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John Edward M Midgley

John Edward M Midgley
North Lakes Clinical · Research & Development

B Sc (Leeds), D Phil (Oxford)

About

145
Publications
21,084
Reads
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2,398
Citations
Additional affiliations
October 1975 - September 1988
Amersham International
Position
  • Clinical Trials Coordinator
Description
  • In charge of clinical trials on in vivo and in vitro diagnostics
October 1967 - October 1975
Newcastle University
Position
  • Lecturer and Senior MRC Research Fellow
October 1962 - September 1967
University of Leeds
Position
  • Lecturer
Education
September 1958 - August 1960
University of Oxford
Field of study
  • Physical Chemistry
October 1954 - July 1958
University of Leeds
Field of study
  • Biochemistry

Publications

Publications (145)
Article
Full-text available
Endocrine regulation in the hypothalamic-pituitary-thyroid (HPT) axis is orchestrated by physiological circuits which integrate multiple internal and external influences. Essentially, it provides either of the two responses to overt biological challenges: to defend the homeostatic range of a target hormone or adapt it to changing environmental cond...
Article
Controversial issues have long surrounded the treatment of subclinical hypothyroidism. The current debate should encourage further efforts to find a more clinically inclusive definition for subclinical thyroid disease, more deserving of this name.
Article
Full-text available
Elevated concentrations of free thyroid hormones are established cardiovascular risk factors, but the association of thyrotropin (TSH) levels to hard endpoints is less clear. This may, at least in part, ensue from the fact that TSH secretion depends not only on the supply with thyroid hormones but on multiple confounders including genetic traits, m...
Article
A recent debate has evaluated the primary test schema for assessing thyroid function, direct measurement of thyroid hormones or the pituitary hormone TSH.
Article
The question arises as to whether clinicians should be mainly interested in central tendency.
Article
Full-text available
Background: Subclinical hyperthyroidism/thyrotoxicosis originates from different causes and clinical conditions, sharing the laboratory constellation of a suppressed TSH in the presence of thyroid hormone concentrations within the reference range. Aim: Presentation of hyperthyroidism can manifest itself in several ways. We questioned whether there...
Article
Background: Defined by thyroid-pituitary feedback control, clinical diagnosis of hypothyroidism and hyperthyroidism has become synonymous with TSH measurement. Study aim: We combined in silico analysis and in vivo data to explore the central influences on thyroidal T3 production. Materials & methods: A system of five coupled first order nonlin...
Article
Full-text available
Background: For significant numbers of patients dissatisfied on standard levothyroxine (LT4) treatment for hypothyroidism, patient-specific responses to T4 could play a significant role. Aim: To assess response heterogeneity to LT4 treatment, identifying confounders and hidden clusters within a patient panel, we performed a secondary analysis using...
Article
Full-text available
Levothyroxine (LT4) therapy has a long history, a well-defined pharmacological profile and a favourable safety record in the alleviation of hypothyroidism. However, questions remain in defining the threshold for the requirement of treatment in patients with subclinical hypothyroidism, assessing the dose adequacy of the drug, and selecting the best...
Article
Full-text available
Background In the treatment for hypothyroidism, a historically symptom-orientated approach has given way to reliance on a single biochemical parameter, thyroid stimulating hormone (TSH). Main body The historical developments and motivation leading to that decision and its potential implications are explored from pathophysiological, clinical and st...
Book
Full-text available
The discovery of the negative feedback of thyroid hormones on pituitary thyroid- stimulating hormone (TSH) secretion, a classical endocrine feedback control system, has shaped diagnosis and treatment of thyroid disease for the last decades. Based on this concept, a unique diagnostic category of subclinical thyroid disorders was introduced, being de...
Article
Full-text available
Randomised controlled trials are deemed to be the strongest class of evidence in evidence-based medicine. Failure of trials to prove superiority of T3/T4 combination therapy over standard LT4 monotherapy has greatly influenced guidelines, while not resolving the ongoing debate. Novel studies have recently produced more evidence from the examination...
Article
Full-text available
Aim The present study examines the relationship between the sensitivity of TSH feedback and thyroid capacity in untreated patients with thyroid autoimmune disease (n= 86) and healthy controls (n= 271). Functional capacity was estimated at maximum TSH stimulation, and pituitary TSH response was FT4‐standardised with two established indices, the TSH...
Article
Aim Patients on levothyroxine-treatment frequently have complaints although TSH is within the reference range. Moreover, FT3 is often low in these patients. The clinical significance of this disequilibrium is studied here. Patients, methods We conducted a retrospective longitudinal study including 319 patients with differentiated thyroid carcinoma...
Article
Full-text available
In thyroid health, the pituitary hormone thyroid-stimulating hormone (TSH) raises glandular thyroid hormone production to a physiological level and enhances formation and conversion of T4 to the biologically more active T3. Overstimulation is limited by negative feedback control. In equilibrium defining the euthyroid state, the relationship between...
Article
Full-text available
Introduction The relationship between pituitary TSH and thyroid hormones is central to our understanding of thyroid physiology and thyroid function testing. Here, we generated distribution patterns by using validated tools of thyroid modelling. Methods We simulated patterns of individual set points under various conditions, based on a homeostati...
Data
S2 Table. De-identified patient data in data interchange format.
Data
S1 File. Supplementary code for the statistical platform R.
Data
S1 Table. De-identified patient data in Office Open XML format.
Data
Supplementary code for the statistical platform R. (DOC)
Data
De-identified patient data in Office Open XML format. (XLSX)
Data
De-identified patient data in data interchange format. (DIF)
Article
Full-text available
The hypothalamus–pituitary–thyroid feedback control is a dynamic, adaptive system. In situations of illness and deprivation of energy representing type 1 allostasis, the stress response operates to alter both its set point and peripheral transfer parameters. In contrast, type 2 allostatic load, typically effective in psychosocial stress, pregnancy,...
Article
Full-text available
Background: Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to differentiate contributions of FT4 and FT3 in controlling pituitary thyroid stimulating hormone (TSH) secretion. Methods: We retrospectively assessed the relationships between TSH and thyroid hormones in 319 patients with thyroid carcinoma through 2914...
Article
Full-text available
Thyroid hormone concentrations only become sufficient to maintain a euthyroid state through appropriate stimulation by pituitary thyroid-stimulating hormone (TSH). In such a dynamic system under constant high pressure, guarding against overstimulation becomes vital. Therefore, several defensive mechanisms protect against accidental overstimulation,...
Article
Full-text available
Background/aim: Operating far from its equilibrium resting point, the thyroid gland requires stimulation via feedback-controlled pituitary thyrotropin (TSH) secretion to maintain adequate hormone supply. We explored and defined variations in the expression of control mechanisms and physiological responses across the euthyroid reference range. Met...
Article
Full-text available
Although technical problems of thyroid testing have largely been resolved by modern assay technology, biological variation remains a challenge. This applies to subclinical thyroid disease, non-thyroidal illness syndrome and those 10% of hypothyroid patients, who report impaired quality of life despite normal thyrotropin (TSH) concentrations under L...
Article
Full-text available
Although pituitary thyrotropin (TSH) and thyroid hormones are physiologically interrelated, interpretation of measurements is conventionally done separately. Classification of subclinical thyroid dysfunction depends by definition solely on an abnormal TSH. This study examines a composite multivariate approach to disease classification. Methods: Bi...
Article
Full-text available
In their Comment in The Lancet Diabetes & Endocrinology,1 Elizabeth McAninch and Antonio Bianco1 raise the important issue of the variable effectiveness of levothyroxine (LT4) monotherapy for hypothyroidism. Residual hypothyroid symptoms in 12% of patients on LT4 treatment in the USA, the European Union, and China translates to more than 13 million...
Article
Full-text available
The long-held concept of a proportional negative feedback control between the thyroid and pituitary glands requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic interrelationships between thyroid hormones and pituitary thyrotropin (TSH). They display a high degree of individuality, thyroid-state-rela...
Article
Full-text available
Objective: Several influences modulate biochemical responses to weight-adjusted levothyroxine (L-T4) replacement dose. We conducted a secondary analysis of the relationship of L-T4 dose to TSH and FT3, using a prospective observational study examining the interacting equilibria between thyroid parameters. Methods: We studied 353 patients on steady-...
Data
Full-text available
Several influences modulate biochemical responses to a weight-adjusted levothyroxine (L-T4) replacement dose. We conducted a secondary analysis of the relationship of L-T4 dose to TSH and free T3 (FT3), using a prospective observational study examining the interacting equilibria between thyroid parameters. We studied 353 patients on steady-state L-...
Article
The objective of the study was to evaluate the roles of central and peripheral T3 regulation. In a prospective study involving 1 796 patients, the equilibria between FT3 and TSH were compared in untreated and L-T4-treated patients with varying functional states, residual thyroid secretory capacities and magnitudes of TSH stimulation. T3 concentrati...
Article
Full-text available
Setting the reference range for thyrotropin (TSH) remains a matter of ongoing controversy. Patients, methods: We used an indirect method to determine the TSH reference range post hoc in a large sample. A total of 399 well characterised subjects showing no evidence of thyroid dysfunction were selected for definition of the TSH reference limits acc...
Data
Full-text available
This is an online supplement to the research paper titled "Homeostatic Equilibria Between Free Thyroid Hormones and Pituitary Thyrotropin Are Modulated By Various Influences Including Age, Body Mass Index and Treatment" (doi 10.1111/cen.12527). It shows correlation between ln TSH and FT3, FT4 and total deiodinase activity (SPINA-GD). Additionally,...
Article
Full-text available
Objective: We examined the interrelationships of pituitary thyrotropin (TSH) with circulating thyroid hormones to determine whether they were expressed either invariably or conditionally and distinctively related to influences such as levothyroxin e (L-T4) treatment. Design and Methods: This prospective study employing 1912 consecutive patients an...
Article
Full-text available
Recently in JACS, Ojomo and coauthors published a retrospective evaluation of patients post-thyroidectomy, concluding that maintenance levothyroxine (L-T4) doses are best predicted by body mass index (BMI) rather than by the traditional practice of measuring body weight. Others concomitantly used an even larger cohort, showing instead that L-T4 dos...
Article
Full-text available
Aims: Understanding the exact relationship between serum thyrotropin/thyroid stimulating hormone (TSH) and free thyroxine (FT(4)) is a prerequisite for improving diagnostic reliability and clinical decision making. Methods: We (1) retrospectively studied the relationship between TSH and FT(4) in a large unselected clinical sample (n=6641) of pri...
Article
Full-text available
Objective: In recognition of its primary role in pituitary-thyroid feedback, TSH determination has become a key parameter for clinical decision-making. This study examines the value of TSH as a measure of thyroid hormone homoeostasis under thyroxine (T(4)) therapy. Design and methods: We have examined the interrelationships between free triiodot...
Article
Full-text available
Background: In light of several recent recommendations to use total thyroxine (T4) measurements in the diagnosis of thyroid function in pregnancy (in particular, "Clinical Practice Guidelines for Hypothyroidism in Adults," cosponsored by the American Thyroid Association and the American Association of Clinical Endocrinologists, which promote the u...
Article
Full-text available
Advances in assay technology have promoted thyrotropin (TSH) measurements from participation in a multi-analyte assessment of thyroid function to a statistically defined screening parameter in its own right. While this approach has been successful in many ways, it has some grave limitations. This includes the basic question of what constitutes an a...
Article
Full-text available
To examine the merits of measuring free analytes by ultrafiltration using either diluted or undiluted serum. Confidence in the accuracy of measurements is affected both by problems identified in current systems using semipermeable membranes, the sensitivity of the system to artefacts and comparisons with other imperfect assays. All "gold standard"...
Article
Full-text available
We have read with interest recent reports of the measurement of free thyroxine and free triiodothyronine by ultrafiltration and tandem mass spectrometry (1)(2)(3)(4). There is, however, a fundamental flaw in these studies that we wish to bring to general attention. Ultrafiltration of serum was routinely carried out close to room temperature (25 °C)...
Article
Full-text available
In the history of clinical immunoassay, even up to the present day, no group of tests has been subjected to more scrutiny and controversy than analog-type free-analyte assays (1)(2)(3)(4). Unfortunately, inappropriate design of many experiments has led users to an incorrect perspective of how analog assays work. An analysis of the important series...
Article
Full-text available
I read with misgivings the recent communication by Fritz et al. (1) alleging that because under some circumstances an analog free thyroxine (FT4) immunoassay correlates total T4 and FT4 values, it does not measure FT4 but something akin to T4. I have shown repeatedly through mass action analyses (2)(3)(4) that many experiments, including the one re...
Article
Full-text available
Thyroid hormone uptake tests perform inadequately in several areas of thyroid function diagnosis. The theory underpinning this class of tests, typified by T3 (triiodo-thyronine)-uptake, has been reexamined using equilibrium Mass Action principles. Regardless of whether labeled T3, or any equivalent substitute, either does or does not saturate the u...
Article
Full-text available
The rules governing one-step analog immunoassays for free thyroid hormones remain controversial. By the use of mass action theory, this commentary seeks to resolve the disagreements by reemphasizing the criteria underpinning valid free thyroxine assays. The legitimacy of one-step immunoassays for free thyroxine has also been questioned from experim...
Article
Full-text available
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...
Article
Full-text available
We describe a one-step, labeled-antibody radioassay for measuring free thyroxin (FT4) in serum or plasma, based on a novel principle. FT4 in the sample competes with a gross molar excess (over antibody) of a cross-reactant (L-triiodothyronine, T3), chemically coupled to magnetizable polymer particles, for binding to avid 125l-labeled monoclonal ant...
Article
Full-text available
Free thyroxin (FT4) estimates by two immunoassays were compared with the concentrations of albumin in serum of apparently euthyroid subjects who either were (n = 99) or were not (n = 327) suffering from severe nonthyroidal illness (sNTI). In neither group was FT4 significantly correlated with albumin (P greater than 0.05), according to a "labeled a...
Article
Full-text available
Free thyroxin (FT4) concentrations, total thyroxin/thyroxin-binding globulin (T4/TBG) ratios, and thyrotropin (TSH) and albumin concentrations were measured in serum in a longitudinal study in each of the three trimesters of 25 normal pregnancies. In late pregnancy, FT4 estimates by assays reputedly either affected or unaffected by albumin were in...
Article
We studied the effect of adding purified human albumin to sera on free thyroxine (FT4) values obtained with Amerlex radioimmunoassays. Apparent FT4 values increased with progressive addition of albumin in vitro. The effect was smallest with low and greatest with high initial FT4 concentrations, which were also linearly correlated with the increment...
Article
Full-text available
We determined binding characteristics of the triiodothyronine (T3) analog tracer used in the Amerlex and Amerlex-M FT3 radioimmunoassay for the three endogenous binding proteins in serum: thyroxin-binding globulin (TBG), thyroxin binding prealbumin (PA), and albumin. Both T3 and its analog bind to the same sites on TBG and PA. However, the analog h...