Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery (2020)

Type of publication:
Journal article

Author(s):
Prete A.; Taylor A.E.; Bancos I.; Smith D.J.; O’Neil D.M.; Karavitaki N.; Arlt W.; Foster M.A.; Lord J.M.; Kohler S.; Fazal-Sanderson V.; Komninos J.; Wass J.A.H.; Vassiliadi D.A.; Mihai R.; *Mowatt C.J. ; Fallowfield J.L.; Annane D.; Keevil B.G.

Citation:
The Journal of Clinical Endocrinology and Metabolism; Volume 105, Issue 7, July 2020

Abstract:
CONTEXT: Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based. OBJECTIVE(S): To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency exposed to major stress. DESIGN AND PARTICIPANTS: Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N=83], sepsis [N=100], and combat stress [N=105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200mg hydrocortisone over 24 hours in four different delivery modes (continuous intravenous infusion; six-hourly oral, intramuscular or intravenous bolus administration). MAIN OUTCOME MEASURE: We measured total serum cortisol and cortisone, free serum cortisol and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modelling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress. RESULT(S): Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modelling identified continuous intravenous infusion of 200mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range. CONCLUSION(S): Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.

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Identification of a thra mutation in a 2yr old child with clinical features of hypothyroidism and multisystem involvement (2019)

Type of publication:
Conference abstract

Author(s):
*Sakremath R.; Moran C.; Lyons G.; Chatterjee K.; Rajanayagam O.; Boelaert K.; Mohamed Z.

Citation:
Hormone Research in Paediatrics; Sep 2019; vol. 91 ; p. 272

Abstract:
Background: Thyroid hormones act via receptors (TRalpha; TRbeta) encoded by separate genes (THRA, THRB). Mutations in THRA are a recently-recognised cause of Resistance to Thyroid Hormone alpha (RTHalpha), a disorder with tissue-specific hypothyroidism but near-normal thyroid function tests. Aim(s): We describe the youngest recorded case of RTHalpha, in a 2yr old boy with disproportionate short stature, global developmental delay, constipation and a heterozygous missense mutation (p.G291S) in THRA. Case Report: A 16-month old male was referred to endocrine clinic with short stature. He had disproportionate stature with reduced subischial leg length (Table 1). He is in care, with a maternal antenatal history of substance abuse (exposure to methadone, heroine and alcohol in utero). He has global developmental delay and is mildly dysmorphic with constipation, all attributed to chromosome 16p13.11 microduplication. Examination revealed coarse facial appearance, depressed nasal bridge, long philtrum and central hypotonia. He had delayed visual maturation, hypermetropia, small kidneys and gastroesophageal reflux. His motor milestones (unable to sit without support) and speech are delayed. Laboratory analysis revealed normocytic anaemia, elevated creatine kinase levels, low-normal T4 and elevated T3 levels leading to altered T4:T3 ratio, with normal TSH levels. THRA sequencing identified a heterozygous missense (p.G291S) mutation, which is homologous to a known pathogenic mutation in THRB (G345S), causing RTHbeta. Correlation of genotype with phenotype and assessment of response to thyroxine therapy (25mcg/day) is being undertaken. Conclusion(s): We suggest that THRA sequencing should be considered in patients with clinical features of hypothyroidism, raised CK, anaemia and near-normal thyroid function tests but altered T4:T3 ratio. This case broadens the phenotypic spectrum of RTHalpha. (Table Presented).

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