BackgroundVery little is known about the epidemiology of adrenal crises (AC) and adrenal insuffic... more BackgroundVery little is known about the epidemiology of adrenal crises (AC) and adrenal insufficiency (AI) in adolescents and young adults.MethodsData on all admissions to Australian hospitals between 2000/1 to 2019/20 for a principal diagnosis of AI (including AC) in 10-24 year olds were extracted from a national repository. Age and sex-specific rates and age-adjusted rates were compared.FindingsOver the study, there were 3386 admissions for a principal diagnosis of AI; 24.0% (n=812) were for an AC and 50·7% (n=1718) were for secondary AI. Age-adjusted AI admissions increased from 31·70/million in 2000/1 to 54·68/million in 2019/20 (p<0·0001). Age-adjusted AC admissions also increased, most notably in the second decade (from 5·80/million in 2010/11 to 15·75/million in 2019/20) (p<0·00001). Average AI and AC admission rates were comparable between the sexes, but rates increased significantly in females, especially in those aged 20 to 24 years, whose AC rate in 2019/20 (39·65/...
Supplemental data to accompany: Aberrant Splicing of SDHC in Families With Unexplained Succinate ... more Supplemental data to accompany: Aberrant Splicing of SDHC in Families With Unexplained Succinate Dehydrogenase-Deficient ParagangliomasJ Endocrinol Soc 2020https://doi.org/10.1210/jendso/bvaa071
Oxford Textbook of Endocrinology and Diabetes 3e, 2021
Diagnosis of adrenal gland dysfunction in pregnancy is complex, and confounded by physiological g... more Diagnosis of adrenal gland dysfunction in pregnancy is complex, and confounded by physiological gestational changes in maternal adrenal hormone metabolism. Management of newly diagnosed or pre-existing adrenal disease in pregnant women requires intensive input from the endocrinologist, and close collaboration with the obstetrician or fetal medicine specialist. Maternal adrenal gland dysfunction during pregnancy encompasses adrenocortical disorders resulting in glucocorticoid and mineralocorticoid deficiency or excess, and medullary disease resulting in catecholamine excess. The aim of this chapter is to review clinical aspects of the most common adrenal disorders in pregnancy, and to discuss approaches to diagnosis and management. Both benign and malignant diseases of the adrenal cortex and medulla will also be discussed.
Corticosteroid‐binding globulin (CBG) transports cortisol and other steroids. High‐affinity CBG (... more Corticosteroid‐binding globulin (CBG) transports cortisol and other steroids. High‐affinity CBG (haCBG) undergoes proteolysis of the reactive center loop (RCL) by neutrophil elastase (NE) altering conformation to low‐affinity CBG (laCBG). Elevated temperature reduces CBG:cortisol binding affinity. Surface plasmon resonance was used to determine binding profiles of 19 steroids to haCBG and laCBG at 25, 37, and 39°C mimicking pyrexia and pH 7.4 and 7.0 mimicking acidosis, pathophysiological conditions relevant to sepsis. An expected 4–8‐fold reduction in affinity for cortisol, cortisone, corticosterone, 11‐deoxycortisol, progesterone, 17‐hydroxyprogesterone, and prednisolone occurred with NE‐mediated haCBG‐to‐laCBG conversion. CBG:cortisol binding affinity was further reduced 3.5‐fold at 39°C relative to 37°C, binding affinity was also reduced by acidosis for both haCBG and laCBG. Using a conformational antibody generated against the RCL, we confirmed RCL antibody binding was eliminat...
Pituitary apoplexy during pregnancy is rare but important to recognise, particularly in the hyper... more 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 on 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.
ObjectiveHydrocortisone stress dosing during illness can prevent adrenal crises (AC) in patients ... more ObjectiveHydrocortisone 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.DesignA cross‐sectional analysis of Australian medical identification jewellery subscription data.PatientsPatients with AI aged 20 years and over with an active subscription to a large medical jewellery provider.MeasurementsSubscription rates by AI subtype, geographic area, age and gender.ResultsThere 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. ...
Corticosteroid-binding globulin (CBG) and albumin transport circulating cortisol. Cleavage of hig... more 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. To determine whether depletion of haCBG is related to mortality in septic shock. 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. 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 <...
Background/Aims: To determine the burden of hospitalisation in children with adrenal insufficienc... more Background/Aims: To determine the burden of hospitalisation in children with adrenal insufficiency (AI)/hypopituitarism in Australia. Methods: A retrospective study of Australian hospitalisation data. All admissions between 2001 and 2014 for patients aged 0–19 years with a principal diagnosis of AI/hypopituitarism were included. Denominator populations were extracted from national statistics datasets. Results: There were 3,779 admissions for treatment of AI/hypopituitarism in patients aged 0–19 years, corresponding to an average admission rate of 48.7 admissions/million/year. There were 470 (12.4%) admissions for an adrenal crisis (AC). Overall, admission for AI/hypopituitarism was comparable between the sexes. Admission rates for all AI, hypopituitarism, congenital adrenal hyperplasia (CAH), and “other and unspecified causes” of AI were highest among infants and decreased with age. Admissions for primary AI increased with age in both sexes. Males had significantly higher rates of a...
Petrosal venous prolactin concentrations have been promoted to improve the diagnostic accuracy of... more Petrosal venous prolactin concentrations have been promoted to improve the diagnostic accuracy of inferior petrosal sinus sampling (IPSS), beyond that achieved with ACTH measurement alone, in diagnosing a pituitary ACTH source, and determining corticotrophinoma side (L/R). Our objective was to assess the effect of using prolactin to confirm adequacy of petrosal cannulation in a cohort of patients with ACTH-dependent Cushing's syndrome. Retrospective cohort study. Thirteen patients with clinical and biochemical Cushing's syndrome who underwent IPSS. Serum prolactin and ACTH in peripheral and inferior petrosal sinus blood before and after corticotrophin-releasing hormone (CRH) injection. Thirteen consecutive patients were diagnosed with Cushing's disease using uncorrected ACTH ratios. The side of PRL excess was the same as the side of ACTH excess in all cases. Use of various published prolactin-related equations suggested that the ACTH non-dominant side was not cannulated ...
A middle-aged woman with diabetic nephropathy on pregabalin for neuropathic pain presented with a... more A middle-aged woman with diabetic nephropathy on pregabalin for neuropathic pain presented with a diarrhoeal illness. She was found to have acute on chronic renal impairment with an estimated glomerular filtration rate (eGFR) of 10 mL/min, and her usual 150 mg/day of pregabalin was abruptly ceased. Although renal recovery to her baseline of eGFR 15 mL/min was achieved within 3 days, her pregabalin was not restarted. She suffered a tonic-clonic seizure 4 days later, thought to be due to pregabalin withdrawal as there were no other likely causes identified. She suffered no further seizures on recommencement of pregabalin at a renally adjusted dose of 75 mg/day.
Maternal total and free cortisol concentrations are reduced in pre-eclampsia and gestational hype... more Maternal total and free cortisol concentrations are reduced in pre-eclampsia and gestational hypertension. However, the effect of this on the hypothalamic-pituitary-adrenal (HPA) axis function in the offspring is unknown. We examined basal HPA axis activity in adolescent offspring of mothers with pre-pregnancy hypertension/gestational hypertension/pre-eclampsia. A total of 1182 participants (mean age 17.1 years) recruited from the Western Australian Pregnancy Cohort (Raine) Study provided fasting morning blood samples for basal HPA axis and concomitant clinical assessments, including blood pressure. Plasma ACTH, total cortisol, corticosteroid-binding globulin (CBG) and free cortisol calculated by Coolens' equation were measured from blood samples collected at home before 10:00 am. Total plasma cortisol (689 ± 153 nmol/L v 583 ± 172 nmol/L, p = 0.024), ACTH (15.5 ± 13 pmol/L v 10.8 ± 5.1 pmol/L, p = 0.040) and calculated free cortisol (52 ± 21 nmol/L v 42 ± 22 nmol/L, p = 0.052) ...
Clinica chimica acta; international journal of clinical chemistry, Jan 29, 2015
High-affinity corticosteroid-binding globulin (haCBG) is cleaved by neutrophil elastase (NE) resu... more High-affinity corticosteroid-binding globulin (haCBG) is cleaved by neutrophil elastase (NE) resulting in permanent transition to the low cortisol-binding affinity form (laCBG), thereby increasing cortisol availability at inflammatory sites. Alpha-1 antitrypsin (AAT) is the major inhibitor of NE. AAT deficiency (AATD) predisposes patients to early-onset emphysema due to increased proteolytic destruction from the inherent proteinase-antiproteinase imbalance. We hypothesized that AATD may result in increased CBG cleavage in vivo. We collected demographic data and blood samples from 10 patients with AATD and 28 healthy controls measuring total CBG and haCBG levels by parallel in-house ELISAs, as well as AAT, total and free cortisol levels. haCBG was higher (median [range]); 329 [210-551] vs. 250 [175-365] nmol/L; P<0.005, and laCBG lower; 174 [68-229] vs. 220 [119-348] nmol/L; P=0.016 in the AATD group, compared with controls. The ratio of haCBG:totalCBG was also higher in AATD; 72 ...
BackgroundVery little is known about the epidemiology of adrenal crises (AC) and adrenal insuffic... more BackgroundVery little is known about the epidemiology of adrenal crises (AC) and adrenal insufficiency (AI) in adolescents and young adults.MethodsData on all admissions to Australian hospitals between 2000/1 to 2019/20 for a principal diagnosis of AI (including AC) in 10-24 year olds were extracted from a national repository. Age and sex-specific rates and age-adjusted rates were compared.FindingsOver the study, there were 3386 admissions for a principal diagnosis of AI; 24.0% (n=812) were for an AC and 50·7% (n=1718) were for secondary AI. Age-adjusted AI admissions increased from 31·70/million in 2000/1 to 54·68/million in 2019/20 (p<0·0001). Age-adjusted AC admissions also increased, most notably in the second decade (from 5·80/million in 2010/11 to 15·75/million in 2019/20) (p<0·00001). Average AI and AC admission rates were comparable between the sexes, but rates increased significantly in females, especially in those aged 20 to 24 years, whose AC rate in 2019/20 (39·65/...
Supplemental data to accompany: Aberrant Splicing of SDHC in Families With Unexplained Succinate ... more Supplemental data to accompany: Aberrant Splicing of SDHC in Families With Unexplained Succinate Dehydrogenase-Deficient ParagangliomasJ Endocrinol Soc 2020https://doi.org/10.1210/jendso/bvaa071
Oxford Textbook of Endocrinology and Diabetes 3e, 2021
Diagnosis of adrenal gland dysfunction in pregnancy is complex, and confounded by physiological g... more Diagnosis of adrenal gland dysfunction in pregnancy is complex, and confounded by physiological gestational changes in maternal adrenal hormone metabolism. Management of newly diagnosed or pre-existing adrenal disease in pregnant women requires intensive input from the endocrinologist, and close collaboration with the obstetrician or fetal medicine specialist. Maternal adrenal gland dysfunction during pregnancy encompasses adrenocortical disorders resulting in glucocorticoid and mineralocorticoid deficiency or excess, and medullary disease resulting in catecholamine excess. The aim of this chapter is to review clinical aspects of the most common adrenal disorders in pregnancy, and to discuss approaches to diagnosis and management. Both benign and malignant diseases of the adrenal cortex and medulla will also be discussed.
Corticosteroid‐binding globulin (CBG) transports cortisol and other steroids. High‐affinity CBG (... more Corticosteroid‐binding globulin (CBG) transports cortisol and other steroids. High‐affinity CBG (haCBG) undergoes proteolysis of the reactive center loop (RCL) by neutrophil elastase (NE) altering conformation to low‐affinity CBG (laCBG). Elevated temperature reduces CBG:cortisol binding affinity. Surface plasmon resonance was used to determine binding profiles of 19 steroids to haCBG and laCBG at 25, 37, and 39°C mimicking pyrexia and pH 7.4 and 7.0 mimicking acidosis, pathophysiological conditions relevant to sepsis. An expected 4–8‐fold reduction in affinity for cortisol, cortisone, corticosterone, 11‐deoxycortisol, progesterone, 17‐hydroxyprogesterone, and prednisolone occurred with NE‐mediated haCBG‐to‐laCBG conversion. CBG:cortisol binding affinity was further reduced 3.5‐fold at 39°C relative to 37°C, binding affinity was also reduced by acidosis for both haCBG and laCBG. Using a conformational antibody generated against the RCL, we confirmed RCL antibody binding was eliminat...
Pituitary apoplexy during pregnancy is rare but important to recognise, particularly in the hyper... more 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 on 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.
ObjectiveHydrocortisone stress dosing during illness can prevent adrenal crises (AC) in patients ... more ObjectiveHydrocortisone 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.DesignA cross‐sectional analysis of Australian medical identification jewellery subscription data.PatientsPatients with AI aged 20 years and over with an active subscription to a large medical jewellery provider.MeasurementsSubscription rates by AI subtype, geographic area, age and gender.ResultsThere 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. ...
Corticosteroid-binding globulin (CBG) and albumin transport circulating cortisol. Cleavage of hig... more 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. To determine whether depletion of haCBG is related to mortality in septic shock. 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. 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 <...
Background/Aims: To determine the burden of hospitalisation in children with adrenal insufficienc... more Background/Aims: To determine the burden of hospitalisation in children with adrenal insufficiency (AI)/hypopituitarism in Australia. Methods: A retrospective study of Australian hospitalisation data. All admissions between 2001 and 2014 for patients aged 0–19 years with a principal diagnosis of AI/hypopituitarism were included. Denominator populations were extracted from national statistics datasets. Results: There were 3,779 admissions for treatment of AI/hypopituitarism in patients aged 0–19 years, corresponding to an average admission rate of 48.7 admissions/million/year. There were 470 (12.4%) admissions for an adrenal crisis (AC). Overall, admission for AI/hypopituitarism was comparable between the sexes. Admission rates for all AI, hypopituitarism, congenital adrenal hyperplasia (CAH), and “other and unspecified causes” of AI were highest among infants and decreased with age. Admissions for primary AI increased with age in both sexes. Males had significantly higher rates of a...
Petrosal venous prolactin concentrations have been promoted to improve the diagnostic accuracy of... more Petrosal venous prolactin concentrations have been promoted to improve the diagnostic accuracy of inferior petrosal sinus sampling (IPSS), beyond that achieved with ACTH measurement alone, in diagnosing a pituitary ACTH source, and determining corticotrophinoma side (L/R). Our objective was to assess the effect of using prolactin to confirm adequacy of petrosal cannulation in a cohort of patients with ACTH-dependent Cushing's syndrome. Retrospective cohort study. Thirteen patients with clinical and biochemical Cushing's syndrome who underwent IPSS. Serum prolactin and ACTH in peripheral and inferior petrosal sinus blood before and after corticotrophin-releasing hormone (CRH) injection. Thirteen consecutive patients were diagnosed with Cushing's disease using uncorrected ACTH ratios. The side of PRL excess was the same as the side of ACTH excess in all cases. Use of various published prolactin-related equations suggested that the ACTH non-dominant side was not cannulated ...
A middle-aged woman with diabetic nephropathy on pregabalin for neuropathic pain presented with a... more A middle-aged woman with diabetic nephropathy on pregabalin for neuropathic pain presented with a diarrhoeal illness. She was found to have acute on chronic renal impairment with an estimated glomerular filtration rate (eGFR) of 10 mL/min, and her usual 150 mg/day of pregabalin was abruptly ceased. Although renal recovery to her baseline of eGFR 15 mL/min was achieved within 3 days, her pregabalin was not restarted. She suffered a tonic-clonic seizure 4 days later, thought to be due to pregabalin withdrawal as there were no other likely causes identified. She suffered no further seizures on recommencement of pregabalin at a renally adjusted dose of 75 mg/day.
Maternal total and free cortisol concentrations are reduced in pre-eclampsia and gestational hype... more Maternal total and free cortisol concentrations are reduced in pre-eclampsia and gestational hypertension. However, the effect of this on the hypothalamic-pituitary-adrenal (HPA) axis function in the offspring is unknown. We examined basal HPA axis activity in adolescent offspring of mothers with pre-pregnancy hypertension/gestational hypertension/pre-eclampsia. A total of 1182 participants (mean age 17.1 years) recruited from the Western Australian Pregnancy Cohort (Raine) Study provided fasting morning blood samples for basal HPA axis and concomitant clinical assessments, including blood pressure. Plasma ACTH, total cortisol, corticosteroid-binding globulin (CBG) and free cortisol calculated by Coolens' equation were measured from blood samples collected at home before 10:00 am. Total plasma cortisol (689 ± 153 nmol/L v 583 ± 172 nmol/L, p = 0.024), ACTH (15.5 ± 13 pmol/L v 10.8 ± 5.1 pmol/L, p = 0.040) and calculated free cortisol (52 ± 21 nmol/L v 42 ± 22 nmol/L, p = 0.052) ...
Clinica chimica acta; international journal of clinical chemistry, Jan 29, 2015
High-affinity corticosteroid-binding globulin (haCBG) is cleaved by neutrophil elastase (NE) resu... more High-affinity corticosteroid-binding globulin (haCBG) is cleaved by neutrophil elastase (NE) resulting in permanent transition to the low cortisol-binding affinity form (laCBG), thereby increasing cortisol availability at inflammatory sites. Alpha-1 antitrypsin (AAT) is the major inhibitor of NE. AAT deficiency (AATD) predisposes patients to early-onset emphysema due to increased proteolytic destruction from the inherent proteinase-antiproteinase imbalance. We hypothesized that AATD may result in increased CBG cleavage in vivo. We collected demographic data and blood samples from 10 patients with AATD and 28 healthy controls measuring total CBG and haCBG levels by parallel in-house ELISAs, as well as AAT, total and free cortisol levels. haCBG was higher (median [range]); 329 [210-551] vs. 250 [175-365] nmol/L; P<0.005, and laCBG lower; 174 [68-229] vs. 220 [119-348] nmol/L; P=0.016 in the AATD group, compared with controls. The ratio of haCBG:totalCBG was also higher in AATD; 72 ...
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Papers by David J Torpy