 consecutive thyroid nodules (THY4 n = 60 or THY5 n = 30) from 90 patients, who subsequently underwent thyroidectomy. Prior to thyroidectomy, all 90 nodules were examined by the US-guided FNAC. A cytology/histology correlation was performed. The results showed that 70 nodules were cancerous (82.2 %, THY4 = 73.3 %, THY5 = 100 %). ICI positive (ICI+) were 53/90 nodules (THY4 = 48.3 %, THY5 = 80.0 %), of which three (all THY4) were benign. The maximum diameter was smaller in the 53 ICI +ve than in the 37 ICI -ve nodules (14.2 ± 5.4 vs. 20.0 ± 9.4 mm, P = 0.0001; median volume 1.32 vs. 4.03 ml). In the THY4 smaller hypoechoic nodules, malignancy rate was 95 % with greater probability to detect ICI compared with non-hypoechoic nodules of >20 mm in maximum diameter (31 (75.6 %) vs. 4 (23.5 %), P = 0.0002). Based on the results, we conclude that ICI detection is associated with relatively smaller size and hypoechoic appearance in THY4 or THY5 nodules. In the THY4 nodules, when coupled with these US characteristics, ICI identification selects lesions with high chances of malignancy.

Increased CXCL9 serum levels in hepatitis C-related mixed cryoglobulinemia, with autoimmune thyroiditis, associated with high levels of CXCL10.

Until now, no study has evaluated CXCL9 in hepatitis C virus (HCV) infection-related mixed cryoglobulinemia (MC) patients in presence/absence of autoimmune thyroiditis (AT). Serum CXCL9 and CXCL10 have been measured in 60 patients with MC (MCo), in 35 patients with MC and AT (MC-AT), in sex and age-matched controls: 60 healthy (Control 1); 35 patients with AT without cryoglobulinemia (Control 2). CXCL9 and CXCL10 were higher in MC-AT patients than Control 2 (P<0.0001) and MCo (P=0.01), in MCo than Control 1 (P<0.0001), and in Control 2 than Control 1 (P<0.001). By defining a high CXCL9 level as a value>2 SD above the mean value of the Control 1 (>122 pg/mL), 5% of Control 1, 34% of Control 2, 91% of MCo, and 97% of MC+AT had high CXCL9 (P<0.0001, chi-square). By simple regression analysis CXCL9 and CXCL10 were related to each other in MCo (r=0.426, P=0.001) and in MC-AT (r=0.375, P=0.001). We first demonstrate high serum levels of CXCL9 in cryoglobulinemic patients, especially with AT. Further, a strong association between serum CXCL9 and CXCL10 has been observed in patients with MC in presence/absence of AT.

Occult leydig cell tumour and androgen-receptor positive breast cancer in a woman with severe hyperandrogenism.

Leydig cell tumours represent more than 75% of all testosterone-secreting ovarian masses. These benign tumours are frequently occult or very small, but cause dramatic virilization. Chronic hyperandrogenism can also induce systemic complications, which increase morbidity and mortality risk. One of the most obvious effects of increased testosterone levels is polycythemia, a complication which induces dermatologic, osteoarticular and gastrointestinal manifestations and is associated with increased thrombotic risk. However, scientific literature reports few data concerning etiopathogenesis and management of polycythemia in patients with Leydig cell tumours. Moreover, no data are available about the effect of androgen excess on other concomitant tumours expressing androgen receptors. In this paper we report for the first time the case of a woman, with previous infertility, dramatic virilisation and chronic erythrocytosis, who was affected by an occult Leydig cell tumour and an androgen receptor positive breast cancer. This association gives us the opportunity to discuss the role of the steroid receptor expression of breast cancer in the presence of circulating androgen excess. Moreover, we demonstrate for the first time that treatment with flutamide (anti-androgen drug) is able to normalize blood cell count and haematocrit, before of achieving the definitive cure of hyperandrogenism by oophorectomy.

Annual increase in the frequency of papillary thyroid carcinoma as diagnosed by fine-needle aspiration at a cytology unit in Sicily.

OBJECTIVE: An increased frequency of papillary thyroid carcinoma (PTC) has been reported in the literature, including studies based on fine-needle aspiration cytology (FNAC). DESIGN: To substantiate our own ascertainment of such an increase, we retrieved all the diagnoses of ultrasound-guided FNAC which was performed on 11,389 patients referred for cytological evaluation of a single or dominant thyroid nodule from 1988 to 2010. FNAC yielded 11,258 adequate specimens. RESULTS: The number of patients with PTC was 200 (age 10-83 yrs) and increased significantly from 1988 to 2010 (r= 0.916, P<0.001). Expressing data as percent of FNAC in any given year, PTC and colloid goiter increased, while adenomatous goiter, follicular lesions and anaplastic or medullary thyroid cancer decreased. PTC accounted for 0% of all FNAC diagnoses in 1988 but for 2% in 2010, with a peak of 2.6% in 2006. Of interest, chronic lymphocytic thyroiditis (CLT) also increased, preceding the increase of PTC by 5-6 years. CONCLUSION: We conclude that in the regions on either side of the Strait of Messina (Italy), PTC has become progressively more frequent during the 23-year period between 1988 and 2010 and that this increase lagged behind the increase of CLT.

Follicular variant of papillary thyroid carcinoma presenting as toxic nodule in an adolescent: coexistent polymorphism of the TSHR and Gsα genes.

BACKGROUND: Autonomously functioning, "hot", thyroid nodules are not common in children and adolescents. Such nodules are not considered alarming because they are assumed to be benign adenomas. Herein, we present a 15-year-old girl with a papillary thyroid carcinoma of 3.5 cm in diameter, which was functionally autonomous and scintigraphically hot. PATIENT FINDINGS: The patient, initially referred to our Endocrine Unit because of a thyroid nodule, returned 6 months later for symptoms of hyperthyroidism. Hyperthyroidism was confirmed biochemically. Radioactive iodine ((131)I) thyroid scintigraphy was consistent with an autonomous thyroid nodule. As per guidelines, the patient underwent surgery and a pathological examination revealed papillary carcinoma, follicular variant. The excised nodule was examined for activating mutations of the thyrotropin receptor (TSHR), Gsα (GNAS1), H-RAS, N-RAS, K-RAS, and BRAF genes by direct sequencing. No mutations were found. Nevertheless, two combined nonfunctioning mutations were detected: a single-nucleotide polymorphism (SNP) of the TSHR gene, in exon 7, at codon 187 (AAT→AAC, both encoding asparagine), and a SNP within exon 8 of the Gsα gene at codon 185 (ATC→ATT, both encoding isoleucine). Both SNPs were also identified in the germline DNA of the patient. The same SNPs were sought in the parents and brother of our patient. Her father was heterozygous for the TSHR SNP, her mother heterozygous for the Gsα SNP, and her brother was wild type. CONCLUSIONS: This case demonstrates that the presence of hyperfunctioning thyroid nodule(s) does not rule out cancer and warrants careful evaluation, especially in childhood and adolescence to overlook malignancy.

A novel formulation of L-thyroxine (L-T4) reduces the problem of L-T4 malabsorption by coffee observed with traditional tablet formulations.

The purpose of this work is to evaluate if the coffee-associated malabsorption of tablet levothyroxine (L-T4) is reduced by soft gel capsule. We recruited 8 patients with coffee-associated L-T4 malabsorption including one hypothyroid patient. For 6 months, the patients were switched to the capsule maintaining the L-T4 daily dose. Patients took the capsule with water, having coffee 1 h later (proper habit, PH) on days 1-90, or with coffee ≤ 5 min later (improper habit, IH) on days 91-180. After 6 months, 2 patients volunteered for an acute loading test of 600 µg L-T4 (capsule) ingested with water (PH) or with coffee (IH). In the single hypothyroid patient, the post-switch TSH ranged 0.06-0.16 mU/L (PH) versus 5.8-22.4 mU/L pre-switch (PH) and 0.025-0.29 mU/L (IH) versus 26-34 mU/L pre-switch (IH). In the other 7 patients, post-switch TSH was 0.41 ± 0.46 (PH) versus 0.28 ± 0.20 pre-switch (PH) (P = 0.61) and 0.34 ± 0.30 (IH) versus 1.23 ± 1.47 pre-switch (IH) (P < 0.001). Importantly, TSH levels in PH versus IH habit did not differ post-switch (P = 0.90), but they did pre-switch (P < 0.0001). The proportions of post-switch TSH levels <0.10 mU/L with PH (33.3 %) or with IH (33.3 %) were borderline significantly greater than the corresponding pre-switch levels with PH (10.3 %) (P = 0.088) or with IH (0 %) (P = 0.0096). In the two volunteers, the L-T4 loading test showed that coffee influenced L-T4 pharmacokinetics minimally. Soft gel capsules can be used in patients who are unable/unwilling to change their IH of taking L-T4.

New targeted therapies for anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is often incurable because it doesn't respond to radioiodine, radiotherapy or chemotherapy, and new therapeutic approaches are needed. Peroxisome proliferator-activated receptor-gamma (PPARg) gene and protein are present in ATC cells, and PPARg ligands inhibit cell proliferation, induce apoptosis, and also down regulate the invasive potential of ATC cells. Also, inhibitors of the Aurora serine/threonine kinases have antineoplastic effect on ATC cells in vitro and on ATC xenografts. Tyrosine kinases inhibitors are actually under evaluation for the treatment of ATC, for example imanitib or sorafenib. Other studies have focused on evaluating antiangiogenic agents for treatment of ATC. These agents include: combretastatin A4 phosphate, aplidin, PTK787/ZK222584, and human VEGF monoclonal antibodies (bevacizumab, cetuximab). Small-molecule adenosine triphosphate (ATP) competitive inhibitors directed intracellularly at epidermal growth factor receptor (EGFR)'s tyrosine kinase, such as erlotinib, or gefitinib are also under evaluation. The development of drugs that have multiple therapeutic targets and the utilization of multiple cancer-targeting agents are both emerging strategies for ATC treatment. For example, a preclinical study evaluated the activity of a dual inhibitor of EGFR and vascular endothelial growth factor (VEGF), NVP-AEE788, alone and in combination with paclitaxel for the treatment of ATC. Even if new therapeutic approaches against ATC are under development, more research is needed to finally identify therapies able to control and to cure this disease. The possibility of testing the sensitivity of primary ATC cells from each subject to different drugs could increase the effectiveness of the treatment in the next future.

Urticaria and thyroid autoimmunity.

BACKGROUND: Chronic urticaria is a common clinical condition whose etiology, in about 75% of cases, is unknown and is therefore called chronic idiopathic urticaria (CIU). A link between CIU and autoimmune thyroid diseases was proposed several decades ago. Here we review this topic. SUMMARY: Several studies have been performed to determine if and to what degree there is an association between CIU and autoimmune thyroid diseases, particularly autoimmune thyroiditis. Many of these studies were not well controlled, however. Approximately one-fourth of CIU patients have serological evidence of thyroid autoimmunity, suggesting that these two disorders are associated. The mechanisms for the apparent association between CIU and serological evidence of thyroid autoimmunity are not clear. There are no data regarding the correlations between CIU and histological features of autoimmune thyroiditis or hypothyroidism. Despite this, there are anecdotal reports regarding L-thyroxine administration in patients with CIU. CONCLUSIONS: Screening for thyroid autoimmunity is probably useful in patients with CIU. More solid evidence, based on still lacking well-conducted controlled studies, is desirable to determine if there is a therapeutic role for L-thyroxine treatment in ameliorating the skin manifestations of urticaria.

Altered intestinal absorption of L-thyroxine caused by coffee.

OBJECTIVE: To report eight case histories, and in vivo and in vitro studies showing coffee's potential to impair thyroxine (T4) intestinal absorption. DESIGN: Of eight women with inappropriately high or nonsuppressed thyroid-stimulating hormone (TSH) when T4 was swallowed with coffee/espresso, six consented to the evaluation of their T4 intestinal absorption. This in vivo test was also administered to nine volunteers. In three separate tests, two 100 microg T4 tablets were swallowed with coffee, water, or water followed, 60 minutes later, by coffee. Serum T4 was assayed over the 4-hour period of the test. Two patients and two volunteers also agreed on having tested the intestinal absorption of T4 swallowed with solubilized dietary fibers. In the in vitro studies, classical recovery tests on known concentrations of T4 were performed in the presence of saline, coffee, or known T4 sequestrants (dietary fibers, aluminium hydroxide, and sucralfate). MAIN OUTCOME: For the in vivo test, average and peak incremental rise of serum T4 (AIRST4 and PIRST4), time of maximal incremental rise of serum T4 (TMIRST4), and area under the curve (AUC) were determined. In patients and volunteers, the four outcome measures were similar in the water and water + coffee tests. In patients and volunteers, compared to water, coffee lowered AIRST4 (by 36% and 29%), PIRST4 (by 30% and 19%), and AUC (by 36% and 27%) and delayed TMIRST4 (by 38 and 43 minutes); bran was a superior interferer. In the in vitro studies, coffee was weaker than known T4 sequestrants. CONCLUSION: Coffee should be added to the list of interferers of T4 intestinal absorption, and T4 to the list of compounds whose absorption is affected by coffee.