Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design.

Approximately 10%-15% of subjects with hypothyroidism on L-thyroxine (LT4) alone have persistent symptoms affecting their quality of life (QoL). Although the cause is unclear, there is evidence that "tissue T3 lack" may be responsible. If so, combining liothyronine (LT3) with LT4 would be helpful. However, randomized controlled trials (RCT), have not established greater efficacy for the LT3 + LT4 combination in these subjects than for LT4 alone. While the trial design may have been responsible, the use of unphysiological, short-acting LT3 preparations and non-thyroid-specific patient-reported outcome measures (PROMs) may have contributed. We recommend attention to the following aspects of trial design for future RCTs of LT3 + LT4 compared to LT4 alone: (a) Subject selection-(i) measurable symptoms (disadvantages should be recognized); (ii) using a validated thyroid specific PROM such as ThyPRO39 or the Composite scale derived from it; (iii) those taking over 1.2 µg/day or 100 µg/day (for pragmatic reasons) of LT4 defining a population likely without intrinsic thyroid activity who depend on exogenous LT4; (iv) recruiting a preponderance of subjects with autoimmune thyroiditis increasing generalisability; and (v) those with a high symptom load with a greater response to combination therapy e.g. those with the deiodinase 2 polymorphism. (b) The use of physiological LT3 preparations producing pharmacokinetic similarities to T3 profiles in unaffected subjects: two long-acting LT3 preparations are currently available and must be tested in phase 2b/3 RCTs. (c) The superiority of a crossover design in limiting numbers and costs while maintaining statistical power and ensuring that all subjects experienced the investigative medication.

Pre-test Cortisol Levels in Predicting Short Synacthen Test Outcome: A Retrospective Analysis.

Objective: Short Synacthen tests (SSTs) are expensive, dependent on Synacthen availability, and need supervision. To reduce SST testing, we examined the utility of pre-test cortisol (Cort0) and related parameters in predicting outcome. Design and Measurements: We retrospectively examined the following in all SSTs; (i) Cort0 (ii) indications (iii) and time and place of testing. Receiver operated characteristic (ROC) curves were devised for Cort0 to obtain the best cut-off for outcome prediction in those who had SSTs between 8 and 10 am (Group 1) and at other times (Group 2). Results: Of 506 SSTs, 13 were unsuitable for analysis. 111/493 SSTs (22.5%) were abnormal. (1) ROC curves predicted - (a) SST failure with 100% specificity when Cort0 was ⩽124 nmol/L (Group 1), or ⩽47 (Group 2); (b) a normal SST with 100% sensitivity when Cort0 ⩾314 nmol/L (Group 1) and ⩾323 nmol/L (Group 2). (2) There was significant correlation between Cort0 and 30-minute cortisol (rs = 0.65-0.78, P < .001). (3) Median Cort0 was lower in those who failed SSTs compared to those who passed (147 vs 298 nmol/L respectively, P < .001). (4) SST failure was commoner in Group 1 vs 2 (P = .001). (5) There was no difference in outcome between out-patient and inpatient SSTs. (6) SST failure was most common for 'steroid related' indications (39.6%, P < .001). Conclusions: This study indicates that (1) Cort0 ⩾ 323 (Group1) and ⩾314 nmol/L (Group 2) predicted a normal SST with 100% sensitivity; (2) Using these cut offs 141/493 (28.6%) tests may have been avoided; (3) supporting evidence should be considered in those with a lower pre-test predictability of failure.

Thyrotrophin receptor antibody concentration and activity, several years after treatment for Graves' disease.

OBJECTIVE: TSH receptor antibodies (TRAb) are responsible for autoimmune hyperthyroid disease (Graves' disease; GD) with TRAb levels tending to decrease following treatment. Measurement of TRAb activity during follow-up could prove valuable to better understand treatment effectiveness. STUDY DESIGN: TRAb concentration and stimulating (TSAb) and blocking (TSBAb) activity of patient serum were assessed following different treatment modalities and follow-up length. METHODS: Sixty-six subjects were recruited following treatment with carbimazole (n = 26), radioiodine (n = 27) or surgery (n = 13). TRAb, TPOAb, TgAb and GADAb were measured at a follow-up visit as well as bioassays of TSAb and TSBAb activity. RESULTS: Forty-five per cent of all patients remained TRAb-positive for more than one year and 23% for more than 5 years after diagnosis, irrespective of treatment method. Overall, TRAb concentration fell from a median (IQR) of 6.25 (3.9-12.7) to 0.65 (0.38-3.2) U/L. Surgery conferred the largest fall in TRAb concentration from 11.4 (6.7-29) to 0.58 (0.4-1.4) U/L. Seventy per cent of TRAb-positive patients were positive for TSAb, and one patient (3%) was positive for TSBAb. TRAb and TSAb correlated well (r = 0.83). In addition, 38/66 patients were TgAb-positive, 47/66 were TPOAb-positive and 6/66 were GADAb-positive at follow-up. CONCLUSIONS: TRAb levels generally decreased after treatment but persisted for over 5 years in some patients. TRAb activity was predominantly stimulatory, with only one patient demonstrating TSBAb. A large proportion of patients were TgAb/TPOAb-positive at follow-up. All treatment modalities reduced TRAb concentrations; however, surgery was most effective.

A Retroperitoneal Leiomyosarcoma Presenting as an Adrenal Incidentaloma in a Subject on Warfarin.

Adrenal incidentalomas (AIs) are mostly benign and nonsecretory. Management algorithms lack sensitivity when assessing malignant potential, although functional status is easier to assess. We present a subject whose AI was a retroperitoneal leiomyosarcoma (RL). Case Presentation. A woman on warfarin with SLE and the antiphospholipid syndrome, presented with left loin pain. She was normotensive and clinically normal. Ultrasound scans demonstrated left kidney scarring, but CT scans revealed an AI. MRI scans later confirmed the AI without significant fat and no interval growth. Cortisol after 1 mg dexamethasone, urinary free cortisol and catecholamines, plasma aldosterone renin ratio, and 17-hydroxyprogesterone were within the reference range. Initially, adrenal haemorrhage was diagnosed because of warfarin therapy and the acute presentation. However, she underwent adrenalectomy because of interval growth of the AI. Histology confirmed an RL. The patient received adjuvant radiotherapy. Discussion. Our subject presented with an NSAI. However, we highlight the following: (a) the diagnosis of adrenal haemorrhage in this anticoagulated woman was revised because of interval growth; (b) the tumour, an RL, was relatively small at diagnosis;

Newer dopaminergic agents cause minimal endocrine effects in idiopathic Parkinson's disease.

OBJECTIVE: We studied the prevalence of endocrine dysfunction in subjects with idiopathic Parkinson's disease (IPD) on newer dopaminergic agents (DA). DA are also used in endocrine hypersecretory states in small doses and we hypothesized that endocrine dysfunction was likely in IPD where DA were used in comparatively much higher dosage. PATIENTS AND METHODS: Twenty-five subjects with IPD, established on DA, were recruited to this cross-sectional study. We measured insulin-like growth factor-1, prolactin, luteinizing hormone, follicle stimulating hormone, thyroid function, oestradiol or testosterone and cortisol levels following a short synacthen test. RESULTS: We studied 18 males and 7 females, whose median age was 72 years, and whose median time from diagnosis, and duration of treatment was 27 months (interquartile range 17-45 and 13-39 months, respectively). (1) Endocrine tests were normal in 19 of 25 subjects at recruitment. Minor abnormalities reverted to normal on repeat testing in three of six with initial abnormalities; two had persistent abnormalities and the third subject could not be further investigated. Therefore, 22 of 24 (92%) with IPD on DA therapy had normal endocrine profiles. (2) The cortisol response to ACTH was normal in 24 of 25 subjects (96%). (3) Eleven subjects (44%) had isolated PRL suppression. There were no differences between the suppressed PRL and "normal" PRL groups. However, a higher number of them were on non-ergoline-derived DA (83% vs 31%; P < 0.05). CONCLUSIONS: We have demonstrated that newer non-ergoline DA therapy caused only minimal endocrine perturbations in subjects with IPD. Their clinical significance can only be speculative currently. The cortisol response to ACTH was normal in almost all but a significant minority had suppressed prolactin levels.

Thyroid peroxidase antibody and screening for postpartum thyroid dysfunction.

Postpartum thyroid dysfunction (PPTD) is a common disorder which causes considerable morbidity in affected women. The availability of effective treatment for hypothyroid PPTD, the occurrence of the disease in subsequent pregnancies and the need to identify subjects who develop long term hypothyroidism, has prompted discussion about screening for this disorder. There is currently no consensus about screening as investigations hitherto have been variable in their design, definitions and assay frequency and methodology. There is also a lack of consensus about a suitable screening tool although thyroid peroxidase antibody (TPOAb) is a leading contender. We present data about the use of TPOAb in early pregnancy and its value as a screening tool. Although its positive predictive value is moderate, its sensitivity and specificity when used in early pregnancy are comparable or better compared to other times during pregnancy and the postpartum period. Recent studies have also confirmed this strategy to be cost effective and to compare favourably with other screening strategies. We also explore the advantages of universal screening.