Hypoglycaemia in adrenal insufficiency
Open accessAbstract
Adrenal insufficiency encompasses a group of congenital and acquired disorders that lead to inadequate steroid production by the adrenal glands, mainly glucocorticoids, mineralocorticoids and androgens. These may be associated with other hormone deficiencies. Adrenal insufficiency may be primary, affecting the adrenal gland’s ability to produce cortisol directly; secondary, affecting the pituitary gland’s ability to produce adrenocorticotrophic hormone (ACTH); or tertiary, affecting corticotrophin-releasing hormone (CRH) production at the level of the hypothalamus. Congenital causes of adrenal insufficiency include the subtypes of Congenital Adrenal Hyperplasia, Adrenal Hypoplasia, genetic causes of Isolated ACTH deficiency or Combined Pituitary Hormone Deficiencies, usually caused by mutations in essential transcription factors. The most commonly inherited primary cause of adrenal insufficiency is Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency; with the classical form affecting 1 in 10,000 to 15,000 cases per year. Acquired causes of adrenal insufficiency can be subtyped into autoimmune (Addison’s Disease), traumatic (including haemorrhage or infarction), infective (e.g. Tuberculosis), infiltrative (e.g. neuroblastoma) and iatrogenic. Iatrogenic acquired causes include the use of prolonged exogenous steroids and post-surgical causes, such as the excision of a hypothalamic-pituitary tumour or adrenalectomy. Clinical features of adrenal insufficiency vary with age and with aetiology. They are often non-specific and may sometimes become apparent only in times of illness. Features range from those related to hypoglycaemia such as drowsiness, collapse, jitteriness, hypothermia and seizures. Features may also include signs of hypotension such as significant electrolyte imbalances and shock. Recognition of hypoglycaemia as a symptom of adrenal insufficiency is important to prevent treatable causes of sudden deaths. Cortisol has a key role in glucose homeostasis, particularly in the counter-regulatory mechanisms to prevent hypoglycaemia in times of biological stress. Affected neonates particularly appear susceptible to the compromise of these counter-regulatory mechanisms but it is recognised that affected older children and adults remain at risk of hypoglycaemia. In this review, we summarise the pathogenesis of hypoglycaemia in the context of adrenal insufficiency. We further explore the clinical features of hypoglycaemia based on different age groups and the burden of the disease, focusing on hypoglycaemic-related events in the various aetiologies of adrenal insufficiency. Finally, we sum up strategies from published literature for improved recognition and early prevention of hypoglycaemia in adrenal insufficiency, such as the use of continuous glucose monitoring or modifying glucocorticoid replacement.
AI snapshot
Written from the paper’s full text.
TL;DR
This narrative review summarizes the pathogenesis, clinical burden, and management of hypoglycaemia in adrenal insufficiency, with a focus on children. It highlights that cortisol deficiency impairs counter-regulatory glucose responses and that hypoglycaemia remains an under-recognised, potentially fatal complication across adrenal insufficiency aetiologies.
Key findings
- In children with primary adrenal insufficiency, 30 out of 165 (18%) experienced hypoglycaemic episodes; all episodes were associated with prior fasting or poor oral intake due to vomiting or viral illness, and affected children had significantly lower basal cortisol levels.
- In a cohort of children with congenital adrenal hyperplasia followed to age 6 years, hypoglycaemia occurred in 16 out of 102 children (15%), with 23 total episodes; 7 episodes were associated with salt loss, loss of consciousness occurred in 13 of the 16 hypoglycaemic episodes, and 5 children had hypoglycaemic seizures.
- Among emergency hospital admissions of children with CAH, 24 admissions (9%) were due to hypoglycaemia, and one third of these presented with hypoglycaemic seizures.
- In adults presenting to an emergency department with hypoglycaemia, adrenal insufficiency was diagnosed in 32 out of 528 patients (6%); symptoms included tremors, palpitations, sweating, hunger, paresthesia, dizziness, weakness, and confusion.
Methods
- Narrative review of published literature on hypoglycaemia in adrenal insufficiency.
- Literature search performed in PubMed using terms including “primary adrenal insufficiency,” “secondary adrenal insufficiency,” “cortisol deficiency,” “hypoadrenalism,” “adrenal crises,” “hypoglycaemia,” and “low blood sugars.”
- Due to lack of reliable available evidence, the authors also included specific conditions known to cause adrenal insufficiency, mainly congenital adrenal hyperplasia, congenital adrenal hypoplasia, panhypopituitarism, and Addison’s disease; all papers related to the search terms were included.
Limitations
- The paper states that data on hypoglycaemia-related deaths in patients with primary adrenal insufficiency are limited, and that the frequency of hypoglycaemia during adrenal crises is not widely studied.
- The authors state it was difficult to ascertain whether hypoglycaemia partly contributed to adrenal crisis-associated deaths, and that the definitive role of continuous glucose monitoring in preventing hypoglycaemia in children with adrenal insufficiency is yet to be established and calls for larger multi-centre studies.
- Evident from the text: this is a narrative review without a systematic search strategy, formal quality appraisal, or meta-analysis, and it relies on heterogeneous studies, including small case series and older cohorts.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
45 of 81 cited sources checked · 27 supported · 0 flagged · accuracy not yet measured
- Premisecitation
More than half of the unexpected deaths in that cohort were thought to have undiagnosed secondary adrenal insufficiency.
“In addition, more than half of the unexpected deaths were thought to have undiagnosed secondary adrenal insufficiency (9).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] Mills, 2004, Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients, J Pediatr source
The Results report that 59 of 106 sudden, unexpected deaths (56%) had a clinical course strongly suggestive of adrenal insufficiency. The paper does not say that more than half had *undiagnosed secondary* adrenal insufficiency; it also describes deaths involving inadequate treatment of adrenal insufficiency. (LLM, conf=0.89)
Experimental — accuracy not yet measured
- Premisecitation
Mortality rates in patients with adrenal insufficiency and accompanying diabetes were higher than those with adrenal insufficiency alone.
“Although it was difficult to ascertain if hypoglycaemia partly contributed to the adrenal crisis-associated deaths, it was identified that mortality rates in patients with AI and accompanying diabetes were higher than those with AI alone (43).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [43] Ngaosuwan, 2021, Increased mortality risk in patients with primary and secondary adrenal insufficiency, J Clin Endocrinol Metab source
- Premisecitation
In a large cohort study of patients who received growth hormone in the United States, 24.5% (106 out of 433) deaths recorded were sudden and unexpected.
“In a large cohort study of patients who received growth hormone in the United States, 24.5% (106 out of the 433) deaths recorded were found to be sudden and unexpected.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] Mills, 2004, Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients, J Pediatr source
- Premisecitation
In one study, 8 out of 63 (12%) children with Addison's disease in a rural and urban Pakistan province presented with hypoglycaemia during an adrenal crisis.
“In one study, 8 out of 63 (12%) children with Addison’s disease in a rural and urban Pakistan province presented with hypoglycaemia during an adrenal crisis (42).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [42] Laghari, 2020, Spectrum of addison’s disease in children, J Coll Physicians Surg Pak source
- Premisecitation
Cortisol has a key role in glucose homeostasis, particularly in the counter-regulatory mechanisms to prevent hypoglycaemia in times of biological stress.
“Cortisol has a key role in glucose homeostasis, particularly in the counter-regulatory mechanisms to prevent hypoglycaemia in times of biological stress.”
Quote in the paperSubstantial claim1 of 4 sources checked- cites [10] Sprague, 2011, Glucose counterregulatory responses to hypoglycemia, Pediatr Endocrinol reviews: PER
- cites [11] De Feo, 1989, Contribution of cortisol to glucose counterregulation in humans, Am J PhysiologyEndocrinol And Metab source
- cites [12] De Feo, 1989, Demonstration of a role for growth hormone in glucose counterregulation, Am J Physiology-Endocrinol And Metab source
- cites [13] Tesfaye, 2010, Neuroendocrine responses to hypoglycemia, Ann New York Acad Sci source
In “The counterregulatory factors” (page not provided), the paper says cortisol helps limit the degree of prolonged hypoglycemia through metabolic effects. It also says cortisol has no immediate role in recovery from acute hypoglycemia. The claim’s broader emphasis on preventing hypoglycemia during biological stress is not established by these passages. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Modified-release hydrocortisone is associated with a significant reduction in body mass index.
“Studies have reported a significant reduction in body mass index, improved lipid profile, better glycaemic control and improved quality of life in those who are in the MR-HC group (58, 59).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [58] Bannon, 2020, Systematic review and meta-analysis of the metabolic effects of modified-release hydrocortisone versus standard glucocorticoid replacement therapy in adults with adrenal insufficiency, Clin Endocrinol source
- cites [59] Delle Cese, 2021, Switching from immediate-release to fractionated dual-release hydrocortisone may improve metabolic control and qol in selected primary adrenal insufficiency patients, Front Endocrinol source
- Premisecitation
In the extension of the clinical trial, the modified-release hydrocortisone group had a significant reduction in 17-OHP variability.
“However, an extension of this clinical trial showed an overall improvement in disease control in the MR-HC group due to lower 17-OHP and androstenedione levels at multiple points throughout the day, with a significant reduction in 17-OHP variability.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [60] Merke, 2021, Modified-release hydrocortisone in congenital adrenal hyperplasia, J Clin Endocrinol Metab source
The Results (Biochemical Disease Control; page unavailable) report significantly reduced 24-hour 17OHP variability in the MR-HC group at 24 weeks of the randomized phase 3 trial (P < .001). The extension study showed sustained improvement in biochemical control, but the paper does not report a significant reduction in 17OHP variability during the extension; its hormone samples were taken at 09:00h and 13:00h rather than across 24 hours (Trial Procedures; page unavailable). (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Premisecitation
The clinical trial comparing immediate-release and modified-release hydrocortisone in patients with congenital adrenal hyperplasia failed to prove its primary outcome.
“In a recent clinical trial comparing immediate-release and MR-HC in patients with CAH, both groups were able to achieve better 24-hour 17-OHP levels at 24 weeks compared to baseline, thus failing to prove their primary outcome.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [60] Merke, 2021, Modified-release hydrocortisone in congenital adrenal hyperplasia, J Clin Endocrinol Metab source
- Premisecitation
Modified-release hydrocortisone is associated with better glycaemic control.
“Studies have reported a significant reduction in body mass index, improved lipid profile, better glycaemic control and improved quality of life in those who are in the MR-HC group (58, 59).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [58] Bannon, 2020, Systematic review and meta-analysis of the metabolic effects of modified-release hydrocortisone versus standard glucocorticoid replacement therapy in adults with adrenal insufficiency, Clin Endocrinol source
- cites [59] Delle Cese, 2021, Switching from immediate-release to fractionated dual-release hydrocortisone may improve metabolic control and qol in selected primary adrenal insufficiency patients, Front Endocrinol source
- Premisecitation
Resolution of hypoglycaemia was seen when the hydrocortisone doses were increased in those children.
“On further review, they found that the daily doses of hydrocortisone were significantly lower in the 3 children and resolution of hypoglycaemia was seen when the doses were increased (49).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [49] Cambiaso, 2013, Nocturnal hypoglycaemia in acth and gh deficient children: role of continuous glucose monitoring, Clin Endocrinol source
- Premisecitation
In that study, full resolution of symptoms was achieved when the timings and dosages of the patients' hydrocortisone were altered based on the continuous glucose monitoring readings.
“Full resolution of symptoms was achieved when the timings and dosages of the patients’ hydrocortisone were altered based on the CGM readings (37).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [37] Watanabe, 2018, Usage of continuous glucose monitoring (cgm) for detecting an unrecognized hypoglycemia and management of glucocorticoid replacement therapy in adult patients with central hypoadrenalism, Endocrine J source
The Discussion (page unavailable) says CGM results were used to fine-tune glucocorticoid doses and regimens, and Table 3 reports no hypoglycemic episodes after modification. But the Discussion describes morning headache and discomfort as diminished, not fully resolved; the case descriptions likewise report improvement rather than complete symptom resolution. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Premisecitation
In a clinical trial comparing immediate-release and modified-release hydrocortisone in patients with congenital adrenal hyperplasia, both groups achieved better 24-hour 17-OHP levels at 24 weeks compared to baseline.
“In a recent clinical trial comparing immediate-release and MR-HC in patients with CAH, both groups were able to achieve better 24-hour 17-OHP levels at 24 weeks compared to baseline, thus failing to prove their primary outcome.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [60] Merke, 2021, Modified-release hydrocortisone in congenital adrenal hyperplasia, J Clin Endocrinol Metab source
The Results (Biochemical Disease Control; page unavailable) explicitly report that both groups had better 24-hour 17OHP profiles at 24 weeks than at baseline and that the trial failed its primary outcome. However, Trial Design and Table 4 describe the comparator as standard glucocorticoid therapy, which included prednisolone and dexamethasone as well as immediate-release hydrocortisone; the claim describes that group too narrowly. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Premisecitation
Continuous glucose monitoring in children with combined congenital central adrenal insufficiency and growth hormone deficiency identified severe asymptomatic nocturnal hypoglycaemia (< 2.7 mmol/L) in 3 out of 11 children, with the period of hypoglycaemia ranging from 30 to 150 minutes.
“CGM in children with combined congenital central adrenal insufficiency and growth hormone deficiency have identified severe asymptomatic nocturnal hypoglycaemia (< 2.7mmol/L) in 3 out of 11 children, with the period of hypoglycaemia ranging from 30 to 150 minutes.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [49] Cambiaso, 2013, Nocturnal hypoglycaemia in acth and gh deficient children: role of continuous glucose monitoring, Clin Endocrinol source
The Results report CGM-detected hypoglycaemia in three of 11 children, predominantly in the early morning, and the Discussion describes it as asymptomatic. The cited paper defines the threshold as <2.78 mmol/L and gives a duration of 30–155 minutes, rather than <2.7 mmol/L and 30–150 minutes. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Premisecitation
Overreplacement of glucocorticoids has been associated with increased mortality.
“Overreplacement of glucocorticoids has been associated with increased mortality (50), and under-replacement may lead to adrenal crises and hypoglycaemia.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [50] Mazziotti, 2017, Management of endocrine disease: risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects, Eur J Endocrinol source
- Premisecitation
Several studies using continuous glucose monitoring in adults with adrenal insufficiency have shown benefits by providing useful information on blood sugar trends.
“Several studies conducted using CGM in adults with AI have shown benefits as they provided useful information on blood sugar trends.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [37] Watanabe, 2018, Usage of continuous glucose monitoring (cgm) for detecting an unrecognized hypoglycemia and management of glucocorticoid replacement therapy in adult patients with central hypoadrenalism, Endocrine J source
The Abstract reports that this study used CGM to detect previously unrecognized hypoglycemia in adults with central hypoadrenalism and used the glucose findings to adjust treatment. It also mentions one earlier CGM study in adults with Addison’s disease. These passages support the benefit of CGM for showing glucose patterns, but document only two adult adrenal-insufficiency studies, not “several.” (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [52] Meyer, 2012, Nocturnal hypoglycemia identified by a continuous glucose monitoring system in patients with primary adrenal insufficiency (addison’s disease), Diabetes Technol Ther source
- Premisecitation
Modified-release hydrocortisone is associated with improved quality of life.
“Studies have reported a significant reduction in body mass index, improved lipid profile, better glycaemic control and improved quality of life in those who are in the MR-HC group (58, 59).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [58] Bannon, 2020, Systematic review and meta-analysis of the metabolic effects of modified-release hydrocortisone versus standard glucocorticoid replacement therapy in adults with adrenal insufficiency, Clin Endocrinol source
The Discussion (page unavailable) reports improvements in metabolic outcomes after switching to modified-release hydrocortisone, but does not report a quality-of-life finding. Searches for “quality of life,” “health-related quality of life,” and “QoL” found those terms in reference titles, not in the review’s reported findings. (LLM, conf=0.69)
Experimental — accuracy not yet measured - cites [59] Delle Cese, 2021, Switching from immediate-release to fractionated dual-release hydrocortisone may improve metabolic control and qol in selected primary adrenal insufficiency patients, Front Endocrinol source
- Premisecitation
In an extension of the clinical trial, the modified-release hydrocortisone group showed overall improvement in disease control due to lower 17-OHP and androstenedione levels at multiple points throughout the day.
“However, an extension of this clinical trial showed an overall improvement in disease control in the MR-HC group due to lower 17-OHP and androstenedione levels at multiple points throughout the day, with a significant reduction in 17-OHP variability.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [60] Merke, 2021, Modified-release hydrocortisone in congenital adrenal hyperplasia, J Clin Endocrinol Metab source
The Results (Biochemical Disease Control; page unavailable) report improved 09:00 disease control for both 17-OHP and androstenedione during the extension. They do not establish lower levels at multiple points throughout the day in the extension: Trial Procedures says extension samples were taken at 09:00 and 13:00, while the 24-hour profiles and significant reduction in 17-OHP variability belong to the 24-week phase 3 study. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
In one study, continuous glucose monitoring detected unrecognised nocturnal hypoglycaemia in 5 out of 6 adults with central hypoadrenalism causing early morning headaches.
“One study detected unrecognised nocturnal hypoglycaemia in 5 out of 6 adults with central hypoadrenalism causing early morning headaches.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [37] Watanabe, 2018, Usage of continuous glucose monitoring (cgm) for detecting an unrecognized hypoglycemia and management of glucocorticoid replacement therapy in adult patients with central hypoadrenalism, Endocrine J source
The Abstract reports that CGM detected unrecognized hypoglycemia around midnight or early morning in five of six adults with central hypoadrenalism. The Discussion says the patients had occasional morning headache and/or discomfort, but describes nocturnal hypoglycemia as a possible cause, not an established cause of headaches in all five. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
In those children, daily doses of hydrocortisone were significantly lower in the 3 children with hypoglycaemia.
“On further review, they found that the daily doses of hydrocortisone were significantly lower in the 3 children and resolution of hypoglycaemia was seen when the doses were increased (49).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [49] Cambiaso, 2013, Nocturnal hypoglycaemia in acth and gh deficient children: role of continuous glucose monitoring, Clin Endocrinol source
- Premisecitation
Both once-daily and twice-daily modified-release hydrocortisone versions are closer mimics of the physiological circadian rhythm than the conventional multiple-dose regimen.
“Both the once-daily (56) and twice-daily (57) modified-released versions have been shown to be a closer mimic of the physiological circadian rhythm, compared to the conventional multiple-dose regimen.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [56] Johannsson, 2012, Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation, J Clin Endocrinol Metab source
- cites [57] Mallappa, 2015, A phase 2 study of chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia, J Clin Endocrinol Metab source
- Rests on an assumption: The modified-release hydrocortisone preparation has a dual-release mechanism with an outer coating for immediate release and an inner core for sustained slower release.
- Premisecitation
In a recent review by Worth et al., hypoglycaemia sensitivity of continuous glucose monitoring reduces as the threshold for hypoglycaemia decreases.
“In a recent review by Worth et al. on the use of CGM, they found that hypoglycaemia sensitivity reduces as the threshold for hypoglycaemia decreases (61).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [61] Worth, 2023, Continuous glucose monitoring for children with hypoglycaemia: evidence in 2023 source
- Premisecitation
The accuracy of continuous glucose monitoring during a hypoglycaemia event is variable and dependent on factors such as insulin levels and rapid glucose changes.
“The accuracy of CGM during a hypoglycaemia event is also variable and dependent on a lot of factors such as insulin levels and rapid glucose changes (64).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [64] Worth, 2020, Continuous glucose monitoring for hypoglycaemia in children: perspectives in 2020, Pediatr Diabetes source
The supplied passage identifies the review but does not address factors affecting CGM accuracy. Searches for insulin levels, rapid glucose changes, and sensor lag returned no relevant full-text passage, so our available copy cannot verify the attributed explanation. (LLM, conf=0.72)
Experimental — accuracy not yet measured
- Premisecitation
Children with secondary adrenal insufficiency may require a lower daily replacement dose (6-8mg/m2/day).
“Children with secondary AI may require a lower daily replacement dose (6-8mg/m2/day) (49).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [49] Cambiaso, 2013, Nocturnal hypoglycaemia in acth and gh deficient children: role of continuous glucose monitoring, Clin Endocrinol source
The Introduction states that 6–8 mg/m²/day of hydrocortisone is considered an optimal replacement regimen for children with central adrenal insufficiency. It does not establish that this dose is lower than a dose required by another group. The Discussion also notes hypoglycaemia near the lower end of the range and favors 8 mg/m²/day to reduce that risk. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
Modified-release hydrocortisone is associated with an improved lipid profile.
“Studies have reported a significant reduction in body mass index, improved lipid profile, better glycaemic control and improved quality of life in those who are in the MR-HC group (58, 59).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [58] Bannon, 2020, Systematic review and meta-analysis of the metabolic effects of modified-release hydrocortisone versus standard glucocorticoid replacement therapy in adults with adrenal insufficiency, Clin Endocrinol source
The Discussion (page not available in our copy) reports lower total cholesterol in longer-term nonrandomised studies and lower LDL cholesterol in one study, offering some support for improved lipids. But the RCT meta-analysis found no significant change in total or LDL cholesterol, while HDL fell and triglycerides rose at three months. The source therefore does not support an unqualified improvement in lipid profile. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [59] Delle Cese, 2021, Switching from immediate-release to fractionated dual-release hydrocortisone may improve metabolic control and qol in selected primary adrenal insufficiency patients, Front Endocrinol source
- Premisecitation
Dose reduction was achievable in the modified-release hydrocortisone group whilst maintaining good disease control.
“Dose reduction was also achievable in the MR-HC group whilst maintaining good disease control (60).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [60] Merke, 2021, Modified-release hydrocortisone in congenital adrenal hyperplasia, J Clin Endocrinol Metab source
- Premisecitation
Patients with congenital adrenal hyperplasia were found to have reduced epinephrine stores which may affect their counter-regulatory mechanism towards hypoglycaemia.
“Patients with CAH were found to have reduced epinephrine stores which may affect their counter-regulatory mechanism towards hypoglycaemia (26).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Weise, 2004, Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glucose elevation in response to high-intensity exercise, J Clin Endocrinol Metab source
- Premisecitation
Adrenal crisis is more common in primary adrenal insufficiency compared to secondary adrenal insufficiency.
“It is more common in PAI (primary adrenal insufficiency) compared to SAI (4, 5).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisenone given
In the adult population with adrenal insufficiency, hypoglycaemia is less common.
“In the adult population with AI, hypoglycaemia is less common.”
Quote in the paperNot a substantial claim - Premisecitation
Patients with adrenal insufficiency are more sensitive to hypoglycaemia due to the lack of epinephrine response during a hypoglycaemic event.
“Patients with AI are also more sensitive to hypoglycaemia due to the lack of epinephrine response during a hypoglycaemic event (28).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] DeRosa, 2004, Hypoglycemia and the sympathoadrenal system: neurogenic symptoms are largely the result of sympathetic neural, rather than adrenomedullary, activation, Am J Physiol-Endocrinol Metab source
- Premisecitation
The incidence of adrenal crises is higher in primary adrenal insufficiency.
“However, this incidence is higher in PAI (33).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Smans, 2016, Incidence of adrenal crisis in patients with adrenal insufficiency, Clin Endocrinol source
- Premisereasoning
The risk of hypoglycaemia is increased in secondary adrenal insufficiency if there is accompanying growth hormone deficiency, due to the counterregulatory role of growth hormone.
“The risk of hypoglycaemia is increased if they have accompanying growth hormone (GH) deficiency, due to the counterregulatory role of GH in hypoglycaemia which is discussed later in this paper.”
Quote in the paperNot a substantial claim - Premisecitation
In a study conducted in France, 30 out of 165 (18%) children and infants with primary adrenal insufficiency experienced hypoglycaemic episodes.
“In children, a study conducted in France reported 30 out of 165 (18%) children and infants with PAI experienced hypoglycaemic episodes.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Artavia-Loria, 1986, Frequency of hypoglycemia in children with adrenal insufficiency, Eur J Endocrinol source
- Premisecitation
All hypoglycaemic episodes in that French study were associated with prior fasting or poor oral intake due to vomiting or viral illness.
“Additionally, all of these hypoglycaemic episodes were associated with prior fasting or poor oral intake due to vomiting or viral illness (38).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Artavia-Loria, 1986, Frequency of hypoglycemia in children with adrenal insufficiency, Eur J Endocrinol source
- Premisecitation
Children and infants with primary adrenal insufficiency who experienced hypoglycaemia had a significantly lower basal cortisol level.
“Those who experienced hypoglycaemia had a significantly lower basal cortisol level.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Artavia-Loria, 1986, Frequency of hypoglycemia in children with adrenal insufficiency, Eur J Endocrinol source
- Premisecitation
Low cortisol levels during controlled hypoglycaemia in neonates with hyperinsulinism were reported in a clinical trial.
“Low cortisol levels during controlled hypoglycaemia in neonates with hyperinsulinism were reported in a clinical trial.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Hussain, 2003, Neonates with symptomatic hyperinsulinemic hypoglycemia generate inappropriately low serum cortisol counterregulatory hormonal responses, J Clin Endocrinol Metab source
- Premisecitation
In a cohort study following children with congenital adrenal hyperplasia up to their 6th year of life, hypoglycaemia episodes were recorded in 16 out of 102 children (15%).
“In a cohort study following children with CAH up to their 6th year of life, hypoglycaemia episodes were recorded in 16 out of 102 children (15%).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Odenwald, 2016, Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life, Eur J Endocrinol source
- Interpretationreasoning
Individuals with adrenal insufficiency are at a higher risk of a hypoglycaemic event, especially when unwell or in an adrenal crisis.
“Individuals with AI are at a higher risk of a hypoglycaemic event, especially when unwell or in an adrenal crisis.”
Quote in the paperSubstantial claim - Premisecitation
In a case series, 3 children with asthma on high dose inhaled corticosteroids were found to have secondary adrenal insufficiency after presenting with hypoglycaemia, accompanied by vomiting, drowsiness and tiredness.
“In a case series, 3 children with a background of asthma who were on a high dose of inhaled corticosteroids, were found to have SAI after presenting with hypoglycaemia, accompanied by vomiting, drowsiness and tiredness.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Macdessi, 2003, Adrenal crises in children treated with high-dose inhaled corticosteroids for asthma, Med J Aust source
- Premisecitation
In a separate case study, a patient with Addison's disease reported better sleep when the evening dose of hydrocortisone was delayed due to detected hypoglycaemia from continuous glucose monitoring.
“In a separate case study, a patient with Addison’s disease reported better sleep when the evening dose of hydrocortisone was delayed due to detected hypoglycaemia from CGM (52).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Meyer, 2012, Nocturnal hypoglycemia identified by a continuous glucose monitoring system in patients with primary adrenal insufficiency (addison’s disease), Diabetes Technol Ther source
- Premisecitation
A review study has found that parental education alone is not sufficient to reduce adverse events from adrenal crises.
“Despite these measures, a review study has found that parental education alone is not sufficient to reduce adverse events from adrenal crises (5).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Rushworth, 2018, Adrenal crises in children: perspectives and research directions, Hormone Res Paediat source
- Premisecitation
Basal secretion of cortisol in children and young adults is known to be between 5-6mg/m2/day.
“The basal secretion of cortisol in children and young adults is known to be between 5-6mg/m2/day (1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Patti, 2018, Central adrenal insufficiency in children and adolescents, Best Pract Res Clin Endocrinol Metab source
- Premisecitation
Psychological barriers to giving intramuscular hydrocortisone remain a challenge for most carers and patients with adrenal insufficiency.
“Psychological barriers to giving intramuscular hydrocortisone still remain a challenge for most carers and patients with AI.”
Quote in the paperSubstantial claim - Premisecitation
The lowest hypoglycaemia sensitivity of continuous glucose monitoring was reported at 17% with a hypoglycaemia threshold of 2.6 mmol/L.
“The lowest hypoglycaemia sensitivity was reported at 17% with a hypoglycaemia threshold of 2.6mmol/L (62), as opposed to the highest hypoglycaemia sensitivity of only 86% with a hypoglycaemia threshold of 3.9mmol/L (63).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [62] Beardsall, 2013, Validation of the continuous glucose monitoring sensor in preterm infants, Arch Dis Childhood-Fetal Neonatal Edition source
- Premisecitation
Children with adrenal insufficiency are prone to hypoglycaemic events if they are not compliant with their steroid replacement.
“Children with AI are prone to hypoglycaemic events if they are not compliant with their steroid replacement (53).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Johnstone, 2008, The impact of fasting and treatment omission on susceptibility to hypoglycaemia in children and adolescents with gh and cortisol insufficiency, Clin Endocrinol source
- May combine two claims. 18
- Classified as probably not a substantial claim. 13
May combine two claims.
PremisecitationCortisol deficiency causes a reduction in endogenous glucose production and an increase in glucose oxidation, which can lead to hypoglycaemia.
“In addition, cortisol deficiency causes a reduction in endogenous glucose production and an increase in glucose oxidation, which can lead to hypoglycaemia (23).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [23] Christiansen, 2007, Effects of cortisol on carbohydrate, lipid, and protein metabolism: studies of acute cortisol withdrawal in adrenocortical failure, J Clin Endocrinol Metab source
May combine two claims.
PremisecitationAdrenal crisis was found to be an associated cause of death in 10% of those with adrenal insufficiency, mainly due to a compromise in the circulatory system.
“Adrenal crisis was found to be an associated cause of death in 10% of those with adrenal insufficiency, and this was mainly due to a compromise in the circulatory system.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [43] Ngaosuwan, 2021, Increased mortality risk in patients with primary and secondary adrenal insufficiency, J Clin Endocrinol Metab source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOne study calculated the standardized mortality ratio (SMR) to be 3 times higher in children with congenital adrenal hyperplasia, and mortality was significantly higher in infancy and children up to 4 years old.
“One study calculated the standardized mortality ratio (SMR) to be 3 times higher in children with CAH, and the mortality was significantly higher in infancy and children up to 4 years old (45), especially in the salt-wasting phenotype (46, 47).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [45] Swerdlow, 1998, Mortality in patients with congenital adrenal hyperplasia: a cohort study, J Pediatr source
- cites [46] Kovacs,´, 2001, Lessons from 30 years of clinical diagnosis and treatment of congenital adrenal hyperplasia in five middle european countries, J Clin Endocrinol Metab source
- cites [47] Falhammar, 2014, Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, J Clin Endocrinol Metab source
The Mortality section reports an overall hazard ratio of 2.8 for patients with CAH versus controls, approximately threefold higher, and says the excess mortality was concentrated in the first year of life. It does not report a standardized mortality ratio for children or establish significantly higher mortality throughout ages 0–4. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn children and young adults with AI, they may have hypoglycaemia, weakness, fatigue, gastrointestinal symptoms, headaches, muscle and joint pains.
“In children and young adults with AI, they may have hypoglycaemia, weakness, fatigue, gastrointestinal symptoms, headaches, muscle and joint pains (1, 2).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [1] Patti, 2018, Central adrenal insufficiency in children and adolescents, Best Pract Res Clin Endocrinol Metab source
- cites [2] Bornstein, 2016, Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline, J Clin Endocrinol Metab source
The General Introduction (page unavailable) lists hypoglycemia, weakness, fatigue, musculoskeletal pain, and abdominal pain as features of primary adrenal insufficiency; Table 1 also lists nausea and vomiting during adrenal crisis. The guideline does not identify headaches as a symptom or specifically establish this full symptom list for children and young adults, and its scope is primary rather than all adrenal insufficiency. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA study in Japan diagnosed adrenal insufficiency in 32 out of 528 patients (6%) after presenting to the emergency department with hypoglycaemia.
“A study in Japan diagnosed adrenal insufficiency in 32 out of 528 patients (6%) after presenting to the emergency department with hypoglycaemia.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [36] Kawahara, 2022, Frequency of adrenal insufficiency in patients with hypoglycemia in an emergency department: A cross-sectional study, J Endocrine Soc source
May combine two claims.
PremisecitationIn a study looking at emergency hospital admissions of children with congenital adrenal hyperplasia, 24 admissions (9%) were due to hypoglycaemia and a third of these presented with hypoglycaemic seizures.
“In a study looking at emergency hospital admissions of children with CAH, 24 admissions (9%) were due to hypoglycaemia and a third of these presented with hypoglycaemic seizures (39).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [39] Donaldson, 1994, Presentation, acute illness, and learning difficulties in salt wasting 21-hydroxylase deficiency, Arch Dis childhood source
The ACUTE ILLNESS section reports hypoglycaemia in 24 (9%) admissions and convulsions with hypoglycaemia in eight of those admissions—one third. It does not say the admissions were due to hypoglycaemia; it says hypoglycaemia was documented during them. The study concerns children with salt-wasting 21-hydroxylase deficiency, a specific form of CAH. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
Premisecitation74% of these unexpected deaths were associated with multiple pituitary hormone deficiencies and hypoglycaemia was highlighted in 31% of these 106 deaths.
“74% of these unexpected deaths were associated with multiple pituitary hormone deficiencies and hypoglycaemia was highlighted in 31% of these 106 deaths.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] Mills, 2004, Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients, J Pediatr source
May combine two claims.
PremisecitationLack of cortisol has been shown to increase insulin sensitivity, which enhances peripheral tissue's uptake of glucose, thereby increasing the risk of a hypoglycaemia event.
“Lack of cortisol has been shown to increase insulin sensitivity (23), which will enhance peripheral tissue’s uptake of glucose, thereby increasing the risk of a hypoglycaemia event.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [23] Christiansen, 2007, Effects of cortisol on carbohydrate, lipid, and protein metabolism: studies of acute cortisol withdrawal in adrenocortical failure, J Clin Endocrinol Metab source
May combine two claims.
PremisecitationOne published cohort study in the UK from 1987 to 2017 showed a significant rise in mortality rates in patients with adrenal insufficiency compared to matched healthy controls, and the risk is significantly higher in patients with primary adrenal insufficiency compared to secondary adrenal insufficiency.
“One published cohort study in the UK from 1987 to 2017 showed a significant rise in mortality rates in patients with AI compared to matched healthy controls, and the risk is significantly higher in patients with PAI compared to SAI.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [43] Ngaosuwan, 2021, Increased mortality risk in patients with primary and secondary adrenal insufficiency, J Clin Endocrinol Metab source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationParents and carers described a reduction in unplanned hospital admissions due to hypoglycaemia with continuous glucose monitoring use.
“Parents and carers also described marked improvement in the quality of life with CGM use and a reduction in unplanned hospital admissions due to hypoglycaemia (65).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [65] Ng, 2023, Paediatric society and hyperinsulinism charity national surveys on cgm access for patients with recurrent hypoglycaemia, J Endocrine Soc source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe highest hypoglycaemia sensitivity of continuous glucose monitoring was reported at 86% with a hypoglycaemia threshold of 3.9 mmol/L.
“The lowest hypoglycaemia sensitivity was reported at 17% with a hypoglycaemia threshold of 2.6mmol/L (62), as opposed to the highest hypoglycaemia sensitivity of only 86% with a hypoglycaemia threshold of 3.9mmol/L (63).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [63] Rayannavar, 2019, Continuous glucose monitoring systems: are they useful for evaluating glycemic control in children with hyperinsulinism, Hormone Res paediat source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA recent large survey in the UK revealed a high demand for continuous glucose monitoring in patients with recurrent hypoglycaemia without diabetes.
“A recent large survey in the UK revealed a high demand for CGM in those patients with recurrent hypoglycaemia without diabetes and it was interesting to see how funding was obtained for some of these patients across the country.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [65] Ng, 2023, Paediatric society and hyperinsulinism charity national surveys on cgm access for patients with recurrent hypoglycaemia, J Endocrine Soc source
May combine two claims.
PremisecitationOne prospective 2-year study monitored and titrated doses of hydrocortisone based on salivary 17-OHP levels in children with congenital adrenal hyperplasia up to 8 years of age, and the outcome was a lower median daily hydrocortisone dose with no observed adrenal crises.
“One prospective 2-year study has closely monitored and titrated the doses of hydrocortisone based on salivary 17-OHP levels in children with CAH up to 8 years of age and the outcome was a lower median daily hydrocortisone dose with no observed adrenal crises (51).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [51] Neumann, 2021, A prospective study of children aged 0–8 years with cah and adrenal insufficiency treated with hydrocortisone granules, J Clin Endocrinol Metab source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDue to gastric acids and hepatic first-pass effect, the recommended glucocorticoid treatment in children with primary adrenal insufficiency is slightly higher, ranging between 6-12mg/m2/day.
“Due to gastric acids and hepatic first-pass effect, the recommended glucocorticoid treatment in children with primary AI is slightly higher, ranging between 6-12mg/m2/day (1, 49).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [1] Patti, 2018, Central adrenal insufficiency in children and adolescents, Best Pract Res Clin Endocrinol Metab source
- cites [49] Cambiaso, 2013, Nocturnal hypoglycaemia in acth and gh deficient children: role of continuous glucose monitoring, Clin Endocrinol source
The Introduction (page unavailable) recommends hydrocortisone replacement for children, but specifies 6–8 mg/m²/day for central adrenal insufficiency, not 6–12 mg/m²/day for primary adrenal insufficiency. The cited paper does not give gastric acids or hepatic first-pass metabolism as the reason for a higher dose. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationA recent qualitative study of parents with young children with adrenal insufficiency demonstrated that most followed hydrocortisone oral stress dosing instructions prior to hospital admission, but only 2 out of 16 parents gave parenteral hydrocortisone at home, and the remaining patients received this from either paramedics or emergency department staff.
“A recent qualitative study of parents with young children with AI demonstrated that most of them followed the hydrocortisone oral stress dosing instructions prior to hospital admission, but only 2 out of 16 parents gave parenteral hydrocortisone at home, and the remaining patients received this from either the paramedics or emergency department staff (54).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [54] Worth, 2021, Acute illness and death in children with adrenal insufficiency, Front Endocrinol source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationParents and carers described marked improvement in quality of life with continuous glucose monitoring use.
“Parents and carers also described marked improvement in the quality of life with CGM use and a reduction in unplanned hospital admissions due to hypoglycaemia (65).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [65] Ng, 2023, Paediatric society and hyperinsulinism charity national surveys on cgm access for patients with recurrent hypoglycaemia, J Endocrine Soc source
May combine two claims.
PremisecitationLack of cortisol results in slow transport and maturation of bile acid synthesis, causing conjugated hyperbilirubinemia with raised liver enzymes, usually presenting at a median age of 13 days of life.
“The lack of cortisol results in slow transport and maturation of bile acid synthesis, causing conjugated hyperbilirubinemia with raised liver enzymes, which usually presents at a median age of 13 days of life (1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Patti, 2018, Central adrenal insufficiency in children and adolescents, Best Pract Res Clin Endocrinol Metab source
May combine two claims.
PremisecitationBlunted epinephrine response was seen in all patients with pituitary adenoma during insulin-induced hypoglycaemia, but the impairment is worst in those patients with secondary adrenal insufficiency.
“Blunted epinephrine response was seen in all patients with pituitary adenoma during insulin-induced hypoglycaemia, but the impairment is worst in those patients with SAI (29).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Morita, 2007, Reduced epinephrine reserve in response to insulin-induced hypoglycemia in patients with pituitary adenoma, Eur J Endocrinol source
May combine two claims.
PremisecitationNewborns with AI typically present with severe hypoglycaemia, seizures, failure to thrive, prolonged cholestatic jaundice, and in some cases coma.
“Newborns with AI typically present with severe hypoglycaemia, seizures, failure to thrive, prolonged cholestatic jaundice, and in some cases coma.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Patti, 2018, Central adrenal insufficiency in children and adolescents, Best Pract Res Clin Endocrinol Metab source
May combine two claims.
PremisecitationIn that cohort, loss of consciousness was seen in 13 out of the 16 hypoglycaemic episodes, and 5 children had hypoglycaemic seizures.
“Loss of consciousness was seen in 13 out of the 16 hypoglycaemic episodes, and 5 children had hypoglycaemic seizures (35).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Odenwald, 2016, Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life, Eur J Endocrinol source
May combine two claims.
PremisecitationHypocortisolaemia in neonates with hyperinsulinism was due to inappropriately low ACTH levels, indicating that neonates with hyperinsulinism may have blunted ACTH response from the hypothalamic-pituitary axis during a hypoglycaemia event.
“This study demonstrated that hypocortisolaemia was due to inappropriately low ACTH levels, indicating that neonates with hyperinsulinism may have blunted ACTH response from the hypothalamic-pituitary axis during a hypoglycaemia event (31).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Hussain, 2003, Neonates with symptomatic hyperinsulinemic hypoglycemia generate inappropriately low serum cortisol counterregulatory hormonal responses, J Clin Endocrinol Metab source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn a study following children with congenital adrenal hyperplasia up to 6 years of age, the number of adrenal crises is roughly 6.5 per 100 patient-years.
“In a study following children with CAH up to 6 years of age, the number of adrenal crises is roughly 6.5 per 100 patient-years (35).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Odenwald, 2016, Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life, Eur J Endocrinol source
May combine two claims.
InterpretationreasoningAffected neonates appear particularly susceptible to compromise of counter-regulatory mechanisms, but affected older children and adults remain at risk of hypoglycaemia.
“Affected neonates particularly appear susceptible to the compromise of these counter-regulatory mechanisms but it is recognised that affected older children and adults remain at risk of hypoglycaemia.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOne study reported 2 deaths in young children with congenital adrenal hyperplasia from hypoglycaemic seizures.
“However, we found one other study that reported 2 deaths in young children with CAH from hypoglycaemic seizures (40).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Pinto, 2003, Followup of 68 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: relevance of genotype for management, J Clin Endocrinol Metab source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe incidence of adrenal crises in individuals with primary or secondary adrenal insufficiency is approximately 5-10 per 100 patient-years.
“The incidence of adrenal crises in individuals with primary or secondary AI is approximately 5-10 per 100 patient-years (4, 5, 32).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] Hahner, 2010, Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies, Eur J Endocrinol source
- cites [5] Rushworth, 2018, Adrenal crises in children: perspectives and research directions, Hormone Res Paediat source
- cites [32] Hahner, 2015, High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study, J Clin Endocrinol Metab source
May combine two claims.
PremisereasoningUnder-replacement of glucocorticoids may lead to adrenal crises and hypoglycaemia.
“Overreplacement of glucocorticoids has been associated with increased mortality (50), and under-replacement may lead to adrenal crises and hypoglycaemia.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationInsulin sensitivity is highest between 0200 and 0400, causing patients with adrenal insufficiency to be at risk of nocturnal hypoglycaemia.
“Insulin sensitivity is also the highest between 0200 and 0400, causing patients with AI to be at risk of nocturnal hypoglycaemia (52).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52] Meyer, 2012, Nocturnal hypoglycemia identified by a continuous glucose monitoring system in patients with primary adrenal insufficiency (addison’s disease), Diabetes Technol Ther source
Classified as probably not a substantial claim.
InterpretationreasoningThe definitive role of continuous glucose monitoring in the prevention of hypoglycaemia in children with adrenal insufficiency is not yet established.
“In summary, the definitive role of CGM in the prevention of hypoglycaemia in children with AI is yet to be established and calls for larger multi-centre studies.”
Quote in the paperSubstantial claim- Rests on an assumption: Use of technology for blood sugar monitoring in children is currently only established in Type 1 diabetes.
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenChildren, especially young children with adrenal insufficiency, are vulnerable to the effects of hypoglycaemia.
“We have summarised the current literature on hypoglycaemia in AI and the significance of this problem as children are vulnerable to the effects of hypoglycaemia, especially young children with AI.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Findings from cited studies of specific adrenal insufficiency subtypes and related conditions (such as congenital adrenal hyperplasia, secondary adrenal insufficiency with growth hormone deficiency, and hyperinsulinism) can be generalised to the broader population of patients with adrenal insufficiency.
“Due to lack of reliable available evidence, we also included specific conditions known to cause AI for a more comprehensive review- mainly congenital adrenal hyperplasia (CAH), congenital adrenal hypoplasia, panhypopituitarism and Addison’s disease.”
The paper relies on this without support.
Use of technology for blood sugar monitoring in children is currently only established in Type 1 diabetes.
“However, the use of technology for blood sugar monitoring in children is currently only established in Type 1 diabetes.”
The paper relies on this without support.
The modified-release hydrocortisone preparation has a dual-release mechanism with an outer coating for immediate release and an inner core for sustained slower release.
“The modified-release preparation has a dual-release mechanism; an outer coating for an immediate release of hydrocortisone, and an inner core for a more sustained slower release.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The mechanisms of hypoglycemia in primary adrenal insufficiency are primarily due to cortisol deficiency.
“The mechanisms of hypoglycemia in primary adrenal insufficiency are primarily due to cortisol deficiency.”
From Onset of Addison Disease in a Patient Using the Advanced Hybrid Closed-Loop MiniMed 780G: Diagnostic Challenges (2025) · cites this paper as [8]
Patients with AI are at increased risk for hypoglycemia because glucocorticoids are involved in the counterregulatory hormonal response to hypoglycemia and are required for appropriate adrenal medulla development and function, including catecholamine production.
“First, glucocorticoids are involved in the counterregulatory hormonal response to hypoglycemia and are required for appropriate adrenal medulla development and function, including the production of catecholamines, which are also involved in the same response [32].”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [32]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting totals for hypoglycaemic episodes
MinorThe cohort is said to have had 23 hypoglycaemic episodes, but the next sentence describes 16 as the number of hypoglycaemic episodes when reporting loss of consciousness. The text does not explain why the denominator changes.
“There were a total of 23 hypoglycaemic episodes and 7 of these episodes were associated with salt loss.”
“Loss of consciousness was seen in 13 out of the 16 hypoglycaemic episodes, and 5 children had hypoglycaemic seizures (35).”
Cites
Bornstein, S. R., Allolio, B., Arlt, W., Barthel, A., Don-Wauchope, A., Hammer, G. D., Husebye, E. S., Merke, D. P., Murad, M. H., Stratakis, C. A., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-1710 · Cited by 1,769 · see citing works
RIZZA, R. A., MANDARINO, L. J., & GERICH, J. E. (1982) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-54-1-131 · Cited by 696 · see citing works
Hahner, S., Spinnler, C., Fassnacht, M., Burger-Stritt, S., Lang, K., Milovanovic, D., Beuschlein, F., Willenberg, H. S., Quinkler, M., & Allolio, B. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3191 · Cited by 394 · cited 1× · see citing works
“The incidence of adrenal crises in individuals with primary or secondary AI is approximately 5-10 per 100 patient-years (4, 5, 32).”
BackgroundHahner, S., Loeffler, M., Bleicken, B., Drechsler, C., Milovanovic, D., Fassnacht, M., Ventz, M., Quinkler, M., & Allolio, B. (2010) · European Journal of Endocrinology · doi:10.1530/eje-09-0884 · Cited by 346 · cited 8× · see citing works
“One published cohort study in the UK from 1987 to 2017 showed a signi fi cant rise in mortality rates in patients with AI compared to matched healthy controls, and the risk is signi fi cantly higher in patients with PAI compared to SAI.”
BackgroundInfluentialJohannsson, G., Nilsson, A. G., Bergthorsdottir, R., Burman, P., Dahlqvist, P., Ekman, B., Engström, B. E., Olsson, T., Ragnarsson, O., Ryberg, M., et al. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1926 · Cited by 329 · see citing works
Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency.
Merke, D. P., Chrousos, G. P., Eisenhofer, G., Weise, M., Keil, M. F., Rogol, A. D., Van Wyk, J. J., & Bornstein, S. R. (2000) · New England Journal of Medicine · doi:10.1056/nejm200011093431903 · Cited by 266 · see citing works
Stimulation of Lipolysis in Humans by Physiological Hypercortisolemia
Divertie, G. D., Jensen, M. D., & Miles, J. M. (1991) · Diabetes · doi:10.2337/diab.40.10.1228 · Cited by 201 · see citing works
Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Falhammar, H., Frisén, L., Norrby, C., Hirschberg, A. L., Almqvist, C., Nordenskjöld, A., & Nordenström, A. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2957 · Cited by 196 · see citing works
(2011) · PubMed · Cited by 187 · see citing works
Effects of growth hormone on glucose metabolism and insulin resistance in human
Kim, S.-H., & Park, M.-J. (2017) · Annals of Pediatric Endocrinology & Metabolism · doi:10.6065/apem.2017.22.3.145 · Cited by 181 · cited 1× · see citing works
“Lipolysis causes an increase in free fatty acids which affects insulin signalling pathways (14).”
BackgroundChristiansen, J. J., Djurhuus, C. B., Gravholt, C. H., Iversen, P., Christiansen, J. S., Schmitz, O., Weeke, J., Jørgensen, J. O. L., & Møller, N. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0445 · Cited by 176 · see citing works
Mallappa, A., Sinaii, N., Kumar, P., Whitaker, M. J., Daley, L.-A., Digweed, D., Eckland, D. J. A., Van Ryzin, C., Nieman, L. K., Arlt, W., et al. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3809 · Cited by 167 · see citing works
Neuroendocrine responses to hypoglycemia
Tesfaye, N., & Seaquist, E. R. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05820.x · Cited by 164 · cited 1× · see citing works
“Growth hormone and cortisol induce lipolysis in fat tissues and encourage hepatic ketogenesis and gluconeogenesis (13).”
BackgroundInsulin Resistance in Cushing’s Syndrome*
NOSADINI, R., DEL PRATO, S., TIENGO, A., VALERIO, A., MUGGEO, M., OPOCHER, G., MANTERO, F., DUNER, E., MARESCOTTI, C., MOLLO, F., et al. (1983) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-57-3-529 · Cited by 146 · see citing works
Frequency and causes of adrenal crises over lifetime in patients with 21-hydroxylase deficiency
Reisch, N., Willige, M., Kohn, D., Schwarz, H.-P., Allolio, B., Reincke, M., Quinkler, M., Hahner, S., & Beuschlein, F. (2012) · European Journal of Endocrinology · doi:10.1530/eje-12-0161 · Cited by 136 · see citing works
Contribution of cortisol to glucose counterregulation in humans
De Feo, P., Perriello, G., Torlone, E., Ventura, M. M., Fanelli, C., Santeusanio, F., Brunetti, P., Gerich, J. E., & Bolli, G. B. (1989) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1989.257.1.e35 · Cited by 134 · see citing works
Incidence of adrenal crisis in patients with adrenal insufficiency
Smans, L. C. C. J., Van der Valk, E. S., Hermus, A. R. M. M., & Zelissen, P. M. J. (2016) · Clinical Endocrinology · doi:10.1111/cen.12865 · Cited by 127 · see citing works
DeRosa, M. A., & Cryer, P. E. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00539.2003 · Cited by 126 · see citing works
Samra, J. S., Clark, M. L., Humphreys, S. M., MacDonald, I. A., Bannister, P. A., & Frayn, K. N. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.2.4547 · Cited by 123 · see citing works
Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients
Mills, J. L., Schonberger, L. B., Wysowski, D. K., Brown, P., Durako, S. J., Cox, C., Kong, F., & Fradkin, J. E. (2004) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2003.12.036 · Cited by 118 · cited 2× · see citing works
“Data looking at hypoglycaemia-related deaths in patients with PAI is limited, however, there are published studies examining the effect of hypoglycaemia on the mortality rates of patients with SAI who are on growth hormones (7 – 9).”
BackgroundBuchanan, C. R., Preece, M. A., & Milner, R. D. G. (1991) · BMJ · doi:10.1136/bmj.302.6780.824 · Cited by 117 · cited 1× · see citing works
“Data looking at hypoglycaemia-related deaths in patients with PAI is limited, however, there are published studies examining the effect of hypoglycaemia on the mortality rates of patients with SAI who are on growth hormones (7 – 9).”
BackgroundBlasetti, A., Chiuri, R. M., Tocco, A. M., Giulio, C. D., Mattei, P. A., Ballone, E., Chiarelli, F., & Verrotti, A. (2011) · Journal of Child Neurology · doi:10.1177/0883073811406730 · Cited by 117 · see citing works
Demonstration of a role for growth hormone in glucose counterregulation
De Feo, P., Perriello, G., Torlone, E., Ventura, M. M., Santeusanio, F., Brunetti, P., Gerich, J. E., & Bolli, G. B. (1989) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1989.256.6.e835 · Cited by 116 · see citing works
Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia
Merke, D. P., Mallappa, A., Arlt, W., Brac de la Perriere, A., Lindén Hirschberg, A., Juul, A., Newell-Price, J., Perry, C. G., Prete, A., Rees, D. A., et al. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab051 · Cited by 109 · see citing works
How Many Deaths Can Be Prevented by Newborn Screening for Congenital Adrenal Hyperplasia?
Grosse, S. D., & Van Vliet, G. (2007) · Hormone Research in Paediatrics · doi:10.1159/000098400 · Cited by 102 · cited 1× · see citing works
“Data from patients with CAH showed mortality rates in developed countries vary between 0 to 4% (44).”
BackgroundPinto, G., Tardy, V., Trivin, C., Thalassinos, C., Lortat-Jacob, S., Nihoul-Fékété, C., Morel, Y., & Brauner, R. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021433 · Cited by 101 · see citing works
KAMBA, A., Daimon, M., Murakami, H., Otaka, H., Matsuki, K., Sato, E., Tanabe, J., Takayasu, S., Matsuhashi, Y., Yanagimachi, M., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0166077 · Cited by 100 · see citing works
Mazziotti, G., Formenti, A. M., Frara, S., Roca, E., Mortini, P., Berruti, A., & Giustina, A. (2017) · European Journal of Endocrinology · doi:10.1530/eje-17-0154 · Cited by 96 · see citing works
Validation of the continuous glucose monitoring sensor in preterm infants
Beardsall, K., Vanhaesebrouck, S., Ogilvy-Stuart, A. L., Vanhole, C., vanWeissenbruch, M., Midgley, P., Thio, M., Cornette, L., Ossuetta, I., Palmer, C. R., et al. (2013) · Archives of Disease in Childhood - Fetal and Neonatal Edition · doi:10.1136/archdischild-2012-301661 · Cited by 82 · see citing works
Subcutaneous hydrocortisone administration for emergency use in adrenal insufficiency
Hahner, S., Burger-Stritt, S., & Allolio, B. (2013) · European Journal of Endocrinology · doi:10.1530/eje-12-1057 · Cited by 81 · see citing works
Mortality in patients with congenital adrenal hyperplasia: a cohort study
Swerdlow, A. J., Higgins, C. D., Brook, C. G. D., Dunger, D. B., Hindmarsh, P. C., Price, D. A., & Savage, M. O. (1998) · The Journal of Pediatrics · doi:10.1016/s0022-3476(98)70060-5 · Cited by 77 · cited 1× · see citing works
“One study calculated the standardized mortality ratio (SMR) to be 3 times higher in children with CAH, and the mortality was signi fi cantly higher in infancy and children up to 4 years old (45), especially in the salt-wasting phenotype (46, 47).”
BackgroundIncreased mortality risk in patients with primary and secondary adrenal insufficiency
Ngaosuwan, K., Johnston, D. G., Godsland, I. F., Cox, J., Majeed, A., Quint, J. K., Oliver, N., & Robinson, S. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab096 · Cited by 77 · see citing works
Weise, M., Drinkard, B., Mehlinger, S. L., Holzer, S. M., Eisenhofer, G., Charmandari, E., Chrousos, G. P., & Merke, D. P. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-032051 · Cited by 75 · see citing works
Central adrenal insufficiency in children and adolescents
Patti, G., Guzzeti, C., Di Iorgi, N., Maria Allegri, A. E., Napoli, F., Loche, S., & Maghnie, M. (2018) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2018.03.012 · Cited by 75 · see citing works
Maturation of the Circadian Rhythm of the Adrenocortical Functions in Human Neonates and Infants
Vermes, I., Dohanics, J., th, G. T. O., & cz, J. P. A. (2008) · Hormone Research · doi:10.1159/000179126 · Cited by 71 · cited 1× · see citing works
“AI treatment aims to mimic the circadian rhythm, and in neonates, this is not fully established until about 3 months of age (48).”
BackgroundWeise, M., Mehlinger, S. L., Drinkard, B., Rawson, E., Charmandari, E., Hiroi, M., Eisenhofer, G., Yanovski, J. A., Chrousos, G. P., & Merke, D. P. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030634 · Cited by 67 · cited 1× · see citing works
“Patients with CAH were found to have reduced epinephrine stores which may affect their counter-regulatory mechanism towards hypoglycaemia (26).”
BackgroundTaback, S. P., & Dean, H. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.5.8626817 · Cited by 65 · see citing works
Hussain, K., Hindmarsh, P., & Aynsley-Green, A. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030135 · Cited by 64 · see citing works
Casertano, A., Rossi, A., Fecarotta, S., Rosanio, F. M., Moracas, C., Candia, F. D., Parenti, G., Franzese, A., & Mozzillo, E. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.684011 · Cited by 61 · see citing works
Presentation, acute illness, and learning difficulties in salt wasting 21-hydroxylase deficiency
Donaldson, M. D., Thomas, P. H., Love, J. G., Murray, G. D., McNinch, A. W., & Savage, D. C. (1994) · Archives of Disease in Childhood · doi:10.1136/adc.70.3.214 · Cited by 60 · see citing works
Odenwald, B., Nennstiel-Ratzel, U., Dörr, H.-G., Schmidt, H., Wildner, M., & Bonfig, W. (2016) · European Journal of Endocrinology · doi:10.1530/eje-15-0775 · Cited by 60 · see citing works
Adrenal Crises in Children: Perspectives and Research Directions
Rushworth, R. L., Torpy, D. J., Stratakis, C. A., & Falhammar, H. (2018) · Hormone Research in Paediatrics · doi:10.1159/000481660 · Cited by 60 · cited 4× · see citing works
“Neonates Frontiers in Endocrinology frontiersin.org education alone is not suf fi cient to reduce adverse events from adrenal crises (5).”
BackgroundInfluentialAdrenal crises in children treated with high-dose inhaled corticosteroids for asthma
Macdessi, J. S., Asperen, P. P., Randell, T. L., Donaghue, K. C., Ambler, G. R., & Mellis, C. M. (2003) · Medical Journal of Australia · doi:10.5694/j.1326-5377.2003.tb05165.x · Cited by 54 · cited 1× · see citing works
“They suggested that adrenal suppression is in fl uenced by patient susceptibility, dose and duration of the inhaled corticosteroids (30).”
BackgroundKovacs, J. (2001) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.7.2958 · Cited by 52 · see citing works
Meyer, G., Hackemann, A., Reusch, J., & Badenhoop, K. (2012) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2011.0158 · Cited by 50 · see citing works
The diagnosis and treatment of adrenal insufficiency during childhood and adolescence
Park, J., Didi, M., & Blair, J. (2016) · Archives of Disease in Childhood · doi:10.1136/archdischild-2015-308799 · Cited by 47 · see citing works
Würzburger, M. I., Prelević, G. M., Sönksen, P. H., et al. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.77.1.267 · Cited by 40 · see citing works
Frequency of hypoglycemia in children with adrenal insufficiency
Artavia-Loria, E., Chaussain, J. L., Bougnères, P. F., & Job, J. C. (1986) · Acta Endocrinologica · doi:10.1530/acta.0.112s275 · Cited by 40 · cited 1× · see citing works
“Additionally, all of these hypoglycaemic episodes were associated with prior fasting or poor oral intake due to vomiting or viral illness (38).”
BackgroundNeumann, U., Braune, K., Whitaker, M. J., Wiegand, S., Krude, H., Porter, J., Digweed, D., Voet, B., Ross, R. J. M., & Blankenstein, O. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa626 · Cited by 38 · see citing works
Continuous glucose monitoring for hypoglycaemia in children: perspectives in 2020
Worth, C., Dunne, M., Ghosh, A., Harper, S., & Banerjee, I. (2020) · Pediatric Diabetes · doi:10.1111/pedi.13029 · Cited by 37 · cited 1× · see citing works
“The accuracy of CGM during a hypoglycaemia event is also variable and dependent on a lot of factors such as insulin levels and rapid glucose changes (64).”
BackgroundRayannavar, A., Elci, O. U., Mitteer, L., & De León, D. D. (2019) · Hormone Research in Paediatrics · doi:10.1159/000506230 · Cited by 31 · see citing works
Hypoglycemia during acute illness in children with classic congenital adrenal hyperplasia
Keil, M. F., Bosmans, C., Van Ryzin, C., & Merke, D. P. (2010) · Journal of Pediatric Nursing · doi:10.1016/j.pedn.2008.06.003 · Cited by 30 · see citing works
Continuous glucose monitoring for children with hypoglycaemia: Evidence in 2023
Worth, C., Hoskyns, L., Salomon-Estebanez, M., Nutter, P. W., Harper, S., Derks, T. G. J., Beardsall, K., & Banerjee, I. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1116864 · Cited by 29 · cited 1× · see citing works
“In a recent review by Worth et al. on the use of CGM, they found that hypoglycaemia sensitivity reduces as the threshold for hypoglycaemia decreases (61).”
BackgroundAdrenocortical control of epinephrine synthesis in health and disease.
Wurtman, R. J., & Pohorecky, L. A. (1971) · Advances in Metabolic Disorders · doi:10.1016/b978-0-12-027305-8.50022-9 · Cited by 27 · cited 1× · see citing works
“Normal glucocorticoid secretion of the adrenal cortex is essential for optimal development and functioning of the adrenal medulla, which is responsible for the production of the majority of epinephrine hormone (25).”
BackgroundWatanabe, T., Ozawa, A., Ishii, S., Tomaru, T., Shibusawa, N., Saito, T., Yamada, E., Horiguchi, K., Nakajima, Y., Matsumoto, S., et al. (2018) · Endocrine Journal · doi:10.1507/endocrj.ej16-0387 · Cited by 22 · see citing works
Cambiaso, P., Schiaffini, R., Pontrelli, G., Carducci, C., Ubertini, G., Crea, F., & Cappa, M. (2013) · Clinical Endocrinology · doi:10.1111/cen.12123 · Cited by 21 · cited 4× · see citing works
“Children with secondary AI may require a lower daily replacement dose (6-8mg/m2/day) (49).”
BackgroundInfluentialAcute illness and death in children with adrenal insufficiency
Worth, C., Vyas, A., Banerjee, I., Lin, W., Jones, J., Stokes, H., Komlosy, N., Ball, S., & Clayton, P. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.757566 · Cited by 16 · see citing works
Delle Cese, F., Corsello, A., Cintoni, M., Locantore, P., Pontecorvi, A., Corsello, S. M., & Paragliola, R. M. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.610904 · Cited by 13 · see citing works
Kawahara, T., Tsuji, M., Tominaga, N., Toyama, N., & Toda, M. (2022) · Journal of the Endocrine Society · doi:10.1210/jendso/bvac119 · Cited by 13 · see citing works
Joersjö, P., & Block, L. (2019) · BMJ Case Reports · doi:10.1136/bcr-2019-231858 · Cited by 9 · cited 1× · see citing works
“Symptoms may sometimes be non-speci fi c such as postural hypotension, syncope, arthralgia, anorexia and mental health issues, as described in a case report of undiagnosed Addison ’ s disease who presented to the hospital in a collapsed state (3).”
BackgroundMorita, S., Otsuki, M., Izumi, M., Asanuma, N., Izumoto, S., Saitoh, Y., Yoshimine, T., & Kasayama, S. (2007) · European Journal of Endocrinology · doi:10.1530/eje-07-0176 · Cited by 8 · see citing works
Bannon, C. A., Gallacher, D., Hanson, P., Randeva, H. S., Weickert, M. O., & Barber, T. M. (2020) · Clinical Endocrinology · doi:10.1111/cen.14275 · Cited by 8 · see citing works
Johnstone, H. C., McNally, R. J. Q., & Cheetham, T. D. (2008) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2008.03210.x · Cited by 7 · see citing works
Spectrum of addison’s disease in children
(2020) · Journal of the College of Physicians and Surgeons Pakistan · doi:10.29271/jcpsp.2020.10.1086 · Cited by 6 · see citing works
Ng, S. M., Dearman, S., Fisher, M., Mushtaq, T., & Randell, T. (2023) · Journal of the Endocrine Society · doi:10.1210/jendso/bvad021 · Cited by 6 · cited 1× · see citing works
“Parents and carers also described marked improvement in the quality of life with CGM use and a reduction in unplanned hospital admissions due to hypoglycaemia (65).”
BackgroundWurzburger, M. I., Prelevic, G. M., Sönksen, P. H., et al. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.77.1.8325951 · Cited by 4
Flagged first, then by citations
4 of the 70 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Paraneoplastic hypoglycemia: An overview for optimal clinical guidance
Karamanolis, N. N., Kounatidis, D. C., Vallianou, N. G., Alexandropoulos, K., Kovlakidi, E., Kaparou, P., Karampela, Ι., Stratigou, T., & Dalamaga, Μ. (2024) · Metabolism Open · doi:10.1016/j.metop.2024.100305 · Cited by 19 · see citing works
“Furthermore, symptoms such as orthostasis, hyponatremia, and weight loss may indicate adrenal insufficiency, which can result from the destruction of adrenal glands due to extensive tumor infiltration [35].”
BackgroundHimmerich, H., Keeler, J. L., King, J. A., Ehrlich, S., Kaufmann, L., Bulik, C. M., Cohen‐Woods, S., Wade, T. D., Steiger, H., Booij, L., et al. (2026) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2026.2626934 · Cited by 22 · see citing works
Non-Diabetic Hypoglycemia: Evaluation and Management in Adults
Looi, E., & Lawler, H. M. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14134393 · Cited by 10 · see citing works
“The mainstay of treatment is to encourage compliance with physiologic glucocorticoid replacement and ensure easy access to simple carbohydrates, parenteral glucagon, and stress-dose steroids for emergency use [32].”
Do, M., Hayes, A. G., & Brzozowska, M. M. (2025) · The Medical Journal of Australia · doi:10.5694/mja2.52647 · Cited by 5 · see citing works
Metabolic emergencies in the NICU
Gupta, R., Joshi, S., Asghar, A., et al. (2024) · Seminars in Perinatology · doi:10.1016/j.semperi.2024.151987 · Cited by 4 · see citing works
A practical approach to diagnosis and treatment in children with primary adrenal insufficiency
Capalbo, D., Illiano, S., Vasaturo, S., Lorello, P., Rotondo, F. R., Mase, R. D., Bizzarri, C., & Salerno, M. (2025) · European Journal of Endocrinology · doi:10.1093/ejendo/lvaf229 · Cited by 3 · see citing works
Thyroid and adrenal autoimmunity in children with newly diagnosed type 1 diabetes mellitus
Dempsey, O., Pinsker, J., Lucas-Herald, A. K., Allison, G., Whyte, K., Kuehne, V. S., Pearce, H., Sharma, A., Rashid, R., McNeilly, J., et al. (2026) · Journal of Pediatric Endocrinology and Diabetes · doi:10.25259/jped_78_2025 · Cited by 3 · see citing works
Adrenal insufficiency in severely wounded men with combat gunshot injury
Seliukova, N. Y., Misiura, K. V., Khoroshun, E. M., Макаров, В. В., Nehoduiko, V. V., Zalyubovska, O. I., & Szucsik, E. (2025) · INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine) · doi:10.22141/2224-0721.20.8.2024.1463 · Cited by 3 · see citing works
Glucocorticoid withdrawal syndrome: Disproportionality analysis of cases using VigiBase data
Mangal, L., Arda, B. E., & Si̇pahi̇, H. (2025) · DARU Journal of Pharmaceutical Sciences · doi:10.1007/s40199-025-00565-y · Cited by 2 · see citing works
“This may be due to acute adrenal crisis, which can result in life-threatening symptoms such as vomiting, diarrhea, fever or hypothermia, acute dehydration, hypotension, hypoglyce - mia, shock, and coma [ 10 , 35].”
Hypoglycemia in Critically Ill Patients
Ma, T., & Chen, L. L. (2024) · Critical Care Nursing Quarterly · doi:10.1097/cnq.0000000000000525 · Cited by 2 · see citing works
Иванов, Д. О., Фомин, С. А., Pshenisnov, K. V., et al. (2024) · Messenger of Anesthesiology and Resuscitation · doi:10.24884/2078-5658-2024-21-4-69-77 · Cited by 1 · see citing works
Huang, Y., Huang, Q., Xie, Y., et al. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1651381 · Cited by 1 · see citing works
Chihaoui, M., Sta, J.-D., Kamoun, E., Belhadjsliman, C., Khessairi, N., Oueslati, I., Yazidi, M., Chaker, F., & Feki, M. (2025) · Journal of Endocrinological Investigation · doi:10.1007/s40618-025-02728-9 · Cited by 2 · see citing works
“The risk of hypoglycaemia is increased during acute decom - pensation, following cessation of treatment, and during fasting or delayed food intake [3–5].”
Endocrine dysfunctions as complications and comorbidities of juvenile idiopathic arthritis
Kamińska, M., Spyra, A., Schröter, M., Sierpińska, A., Moczyróg, K., & Rosół, I. (2025) · Reumatologia/Rheumatology · doi:10.5114/reum/204738 · Cited by 1 · see citing works
Alamri, R. H., Alshamrani, A. A., Mawar, H. E., et al. (2026) · Clinical Case Reports · doi:10.1002/ccr3.73324 · Cited by 1 · see citing works
Dysglycaemia in Ebola virus disease: a retrospective analysis from the 2018 to 2020 outbreak
Claude, K. M., Mukadi‐Bamuleka, D., Richard, K.-O., Mbahweka, F. K., Mwalitsa, J. P. P., Muliwavyo, K., Edidi-Atani, F., Matondo-Kuamfumu, M., Mulangu, S., Tshiani-Mbaya, O., et al. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105241 · Cited by 1 · see citing works
Acute Adrenal Insufficiency in Childhood: Etiopathogenesis, Clinical Picture, and Intensive Care
Bykov, Y. V., Обедин, А. Н., Фишер, В. В., Volkov, E. V., Yatsuk, I. V., Muravyeva, A. A., & Zinchenko, О. V. (2024) · Ural Medical Journal · doi:10.52420/umj.23.5.125 · Cited by 1 · see citing works
Cognitive Assessment in Adults With Adrenal Cortisol Insufficiency: Challenges and Opportunities
Ben-Shlomo, A., Koh, M., Kremen, S. A., & Wertheimer, J. C. (2025) · Endocrine Reviews · doi:10.1210/endrev/bnaf029 · Cited by 1 · see citing works
Mera-Carreiro, S., Jiménez-Varas, I., Martínez-Suero, L., Sánchez-Maroto-García, N., De-Miguel-Novoa, P., & Cuesta-Hernández, M. (2025) · JCEM Case Reports · doi:10.1210/jcemcr/luaf181
“A lack of cortisol also compromises the normal counter-regulatory response to hypoglycemia, since cortisol is necessary for catecholamines and glucagon to have their full effect in raising blood glucose [8].”
Borazan, İ., Top, A. A., Ferhatlar, M. E., Şentürk, M., Danış, F., Oymak, M. S., Karcıoğlu, Ö., Beşer, Z., Karabay, O., Kabakçı, A., et al. (2024) · Akademisyen Kitabevi eBooks · doi:10.37609/akya.3074
Glycemic Control in the Intensive Care Unit
Grucz, T. M., DiCesare, M. A., & Sugrue, D. (2025) · Springer eBooks · doi:10.1007/978-3-031-77335-8_52
A new index for predicting epileptic seizures: glucose potassium ratio
Köksal, A., Sarıbaş, M. S., Çaltekin, İ., Aygün, A., KAYGISIZ, Ş., & Tomakin, M. (2025) · Çukurova medical journal (Online)/Çukurova medical journal · doi:10.17826/cumj.1639560
Mori, J.-I., Yamashita, K., & Aizawa, T. (2025) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/ggi.70240
Adrenal injury induced by real-ambient PM2.5: Mechanisms of disrupted Shh/Wnt signaling crosstalk
Zhang, Z., Tang, S., Hao, H., Ding, H., Guo, X., Li, D., Chen, W., Zhang, R., Chen, R., & Piao, J. (2025) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2025.119497
Dravecká, I., Galajda, P., & Mokáň, M. (2025) · IntechOpen eBooks · doi:10.5772/intechopen.1013682
Addison's Disease: The Critical Role of Timely Diagnosis
Armstrong, K., & Wade, H. N. (2026) · The Journal for Nurse Practitioners · doi:10.1016/j.nurpra.2025.105669
The Clinical Impact of Corticosteroid Supplementation in Febrile Patients with Adrenal Insufficiency
Kwon, H., Lee, S. E., Park, J. H., Ko, J. W., & Kim, B. (2026) · Yonsei Medical Journal · doi:10.3349/ymj.2025.0008
Self-citationMachineni, P., Ranjan, A., Asirvatham, A. R., & Mahadevan, S. (2026) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/ijem.ijem_925_25
Yang, J., Li, L., Sun, Y., et al. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1740124
Seronegative Doege-Potter syndrome in a patient with a pleural-based solitary fibrous tumour
Nalamalapu, R., Reardon, J., & Mouallem, N. E. (2026) · BMJ Case Reports · doi:10.1136/bcr-2025-270532
Subacute Haemorrhagic Pituitary Apoplexy Leading to Secondary Adrenal Insufficiency: A Case Report
Jackson-Wade, R., Fogarty, O., Nge, N. N., et al. (2026) · Cureus · doi:10.7759/cureus.106333
“Cortisol deficiency increases insulin sensitivity and reduces hepatic gluconeogenesis, which lowers blood glucose and increases peripheral glucose uptake [10].”
Zhao, Y., Mu, J., & Zou, H. (2026) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2026-0058
- Authors
- Lee, S. C., Baranowski, E. S., Sakremath, R., Saraff, V., & Mohamed, Z.
- Affiliations
- Birmingham Women's Hospital (GB)
- Corresponding author
- Lee, Shien Chen
- Mohamed, Zainaba
- Venue
- Frontiers in Endocrinology
- Publisher
- Frontiers Media SA
- Published
- 2023-11-20
- Volume
- 14
- Pages
- 1198519-1198519
- ISSN
- 1664-2392 (ISSN-L)
- PMC
- PMC10694272
- OpenAlex
- W4388832235
- Semantic Scholar
- 7ce13f978c7ec86f056e5c740e89ceafe687ac15
- Cited by
- 32
- References
- 70
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 7
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Endocrinology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- adrenal insufficiency, hypoglycemia, cortisol, counter-regulatory mechanisms, glucose homeostasis, Addison's disease, congenital adrenal hyperplasia, 21-hydroxylase deficiency, adrenal hypoplasia, ACTH deficiency, iatrogenic adrenal insufficiency, adrenal hemorrhage, adrenal tuberculosis, neuroblastoma, hypoglycemic coma
- MeSH terms
- Adolescent, Adrenal Insufficiency, Adrenal Hyperplasia, Congenital, Adrenocorticotropic Hormone, Adult, Blood Glucose, Child, Glucocorticoids, Humans, Hydrocortisone, Hypoglycemia, Iatrogenic Disease, Infant, Newborn, Blood Glucose Self-Monitoring
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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