USE OF THE FREE THYROXINE INDEX TO REFINE THE LOWER LIMIT OF A FREE THYROXINE IMMUNOASSAY FOR DETECTION OF SECONDARY HYPOTHYROIDISM

Objective: To determine the utility of measuring free T4 index (FT4I) in patients with low free T4 (FT4) by immunoassay and normal TSH in the evaluation for secondary hypothyroidism. Methods: We performed a retrospective medical chart review of patients seen at a single institution as outpatients who had a simultaneously normal TSH, low FT4, and any FT4I measured between June 2014 and October 2016. Demographic, laboratory, and imaging data were collected. Using FT4I level as the reference for diagnosis of hypothyroidism, the sensitivity and specificity of FT4 immunoassay lower limit thresholds were determined. Within each threshold group, available brain imaging and biochemical evaluation was categorized according to presence or absence of pituitary disease. Results: A total of 155 sets of result pairs (FT4 and FT4I) performed on 118 subjects were analyzed. The lower limit of normal FT4 by immunoassay at this institution is 0.93 ng/dL, though all pairs with FT4 ≥ 0.89 ng/dL had a normal FT4I. All pairs with FT4 ≤ 0.67 ng/dL had a low FT4I. No pituitary macroadenomas were identified in any subjects, though rates of pituitary imaging in this patient sample were low. Conclusions: Patients with a borderline low FT4 by immunoassay often have a normal FT4I. In such patients at our center, significant structural and biochemical pituitary pathology was uncommon. Abbreviations: ACTH = adrenocorticotropic hormone; AUC = area under the curve; BIDMC = Beth Israel Deaconess Medical Center; FSH = follicle-stimulating hormone; FT4 = free thyroxine; FT4I = free thyroxine index; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; PPV = positive predictive value; ROC = receiver operating characteristic; SD = standard deviation; TSH = thyroid stimulating hormone.

Measurement of Serum Free Thyroxine Index May Provide Additional Case Detection Compared to Free Thyroxine in the Diagnosis of Central Hypothyroidism

The diagnosis of central hypothyroidism is often suspected in patients with hypothalamic/pituitary pathology, in the setting of low, normal, or even slightly elevated serum TSH and low free thyroxine (FT4). We present four cases of central hypothyroidism (three had known pituitary pathology) in whom central hypothyroidism was diagnosed after the serum free thyroxine index (FTI) was found to be low. All had normal range serum TSH and free thyroxine levels. This report illustrates that the assessment of the serum FTI may be helpful in making the diagnosis of central hypothyroidism in the appropriate clinical setting and when free T4 is in the low-normal range, particularly in patients with multiple anterior pituitary hormone deficiencies and/or with symptoms suggestive of hypothyroidism.

Hypothyroidism in patients with Bipolar I Disorder treated primarily with lithium

SUMMARYAims – This study evaluated the frequency and clinical significance of abnormal Thyroid Stimulating Hormone (TSH) and Free Thyroxine Index (FTI) in patients with bipolar I disorder treated primarily with lithium. Method – We evaluated the medical records of 143 participants in the Pittsburgh study of Maintenance Therapies in Bipolar Disorder who did not have a thyroid abnormality at entry. Results – Thirty-six percent of the 143 patients developed abnormal TSH and/or FTI values. Thirty-eight percent of the 135 patients who received lithium developed abnormal TSH and/or FTI, spent significantly longer time in the acute treatment phase (t = -3.6, df = 133, p = .0004), and had significantly higher mean Hamilton Scale for Depression scores over the course of the maintenance phase (t = -2.3, df = 71.6, p = .03). Time on lithium and development of abnormal TSH and/or FTI were positively correlated (r = .25, p = .004). Conclusions – Thyroid dysfunction can be frequent in patients exposed to lithium treatment for bipolar I disorder; it also appears to be correlated with a slower response to acute treatment, and may be related to poorer quality of long-term remission. A prospective study is needed to confirm our findings and determine whether more aggressive thyroid replacement can optimize thyroid function to facilitate clinical recovery.Declaration of Interest: Supported in part by National Institute of Mental Health Grants MH 029618 (Drs. Frank and Fagiolini) and MH 030915 (Drs. Kupfer and Fagiolini), and the Bosin Memorial Fund of The Pittsburgh Foundation (Drs. Fagiolini, Kupfer, Cook, Scott, Novick and Frank). Dr. Fagiolini is on the advisory board and a consultant to Pfizer Inc, and Bristol Myers Squibb, and is on the speaker bureau of Bristol Myers Squibb, Eli Lilly Italy, Pfizer Inc, and Shire. Dr. Frank is on the advisory board of Pfizer Inc. and Eli Lilly & Company, and is a consultant to Pfizer Italia and Sender Amerique. Dr. Kupfer is on the advisory board of Pfizer, Inc., Forest Pharmaceuticals, Inc., and Solvay-Wyeth Pharmaceuticals, and is a consultant to Servier Amerique.

Resumption of methimazole after 131I therapy of hyperthyroid diseases: effect on thyroid function and volume evaluated by a randomized clinical trial

OBJECTIVE: Retrospective studies have indicated that anti-thyroid drugs (ATD) might possess a radioprotective effect, leading to a higher rate of recurrence of hyperthyroidism after iodine-131 ((131)I) therapy. DESIGN: A randomized clinical trial was performed to clarify whether resumption of methimazole after (131)I influences the final outcome of this treatment. METHODS: We assigned 149 patients with Graves' disease or a toxic nodular goitre to groups either to resume (+ATD) or not to resume (-ATD) methimazole 7 days after (131)I. Before (131)I therapy, all patients were rendered euthyroid by methimazole, which was discontinued 4 days before the (131)I therapy. RESULTS: During the follow-up period of 12 Months, 13 patients developed hypothyroidism, 42 were euthyroid, and 18 had recurrence of hyperthyroidism in the +ATD group; the respective numbers in the -ATD group were 16, 42 and 18 (P=0.88). At 3 weeks after (131)I therapy, the serum free-thyroxine index was slightly decreased (by 5.7%; 95% confidence interval (CI) -15.5 to 5.4%) in the +ATD group, in contrast to an increase of 35.9% (95% CI 18.8 to 55.5%) in the -ATD group (P<0.001 between groups). In the subgroup that remained euthyroid during follow-up, thyroid Volume reduction, assessed by ultrasonography, was smaller in the +ATD group [38.7% (95% CI 33.3 to 44.1%)] than in the -ATD group [48.6% (95% CI: 41.5-55.6%)] (P<0.05). CONCLUSION: No radioprotective effect could be demonstrated, with regard to final thyroid function, for the resumpton of methimazole 7 days after (131)I therapy. Although resumption of methimazole slightly reduced the magnitude of shrinkage of the goitre obtained by (131)I, the prevention of a temporary thyrotoxicosis in the early period after radiation favours this regimen.

Direct and Indirect Free Thyroxine Assay Methods: Theory and Practice

Background: For the diagnosis of thyroid disease, measurement of “free hormone” is generally accepted as an appropriate measure. However, valid assays measuring the free fraction of thyroxine (FT4) ideally must perform without bias, despite large variations in the concentrations and affinities of serum T4-binding proteins in the population. Several approaches have been taken to overcome such bias, and these have created considerable controversy in the field over the past decade. Approach: This review, from both a historical and an analytical standpoint, charts the progress made over more than 30 years in improvements to the performance of assays in common use for the measurement of FT4 in serum or plasma. It reexamines the theory behind early approaches to such assays [for example, the free thyroxine index (FTI) method], that preceded more accurate, two-step immunoassays or one-step analog techniques. It evaluates the continuous refinements to the latter assays that by now have largely supplanted the FTI approach and where the deficiencies that so exercised clinical chemists in the past have been virtually eliminated in the leading assays. Content: The basic Mass Action theory underpinning all such methods is discussed by assessing how far each particular approach obeys the criteria the theory imposes. In this, it is not the intention of the review to dissect individual commercial or academic assays, but rather to give guidance where appropriate as to how any assay said to measure FT4 can be conveniently evaluated by those intending to use it. Examples are given where inappropriate tests may wrongly imply assay invalidity by misinterpreting how FT4 assays work. Summary: Detailed knowledge of the underlying theory is essential when devising tests for direct FT4 assays, to ensure that such tests do not overstep the practical limits of assay validity.