The diagnostic utility of late night salivary cortisol (LNSF) and cortisone (LNSE) in Cushing's syndrome.

BACKGROUND: Measurement of late night salivary cortisol (LNSF) is useful in the identification of cyclical Cushing's syndrome (CS); the usefulness of its metabolite cortisone (late night salivary cortisone, LNSE) is less well described. AIM: The aim of this study was to determine the utility of measuring LNSE in patients with confirmed CS compared with other diagnostic tests and to analyse serial LNSF measurements for evidence of variable hormonogenesis. METHODS: This was a retrospective observational study including patients with confirmed CS in whom LNSF and LNSE were measured. RESULTS: Twenty-three patients with confirmed CS were included, 21 with Cushing's disease. LNSF had a sensitivity of 92%, LNSE 87% and combined LNSF/LNSE 94% per sample. Four patients had cyclical hormonogenesis, when the definition of one trough and two peaks was applied to LNSF measurements, and a fifth patient fell just outside the criteria. Six patients had evidence of variable hormonogenesis, defined as doubling of LNSF concentration on serial measurements. Sensitivity of 24-h urinary free cortisol (UFC) was 89% per collection. Sixteen patients had simultaneous measurements of LNSF and UFC; in three patients, they provided discordant results. CONCLUSION: LNSF appears more sensitive than LNSE and UFC in the diagnosis of CS, combining LNSF and LNSE results leads to superior sensitivity. Half of our cohort had evidence of cyclical or variable hormonogenesis. Fluctuations in LNSF did not always correlate with changes in UFC concentration, emphasising the importance of performing more than one screening test, particularly if pretest clinical suspicion is high.

Mortality rates are lower in SIAD, than in hypervolaemic or hypovolaemic hyponatraemia: Results of a prospective observational study.

OBJECTIVE: Hyponatraemia is associated with increased mortality, but the mortality associated specifically with SIAD is not known. We hypothesized that mortality in SIAD was elevated, but that it was less than in hypervolaemic (HEN) or hypovolaemic (HON) hyponatraemia. DESIGN: Mortality rates are presented as risk ratios (RR),with 95% confidence intervals (CI), and compared to normonatraemic controls (NN). METHODS: Prospective, single centre, noninterventional study of all patients with hyponatraemia (≤130 mmol/L) admitted to hospital. RESULTS: A total of 1323 admissions with hyponatraemia were prospectively evaluated and 1136 contemporaneous NN controls. 431(32.6%) hyponatraemic patients had HON, 573(43.3%) had SIAD and 275(20.8%) patients had HEN. In patient mortality was higher in hyponatraemia than NN (9.1% vs 3.3%, P<.0001). The RRs for in-hospital mortality compared to NN were: SIAD, 1.76 (95% CI 1.08-2.8, P=.02), HON 2.77 (95% CI 1.8-4.3, P<.0001) and HEN, 4.9 (95% CI 3.2-7.4, P<.0001). The mortality rate was higher in HEN (RR 2.85; 95% CI 1.86-4.37, P<.0001) and in HON, (RR 1.6; 95% CI 1.04-2.52; P=.03), when compared to SIAD. The Charlson Comorbidity Index was lower in SIAD than in eunatraemic patients (P<.0001). 9/121(7.4%) patients died with plasma sodium <125 mmol/L and 4(3.3%) with plasma sodium <120 mmol/L. However, 69/121(57%) patients died with a plasma sodium above 133 mmol/L. CONCLUSIONS: We confirmed higher all-cause mortality in hyponatraemia than in NN. Mortality was higher in SIAD than in normonatraemia and was not explained on the basis of co-morbidities. Mortality was higher in HON and HEN than in SIAD. Mortality rates reported for all-cause hyponatraemia in the medical literature are not applicable to SIAD.

Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.

The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre study.

OBJECTIVE: The syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia. Data on SIAD are mainly derived from retrospective studies, often with poor ascertainment of the minimum criteria for the correct diagnosis. Reliable data on the incidence of adrenal failure in SIAD are therefore unavailable. The aim of the study was to describe the aetiology of SIAD and in particular to define the prevalence of undiagnosed adrenal insufficiency. DESIGN: Prospective, single centre, noninterventional, observational study of patients admitted to Beaumont Hospital with euvolaemic hyponatraemia (plasma sodium ≤ 130 mmol/l) between January 1st and October 1st 2015. PATIENTS: A total of 1323 admissions with hyponatraemia were prospectively evaluated; 576 had euvolaemic hyponatraemia, with 573 (43·4%) initially classified as SIAD. MAIN OUTCOME MEASURES: (i) Aetiology of SIAD, defined by diagnostic criteria; (ii) Incidence of adrenal insufficiency. RESULTS: Central nervous system diseases were the commonest cause of SIAD (n = 148, 26%) followed by pulmonary diseases (n = 111, 19%), malignancy (n = 105, 18%) and drugs (n = 47, 8%). A total of 22 patients (3·8%), initially diagnosed as SIAD, were reclassified as secondary adrenal insufficiency on the basis of cortisol measurements and clinical presentation; 9/22 cases had undiagnosed hypopituitarism; 13/22 patients had secondary adrenal insufficiency due to exogenous steroid administration. CONCLUSIONS: In a large, prospective and well-defined cohort of euvolaemic hyponatraemia, undiagnosed secondary adrenal insufficiency co-occurred in 3·8% of cases initially diagnosed as SIAD. Undiagnosed pituitary disease was responsible for 1·5% of cases presenting as euvolaemic hyponatraemia.