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Simon H. S. Pearce, Nicholas B. Argent, and Peter H. Baylis

Abstract.

We report the case of a young man who became adipsic following a subarachnoid hemorrhage and subsequently had two episodes of life-threatening hypernatremia. Investigations demonstrated that he had defective osmoregulated thirst and AVP release, but normal AVP responses to hypotension and nausea. There is also evidence that he had intact baroregulated thirst. We discuss the results of our investigations in the context of current models of hypothalamic-neurohypophysial function.

Free access

Salman Razvi, Bijay Vaidya, Petros Perros, and Simon H S Pearce

Block-replace and titration antithyroid drug regimens both give similar rates of medium- to long-term remission of hyperthyroid Graves’ disease. Recent meta-analysis, however, has suggested that titration regimens may be preferable owing to a higher rate of adverse events seen in the block-replace arms of published comparative studies. This article critically re-evaluates the evidence upon which these meta-analyses were based. We suggest that there is little objective evidence that is pertinent to current clinical practice to separate block-replace from titration antithyroid drug regimens and that both remain satisfactory approaches to the medical management of hyperthyroid Graves’ disease.

Open access

Earn H Gan, Katie MacArthur, Anna L Mitchell, and Simon H S Pearce

Background

Autoimmune Addison's disease (AAD) is a rare condition with a complex genetic basis. A panel of rare and functionally defective genetic variants in the sialic acid acetylesterase (SIAE) gene has recently been implicated in several common autoimmune conditions. We performed a case–control study to determine whether these rare variants are associated with a rarer condition, AAD.

Method

We analysed nine SIAE gene variants (W48X, M89V, C196F, C226G, R230W, T312M, Y349C, F404S and R479C) in a United Kingdom cohort of 378 AAD subjects and 387 healthy controls. All samples were genotyped using Sequenom iPlex chemistry to characterise primer extension products.

Results

A heterozygous rare allele at codon 312 (312*M) was found in one AAD patient (0.13%) but was not detected in the healthy controls. The commoner, functionally recessive variant at codon 89 (89*V) was found to be homozygous in two AAD patients but was only found in the heterozygous state in controls. Taking into account all nine alleles examined, 4/378 (1.06%) AAD patients and 1/387 (0.25%) healthy controls carried the defective SIAE alleles, with a calculated odds ratio of 4.13 (95% CI 0.44–97.45, two-tailed P value 0.212, NS).

Conclusion

We demonstrated the presence of 89*V homozygotes and the 312*M rare allele in the AAD cohort, but overall, our analysis does not support a role for rare variants in SIAE in the pathogenesis of AAD. However, the relatively small collection of AAD patients limits the power to exclude a small effect.

Free access

Wiebke Arlt, Stephanie E Baldeweg, Simon H S Pearce, and Helen L Simpson

We provide guidance on prevention of adrenal crisis during the global COVID-19 crisis, a time with frequently restricted access to the usual level of healthcare. Patients with adrenal insufficiency are at an increased risk of infection, which may be complicated by developing an adrenal crisis; however, there is currently no evidence that adrenal insufficiency patients are more likely to develop a severe course of disease. We highlight the need for education (sick day rules, stringent social distancing rules), equipment (sufficient glucocorticoid supplies, steroid emergency self-injection kit) and empowerment (steroid emergency card, COVID-19 guidelines) to prevent adrenal crises. In patients with adrenal insufficiency developing an acute COVID-19 infection, which frequently presents with continuous high fever, we suggest oral stress dose cover with 20 mg hydrocortisone every 6 h. We also comment on suggested dosing for patients who usually take modified release hydrocortisone or prednisolone. In patients with adrenal insufficiency showing clinical deterioration during an acute COVID-19 infection, we advise immediate (self-)injection of 100 mg hydrocortisone intramuscularly, followed by continuous i.v. infusion of 200 mg hydrocortisone per 24 h, or until this can be established, and administration of 50 mg hydrocortisone every 6 h. We also advise on doses for infants and children.

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Marissa Penna-Martinez, Gesine Meyer, Anette Bøe Wolff, Beate Skinningsrud, Corrado Betterle, Alberto Falorni, William Er Ollier, Dag Undlien, Eystein Sverre Husebye, Simon H S Pearce, Anna L Mitchell, and Klaus Badenhoop

OBJECTIVE

While vitamin D regulates immune cells, little is known about it in autoimmune Addison´s disease (AAD). We investigated the vitamin D status in AAD patients from five European populations to assess its deficiency. In addition, we studied two case-control cohorts for vitamin D metabolism and pathway genes.

DESIGN

Cross-sectional study

METHODS

A total of 1028 patients with AAD from Germany (n=239), Italy (n=328), Norway (n=378), UK (n=44) and Poland (n=39) and 679 controls from Germany (n=301) and Norway (n=378) were studied for 25(OH)D3 (primary objective). Secondary objectives (1,25(OH)2D3 and pathway genes) were examined in case-controls from Germany and Norway correlating 25(OH)D3 and single nucleotide polymorphisms within genes encoding the vitamin D receptor (VDR), 1-α-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1); 24-hydroxylase (CYP24A1) and vitamin D binding protein (GC/DBP).

RESULTS

Vitamin D deficiency (25(OH)D3 10-20 ng/ml) was highly prevalent in AAD patients (34-57%), 5-22% were severely deficient (<10 ng/ml), 28-38% insufficient (20-30 ng/ml) and only 7-14% sufficient (>30 ng/ml). Lower 25(OH)D3 and 1,25(OH)2D3 levels were observed both in Norwegian and German AAD (p = 0.03/0.003 and p = 1 x 10-5/< 1 x 10-7, respectively) the former was associated with CYP2R1 (rs1553006) genotype G. Whereas controls achieved sufficient median 25(OH)D3 in summers (21.4 to 21.9 ng/ml), AAD patients remained largely deficient (18.0 to 21.2 ng/ml) and synthesize less 1,25(OH)2D3.

CONCLUSION

Vitamin D deficiency and insufficiency are highly prevalent in AAD patients. The vitamin D status of AAD may be influenced by genetic factors and suggests individual vitamin D requirements throughout the year.

Open access

Claire L Wood, Michael Cole, Malcolm Donaldson, David B Dunger, Ruth Wood, Niamh Morrison, John N S Matthews, Simon H S Pearce, Timothy D Cheetham, and the British Society for Paediatric Endocrinology and Diabetes (BSPED)

Objective

First-line treatment of thyrotoxicosis in young people is thionamide anti-thyroid drug (ATD) in a blocking dose with levothyroxine replacement (block and replace, BR) or in a smaller dose tailored to render the patient euthyroid (dose titration, DT). Our objective was to determine which regimen provides more stable biochemical control.

Design

A multi-centre phase III, open-label randomised trial comparing BR with DT in patients aged 2–17 years with newly diagnosed thyrotoxicosis at 15 UK centres.

Methods

Patients were randomised shortly after diagnosis and treated for 3 years. The primary outcome was the percentage of serum thyroid-stimulating hormone (TSH) levels in the reference range between 6 months and 3 years. Secondary outcomes included the proportion of Free thyroxine (FT4) levels in the reference range, adverse event frequency and 4 years outcome (remission/relapse).

Results

Eighty-two patients were randomised, with details on clinical course in 81 (62 Female); 40 were allocated to BR (41 DT). Three withdrew with one ineligible. The mean percentage of serum TSH within reference range was 60.2% in BR and 63.8% in DT patients; adjusted difference 4.3%, 95% CI (−7.8 to 16.4); P = 0.48. Proportions for FT4 were 79.2% in BR and 85.7% in DT patients; adjusted difference 6.8%, (−0.2 to 15.6); P = 0.13. Three patients developed neutropenia – all on BR. 6 BR and 10 DT patients were in remission at 4y.

Conclusion

This randomised trial has shown no evidence to suggest that BR, when managing the young patient with thyrotoxicosis, is associated with improved biochemical stability when compared to DT.