New-generation thyroglobulin assay: Performance and implications for follow-up of differentiated thyroid carcinoma

Objectives

Differentiated thyroid cancer (DTC) requires long-term follow-up by serum thyroglobulin assay and cervical ultrasound, due to the risk of recurrence. Guidelines recommend basal assay under hormone therapy at 3 months, repeated at 6–12 months post-surgery, with or without associated isotopic ablation, after stimulation by recombinant human TSH to improve assay sensitivity. It was hypothesized that a new-generation assay kit with lower limits of detection and quantification would improve the sensitivity of the basal assay, enhance detection of premature recurrence and decrease the rate of false-negatives, thereby avoiding the need for the complementary stimulation test.

Material and methods

A validation study of the second-generation thyroglobulin serum assay was performed in the laboratory of the Lyon Sud Hospital Centre (Lyon, France), with comparison to stimulation test results. Low-concentration serum pools were constituted, including patients followed for stage I to III DTC for whom basal and post-stimulation samples were available in the serum bank.

Results

The new assay proved robust and reliable, with good correlation with the technique presently used in the Lyon hospitals. None of the 54 patients showed false-negative results, which was the objective of our choice of threshold, and 5 were false-positive, for thyroglobulin thresholds of 0.1 μg/L at baseline and 1.0 μg/L post-stimulation. Positive and negative predictive values were 100% and 87.8% respectively.

Conclusion

These results allow an improvement in the follow-up algorithm for DTC, replacing the stimulation test by the new-generation thyroglobulin assay in post-therapeutic assessment.     

False-positive Iodine-131 whole-body scan findings in patients with differentiated thyroid carcinoma: Report of 11 cases and review of the literature

Background

Iodine-131 (I-131) whole-body scan (WBS) plays an important role in the management of patients with differentiated thyroid carcinoma (DTC), to detect normal thyroid remnants and recurrent or metastatic disease. A focus of I-131 accumulation outside the thyroid bed and the areas of physiological uptake is strongly suggestive of a distant functioning metastasis. However, many false-positive I-131 WBS findings have been reported in the literature.

Patient findings

We describe a series of 11 personal cases of patients with DTC, collected from 1992 to 2011, in whom diagnostic or post-treatment WBS showed false-positive retention of I-131 in various locations.

Summary

False-positive accumulations of I-131 on WBS may be classified according to the underlying pathophysiological mechanisms: external and internal contaminations by body secretions, ectopic normal thyroid and gastric tissues, inflammatory and infectious diseases, benign and malignant tumors, cysts and effusions of serous cavities, thymic uptake, and other non classified causes.

Conclusions

Clinicians must be aware of possible false-positive findings to avoid misinterpretations of the I-131 WBS, which could lead to inappropriate treatments.     

Relationship Among Pulmonary Hypertension,Autoimmunity, Thyroid Hormones and Dyspnea in Patients With Hyperthyroidism

Objective

Previous studies have reported conflicting results regarding the mechanisms underlying the pathophysiology of pulmonary hypertension (PHT) in patients with hyperthyroidism. Therefore, in this study, we investigated the association between PHT and thyroid-stimulating hormone (TSH) receptor antibody, thyroid peroxidase antibody, thyroglobulin antibody, TSH, fT3, fT4 and dyspnea during daily activities in a large population of patients with hyperthyroidism.

Prognostic impact of subclinical thyroid dysfunction in heart failure

Background

Therapeutic and prognostic implications of subclinical thyroid dysfunction in patients with heart failure (HF) are unclear. We compared the prognostic impact of euthyroidism, subclinical thyroid dysfunction, and euthyroid sick syndrome (ESS) in systolic HF.

Methods

We included 1032 patients hospitalized for systolic HF (left ventricular ejection fraction [LVEF] ≤ 40%) who participated in a randomized trial assessing the effects of a HF disease management program. Patients with incomplete thyroid function tests or thyrotropic medication were excluded. In the remaining 758 subjects, the risk of all-cause death was estimated based on TSH only, or full thyroid function profile. Changes of thyroid function after six months were assessed in 451 subjects.

Results

Subclinical thyroid dysfunction was present in 103 patients at baseline (14%). No differences were found between groups regarding NYHA class (P = 0.29), and LVEF (P = 0.60). After a median follow-up of three years patients with ESS (n = 13) had a 3-fold age-adjusted increased risk of death compared to euthyroid patients (P = 0.001). However, neither subclinical hyperthyroidism (HR 1.18, 95%CI:0.82–1.70) nor hypothyroidism (HR 1.07, 95%CI:0.58–1.98) were associated with increased age-adjusted mortality risk. Subclinical thyroid dysfunction had normalized spontaneously at follow-up in 77% of patients. However, persistent subclinical thyroid dysfunction was also not associated with worse outcome.

Conclusions

In this large well-characterized HF cohort, subclinical thyroid dysfunction did not predict an increased mortality risk. Thus, in patients with moderate to severe HF, further diagnostic and therapeutic procedures for subclinical thyroid dysfunction appear dispensable. ESS was an infrequent but important indicator of a poor prognosis in HF.

Clinical trial registration

URL: http://www.controlled-trials.com. Unique identifier: ISRCTN23325295.     

TSH signaling pathways that regulate MCP-1 in human differentiated adipocytes

Objective

Adipose tissue is an extra-thyroidal thyroid-stimulating hormone (TSH) target. Increases in lipolysis and in expression and release of interleukin-6 (IL-6) occur in TSH-stimulated adipocytes, and levels of circulating free fatty acids and IL-6 rise following TSH administration to patients with previous thyroidectomy and radioablation for thyroid cancer. Our first objective was to compare how TSH stimulates protein kinase A (PKA) and inhibitor of κB (IκB) kinase (IKK)-β. Our second objective was to investigate whether TSH induces other cytokines besides IL-6.

Methods

TSH stimulation of either CHO cells expressing human TSH receptor or human abdominal subcutaneous differentiated adipocytes.

Results

Signaling studies showed TSH increased NADPH oxidase activity, and either diphenyleneiodonium (oxidase inhibitor) or N-acetyl cysteine (scavenger of reactive oxygen species) reduced IKKβ phosphorylation. Phosphorylation of protein kinase C-δ, an upstream regulator of NADPH oxidase, was increased by TSH, and rottlerin (PKCδ inhibitor) reduced TSH-stimulated IKKβ phosphorylation. TSH upregulated monocyte chemoattractant protein-1 (MCP-1) mRNA expression and the release of MCP-1 protein in human abdominal differentiated adipocytes. H89 (PKA inhibitor) and sc-514 (IKKβ inhibitor) each blocked TSH-stimulated MCP-1 mRNA expression and protein release, suggesting PKA and IKKβ participate in this pathway.

Conclusions

These data provide new information about TSH signaling in human differentiated adipocytes, and add to the evidence that TSH is a pro-inflammatory stimulus of adipocytes.     

Subclinical thyroid dysfunction and cardiac function amongst minority ethnic groups in the UK: A cross sectional study

Background

Subclinical thyroid disease is associated with abnormal cardiovascular haemodynamics and increased risk of heart failure. The burden of raised/low thyroid stimulating hormone (TSH) levels amongst South Asian (SA) and African–Caribbean (AC) minority groups in the UK is not well defined. Given that these groups are particularly susceptible to CVD, we hypothesised that STD would reflect abnormal cardiac function and heightened cardiovascular risk in these ethnic groups.

Methods

We examined SA (n = 1111, 56% male, mean age 57.6 yrs) and AC (n = 763, 44% male, mean age 59.2 yrs) participants from a large heart failure screening study. Euthyroidism is defined as TSH (0.4 – 4.9 mlU/l), subclinical hypothyroidism is defined as a raised TSH with normal serum free thyroxine (FT4) concentrations (9–19 pmol/l). Subclinical hyperthyroidism is defined as a low TSH with both FT4 and free triiodothyronine (FT3) concentrations within range (2.6–5.7 pmol/l).

Results

Across ethnic groups, prevalence of subclinical hypothyroidism was 2.9% (95% CI 2.1–3.7), and of hyperthyroidism was 2.0% (1.4–2.7). Hyperthyroidism was more common amongst SA compared to AC (2.8% vs. 0.9%, P = 0.017), while rates of subclinical hypothyroidism were similar. On multivariate analysis of variations in subclinical thyroid function, ethnicity was not independently significant.

Conclusion

The prevalence of subclinical thyroid disorders amongst SA and AC minority groups in Britain reflects levels reported in other populations. The clinical cardiovascular significance of subclinical thyroid disease is unclear, and it does not appear to be ethnically specific.     

Coexistence of Graves’ disease,papillary thyroid carcinoma and unilateral benign struma ovarii: Case report and review of the literature

Background

Struma ovarii is a rare cause of hyperthyroidism, while coexistence with Graves’ disease has been scarcely reported.

Patient Findings

We report a patient with Graves’ disease and unilateral benign functioning struma ovarii, accompanied by ascites, pleural effusion and elevated cancer antigen-125 (CA-125) levels. In subsequent thyroidectomy, incidental papillary thyroid carcinoma was also identified. The functionality of struma ovarii tissue in our patient was supported by the immunohistochemical identification of TSH receptors (TSHR), which may stimulate growth and thyroid hormone production in the presence of circulating TSHR stimulating antibodies (TSHR-Ab).

Review of the literature

A systematic review of reported cases of coexistent Graves’ disease and struma ovarii was performed.

Conclusions

The diagnosis of struma ovarii may be masked by Graves’ disease and, therefore, be delayed for several years. Furthermore, ascites, pleural effusion and increased CA-125 may result from a benign struma ovarii. The presence of TSHR in the struma ovarii tissue along with their absence in the surrounding ovarian tissue indirectly suggests that struma ovarii is functional. It is unclear whether TSHR-Ab play a role in the development of thyroid carcinomas in such patients.     

Manifestations and prognosis of thyrotropin-secreting pituitary adenomas: a case series of three patients

Introduction

Among pituitary adenomas, thyrotropinomas were previously considered as extremely rare and resistant to therapy. However, the common use of the sensitive TSH measurement and the improvement of pituitary imaging have modified their clinical and hormonal presentation.

Case reports

We here report three cases of TSH secreting pituitary adenoma that highlight the great diversity of the clinical, hormonal and morphological presentation, and their better prognosis. In the presence of an inappropriate TSH secretion, the main differential diagnosis is the syndrome of thyroid hormone resistance. The role of somatostatin analogue prior to the surgical treatment of TSH secreting pituitary adenoma is also underlined in this report.

Conclusion

The increasing frequency and early diagnosis of TSH secreting pituitary adenoma may be explained by ultrasensitive methods now used for TSH measurement and progress in pituitary imaging, mainly with MRI. This changing spectrum in the presentation and the excellent response to somatostatin analogues improved in the prognosis of the disease.     

Recurrences in tuberculosis in a cohort of human immunodeficiency virus-infected patients: The influence of highly active antiretroviral therapy

Background

Little is known about recurrent tuberculosis (TB) among HIV-infected patients and the influence of highly active antiretroviral therapy (HAART).

Methods

A population-based retrospective longitudinal study was conducted on all HIV-infected TB patients in Barcelona (Spain) notified in 1987–2003, and followed up until 2005. TB recurrence and HAART influence were analysed according to calendar period.

Results

Patients with no-treatment and those in pre-HAART had more risk of TB recurrence (RR: 2.3; CI: 1–5.8 and RR: 4.8; CI: 2–12).

Conclusions

HAART decreases probability of TB recurrence and should be extended to all cases.     

Clinical and sociodemographic correlates of referral for cardiac rehabilitation following cardiac revascularization in Ontario

Objectives

Describe rates of, and examine factors affecting, referral to cardiac rehabilitation (CR) following revascularization in Ontario.

Background

CR reduces mortality following cardiac revascularization, but is largely underutilized, partly due to poor referral rates.

Methods

In this retrospective study, the sample consisted of all CR-indicated patients who underwent revascularization at the Cardiac Care Network of Ontario hospitals between October 2011 through March 2012. Referral rates were described, and multivariate analyses performed to identify disparities.

Results

Of the 3739 patients included, 51.8% were referred to CR. Patients aged ≥85 or requiring a translator, and patients with hyperlipidemia, heart failure, or comorbid pulmonary, renal or peripheral vascular disease, were significantly less likely to be referred. Patients with a history of smoking or myocardial infarction, or who underwent coronary artery bypass graft surgery, were significantly more likely.

Conclusions

A national policy statement recommends 85% referral of indicated patients to CR, a target currently missed by almost 35%.     

Obesity with and without metabolic syndrome: Do vitamin D and thyroid autoimmunity have a role?

Aims

To investigate serum levels of thyroid stimulating hormone (TSH), anti-thyroid peroxidase antibody (TPO), and 25(OH)D in the presence or absence of metabolic syndrome in an obese population.

Methods

Data from a prospectively generated “Obesity Polyclinic” database that includes socio-demographic characteristics, anthropometric, and laboratory measurements of obese subjects were retrospectively analyzed. Subjects with body-mass index (BMI) ≥30 kg/m² were eligible. After detailed analysis and exclusion of unavailable cases, subjects diagnosed with and without metabolic syndrome were compared for TSH, anti-TPO, and 25(OH)D.

Results

Of the study participants (n = 548; men/women, 64/484), 277 were diagnosed with metabolic syndrome [Met-S (+)]. Met-S (+) patients had a higher mean BMI (36.4 vs. 32.3 kg/m², p < .001) and percentage body fat (PBF) (39.2 vs. 35.3%, p < .001), but similar TSH (2.1 vs. 2.2 mIU/mL, p = .759), anti-TPO (12 vs. 13 IU/mL, p = .483), 25(OH)D (13.2 vs. 12.6 ng/mL, p = .409), and calcium–phosphorus product (28.7 vs. 29.5 mg/dL, p = 0.275), compared to Met-S (−) subjects. When serum TSH, anti-TPO, and 25(OH)D levels were analyzed according to tertiles for comparisons of fasting plasma glucose, triglycerides, high-density lipoprotein cholesterol, BMI, and PBF, only 25(OH)D levels were negatively correlated with BMI and PBF.

Conclusions

Although decreased 25(OH)D levels were related to the degree of obesity in obese subjects, serum 25(OH)D levels per se did not seem to be associated with metabolic syndrome. The prevalence of thyroid autoimmunity and hypothyroidism were high in this obese sample; however, neither serum TSH nor anti-TPO levels correlated with metabolic syndrome. Our findings did not support the hypothesis that thyroid autoimmunity and/or vitamin D status have a role in the development of metabolic disturbances in the obese population.     

Uses for recombinant human TSH in patients with thyroid cancer and nodular goiter

Recombinant human TSH (rhTSH) has revolutionized the care of patients with differentiated thyroid cancer. Since its approval for clinical use in 2001 in Europe (1998 in the USA), rhTSH has greatly enhanced the surveillance of these patients by allowing the avoidance of hypothyroidism for TSH stimulation. Previously, a hypothyroid state was required for TSH stimulated diagnostic whole-body radio-iodine scans (DxWBS) and thyroglobulin (Tg) levels. Patients generally prefer rhTSH as a mechanism for TSH stimulation because symptoms of hypothyroidism can be completely avoided. Currently, rhTSH is only approved for diagnostic monitoring of differentiated thyroid cancer patients. There are many other potential uses for rhTSH, including facilitation of treatment of patients with thyroid cancer and nodular goiter. The diagnostic and therapeutic role of rhTSH in patients with differentiated thyroid cancer and nodular goiter will be discussed in this review.     

Baja prevalencia de resistencias primarias frente al virus de la hepatitis B en el sur de España

Introduction

To know the prevalence of primary resistance in chronic hepatitis B naïve patients is essential to decide on the need of routine laboratory testing.

Patients and methods

The genetic sequence of the HBV polymerase from 105 naïve patients was analysed.

Results

rtV173L, a lamivudine compensatory mutation, was detected in two patients (1.9%), rtI233V in one patient, and another one carried the sG145R vaccine escape mutation.

Conclusion

Our study shows that studying HBV resistance in naïve patients should not be recommended in the routine laboratory setting, for the time being     

Valuable predictive features of relapse of Graves’ disease after antithyroid drug treatment

Purpose

Antithyroid drug treatment (ATDT) effectively achieves euthyroidism in patients with Graves’ disease (GD). However, apparently successful treatment may be followed by relapse. We investigated the outcome of ATDT in Chinese patients with GD to identify predictive features of relapse.

Methods

In total, 133 patients with mild to moderate goiter were included in this analysis. All patients received methimazole for 12 to 40 months and were subsequently followed up for at least 1 year. Lasting remission was defined as the presence of clinical and laboratory features of euthyroidism for ≥ 1 year after stopping methimazole.

Results

Most patients (118 of 133, 88.7%) remained in remission after the follow-up period; 15 patients (11.3%) developed relapse. A history of GD, larger goiter at the time of drug withdrawal, a positive thyroid-stimulating antibody titer and restauration of low thyroid-stimulating hormone levels during the maintenance period were related to a subsequent risk of relapse according to stepwise logistic regression analysis results. However, other clinical and biological features (age, sex, initial goiter, ophthalmopathy, thyroxine and triiodothyronine levels and thyroglobulin antibody and thyroid microsomal antibody titers) did not reach statistical significance.

Conclusion

Regular, individualized ATDT achieved an 88.7% remission rate in Chinese patients with GD. The features associated with probable relapse were a history of GD, larger goiter at the time of drug withdrawal, a positive thyroid-stimulating antibody titer at the time of drug withdrawal and redevelopment of low thyroid-stimulating hormone levels during the maintenance period.     

Fall in thyroid stimulating hormone (TSH) may be an early marker of ipilimumab-induced hypophysitis

Purpose

Hypophysitis develops in up to 19% of melanoma patients treated with ipilimumab, a cytotoxic T-lymphocyte antigen-4 antibody. Early detection may avert life-threatening hypopituitarism. We aimed to assess the incidence of ipilimumab-induced hypophysitis (IH) at a quaternary melanoma referral centre, and to determine whether cortisol or thyroid stimulating hormone (TSH) monitoring could predict IH onset.

Methods

We performed a retrospective cohort study of ipilimumab-treated patients at a quaternary melanoma referral centre in Australia. The inclusion criteria were patients with metastatic or unresectable melanoma treated with ipilimumab monotherapy, and cortisol and TSH measurements prior to ≥?2 infusions. The main outcomes were IH incidence and TSH and cortisol patterns in patients who did and did not develop IH.

Results

Of 78 ipilimumab-treated patients, 46 met the study criteria and 9/46 (20%) developed IH at a median duration of 13.0 weeks (range 7.7–18.1) following ipilimumab initiation. All patients whose TSH fell ≥?80% compared to baseline developed IH, and, in 5/9 patients with IH, TSH fell prior to cortisol fall and IH diagnosis. Pre-cycle-4 TSH was significantly lower in those who developed IH (0.31 vs. 1.73 mIU/L, P?=?0.006). TSH fall was detected at a median time of 9.2 (range 7.7–16.4) weeks after commencing ipilimumab, and a median of 3.6 (range of ??1.4 to 9.7) weeks before IH diagnosis. There was no difference in TSH between the groups before cycles 1–3 or in cortisol before cycles 1–4.

Conclusions

TSH fall ≥?80% may be an early marker of IH. Serial TSH measurement during ipilimumab therapy may be an inexpensive tool to expedite IH diagnosis.

     

Symptom burden in stable COPD patients with moderate or severe airflow limitation

Objectives

To describe a multidimensional symptom profile in patients with stable chronic obstructive pulmonary disease (COPD) and determine whether symptom experience differed between patients with moderate or severe airflow limitations.

Background

Patients with severe airflow limitation experience numerous symptoms, but little is known regarding patients with moderate airflow limitation.

Methods

A multidimensional symptom profile (Memorial Symptom Assessment Scale) was assessed in 42 outpatients with moderate and 49 with severe airflow limitations.

Results

The mean number of symptoms in the total sample was 7.9 (±4.3) with no difference between patients with moderate and severe airflow limitations. The most prevalent symptoms with the highest MSAS symptom burden scores were shortness of breath, dry mouth, cough, sleep problems, and lack of energy in both groups.

Conclusions

Patients with moderate or severe airflow limitations experience multiple symptoms with high severity and distress. An assessment of their multidimensional symptom profile might contribute to better symptom management.     

Syndrome des antisynthétases et adénocarcinome pulmonaire : une association fortuite ?

Introduction

Dermatomyositis and polymyositis are sometimes associated with neoplasia. Conversely, a link between antisynthetase syndrome and neoplasia has not been clearly demonstrated.

Case report

We report a 54-year-old smoker male patient who presented with an antisynthetase syndrome with anti-Jo1 and anti-Ro-52 antibodies. An adenocarcinoma of the lung was diagnosed at the same time.

Conclusion

Two recent studies showed that patients with an antisynthetase syndrome associated with anti-Jo1 antibodies have more severe prognosis than antisynthetase syndrome associated with other antibodies (i.e. PL7/PL12). The risk of cancer occurrence seems to be increased when the anti-Jo1 antisynthetase syndrome is associated with anti-Ro-52 antibodies. To date, there is no demonstrated association between antisynthetase syndrome and neoplasia.