Paul G. Walfish

Randomized comparison of the effects of the vitamin D 3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients

BackgroundFor adults, vitamin D intake of 100 mcg (4000 IU)/day is physiologic and safe. The adequate intake (AI) for older adults is 15 mcg (600 IU)/day, but there has been no report focusing on use of this dose.MethodsWe compared effects of these doses on biochemical responses and sense of wellbeing in a blinded, randomized trial. In Study 1, 64 outpatients (recruited if summer 2001 25(OH)D <61 nmol/L) were given 15 or 100 mcg/day vitamin D in December 2001. Biochemical responses were followed at subsequent visits that were part of clinical care; 37 patients completed a wellbeing questionnaire in December 2001 and February 2002. Subjects for Study 2 were recruited if their 25(OH)D was <51 nmol/L in summer 2001. 66 outpatients were given vitamin D; 51 completed a wellbeing questionnaire in both December 2002 and February 2003.ResultsIn Study 1, basal summer 25-hydroxyvitamin D [25(OH)D] averaged 48 ± 9 (SD) nmol/L. Supplementation for more than 6 months produced mean 25(OH)D levels of 79 ± 30 nmol/L for the 15 mcg/day group, and 112 ± 41 nmol/L for the 100 mcg/day group. Both doses lowered plasma parathyroid hormone with no effect on plasma calcium. Between December and February, wellbeing score improved more for the 100-mcg/day group than for the lower-dosed group (1-tail Mann-Whitney p = 0.036). In Study 2, 25(OH)D averaged 39 ± 9 nmol/L, and winter wellbeing scores improved with both doses of vitamin D (two-tail p < 0.001).ConclusionThe highest AI for vitamin D brought summertime 25(OH)D to >40 nmol/L, lowered PTH, and its use was associated with improved wellbeing. The 100 mcg/day dose produced greater responses. Since it was ethically necessary to provide a meaningful dose of vitamin D to these insufficient patients, we cannot rule out a placebo wellbeing response, particularly for those on the lower dose. This work confirms the safety and efficacy of both 15 and 100 mcg/day vitamin D3 in patients who needed additional vitamin D.

Prospective management of nodal metastases in differentiated thyroid cancer

Previous studies have concluded that lymph node metastases do not affect survival rates in patients with differentiated thyroid carcinoma and, therefore, nodal metastasis has not been evaluated as a prognostic factor in recent definitions of risk groups. To determine the significance of nodal disease, we reviewed 227 consecutive patients with differentiated thyroid carcinoma (173 with papillary, 37 with follicular, and 17 with Hürthle cell carcinoma). Of 70 (31%) patients with lymph node metastases (14 [20%] palpable preoperatively and 56 [80%] detected by routine sampling of middle and lower cervical nodes), 13 (19%) developed a recurrence compared with only 3 of 157 (2%) without nodal disease (p less than 0.01). Sixty-eight patients were treated with modified neck dissection, 63 of whom received adjuvant radioiodine. There were 10 recurrences in 63 patients (16%) who had been treated with radioiodine, compared with 3 recurrences in 7 (42%) patients who did not receive adjuvant radioiodine. Follow-up ranged from 2 to 28 years, with a mean of 8 years. Involvement of the lymph nodes was a marker for systemic disease occurring synchronously in 4 of 5 patients who presented with distant metastases and preceding systemic recurrence in 9 of 10 patients. Four patients (2%), all with lymph node metastases (three with concomitant extrathyroidal invasion and one with systemic metastases at initial presentation), died of thyroid carcinoma. Cervical lymph node metastases were associated with a higher incidence of recurrence and occurred synchronously or preceded the development of distant metastases in 13 of 15 (87%) patients. Although these findings were not statistically significant for overall survival, they lend support to routine cervical lymph node sampling for detection of and modified neck dissection with adjuvant radioiodine therapy for treatment of lymph node metastases. Such measures should reduce the subsequent recurrence rate and permit early detection and treatment of systemic disease.

Prevalence and characteristics of post-partum thyroid dysfunction : results of a survey from Toronto, Canada

In order to determine the prevalence of post-partum thyroid dysfunction in our region, 1,376 randomly selected mothers were enrolled immediately post-partum and followed prospectively over a 2 year period in a large single-center survey. Beginning at delivery, sequential clinical and laboratory assessments were conducted at 6–8 week intervals up to 1 year post-partum and a questionnaire was administered at 3 months post-partum. Among the 1,376 mothers who qualified for entry into this study, 495 (36%) completed at least 3 months fol-low-up and 300 (22%) completed at least 1 year of follow-up. Abnormalities in post-partum thyroid function (PTD) were detected in 82 of the 1,376 enrolled mothers for an overall minimum prevalence rate of 6.0%. Hyperthyroidism confirmed to be associated with a low 24h radioactive iodine thyroid uptake (RAIU), compatible with the post-partum painless thyroiditis syndrome (PPT) was documented in 44 (3.2% minimum prevalence of typical PPT) of which 39 (89%) had a typical biphasic (hyperthyroid to hypothyroid) PTD while 5 (11%) had only a hyperthyroid phase with a suppressed RAIU without a subsequent hypothyroid phase. Another 17 (1.2%) had transient hyperthyroidism likely due to PPT but were not confirmed by an RAIU test and did not evolve to a detectable hypothyroid phase; and, 17 mothers (1.2%) had hypothyroidism between 5–7 months post-partum without preceding hyperthyroidism, resulting in an overall minimum prevalence of 5.7% for all variants of PPT. Graves’ hyperthyroidism oc-curred in 3 (0.2%) and toxic nodular goiter was present in 1 (0.07%). The overall prevalence of antimicrosomal antibody (A-Mc) titre at delivery was 8.2% and a positive anti-Mc Ab titre occurred in 88% of mothers with post-partum thyroiditis during the course of their illness. For the 44 mothers who developed PPT, peak titers of A-Mc Ab correlated with peak TSH values in mothers at 5 to 6 months postpartum. Among the 42 mothers with typical PPT followed at least 1 year post partum 4 (10%) had persistent hypothyroidism requiring T4 replacement and 6 (14%) were asymptomatic but biochemically hypothyroid. From the completed questionnaires received at 3 months after delivery from 24 mothers with PPT vs 184 unaffected mothers, a logistic regression analysis indicated that the overall differences in symptomatology was highly significant (p=<0.0001) with palpitations, heat intolerance and nervousness being the best discriminators of hyperthyroidism. A significant correlation could not be established at 3 months post-partum in PPT vs normal mothers for either a family history of thyroid disease and the presence of anti-Mc Ab or the occurrence of post-partum depression. From these observations, it is concluded that post-partum thyroid dysfunction occurs frequently in our region and represents a significant cause of post-partum morbidity.

Application of post-surgical stimulated thyroglobulin for radioiodine remnant ablation selection in low-risk papillary thyroid carcinoma.

We present our ongoing experience in the use of postsurgical stimulated serum thyroglobulin (Stim‐Tg) to assist in radioiodine remnant ablation (RRA) decision‐making.

EpCAM nuclear localization identifies aggressive Thyroid Cancer and is a marker for poor prognosis

BackgroundProteolytic cleavage of the extracellular domain (EpEx) of Epithelial cell adhesion molecule (EpCAM) and nuclear signaling by its intracellular oncogenic domain Ep-ICD has recently been implicated in increased proliferation of cancer cells. The clinical significance of Ep-ICD in human tumors remains an enigma.MethodsEpEx, Ep-ICD and β-catenin immunohistochemistry using specific antibodies was conducted on 58 archived thyroid cancer (TC) tissue blocks from 34 patients and correlated with survival analysis of these patients for up to 17 years.ResultsThe anaplastic (ATC) and aggressive thyroid cancers showed loss of EpEx and increased nuclear and cytoplasmic accumulation of Ep-ICD. In contrast, the low grade papillary thyroid cancers (PTC) showed membranous EpEx and no detectable nuclear Ep-ICD. The ATC also showed concomitant nuclear expression of Ep-ICD and β-catenin. Kaplan-Meier Survival analysis revealed reduced overall survival (OS) for TC patients showing nuclear Ep-ICD expression or loss of membranous EpEx (p < 0.0004), median OS = 5 months as compared to 198 months for patients who did not show nuclear Ep-ICD or demonstrated only membranous EpE.ConclusionWe report reciprocal loss of membrane EpEx but increased nuclear and cytoplasmic accumulation of Ep-ICD in aggressive TC; nuclear Ep-ICD correlated with poor OS of TC patients. Thus nuclear Ep-ICD localization may serve as a useful biomarker for aggressive TC and may represent a novel diagnostic, prognostic and therapeutic target for aggressive TC.

INAPPROPRIATE TRIIODOTHYRONINE (T3) AND THYROXINE (T4) RADIOIMMUNOASSAY LEVELS SECONDARY TO CIRCULATING THYROID HORMONE AUTOANTIBODIES

A 16‐year‐old boy with chronic lymphocytic thyroiditis was noted to have a low free thyroxine (T4) level, low triiodothyronine resin uptake (T3U), and high serum thyrotropin (TSH) values. Unexpectedly, markedly elevated T3 radioimmunoassay (RIA) and T4 (RIA) values, using a double antibody technique were obtained when performed directly on unextracted serum samples. Extremely low T4 (RIA) values were noted when polyethylene glycol (PEG) was used to separate bound from free hormone. The presence of circulating T3‐ and T4‐binding immunoglobulins was suspected and confirmed with the following special studies. With undiluted serum in a T3 (RIA) system, using dextran‐coated charcoal separation, 82% binding of 125I‐labelled T3 occurred in the absence of specific first antibody, with 55% binding retained at 1: 7 dilution with T3‐free serum. Comparable results were obtained in the T4 (RIA) system using polyethylene glycol separation. Following ethanol extraction, low T4 (RIA) and low normal T3 (RIA) values were obtained, using a double antibody technique. There was ten‐fold greater binding by the patients serum to rabbit anti‐human IgG in both the T3 and T4 radioassay systems as compared to controls. No preferential binding to rabbit anti‐human IgM was noted. Scatchard plot analyses for the antibodies against T3 and T4 showed high affinity constants for these hormones. With adequate l‐thyroxine therapy, an appropriate decline in serum TSH to normal was achieved. It is concluded that where RIA determinations of T3 and T4 are inconsistent with other laboratory and clinical indices, the presence of autoantibodies to thyroid hormones should be suspected and appropriate tests undertaken.

B-Mode Ultrasonography in Assessment of Thyroid Gland Lesions

Abstract We have used B-mode ultrasonography in a study of 150 cases to differentiate between cystic and solid characteristics of thyroid nodules, properties that could not be reliably determined b...

Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies.

CONTEXT Immunotherapies against immune checkpoints that inhibit T cell activation [cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1)] are emerging and promising treatments for several metastatic malignancies. However, the precise adverse effects of these therapies on thyroid gland function have not been well described. CASE DESCRIPTION We report on 10 cases of painless thyroiditis syndrome (PTS) from a novel etiology, following immunotherapy with anti-PD-1 monoclonal antibodies (mAb) during treatment for metastatic malignancies. Six patients presented with transient thyrotoxicosis in which thyrotropin binding inhibitory immunoglobulins (TBII) were absent for all, whereas four patients had evidence of positive antithyroid antibodies. All thyrotoxic patients required temporary beta-blocker therapy and had spontaneous resolution of thyrotoxicosis with subsequent hypothyroidism. Four patients presented with hypothyroidism without a detected preceding thyrotoxic phase, occurring 6-8 weeks after initial drug exposure. All of these patients had positive antithyroid antibodies and required thyroid hormone replacement therapy for a minimum of 6 months. CONCLUSIONS Patients receiving anti-PD-1 mAb therapy should be monitored for signs and symptoms of PTS which may require supportive treatment with beta-blockers or thyroid hormone replacement. The anti-PD-1 mAb is a novel exogenous cause of PTS and provides new insight into the possible perturbations of the immune network that may modulate the development of endogenous PTS, including cases of sporadic and postpartum thyroiditis.

Three-week thyroxine withdrawal thyroglobulin stimulation screening test to detect low-risk residual/recurrent well-differentiated thyroid carcinoma

Measurement of serum TSH-stimulated thyroglobulin (Tg) is recognized as a sensitive method for detecting residual/recurrent well-differentiated thyroid carcinoma (WDTC) in patients previously treated by surgery and radioactive iodine (RAI) ablation therapy. WDTC patients who have an undetectable serum Tg on thyroid hormone therapy (THT) in the absence of Tg-antibody interference are considered to be at low risk for residual/recurrent disease. Traditional management has been to withdraw T4 for 4–6 weeks or T3 for 2 weeks to stimulate endogenous TSH. However, this prolonged THT withdrawal induces hypothyroidism and its concomitant morbidity. In the present study, we assess the efficacy of shortening the time of T4 withdrawal to only 3 weeks for detecting residual/recurrent WDTC as a sufficient serum TSH stimulus for obtaining a positive serum Tg result without a routine diagnostic whole body scan (WBS). Additionally, we have evaluated the impact of such a T4 withdrawal interval on quality of life and loss of employment time. A total of 181 patients with WDTC selected for study had previously been treated with a bilateral surgical thyroidectomy followed by RAI ablation therapy (average post-surgery to follow-up interval of 10.8 yr). All of the cohort had an un-detectable (<1 μg/l) serum Tg on THT without Tg-antibody interference. Serum TSH and Tg were measured before and after cessation of T4 therapy for 3 weeks. A serum Tg ≽2 μg/l was considered positive for residual/recurrent disease. A quality of life questionnaire [Short-Form 36 (SF-36)] was administered before withdrawal, at peak TSH and after resumption of therapy. From the completed SF-36 questionnaires, the overall degree of functional impairment was not severe and did not result in loss of employment time. Moreover, this protocol identified three possible responses to the 3-week T4 withdrawal interval as follows: a) serum Tg undetectable with TSH ≽25 mIU/l (≈75% of total cohort); b) serum Tg ≽2μg/l (≈10% of total cohort) which will require further investigation and treatment for residual/recurrent disease; c) undetectable serum Tg with inadequate TSH rise (≈15% of total cohort), which will require TSH stimulation by either longer T4 withdrawal or recombinant human TSH to exclude residual disease. We conclude that a stimulated serum Tg test performed 3 weeks after T4 withdrawal is a simple and cost-effective first-line screening test with minimal morbidity which is sufficient to evaluate low-risk WDTC patients for recurrent/residual carcinoma.

INFLUENCE OF AGE AND PRIMARY TUMOR SIZE ON THE RISK FOR RESIDUAL/RECURRENT WELL-DIFFERENTIATED THYROID CARCINOMA

Though age and primary tumor size predict cancer‐specific survival in well‐differentiated thyroid carcinoma (WDTC), their influence on residual/recurrent disease has not been elucidated.