Is high salt intake inducing obesity via production of cortisol? A novel working hypothesis and pilot study.

PURPOSE: Evidence is growing that high salt intake is an independent risk factor for obesity, but the mechanisms are unknown. Our novel working hypothesis is that high salt intake drives cortisol production, which in turn, drives obesity. The current study aimed to demonstrate an acute cortisol response following a single high salt meal. METHODS: Eight participants (age 30.5 ± 9.8 years [mean ± SD], 50% female), consumed high salt (3.82 g; 1529 mg sodium) and low salt (0.02 g; 9 mg sodium) meals in a randomized cross-over design. RESULTS: Urinary and salivary cortisol and plasma adrenocorticotropic hormone (ACTH) demonstrated order effects. When high salt was given second, there was a peak above baseline for urinary cortisol (26.3%), salivary cortisol (9.4%) and plasma ACTH (4.1%) followed by a significant decline in each hormone (treatment*time, F[9, 18] = 2.641, p = 0.038, partial η2 = 0.569; treatment*time, F[12, 24] = 2.668, p = 0.020, partial η2 = 0.572; treatment*time, F[12, 24] = 2.580, p = 0.023, partial η2 = 0.563, respectively), but not when high salt was given first (p > 0.05 for all). CONCLUSION: These intriguing findings provide partial support for our hypothesis and support a need for further research to elucidate the role of high salt intake in cortisol production and, in turn, in the aetiology of obesity. TRIAL REGISTRATION NUMBER: ACTRN12623000490673; date of registration 12/05/2023; retrospectively registered.

ARMC5 is part of an RPB1-specific ubiquitin ligase implicated in adrenal hyperplasia.

ARMC5 is implicated in several pathological conditions, but its function remains unknown. We have previously identified CUL3 and RPB1 (the largest subunit of RNA polymerase II (Pol II) as potential ARMC5-interacting proteins. Here, we show that ARMC5, CUL3 and RBX1 form an active E3 ligase complex specific for RPB1. ARMC5, CUL3, and RBX1 formed an active E3 specific for RPB1. Armc5 deletion caused a significant reduction in RPB1 ubiquitination and an increase in an accumulation of RPB1, and hence an enlarged Pol II pool in normal tissues and organs. The compromised RPB1 degradation did not cause generalized Pol II stalling nor depressed transcription in the adrenal glands but did result in dysregulation of a subset of genes, with most upregulated. We found RPB1 to be highly expressed in the adrenal nodules from patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) harboring germline ARMC5 mutations. Mutant ARMC5 had altered binding with RPB1. In summary, we discovered that wildtype ARMC5 was part of a novel RPB1-specific E3. ARMC5 mutations resulted in an enlarged Pol II pool, which dysregulated a subset of effector genes. Such an enlarged Pol II pool and gene dysregulation was correlated to adrenal hyperplasia in humans and KO mice.

Adrenal insufficiency in pregnancy: Physiology, diagnosis, management and areas for future research.

Adrenal insufficiency requires prompt diagnosis in pregnancy, as untreated, it can lead to serious consequences such as adrenal crisis, intrauterine growth restriction and even foetal demise. Similarities between symptoms of adrenal insufficiency and those of normal pregnancy can complicate diagnosis. Previously diagnosed adrenal insufficiency needs monitoring and, often, adjustment of adrenal hormone replacement. Many physiological changes occur to the hypothalamic-pituitary-adrenal (HPA) axis during pregnancy, often making diagnosis and management of adrenal insufficiency challenging. Pregnancy is a state of sustained physiologic hypercortisolaemia; there are multiple contributing factors including high plasma concentrations of placental derived corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH) and increased adrenal responsiveness to ACTH. Despite increased circulating concentrations of CRH-binding protein (CRH-BP) and the major cortisol binding protein, corticosteroid binding globulin (CBG), free concentrations of both hormones are increased progressively in pregnancy. In addition, pregnancy leads to activation of the renin-angiotensin-aldosterone system. Most adrenocortical hormone diagnostic thresholds are not applicable or validated in pregnancy. The management of adrenal insufficiency also needs to reflect the physiologic changes of pregnancy, often requiring increased doses of glucocorticoid and at times mineralocorticoid replacement, especially in the last trimester. In this review, we describe pregnancy induced changes in adrenal function, the diagnosis and management of adrenal insufficiency in pregnancy and areas requiring further research.

The clinical and genetic features of hereditary pancreatitis in South Australia.

OBJECTIVE: To characterise the clinical phenotypes and genetic variants of hereditary pancreatitis in people diagnosed in South Australia. DESIGN, SETTING, PARTICIPANTS: Cross-sectional study of people who received molecular diagnoses of hereditary pancreatitis from one of four major diagnostic services in South Australia, 1 January 2006 - 30 June 2021. MAIN OUTCOME MEASURES: Genotypic and clinical features of people with hereditary pancreatitis, including age at onset, attack frequency, pain indices, use of opioid medications, and physical and mental health impact of hereditary pancreatitis. RESULTS: We identified 44 people from ten families who received molecular diagnoses of hereditary pancreatitis during 2006-21 (including 25 Indigenous people [57%] and 27 women [61%]): 36 with PRSS1, five with SPINK1, and three with PRSS1 and SPINK1 mutations (determined by whole exome sequencing). Symptom onset before the age of ten years was reported by 37 people (84%). Pancreatitis-related pain during the preceding four weeks was described as moderate or high by 35 people (79%); 38 people regularly used opioids (86%). Fifteen patients had diabetes mellitus (34%), and eight had undergone pancreatic surgery (18%). The estimated prevalence of hereditary pancreatitis was 1.1 (95% CI, 0.72-1.4) cases per 100 000 population for non-Indigenous and 71 (95% CI, 66-77) cases per 100 000 population for Indigenous South Australians. Among people with adult-onset chronic pancreatitis admitted to South Australian public hospitals during 2001-2019, the proportions of Indigenous people (12%) and women (38%) were smaller than we report for hereditary pancreatitis. CONCLUSION: The estimated prevalence of hereditary pancreatitis in South Australia is higher than in Europe. PRSS1 gene mutations are important causes, particularly among Indigenous young people.

Acute illness in children with secondary adrenal insufficiency.

OBJECTIVE AND BACKGROUND: Secondary adrenal insufficiency (SAI) is a rare condition in childhood which can be associated with high levels of morbidity in some patients. The causes of increased levels of illness are not well defined and warrant further investigation. METHODS: A retrospective cohort of patients with SAI was constructed by examining records of all attendances for acute illness by SAI patients at the emergency department of the two specialist paediatric hospitals in Sydney, Australia between 2004 and 2016. Demographic, clinical, and physiological characteristics together with pre-hospital illness management strategies were assessed. RESULTS: There were 168 presentations for an acute illness by 47 children with SAI. Comorbid diabetes insipidus (DI) was present in 46.8% (n = 22), 77.3% (n = 17) of whom were male (P < .05). Patients with comorbid DI were more likely to be admitted (86.7%, n = 65 vs 60.2%, n = 56 for non-DI, P < .01); had a longer hospital stay (6.5 (8.7) vs 2.5 (2.6) days, P < .001); and higher rates of IV HC administration (56.0%, n = 42 vs 35.5%, n = 33), P < .01). The medically-diagnosed adrenal crisis (AC) rate was 3.68 ACs/100PY. Stress dose use was reported by fewer DI patients (58.7%, n = 44) than non-DI patients (78.5%, n = 73, P < .01). Previous attendance at hospital was positively associated with stress dose use (OR = 1.08, 95% CI 1.00, 1.16). CONCLUSION: Secondary adrenal insufficiency can cause significant morbidity in children. Comorbid DI is associated with higher levels of hospitalisation, longer hospital stays and lower levels of pre-emergent stress dose use. Educational interventions in this subgroup of SAI patients may reduce the burden of morbidity.

The epidemiology of primary and secondary adrenal malignancies and associated adrenal insufficiency in hospitalised patients: an analysis of hospital admission data, NSW, Australia.

BACKGROUND: Adrenal insufficiency (AI) causes considerable morbidity but may remain undiagnosed in patients with adrenal malignancy (AM). The epidemiology of AI and adrenal crises (AC) in AM is uncertain. METHODS: This was a retrospective study examining hospital admission data from 2006 to 2017. All admissions to all hospitals in NSW, Australia over this period with a principal or comorbid diagnosis of an adrenal malignancy were selected. Data were examined for trends in admissions for AM and associated AI/AC using population data from the corresponding years. RESULTS: There were 15,376 hospital admissions with a diagnosis of AM in NSW over the study period, corresponding to 1281 admissions/year. The AM admission rate increased significantly over the study period from 129.9/million to 215.7/million (p < 0.01). An AI diagnosis was recorded in 182 (1.2%) admissions, corresponding to an average of 2.1/million/year. This rate increased significantly over the years of the study from 1.2/million in 2006 to 3.4/million in 2017 (p < 0.01). An AC was identified in 24 (13.2%) admissions with an AI diagnosis. Four patients (16.7%) with an AC died during the hospitalisation. CONCLUSION: Admission with a diagnosis of AM has increased over recent years and has been accompanied by an increase in AI diagnoses. While AI is diagnosed in a small proportion of patients with AM, ACs do occur in affected patients.

Flash Glucose Monitoring Compared to Capillary Glucose Levels in Patients With Diabetic Ketoacidosis: Potential Clinical Applications.

OBJECTIVE: Frequent, finger-prick capillary blood glucose measurement is standard care, used to drive insulin infusion rates for inpatients being resuscitated from diabetic ketoacidosis (DKA). Over recent years there has been a shift toward continuous interstitial glucose monitoring, allowing monitoring of glucose without repeated invasive testing. While continuous interstitial glucose monitoring has been safely and reliably utilized in the outpatient setting, it has yet to be studied in acutely unwell patients with DKA. The aim of this study, allowing for physiologically lower interstitial compared to capillary glucose, was to determine if interstitial flash glucose monitoring (FGM) would lead to insulin infusion rates that were similar to capillary blood glucose (CapBG) in DKA. METHODS: In this study, 10 patients with diabetes mellitus, assessed to be in DKA, were enrolled. At the same time as standard DKA management commencement, simultaneous FGM measurements were obtained. Duplicate paired glucose readings were then analyzed for agreement. RESULTS: Actual (CapBG-driven) and predicted (FGM determined) insulin infusion rates were similar. Minor differences in predicted insulin infusion rates were noted in 2/10 patients at higher glucose concentrations, which may relate to the lag in change in glucose in the interstitial space. CONCLUSION: Based on our results, a trial of clinical outcomes in patients with DKA treated with insulin infusion rates driven by CapBG versus subcutaneous FGM appears justified. The FGM method of testing may improve patient comfort, obviate fatigue, improve staff time and direct patient contact, and potentially facilitate rapid discharge.

Acute illness in patients with concomitant Addison's disease and type 1 diabetes mellitus: Increased incidence of hypoglycaemia and adrenal crises.

BACKGROUND: Patients with Addison's disease (AD) and comorbid type 1 diabetes mellitus (T1DM) are at increased risk of certain acute metabolic disorders relative to patients with one of these conditions only. The reasons for this are unknown. METHODS: All attendances for acute illness by AD patients at the emergency department of a Sydney hospital between 2000 and 2017 were reviewed. Physiological parameters and illness management strategies were compared between AD patients, those with T1DM and AD combined, and a control group of patients with T1DM. RESULTS: There were 39 presentations for an acute medical illness by 20 nondiabetic AD (28 attendances) and 5 diabetic AD patients (11 presentations) and 40 attendances by 10 T1DM controls. In AD patients, 17 (43.6%) attendances were medically diagnosed adrenal crises (AC) (63.6% [n = 7] in diabetic AD and 35.7% [n = 10] in nondiabetic AD). This corresponded to an estimated incidence of 12.5 AC/100 patient-years (PY) for diabetic AD patients compared to 4.7 AC/100PY for nondiabetic AD patients (P < .05). Glucocorticoid stress doses preceded 61.5% (n = 24) of all attendances. Patients who used stress doses had more presentations than those who did not (2.0 ± 1.3 vs 1.2 ± 0.5, P = .01). Diabetic AD patients had a lower mean blood glucose level on presentation (5.6 ± 3.9 mmol/L) than the T1DM control sample (11.6 ± 6.2 mmol/L) P < .001. No T1DM patients had hypoglycaemia in the 3.0-3.9 mmol/L range but 2 (18.2%) of the diabetic AD patients had presenting blood glucose levels in this category (P < .05). Hyperglycaemia was more common among T1DM control patients (62.5%, n = 26) than diabetic AD patients (18.2%, n = 2), P < .01. CONCLUSION: Addison's disease patients with T1DM have a higher incidence of adrenal crisis (AC) and hypoglycaemia than nondiabetic AD patients and a lower incidence of hyperglycaemia than those with T1DM alone. This information may be of value in counselling patients with T1DM and AD about AC and hypoglycaemia prevention.

The effect of patient-managed stress dosing on electrolytes and blood pressure in acute illness in children with adrenal insufficiency.

BACKGROUND: Adrenal crises (AC) are acute episodes of adrenal insufficiency (AI). Manifestations include hypotension and electrolyte disturbances. Glucocorticoid stress dosing (SD) can prevent AC progression, but its effect on physiological parameters has not been assessed in a 'real world setting'. AIMS: To assess the effect of prior self-managed glucocorticoid dose escalation on physiological markers in children with congenital adrenal hyperplasia (CAH) presenting to hospital for an acute illness. METHODS: An audit of records of all children with CAH presenting to paediatric referral hospital between 2000 and 2015. Potassium, sodium and glucose levels, and hypotension were compared between children who had and had not used SD. RESULTS: There were 321 attendances by patients with CAH and an acute illness during the study period. Any form of SD was used by 64.2% (n = 206); intramuscular (IM) hydrocortisone was used by 22.1% (n = 71) and oral only by 41.7% (n = 134). Use of SD (oral and/or IM) was associated with a significantly lower mean potassium level (4.02 ± 0.71 vs. 4.27 ± 0.79 mmol/l, P < .05). Linear regression analysis showed that age (beta: -0.04 years (95% CI -0.06, -0.02)), diarrhoea (beta: -0.41 (95% CI -0.06, -0.02)) and any form of stress dosing (oral, IM or both) (beta: -0.29 (95% CI -0.55, -0.04)) were each independently and significantly associated with potassium levels. SD was not significantly associated with sodium or glucose concentrations or with estimates of hypotension. CONCLUSION: Patient-initiated SD resulted in a significant reduction in hyperkalaemia and lowered mean potassium levels in paediatric patients with CAH but did not alter significantly sodium and glucose concentrations or incidences of hypotension.

A putative role for the aryl hydrocarbon receptor (AHR) gene in a patient with cyclical Cushing's disease.

BACKGROUND: Apart from PRKAR1A mutations in a subset of cyclical Cushing's syndrome due to primary pigmented nodular adrenocortical disease, the molecular basis of cyclical Cushing's syndrome has not been investigated. We speculated that cyclical Cushing's syndrome may be due to mutations in the clock genes that govern circadian rhythms, including the hypothalamic-pituitary-adrenal axis. CASE PRESENTATION: A 47-year-old man presented with mass effects from a sellar lesion. He was ultimately diagnosed with cyclical Cushing's disease due to a giant corticotrophinoma. We performed whole exome sequencing of germline and tumour DNA, SNP array of tumour DNA and tumour immunohistochemistry in order to detect variants in candidate circadian/pituitary-associated genes. We identified a rare germline missense variant in the aryl hydrocarbon receptor (AHR) gene, which has previously been indirectly linked to pituitary tumorigenesis and clock system disruption. The AHR variant was found in a highly conserved site involved in phosphorylation. It was predicted to be damaging by multiple in silico tools and AHR tumour immunohistochemistry demonstrated loss of the normal nuclear staining pattern, suggestive of an inactivating mutation. We also found a novel, damaging germline missense variant in the retinoid X receptor gamma (RXRG) gene, multiple somatic chromosomal gains (including AHR), and a somatic mutational signature consistent with oncogenesis that may have acted synergistically with the AHR variant. CONCLUSIONS: This is the first report of an AHR variant with predicted pathogenicity in the pituitary adenoma setting. Our preliminary data suggest that the highly conserved AHR gene may represent a link between pituitary tumorigenesis, the hypothalamic-pituitary-adrenal axis and the clock system. Further research may indicate a role for the gene in the development of cyclical Cushing's disease.

Diabetes insipidus complicating apoplexy during pregnancy: the potential use of copeptin.

Pituitary apoplexy during pregnancy is rare but important to recognise, particularly in the hyperoestrogenaemic state when known lactotroph hyperplasia occurs. Untreated, the complication rates from pituitary adenomas depend upon the size of the adenoma before pregnancy. A history of thirst plus polydipsia during pregnancy raises suspicion for diabetes insipidus and a 24-h urine collection quantifying polyuria with an inappropriately low urine osmolality confirms the diagnosis. Further evaluation for assessing diabetes insipidus in pregnancy may be facilitated by the use of a copeptin.

The use of medical identification jewellery in adults with adrenal insufficiency in Australia.

OBJECTIVE: Hydrocortisone stress dosing during illness can prevent adrenal crises (AC) in patients with adrenal insufficiency (AI). When patients cannot communicate, medical identification jewellery may facilitate parenteral hydrocortisone provision but patient adoption rates are not known. DESIGN: A cross-sectional analysis of Australian medical identification jewellery subscription data. PATIENTS: Patients with AI aged 20 years and over with an active subscription to a large medical jewellery provider. MEASUREMENTS: Subscription rates by AI subtype, geographic area, age and gender. RESULTS: There were 1955 patients with AI and an active subscription in the database, corresponding to a subscription rate of 105.79/million or approximately one-third of the AI population. The subscription rate was substantially higher in primary AI (60.72/million) than secondary AI (23.16/million), corresponding to approximately 60.7% and 11.6% of the estimated population prevalence of each disorder, respectively. There was substantial variation in use by state/territory, with the highest subscribing state having a rate of over four times that of the lowest (P < 0.001). Women comprised 64.8% (n = 1266) of the group. Subscription also varied by age, being highest in the 60-69 year age group (165.15/million) and lowest in those aged 30-39 years (47.23/million) (P < 0.001). Few patients (4.8%, n = 94) mentioned, either in their record or on their jewellery, the need for urgent parenteral hydrocortisone in the event of severe illness. CONCLUSIONS: Medical jewellery is a component of AC risk reduction. However, subscription appears to be underutilised in the Australian AI population, especially among patients with secondary AI. Urgent treatment recommendations should be inscribed on the jewellery.

Total and high-affinity corticosteroid-binding globulin depletion in septic shock is associated with mortality.

CONTEXT: Corticosteroid-binding globulin (CBG) and albumin transport circulating cortisol. Cleavage of high-affinity CBG (haCBG) by neutrophil elastase at inflammatory sites causes cortisol release into tissues, facilitating immunomodulatory effects. OBJECTIVE: To determine whether depletion of haCBG is related to mortality in septic shock. DESIGN: A single-center prospective observational cohort study of patients recruited with critical illness or septic shock, using serum samples collected at 0, 8, 24, 48 and 72 hours. Serum total and haCBG, and total and free cortisol were assayed directly. Glucocorticoid treatment was an exclusion criterion. Mortality was assessed at 28 days from Intensive Care Unit admission. RESULTS: Thirty septic shock (SS) and 42 nonseptic critical illness (CI) patients provided 195 serum samples. SS/CI patients had lower total CBG, haCBG and low-affinity CBG (laCBG) than controls. Total CBG and haCBG were significantly lower in septic shock patients who died than in those that survived (P < 0.009, P = 0.021, respectively). Total and free cortisol were higher in septic than nonseptic individuals. Free/total cortisol fractions were higher in those with low haCBG as observed in septic shock. However, cortisol levels were not associated with mortality. Albumin levels fell in sepsis but were not related to mortality. CONCLUSIONS: Low circulating haCBG concentrations are associated with mortality in septic shock. These results are consistent with an important physiological role for haCBG in cortisol tissue delivery in septic shock.

Variations in the management of acute illness in children with congenital adrenal hyperplasia: An audit of three paediatric hospitals.

OBJECTIVE: Episodes of acute adrenal insufficiency (AI)/adrenal crises (AC) are a serious consequence of congenital adrenal hyperplasia (CAH). This study aimed to assess morbidity from acute illness in CAH and identify factors associated with use of IV hydrocortisone, admission and diagnosis of an AC. METHOD: An audit of acute illness presentations among children with CAH to paediatric hospitals in New South Wales, Australia, between 2000 and 2015. RESULTS: There were 321 acute presentations among 75 children with CAH. Two-thirds (66.7%, n = 214) of these resulted in admission and 49.2% (n = 158) of the patients received intravenous (IV) hydrocortisone. An AC was diagnosed in (9.0%). Prior to presentation, 64.2% (n = 206) had used oral stress dosing and 22.1% (n = 71) had been given intramuscular (IM) hydrocortisone. Vomiting was recorded in 61.1% (n = 196), 32.7% (n = 64) of whom had used IM hydrocortisone. Admission, AC diagnosis and use of stress dosing varied significantly between hospitals. IM use varied from 7.0% in one metropolitan hospital to 45.8% in the regional hospital. Children aged up to 12 months had the lowest levels of stress dosing and IV hydrocortisone administration. Higher numbers of prior hospital attendances for acute illness were associated with increased use of IM hydrocortisone. CONCLUSION: Prehospital and in-hospital management of children with CAH can vary between health services. Children under 12 months have lower levels of stress dosing prior to hospital than other age groups. Experience with acute episodes improves self-management of CAH in the context of acute illness in educated patient populations.

GLUCOCORTICOID-INDUCED ADRENAL INSUFFICIENCY: A STUDY OF THE INCIDENCE IN HOSPITAL PATIENTS AND A REVIEW OF PERI-OPERATIVE MANAGEMENT.

OBJECTIVE: Glucocorticoid (GC) pharmacotherapy is an effective treatment for a range of diseases, but exposure can suppress the hypothalamic-pituitary-adrenal axis, leading to glucocorticoid-induced adrenal insufficiency (GC-AI) in some patients. However, the incidence of diagnosed GC-AI and the associated health burden, including the incidence of adrenal crises (ACs), are unknown. Although GC-AI treatment is based on well-established principles, there are no agreed protocols regarding the peri-operative management of exposed patients. The aims of this study were to assess the incidence of diagnosed GC-AI in hospital patients and review current approaches to peri-operative management of surgical patients with GC exposure. METHODS: An analysis of hospital admission data concerning adult patients diagnosed with GC-AI and a review of published recommendations for peri-operative GC cover. RESULTS: Between 2001 and 2013, admission with a diagnosis of GC-AI in New South Wales, Australia was rare (annual average of 22.5 admissions/year) and ACs were even more rare (n = 3). Almost two-thirds (64.4%, n = 188) of the patients with diagnosed GC-AI were aged between 50 and 79 years and 45.2% (n = 132) had a comorbid infection. The current approach to peri-operative management of patients with GC exposure appears to be influenced by both the absence of clear guidelines and historic practices. This results in the exposure of some patients to supraphysiologic doses of GCs during the peri-operative period. CONCLUSION: Hospital admission with a diagnosis of GC-AI (with or without an AC) is very rare. Clear guidelines on peri-operative GC cover are necessary to avoid overreplacement with supraphysiologic doses in susceptible patients. ABBREVIATIONS: AC = adrenal crisis; ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; CI = confidence interval; GC = glucocorticoid; GC-AI = glucocorticoid-induced adrenal insufficiency; HPA = hypothalamic-pituitary-adrenal; OR = odds ratio.