Pediatric Adrenal Insufficiency: Challenges and Solutions

Authors NisticĂČ D , Bossini B, Benvenuto S, Pellegrin MC, Tornese G

Received 29 October 2021

Accepted for publication 28 December 2021

Published 11 January 2022 Volume 2022:18 Pages 47—60

DOI https://doi.org/10.2147/TCRM.S294065

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Garry Walsh

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Daniela NisticĂČ,1 Benedetta Bossini,1 Simone Benvenuto,1 Maria Chiara Pellegrin,1 Gianluca Tornese2

1University of Trieste, Trieste, Italy; 2Department of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy

Correspondence: Gianluca Tornese
Department of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell’Istria 65/1, Trieste, 34137, Italy
Tel +39 040 3785470
Email gianluca.tornese@burlo.trieste.it

Abstract: Adrenal insufficiency is an insidious diagnosis that can be initially misdiagnosed as other life-threatening endocrine conditions, as well as sepsis, metabolic disorders, or cardiovascular disease. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice. Subclinical adrenal insufficiency is a particular challenge for a pediatric endocrinologist, representing the preclinical stage of acute adrenal insufficiency. Although often included in the extensive work-up of an unwell child, a single cortisol value is usually difficult to interpret; therefore, in most cases, a dynamic test is required for diagnosis to assess the hypothalamic-pituitary-adrenal axis. Stimulation tests using corticotropin analogs are recommended as first-line for diagnosis. All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy, and oral hydrocortisone is the first-choice replacement treatment in pediatric. However, children that experience low cortisol concentrations and symptoms of cortisol insufficiency can take advantage using a modified release hydrocortisone formulation. The acute adrenal crisis is a life-threatening condition in all ages, treatment is effective if administered promptly, and it must not be delayed for any reason.

Keywords: adrenal gland, primary adrenal insufficiency, central adrenal insufficiency, Addison disease, children, adrenal crisis, hydrocortisone

Introduction

Primary adrenal insufficiency (PAI) is a condition resulting from impaired steroid synthesis, adrenal destruction, or abnormal gland development affecting the adrenal cortex.1 Acquired primary adrenal insufficiency is termed Addison disease. Central adrenal insufficiency (CAI) is caused by an impaired production or release of adrenocorticotropic hormone (ACTH). It can originate either from a pituitary disease (secondary adrenal insufficiency) or arise from an impaired release of corticotropin-releasing hormone (CRH) from the hypothalamus (tertiary adrenal insufficiency). An underlying genetic cause should be investigated in every case of adrenal insufficiency (AI) presenting in the neonatal period or first few months of life, although AI is relatively rare at this age (1:5.000–10.000).2

Physiology of the Adrenal Gland

The adrenal cortex consists of three zones: the zona glomerulosa, the zona fasciculata, and the zona reticularis, responsible for aldosterone, cortisol, and androgens synthesis, respectively.3 Aldosterone production is under the control of the renin-angiotensin system, while cortisol is regulated by the hypothalamic-pituitary-adrenal axis (HPA).4 This explains why patients affected by CAI only manifest glucocorticoid deficiency while mineralocorticoid function is spared. CRH is secreted from the hypothalamic paraventricular nucleus into the hypophyseal-portal venous system in response to light, stress, and other inputs. It binds to a specific cell-surface receptor, the melanocortin 2 receptor, stimulating the release of preformed ACTH and the de novo transcription of the precursor molecule pro-opiomelanocortin (POMC). ACTH is derived from the cleavage of POMC by proprotein convertase-1.5–9 ACTH binds to steroidogenic cells of both the zona fasciculata and reticularis, activating adrenal steroidogenesis. It also has a trophic effect on adrenal tissue; therefore, ACTH deficiency determines adrenocortical atrophy and decreases the capacity to secrete glucocorticoids. Circulating cortisol is 75% bound to corticosteroid-binding protein, 15% to albumin, and 10% free. The endogenous production rate is estimated between 6 and 10 mg/m2/day, even though it depends on age, gender, and pubertal development. Glucocorticoids have multiple effects: they regulate immune, circulatory, and renal function, influence growth, development, energy and bone metabolism, and central nervous system activity. Several studies reported higher cortisol plasma concentrations in girls than in boys and younger children.3,4,8

Cortisol secretion follows a circadian and ultradian rhythm according to varying amplitudes of ACTH pulses. Pulses of ACTH and cortisol occur every 30–120 minutes, are highest at about the time of waking, and decline throughout the day, reaching a nadir overnight.3,8,9 This pattern can change in the presence of serious illness, major surgery, and sleep deprivation. During stressful situations, glucocorticoid secretion can increase up to 10-fold to enhance survival through increased cardiac contractility and cardiac output, sensitivity to catecholamines, work capacity of the skeletal muscles, and availability of energy stores.3

The interaction between the hypothalamus and the two endocrine glands is essential to maintain plasma cortisol homeostasis (Figure 1). Cortisol exerts double-negative feedback on the HPA axis. It acts on the hypothalamus and the corticotrophin cells of the anterior pituitary, reducing CRH and ACTH synthesis and release.6 ACTH inhibits its secretion through a feedback effect mediated at the level of the hypothalamus.3 Increased androgen production occurs in the case of cortisol biosynthesis enzymatic deficits.

Figure 1 The hypothalamic–pituitary–adrenal axis.

Primary Adrenal Insufficiency

PAI affects 10–15 per 100,000 individuals and recognizes different classes of genetic causes (Table 1). Congenital adrenal hyperplasia (CAH) is the main cause of PAI in the neonatal period, being included among the disorders of steroidogenesis secondary to deficits in enzymes. It has an autosomal recessive transmission.1,10,11 The estimated incidence ranges between 1:10,000 and 1:20,000 births. CAH phenotype depends on disease-causing mutations and residual enzyme activity. 21-hydroxylase deficiency (21OHD) accounts for more than 90% of cases, 21-hydroxylase converts cortisol and aldosterone precursors, respectively 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol and progesterone to deoxycortisone. Less frequent forms of CAH include 11 ÎČ -hydroxylase deficiency (11BOHD, 8% of cases), 17α-hydroxylase/17–20 lyase deficiency (17OHD), 3ÎČ-hydroxysteroid dehydrogenase deficiency (3BHDS), P450 oxidoreductase deficiency (PORD).12 Steroidogenesis may also be impaired by steroidogenic acute regulatory (StAR) protein deficiency, which is involved in cholesterol transport into mitochondria, or P450 cytochrome side-chain cleavage (P450scc) deficiency, that converts cholesterol into pregnenolone.12,13 Of these conditions, 21OHD and 11BOHD only affect adrenal steroidogenesis, whereas the other deficits also impact gonadal steroid production. In classic CAH, enzyme activity can be absent (salt-wasting form) or low (1–2% enzyme activity, simple virilizing form). The salt-wasting form is the most severe and affects 75% of patients with classic 21OHD.1,10,12,14 Non-classic CAH (NCCAH) is more prevalent than the classic form, in which there is 20–50% of residual enzymatic activity. Two-thirds of NCCAH individuals are compound heterozygotes with different CYP21A2 mutations in two different alleles (classic severe mutation plus mild mutation in two different alleles or homozygous with two mild mutations). Notably, 70% of NCCAH patients carry the point mutation Val281Leu.

Table 1 Causes of Primary Adrenal Insufficiency (PAI)

Central Adrenal Insufficiency

CAI incidence is estimated between 150 and 280 per million, and it should be suspected when mineralocorticoid function is preserved. When, rarely, isolated is due to iatrogenic HPA suppression secondary to prolonged glucocorticoid therapy or the removal of an ACTH- or cortisol-producing tumor (Cushing syndrome).15 Defects in POMC,16 characterized by red or auburn-haired children, pale skin (due to melanocyte stimulating hormone [MSH] – deficiency) and hyperphagia later in life, and in transcription factor TPIT,17 which regulates POMC synthesis in corticotrope cells, are the two leading genetic causes of isolated ACTH deficiency (Table 2). Mainly, it occurs as part of complex syndromes in which a combined multiple pituitary hormone deficiency (CMPD) is associated with craniofacial and midline defects, such as Prader-Willi syndrome, CHARGE syndrome, Pallister-Hall syndrome (anatomical pituitary abnormalities), white vanishing matter disease (progressive leukoencephalopathy).5 Individuals with an isolated pituitary deficiency, usually a growth hormone deficiency (GHD), may develop multiple pituitary hormone deficiencies over the years. Therefore, excluding a latent CAI at GHD onset and periodically monitoring of HPA axis is of utmost importance. Notably, cortisol reduction secondary to an increased basal metabolism when starting GHD or thyroxin substitutive therapy may unleash a misdiagnosed CAI. CMPD can be caused by several defective genes, such as GLI1, LHX3, LHX4, SOX2, SOX3, HESX1: in such cases, hypoglycemia or small penis with undescended testes may respectively suggest concomitant GH and gonadotropins deficits.18

Table 2 Causes of Central Adrenal Insufficiency (CAI)

Clinical Manifestations of Adrenal Insufficiency

AI is an insidious diagnosis presenting non-specific symptoms and may be mistaken with other life-threatening endocrine conditions (septic shock unresponsive to inotropes or recurrent sepsis, acute surgical abdomen).1,19 Children can be initially misdiagnosed as having sepsis, metabolic disorders, or cardiovascular disease, highlighting the need to consider adrenal dysfunction as a differential diagnosis for an unwell or deteriorating infant. With age-related items, clinical features depend on the type of AI (primary or central) and could manifest in an acute or chronic setting (Table 3).

Table 3 Features of Isolated Adrenal Insufficiency in Pediatric Age

Clinical signs of PAI are based on the deficiency of both gluco- and mineralocorticoids. Signs due to glucocorticoid deficiency are weakness, anorexia, and weight loss. Hypoglycemia with normal or low insulin levels is frequent and often severe in the pediatric population. Mineralocorticoid deficiency contributes to hyponatremia, hyperkalemia, acidosis, tachycardia, hypotension, and salt craving. The lack of glucocorticoid-negative feedback is responsible for the elevated ACTH levels. The high levels of ACTH and other POMC peptides, including the various forms of MSH, cause melanin hypersecretion, stimulating mucosal and cutaneous hyperpigmentation. Searching for an increased pigmentation may represent an essential diagnostic tool since all the other symptoms of PAI are non-specific. However, hyperpigmentation is variable, dependent on ethnic origin, and more prominent in skin exposed to sun and in extension surface of knees, elbows, and knuckles.15 In autoimmune PAI, vitiligo may be associated with hyperpigmentation.

In the classic CAH simple virilizing form, salt wasting is absent due to the presence of aldosterone production. In males, diagnosis typically occurs between 3 and 4 years of age with pubarche, accelerated growth velocity, and advanced bone age at presentation.1,10,12,14

NCCAH may occur in late childhood with signs of hyperandrogenism (premature pubarche, acne, adult apocrine odor, advanced bone age) or be asymptomatic. In adolescents and adult women, conditions of androgen excess (acne, oligomenorrhea, hirsutism) may underlie an NCCAH.20,21

The clinical presentation of CAI may be more complex when caused by an underlying central nervous system disease or by CMPD. In the case of a pituitary or hypothalamic tumor, patients may present headache, vomiting, visual disturbances, short stature, delayed or precocious puberty. In the case of CMPD, manifestations vary considerably and depend on the number and severity of the associated hormonal deficiencies. In CAI, aldosterone production is spared, which means that serum electrolytes are usually normal. However, cortisol contributes to regulating free water excretion, so patients with CAI are at risk for dilutional hyponatremia, with normal serum potassium levels. Since adrenal androgen secretion is under the control of ACTH, girls with ACTH deficiency may present light pubic hair. Patients with partial and isolated ACTH defects can be “asymptomatic”, and adrenal crisis appears during stress or in case of major illness (high fever, surgery).

The acute adrenal crisis is a life-threatening condition in all ages. Patients present with profound malaise, fatigue, nausea, vomiting, abdominal or flank pain, muscle pain or cramps, and dehydration, which lead to hypotension, shock, and metabolic acidosis. Hyponatremia and hyperkalemia are less common in CAI than in PAI, but possible in acute AI. Severe hypoglycemia causes weakness, pallor, sweatiness, and impaired cognitive function, including confusion, loss of consciousness, and coma. Immediate treatment is required (see below).

Children and adolescents affected by autoimmune primary adrenal insufficiency develop a chronic AI, with an insidious onset and slow progress to an acute adrenal crisis over months or even years. Initial symptoms are decreased appetite, anorexia, nausea, abdominal pain, unintentional weight loss, lethargy, headache, weakness, and fatigue, with prominent pain in the joints and muscles. Due to salt loss through the urine and the subsequent reduction in blood volume, blood pressure decreases, and orthostatic hypotension develops together with salt craving. An increased risk of infection in AI patients is reported only in those exposed to glucocorticoids. However, in APECED (Autoimmune Polyendocrinopathy-Candidiasis- Ectodermal-Dystrophy) patients, there is an increased risk of candidiasis and splenic atrophy increases the likelihood for severe infections.

In neonates, AI classically presents with failure to thrive and hypoglycemia, commonly severe and associated with seizures. The condition can be life-threatening and, if misdiagnosed, may result in coma and unexplained neonatal death. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice with persistently raised serum liver enzymes. The cholestasis can be resolved within ten weeks of correct treatment. StAR deficiency and P450scc cause salt-losing AI with female external genitalia in genetically male neonates.22 In the classic CAH salt-wasting form, the mineralocorticoid deficiency presents with the adrenal crisis at 10–20 days of life. Females show atypical genitalia with signs of virilization (clitoral enlargement, labial fusion, urogenital sinus), whereas males have normal-appearing genitalia, except for subtle signs as scrotal hyperpigmentation and enlarged phallus.1,10,12,14 Neonates with CMPD may display non-specific symptoms including hypoglycemia, lethargy, apnea, poor feeding, jaundice, seizures, hyponatremia without hyperkalemia, temperature and hemodynamic instability, recurrent sepsis, and poor weight gain. A male with hypogonadism may have undescended testes and micropenis. Infants with optic nerve hypoplasia or agenesis of the corpus callosum may present with nystagmus. Furthermore, infants with midline defects may have various neuro-psychological problems or sensorineural deafness.

Genetic Disorders and Other Conditions at Increased Risk for Adrenal Insufficiency

Among the cholesterol biosynthesis disorder, there is the Smith-Lemli-Opitz syndrome,23 where microcephaly, micrognathia, low-set posteriorly rotated ears, syndactyly of the second and third toes, and atypical genital may, although rarely, combine with AI; this autosomal recessive disorder is due to defective 7-dehydrocholesterol reductase so that elevated 7-dehydrocholesterol is diagnostic. In lysosomal acid lipase A deficiency,24 AI is due to calcification of the adrenal gland as a result of the accumulation of esterified lipids; in infantile form, that is Wolman disease, hepatosplenomegaly with hepatic fibrosis and malabsorption lead to death in the first year of life, if not treated with enzyme replacement therapy such as sebelipase alfa.25

Adrenal development may be impaired in X-linked congenital adrenal hypoplasia (AHC),13,26 a disorder caused by defective nuclear receptor DAX-1, presenting with salt-losing AI in infancy in approximately half of the cases, but also later in childhood or adolescence with two other key features such as hypogonadotropic hypogonadism and impaired spermatogenesis. Two syndromes combine adrenal hypoplasia with intrauterine growth restriction (IUGR): in IMAGe syndrome,27 caused by CDKN1C gain-of-function mutations, IUGR and AI present with metaphyseal dysplasia and genitourinary anomalies; MIRAGE syndrome28 is instead characterized by myelodysplasia, infections, genital abnormalities, and enteropathy, as a result of gain-of-function mutations in SAMD9, with elevated mortality rates.

In some other conditions, AI is due to ACTH resistance. Familial Glucocorticoid Deficiency type 1 (FGD1)13,29 and type 2 (FGD2)30 derive from defective ACTH receptor (MC2R) or its accessory protein MRAP, and both present with early glucocorticoid insufficiency (hypoglycemia, prolonged jaundice) and pronounced hyperpigmentation; there is usually an excellent response to cortisol replacement therapy, even though ACTH levels remain elevated.

In Allgrove or Triple-A Syndrome,13,31 defective Aladin protein (an acronym for alacrimia-achalasia-adrenal insufficiency) leads to primary ACTH-resistant adrenal insufficiency with achalasia and absent lacrimation, often combined with neurological dysfunction, either peripheral, central, or autonomic. It is an autosome recessive condition, phenotypically characterized by microcephaly, short stature, and skin hyperpigmentation.32,33

Among metabolic disorders associated with AI, Sphingosine-1-Phosphate Lyase (SGPL1) Deficiency34 is a sphingolipidosis with various features such as steroid-resistant nephrotic syndrome, primary hypothyroidism, undescended testes, neurological impairment, lymphopenia, ichthyosis; interestingly, in cases where nephrotic syndrome develops before AI, the latter may be masked by glucocorticoid treatment.

Adrenoleukodystrophy (ALD)35–37 is an X-linked recessive proximal disorder of beta-oxidation due to defective ABCD1, where the accumulation of very-long-chain fatty acids (VLCFA) affects in almost all cases adrenal gland among other tissues. Most patients present with progressive neurological impairment, but in some, AI is the only (approximately 10%) or first manifestation, so that every unexplained AI in boys should receive plasma VLCFA evaluation to diagnose ALD and reduce cerebral involvement through a low VLCFAs diet (Lorenzo’s oil) and allogeneic bone marrow transplantation. Early disease-modifying therapies have been developed. Gene therapy adds new functional copies of the ABCD1 gene in hematopoietic stem cells through a lentiviral vector reinfusing the modified cells in the patient’s bloodstream. Recent trials show encouraging results.38

In Zellweger syndrome, caused by mutations in peroxin genes (PEX), peroxisomes are absent, and disease presentation occurs in the neonatal period, with low survival rates after the first year of life. Finally, mitochondrial disorders have been described to occasionally develop AI: Pearson syndrome (sideroblastic anemia, pancreatic dysfunction), MELAS syndrome (encephalopathy with stroke-like episodes), and Kearns-Sayre syndrome (external ophthalmoplegia, heart block, retinal pigmentary changes) belong to this class.39

Autoimmune pathogenesis (Addison disease) accounts for approximately 15% of cases of primary AI in children, in contrast with adolescents and adults where it is the most common mechanism; half of these children present other glands involvement as well. Two syndromes recognize specific combinations: in Autoimmune Polyglandular Syndrome Type 1 (APS1, or APECED)40 defective autoimmune regulator AIRE causes AI, hypoparathyroidism, hypogonadism, malabsorption, chronic mucocutaneous candidiasis; APS2 usually present later in life (third-fourth decades) with AI, thyroiditis, and type 1 diabetes mellitus (T1DM). Antibodies against 21-hydroxylase enzyme are the hallmark of APS.

Apart from a genetic disorder, a strong link between autoimmune conditions and autoimmune primary AI has been established, with more than 50% of patients with the latter also having one or more other autoimmune endocrine disorders; on the other hand, only a few patients with T1DM or autoimmune thyroiditis or Graves’ disease develop AI. As an example, in a study of 629 patients with T1DM, only 11 (1.7%) presented 21-hydroxylase autoantibodies, with three of them having AI.41 Nevertheless, these patients are to be considered at increased risk for a condition that is potentially fatal yet easy to diagnose and treat; that is why it is reasonable to screen for autoimmune AI at least patients with T1DM, significantly if associated with DQ8 HLA combined with DRB*0404 HLA alleles, who have been observed to develop AI in 80% of cases if also 21-hydroxylase autoantibodies positive.42

Regarding immunological disruption, the link with celiac disease is instead well established: celiac patients have an 11-fold increased risk for AI, while in a study, 6 of 76 patients with AI had celiac disease, so that mutual evaluation should be granted in these patients.43,44

Subclinical Adrenal Insufficiency

Subclinical AI is a particularly insidious challenge for a pediatric endocrinologist. It represents the preclinical stage of Addison disease when 21-hydroxylase autoantibodies are already detectable but still absent from evident symptoms. 21-hydroxylase autoantibodies positivity carries a greater risk to develop overt AI in children than in adults: in a study, estimated risk was 100% in children versus 32% in adults on a medium six-year period of follow-up.45 As the adrenal crisis is a potentially lethal condition, it is essential to recognize and adequately manage subclinical AI.

Although asymptomatic by definition, subclinical AI may present with non-specific symptoms such as fatigue, lethargy, gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation), hypotension; physical or psychosocial stresses may sometimes exacerbate these symptoms. When symptoms lack, subclinical AI may be identified thanks to the co-occurrence with other autoimmune endocrinopathies.46

21-hydroxylase autoantibodies titer is considered a marker of autoimmune activity and correlates with disease progression.47 Other reported risk factors for the disease evolution include young age, male sex, hypoparathyroidism or candidiasis coexistence, increased renin activity, or an altered synacthen test with normal baseline cortisol and ACTH.45 ACTH elevation has been reported as the best predictor of progression to the clinical stage in 2 years (94% sensitivity and 78% specificity).48

Management of patients with subclinical AI should include serum cortisol, ACTH, renin measurement, and a synacthen test. If normal, cortisol and ACTH should be repeated in 12–18 months, while synacthen test every two years. After synacthen test results are subnormal, cortisol and ACTH should be assessed every 6–9 months if ACTH remains in range or every six months if ACTH becomes elevated.49 In the latter case, therapy with hydrocortisone should be started.19 This strategy will prevent acute crises and possibly improve the quality of life in patients reporting non-specific symptoms.

Diagnosis

Laboratory evaluation of a stable patient with suspected AI should start with combined early morning (between 6 and 8 AM) serum cortisol and ACTH measurements (Figure 2).

Figure 2 Diagnostic algorithm for adrenal insufficiency.

Although often included in the extensive work-up of an unwell child, a single cortisol value is usually challenging to interpret: circadian cortisol rhythm is highly variable and morning peak is unpredictable; morning cortisol levels in children with diagnosed AI may range up to 706 nmol/L (97th percentile); several factors, such as exogenous estrogens, may alter total serum cortisol values by influencing the free cortisol to cortisol binding globulin or albumin-bound cortisol ratio.7

Significant variability is also observed depending on the specific type of cortisol assay; therefore, it is recommended to check the reference ranges with the laboratory. Mass spectrometry analysis and the new platform methods (Roche Diagnostics Elecsys Cortisol II)50 have more specificity because it detects lower cortisol concentrations than standard immunoassays.15 Low serum cortisol with normal or low ACTH levels is compatible with CAI. In such cases, morning serum cortisol levels below 3 ”g/dL (83 nmol/L) best predict AI, while greater than 13 ”g/dL (365 nmol/L) values tend to exclude it.51 This is why in most cases, a dynamic test is required for diagnosis and has been introduced to assess the hypothalamic-pituitary-adrenal (HPA) axis in case of intermediate values.5

The insulin tolerance test (ITT) is considered the gold standard for CAI diagnosis as hypoglycemia results in an excellent HPA axis activation; moreover, it allows simultaneous growth hormone evaluation in patients with suspected CPHD. Serum cortisol is measured at baseline and 15, 30, 45, 60, 90, and 120 minutes after intravenous administration of 0.1 UI/Kg regular insulin; the test is valid if serum glucose is reduced by 50% or below 2.2 mmol/L (40 mg/dL).52 CAI is diagnosed for a <20 ”g/dL (550 nmol/L) cortisol value at its peak.15 Hypoglycemic seizures and hypokalemia (due to glucose infusion) are the main risks of this test so that it is contraindicated in case of a history of seizures or cardiovascular disease.

Glucagon stimulation test (GST, 30 ”g/Kg up to 1 mg i.m. glucagon with cortisol measurements every 30 min for 180 min) allows both CAI and growth hormone deficiency evaluation as well but is characterized by frequent gastrointestinal side effects and poor specificity.8

Metyrapone is an 11-hydroxylase inhibitor, thereby decreasing cortisol synthesis and removing its negative feedback on ACTH release. Overnight metyrapone test is based on oral administration of 30 mg/Kg metyrapone at midnight, and 11-deoxycortisol measurement on the following morning: in case of CAI, its level will not reach 7 ”g/dL (200 nmol/L). This test may, however, induce an adrenal crisis so that it is rarely performed.

Given their safety profile and accuracy, corticotropin analogs such as tetracosactrin (SynacthenÂź) or cosyntropin (CortrosynÂź) are recommended as first-line stimulation tests. Nevertheless, false-negative results are probable in the case of recent or moderate ACTH deficiency, which would not have induced adrenal atrophy. The standard dose short synacthen test (SDSST) is based on a 250 ”g Synacthen vial administration with serum cortisol measurement at baseline and 30 and 60 minutes after. CAI is diagnosed if peak cortisol level is <16 ”g/dL (440 nmol/L), or excluded if >39 ”g/dL (1076 nmol/L). However, the cut-offs for both the new platform immunoassay and mass spectrometry serum cortisol assays are 13.5 to 14.9 mcg/dL (373 to 412 nmol/L).53 The 250 ”g Synacthen dose is considered a supraphysiological stimulus since it is 500 times greater than the minimum ACTH dose reported to induce a maximal cortisol response (500 ng/1.73 m2). The low dose short synacthen test (LDSST) has been introduced as a more sensitive first-line test in children greater than two years.54 The recommended dose is 1 ”g55, which is contained in 1 mL of the solution obtained by diluting a 250 ”g vial into 250 mL saline. Serum cortisol level is then measured at baseline and after 30 minutes, resulting in diagnose of CAI if <16 ”g/dL (440 nmol/L), otherwise ruling it out if >22 ”g/dL (660 nmol/L). Using these thresholds, LDSST is more precise than SDSST in children, with an area under the ROC curve of 0.99 (95% CI 0.98–1.00).56 LDSST has not been validated in acutely ill patients, pituitary acute disorders or surgery or radiation therapy, and impaired sleep-wake cycle. Patients with an indeterminate LDSST result should be furtherly studied with ITT or metyrapone test.

Finally, the CRH test is based on 1 ”g/Kg human CRH (FerringŸ) administration and may differentiate secondary from tertiary AI, but its thresholds are still not precisely defined.57

Once CAI is diagnosed, other pituitary hormones should be assessed (prolactin, IGF1, LH, FSH, fT4, TSH), and an MRI of the pituitary region should be performed to exclude neoplastic or infiltrative processes.

Primary adrenal insufficiency (PAI) should be suspected in case of low serum cortisol with elevated ACTH levels. When hypocortisolemia has been confirmed, ACTH levels >66 pmol/L or greater than twice the upper limit best predict PAI. Nevertheless, a confirmatory dynamic test is always recommended for diagnosis.19 Given the comparable accuracy between standard and low dose SST reported in these patients, SDSST is recommended as the most feasible test.58 Moreover, suspected PAI cases should receive plasma renin activity or direct renin and aldosterone assessment to evaluate mineralocorticoid deficiency.

Etiologic work-up of confirmed PAI should start from 21-hydroxylase antibodies assessment: if positive, differential diagnosis will include Addison disease and APS1 or APS2. Adrenal autoantibody negative patients should instead be screened for CAH by measuring 17-hydroxyprogesterone, ALD (if young male) by assessing VLCFA, and tuberculosis if endemic; adrenal glands imaging will complete the work-up in order to exclude infection, hemorrhage, or tumor.6

While universal newborn screening is already implemented for CAH in many countries, allowing a timely replacement therapy, basal salivary cortisol, and salivary cortisone measurements could improve CAI screening in the future: this technique is simple, cost-effective, and independent of binding proteins.15

Treatment

All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy. Individuals with PAI also require mineralocorticoids replacement, together with salt intake as required (Table 4). Otherwise, guidelines do not recommend androgen replacement.5,9,19

Table 4 Management of Adrenal Insufficiency (AI)

Oral hydrocortisone is the first-choice replacement treatment in children due to its short half-life, rapid peak in plasma concentration, lower potency, and fewer adverse effects than prednisolone and dexamethasone.5,8 Based on endogenous production, dosing replacement regimens vary from 7.5 to 15 mg/m2/day, divided into two, three, or four doses.19 The first and largest dose should be taken at awakening, the next in the early afternoon to avoid sleep disturbances. Small and frequent dosing mimic the physiological rhythm of cortisol secretion, but high peak cortisol levels after drug assumption and prolonged periods of hypocortisolemia between doses are described.8,9 Some children experience low cortisol concentrations and symptoms of cortisol insufficiency (eg, fatigue, nausea, headache) despite modifications in dosing. This cohort of patients can take advantage of using a modified-release hydrocortisone formulation, such as ChronocortŸ and PlenadrenŸ. PlenadrenŸ, approved for adults, consists of a coating of hydrocortisone released rapidly, followed by a slow release of hydrocortisone from the tablet center. It is available as 5 and 20 mg tablets. Park et al demonstrate smoother cortisol profiles and normal growth and weight gain patterns using PlenadrenŸ in children.59 In a few cases, the continuous subcutaneous infusion of hydrocortisone using insulin pump technology proved to be a feasible, well-tolerated and safe option for selected patients with poor response to conventional therapy.19

Monitoring glucocorticoid therapy is based on growth, weight gain, and well-being. Cortisol measurements are usually not useful, apart from cases when a discrepancy between daily doses and patient symptoms exists.15 The concomitant use of hydrocortisone and CYP3A4 inducers, such as Rifampicin, Phenytoin, Carbamazepine, requires an increased dose of glucocorticoids. Conversely, the inhibition of CYP3A4 impairs hydrocortisone metabolism.5

Mineralocorticoid replacement is unnecessary if the patient has a normal renin-angiotensin-aldosterone axis and, hence, normal aldosterone secretion, as well as in CAI. By contrast, patients with PAI and confirmed aldosterone deficiency need fludrocortisone at the dosage of 0.1–0.2 mg/day when given together with hydrocortisone, which has some mineralocorticoid activity. When using other synthetic glucocorticoids for replacement, higher fludrocortisone doses may be needed. Infants younger than one year should also be supplemented with sodium chloride due to their relatively low dietary sodium intake and relative renal resistance to mineralocorticoids. The dose is approximately 1 gram (17 mEq) daily.19

Surgery and anesthesia increase the glucocorticoid requirement during the pre-, intra-, and post-operative periods (Table 4). All children with AI should receive an intravenous dose of hydrocortisone at induction (2 mg/kg for minor or major surgery under general anesthesia). For minor procedures or sedation, the child should receive a double morning dose of hydrocortisone orally.60

Adrenal crisis is a life-threatening condition, treatment is effective if administered promptly, and it must not be delayed for any reason. Hydrocortisone should be administered as soon as possible with an intravenous bolus of 4 mg/kg followed by a continuous infusion of 2 mg/kg/day until stabilization. In the alternative, it can be administered as a bolus every four hours intravenous or intramuscular. In difficult peripheral venous access, the intramuscular route must be used as the first choice. In order to counteract hypotension, a bolus of normal saline 0.9% should be given at a dose of 20 mL/kg; it can repeat up to a total of 60 mL/kg within one hour for shock. If there is hypoglycemia, 10% dextrose at a 5 mL/kg dose should be administered.5,19,61,62

Patients with AI require additional doses of glucocorticoids in case of physiologic stress such as illness or surgical procedures to avoid an adrenal crisis. Home management of illness with a fever (> 38°C), vomiting or diarrhea, is based on the increase from two to three times the usual dose orally. If the child is unable to tolerate oral therapy, intramuscular injection of hydrocortisone should be administered (Table 4).

Education for caregivers and patients (if adolescent) is crucial to prevent adrenal crisis. They should recognize signs and symptoms of adrenal crisis and should receive a steroid emergency card with the sick day rules. Prescribing doctors should provide for additional oral glucocorticoids and adequate training in hydrocortisone emergency self-injection.

Abbreviations

AI, adrenal insufficiency; PAI, primary adrenal insufficiency; CAI, central adrenal insufficiency; HPA, hypothalamic-pituitary-adrenal axis; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; POMC, pro-opiomelanocortin; CAH, congenital adrenal hyperplasia; STAR, steroidogenic acute regulatory; 21OHD, 21-hydroxylase deficiency; 11BOHD, 11-B-hydroxylase deficiency; P450scc, P450 cytochrome side-chain cleavage deficiency; 17-OHP, 17-hydroxyprogesterone; NCCAH, non-classic congenital adrenal hyperplasia; ALD, adrenoleukodystrophy; VLCFA, very long-chain fatty acids; CMPD, combined multiple pituitary hormone deficiency; GHD, growth hormone deficiency; MSH, melanocyte stimulating hormone; IUGR, intrauterine growth restriction; APS1, autoimmune polyglandular syndrome type 1; SDSST, standard dose short synacthen test; LDSST, low dose short synacthen test.

Take Home Messages

  1. In neonates and infants CAH is the commonest cause of PAI, causing almost 71.8% of cases.
  2. Adrenoleukodystrophy should be considered in any male with hypoadrenalism.
  3. Unexplained hyponatremia, hyperpigmentation and the loss of pubic and axillary hair should raise the suspicion of AI.
  4. Adrenal insufficiency can present with non-specific clinical features; therefore a single cortisol measurement should be included in the biochemical work-up of an unwell child.
  5. Patients and parents should be well-trained in adrenal crisis recognition and management.

Disclosure

The authors report no conflicts of interest in this work.

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Adrenal Fatigue: Faux Diagnosis?

This article is based on reporting that features expert sources.

U.S. News & World Report

Adrenal Fatigue: Is It Real?

You may have heard of so-called ‘adrenal fatigue,’ supposedly caused by ongoing emotional stress. Or you might have come across adrenal support supplements sold online to treat it. But if someone suggests you have the controversial, unproven condition, seek a second opinion, experts say. And if someone tries to sell you dietary supplements or other treatments for adrenal fatigue, be safe and save your money.

Tired man sitting at desk in modern office

(GETTY IMAGES)

Physicians tend to talk about ‘reaching’ or ‘making’ a medical diagnosis. However, when it comes to adrenal fatigue, endocrinologists – doctors who specialize in diseases involving hormone-secreting glands like the adrenals – sometimes use language such as ‘perpetrating a diagnosis,’ ‘misdiagnosis,’ ‘made-up diagnosis,’ ‘a fallacy’ and ‘nonsense.’

About 20 years ago, the term “adrenal fatigue” was coined by Dr. James Wilson, a chiropractor. Since then, certain practitioners and marketers have promoted the notion that chronic stress somehow slows or shuts down the adrenal glands, causing excessive fatigue.

“The phenomenon emerged from the world of integrative medicine and naturopathic medicine,” says Dr. James Findling, a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. “It has no scientific basis, and there’s no merit to it as a clinical diagnosis.”

An online search of medical billing code sets in the latest version of the International Classification of Diseases, or the ICD-10, does not yield a diagnostic code for ‘adrenal fatigue’ among the 331 diagnoses related either to fatigue or adrenal conditions or procedures.

In a March 2020 position statement, the American Association of Clinical Endocrinologists and American College of Endocrinology addressed the use of adrenal supplements “to treat common nonspecific symptoms due to ‘adrenal fatigue,’ an entity that has not been recognized as a legitimate diagnosis.”

The position statement warned of known and unknown health risks of off-label use and misuse of hormones and supplements in patients without an established endocrine diagnosis, as well as unnecessary costs to patients and the overall health care system.

Study after study has refuted the legitimacy of adrenal fatigue as a medical diagnosis. An August 2016 systematic review combined and analyzed data from 58 studies on adrenal fatigue including more than 10,000 participants. The conclusion in a nutshell: “Adrenal fatigue does not exist,” according to review authors in the journal BMC Endocrine Disorders.

Adrenal Action

You have two adrenal glands in your body. These small triangular glands, one on top of each kidney, produce essential hormones such as aldosterone, cortisol and male sex hormones such as DHEA and testosterone.

Cortisol helps regulate metabolism: How your body uses fat, protein and carbohydrates from food, and cortisol increases blood sugar as needed. It also plays a role in controlling blood pressure, preventing inflammation and regulating your sleep/wake cycle.

As your body responds to stress, cortisol increases. This response starts with signals between two sections in the brain: The hypothalamus and the pituitary gland, which act together to release a hormone that stimulates the adrenal glands to make cortisol. This interactive unit is called the hypothalamic pituitary adrenal axis.

While some health conditions really do affect the body’s cortisol-making ability, adrenal fatigue isn’t among them.

“There’s no evidence to support that adrenal fatigue is an actual medical condition,” says Dr. Mary Vouyiouklis Kellis, a staff endocrinologist at Cleveland Clinic. “There’s no stress connection in the sense that someone’s adrenal glands will all of a sudden just stop producing cortisol because they’re so inundated with emotional stress.”

If anything, adrenal glands are workhorses that rise to the occasion when chronic stress occurs. “The last thing in the body that’s going to fatigue are your adrenal glands,” says Dr. William F. Young Jr., an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota. “Adrenal glands are built for stress – that’s what they do. Adrenal glands don’t fatigue. This is made up – it’s a fallacy.”

The idea of adrenal glands crumbling under stress is “ridiculous,” Findling agrees. “In reality, if you take a person and subject them to chronic stress, the adrenal glands don’t shut down at all,” Findling says. “They keep making cortisol – it’s a stress hormone. In fact, the adrenal glands are just like the Energizer Bunny – they just keep going. They don’t stop.”

Home cortisol tests that allow consumers to check their own levels can be misleading, Findling says. “Some providers who make this (adrenal fatigue) diagnosis, provide patients with testing equipment for doing saliva cortisol levels throughout the day,” he says. “And then, regardless of what the results are, they perpetrate this diagnosis of adrenal fatigue.”

Saliva cortisol is a legitimate test that’s frequently used in diagnosing Cushing’s syndrome, or overactive adrenal glands, Findling notes. However, he says, a practitioner pursuing an adrenal fatigue diagnosis could game the system. “What they do is: They shape a very narrow normal range, so narrow, in fact, that no normal human subject could have all their saliva cortisol (levels) within that range throughout the course of the day,” he says. “Then they convince the poor patients that they have adrenal fatigue phenomena and put them on some kind of adrenal support.”

Loaded Supplements

How do you know what you’re actually getting if you buy a dietary supplement marketed for adrenal fatigue or ‘adrenal support’ use? To find out, researchers purchased 12 such supplements over the counter in the U.S.

Laboratory tests revealed that all supplements contained a small amount of thyroid hormone and most contained at least one steroid hormone, according to the study published in the March 2018 issue of Mayo Clinic Proceedings. “These results may highlight potential risks for hidden ingredients in unregulated supplements,” the authors concluded.

Supplements containing thyroid hormones or steroids can interact with a patient’s prescribed medications or have other side effects.

“Some people just assume they have adrenal fatigue because they looked it up online when they felt tired and they ultimately buy these over-the-counter supplements that can be very dangerous at times,” Vouyiouklis Kellis says. “Some of them contain animal (ingredients), like bovine adrenal extract. That can suppress the pituitary axis. So, as a result, your body stops making its own cortisol or starts making less of it, and as a result, you can actually worsen the condition rather than make it better.”

Any form of steroid from outside the body, whether a prescription drug like prednisone or extract from cows’ adrenal glands, “can shut off the pituitary,” Vouyiouklis Kellis explains. “Because it’s signaling to the pituitary like: Hey, you don’t need to stimulate the adrenals to make cortisol, because this patient is taking it already. So, as a result, the body ultimately doesn’t produce as much. And, so, if you rapidly withdraw that steroid or just all of a sudden decide not to take it anymore, then you can have this acute response of low cortisol.”

Some adrenal support products, such as herbal-only supplements, may be harmless. However, they’re unlikely to relieve chronic fatigue.

Fatigue: No Easy Answers

If you’re suffering from ongoing fatigue, it’s frustrating. And you’re not alone. “I have fatigue,” Young Jr. says. “Go to the lobby any given day and say, ‘Raise your hand if you have fatigue.’ Most of the people are going to raise their hands. It’s a common human symptom and people would like an easy answer for it. Usually there’s not an easy answer. I think ‘adrenal fatigue’ is attractive because it’s like: Aha, here’s the answer.”

There aren’t that many causes of endocrine-related fatigue, Young Jr. notes. “Hypothyroidism – when the thyroid gland is not working – is one.” Addison’s disease, or adrenal insufficiency, can also lead to fatigue among a variety of other symptoms. Established adrenal conditions – like adrenal insufficiency – need to be treated.

“In adrenal insufficiency, there is an intrinsic problem in the adrenal gland’s inability to produce cortisol,” Vouyiouklis Kellis explains. “That can either be a primary problem in the adrenal gland or an issue with the pituitary gland not being able to stimulate the adrenal to make cortisol.”

Issues can arise even with necessary medications. “For example, very commonly, people are put on steroids for various reasons: allergies, ear, nose and throat problems,” Vouyiouklis Kellis says. “And with the withdrawal of the steroids, they can ultimately have adrenal insufficiency, or decrease in cortisol.”

Opioid medications for pain also result in adrenal sufficiency, Vouyiouklis Kellis says, adding that this particular side effect is rarely discussed. People with a history of autoimmune disease can also be at higher risk for adrenal insufficiency.

Common symptoms of adrenal insufficiency include:

  • Fatigue.
  • Weight loss.
  • Decreased appetite.
  • Salt cravings.
  • Low blood pressure.
  • Abdominal pain.
  • Nausea, vomiting or diarrhea.
  • Muscle weakness.
  • Hyperpigmentation (darkening of the skin).
  • Irritability.

Medical tests for adrenal insufficiency start with blood cortisol levels, and tests for the ACTH hormone that stimulates the pituitary gland.

“If the person does not have adrenal insufficiency and they’re still fatigued, it’s important to get to the bottom of it,” Vouyiouklis Kellis says. Untreated sleep apnea often turns out to be the actual cause, she notes.

“It’s very important to tease out what’s going on,” Vouyiouklis Kellis emphasizes. “It can be multifactorial – multiple things contributing to the patient’s feeling of fatigue.” The blood condition anemia – a lack of healthy red blood cells – is another potential cause.

“If you are fatigued, do not treat yourself,” Vouyiouklis Kellis says. “Please seek a physician or a primary care provider for evaluation, because you don’t want to go misdiagnosed or undiagnosed. It’s very important to rule out actual causes that would be contributing to symptoms rather than ordering supplements online or seeking an alternative route like self-treating rather than being evaluated first.”

SOURCES

The U.S. News Health team delivers accurate information about health, nutrition and fitness, as well as in-depth medical condition guides. All of our stories rely on multiple, independent sources and experts in the field, such as medical doctors and licensed nutritionists. To learn more about how we keep our content accurate and trustworthy, read our editorial guidelines.

James Findling, MDFindling is a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin.

Mary Vouyiouklis Kellis, MDVouyiouklis Kellis is a staff endocrinologist at Cleveland Clinic.

William F. Young Jr., MDYoung Jr. is an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota

From https://health.usnews.com/health-care/patient-advice/articles/adrenal-fatigue-is-it-real?

Novel Predictive Model for Adrenal Insufficiency in Dermatological Patients with Topical Corticosteroids Use: A Cross-Sectional Study

Purpose: This study aimed to identify predictive factors and to develop a predictive model for adrenal insufficiency (AI) related to topical corticosteroids use.
Methods: The research was conducted using a cross-sectional design. Adult patients with dermatological conditions who had been prescribed topical steroids for at least 12 months by the dermatology outpatient departments of the Faculty of Medicine, Chiang Mai University from June through October 2020 were included. Data on potential predictors, including baseline characteristics and laboratory investigations, were collected. The diagnoses of AI were based on serum 8AM cortisol and low-dose ACTH stimulation tests. Multivariable logistic regression was used for the derivation of the diagnostic score.
Results: Of the 42 patients, 17 (40.5%) had AI. The statistically significant predictive factors for AI were greater body surface area of corticosteroids use, age < 60 years, and basal serum cortisol < 7 ÎŒg/dL. In the final predictive model, duration of treatment was added as a factor based on its clinical significance for AI. The four predictive factors with their assigned scores were: body surface area involvement 10– 30% (20), > 30% (25); age < 60 years old (15); basal serum cortisol of < 7 ÎŒg/dL (30); and duration of treatment in years. Risk of AI was categorized into three groups, low, intermediate and high risk, with total scores of < 25, 25– 49 and ≄ 50, respectively. The predictive performance for the model was 0.92 based on area under the curve.
Conclusion: The predictive model for AI in patients using topical corticosteroids provides guidance on the risk of AI to determine which patients should have dynamic ACTH stimulation tests (high risk) and which need only close follow-up (intermediate and low risk). Future validation of the model is warranted.

Keywords: adrenal insufficiency, topical corticosteroids, predictive model, skin diseases

Introduction

Topical corticosteroids are frequently used for inflammatory skin diseases owing to their anti-inflammatory and immunosuppressive effects. Common indications for use include diseases such as psoriasis, eczema, atopic dermatitis, and vitiligo.1 In clinical practice, a variety of delivery vehicles and potencies of topical corticosteroids are used.1 Prolonged and/or inappropriate use of topical corticosteroids can lead to adverse side effects.2 These adverse side effects can be categorized as cutaneous and systemic side effects. The most common cutaneous side effect is skin atrophy. Systemic side effects include hypothalamic-pituitary-adrenal (HPA) axis suppression, glaucoma, hyperglycemia and hypertension.3

One of the most worrisome adverse side effects from the use of topical corticosteroids is adrenal insufficiency (AI) resulting from HPA axis suppression. Topically applied corticosteroids can be absorbed systemically through the skin and can suppress the HPA axis.4–8 This adverse outcome, the inability to increase cortisol production after stress, can lead to adrenal crisis, which is potentially life-threatening. Tests that are normally used to diagnose or exclude AI include serum morning cortisol and the dynamic ACTH stimulation test.9

Secondary AI from percutaneous absorption of topical corticosteroids is less common than with parenteral or oral administration. The cumulative doses and the durations of oral corticosteroid therapy associated with HPA axis suppression have been well documented.10 Data regarding the dose and duration of oral corticosteroids and HPA axis suppression have similarly been well established. A study by Curtis et al reported that the use of oral prednisolone >7.5 mg/day for an extended period (>3 weeks) was linked to this adverse event, and that the incidence increased with duration.10 However, corresponding data for topical corticosteroids has been limited. The degree of risk of HPA axis suppression from topical corticosteroids use is associated with the level of percutaneous absorption which, in turn, depends on numerous factors including the age of the patient (younger patients are more susceptible), body surface area treated, quantity of topical corticosteroids used, potency of the drug, duration of therapy, body region of application, the associated compounds used, eg, urea or salicylic acid, the characteristics of the diseased skin, the degree of impairment of skin integrity, and the coexistence of hepatic and/or renal disease.11–13 One study reported that HPA axis suppression occurs when high potency steroids are administered at a cumulative dose per week of >50 g.2

Presently, there is a lack of data on predictive factors for AI and no predicative model of the relationship between secondary AI resulting from HPA axis suppression and topical corticosteroids use. A simple predictive model which could help preclude and predict the risk of AI which incorporates both demographic and biochemical data could potentially reduce the number of dynamic ACTH stimulation tests performed. This study aimed to identify potential predictive factors and to design an easy-to-use model for predicting the risk of AI following topical corticosteroids use in dermatological patients.

Materials and Methods

This cross-sectional study was conducted with 42 patients who were seen at the dermatology outpatient departments at the Faculty of Medicine, Chiang Mai University Hospital over a 5-month period (June – October 2020). The study protocol was approved by the Faculty of Medicine, Chiang Mai University, Ethical Committee (Ethical number: MED-2563-07037). Recruited participants were adult dermatological patients (≄18 years) who had used topical corticosteroids for at least 12 months. Patients with pituitary or adrenal diseases, pregnant women and patients who had been treated with either systemic corticosteroids or other local corticosteroids were excluded. Those who meet all the inclusion criteria gave their informed consent prior to the study. This study was conducted in accordance with the Declaration of Helsinki.

Adrenal Function Evaluation

Adrenal function was evaluated by serum morning (8 AM) cortisol and the low-dose ACTH stimulation test. Patients were instructed to suspend use of topical corticosteroids for at least 24 hours before serum morning cortisol measurement and ACTH stimulation tests. In those with serum morning cortisol between 3 and 17.9 ”g/dL, ACTH stimulation tests were performed on the same day between 9–11AM to either exclude or diagnose AI. Serum cortisol concentrations were measured at 8 AM 0 (basal cortisol) as well as 20 and 40 minutes after 5 ”g ACTH was administered intravenously.

Data Collection

Epidemiological data collected included gender, age, blood pressure, underlying dermatologic diseases, other underlying diseases, body surface area involvement, sensitive area involvement, topical corticosteroid potency, amount and duration of topical corticosteroids use, symptoms of AI and the presence of Cushingoid features. Biochemical data included serum cortisol at 8 AM, 0 (basal cortisol) and at 20 and 40 minutes after ACTH intravenous injection, serum creatinine, electrolytes and albumin. Serum cortisol levels were measured by electrochemiluminescence assay (ECLIA) (ElecsysŸ Cortisol II assay, Roche Diagnostics GmbH, Mannheim, Germany).

Definitions

An 8AM cortisol level of ❀ ”g/dL or a peak serum cortisol level of <18 ”g/dL at 20 or 40 minutes after an ACTH stimulation test was defined as having AI.14 Sensitive area involvement included the axilla, groin, face and genitalia. Topical corticosteroids are classified by potency based on a skin vasoconstriction assay, and range from ultra-high potency (class I) to low potency (class VII).15 Since some patients had concurrently used more than one class of corticosteroids in one treatment period, the new variable potency·dose·time (summary of corticosteroids potency (I–VII)16 multiplied by total doses (mg) of corticosteroids use and multiplied by duration (months) of corticosteroids use) was created. Symptoms of AI included lethargy, nausea and vomiting, orthostatic hypotension and significant weight loss. Significant weight loss was defined as a loss of 5% of body weight in one month or a loss of 10% over a period of six months.17 Having Cushingoid features was defined as at least one of the excess glucocorticoid features, eg, easy bruising, facial plethora, proximal myopathy, striae, dorsocervical fat pad, facial fullness, obesity, supraclavicular fullness, hirsutism, decreased libido and menstrual abnormalities.

Statistical Analysis

All statistical analyses were performed using Stata 16 (StataCorp, College Station, Texas, USA). Categorical variables are reported as frequency and percentage, while continuous variables are reported as mean ± standard deviation or median and interquartile range (IQR), according to their distribution. For univariable comparison, Fisher’s exact probability test was used for categorical variables, and the independent t-test or the Mann–Whitney U-test was used for continuous variables. p-values less than 0.05 were considered statistically significant.

Multivariable logistic regression was used in the derivation of the prediction model for AI. Predictors with significant p-values in the univariable analysis were included in the multivariable model. We also included age and treatment duration in the model due to the clinical significance of those factors.4,18 The clinical collinearity among the predictors was also evaluated before the selection of the predictors. We generated a weighted score for each predictor by dividing the logit coefficient of the predictor by the lowest coefficient in the model. The discriminative ability of the final multivariable model was assessed using the area under the receiver operating characteristics (ROC) curve. The calibration of the scores was evaluated using the Hosmer-Lemeshow goodness-of-fit test, where a p-value >0.01 was considered a good fit. For clinical applicability, the appropriate cut-off points for the scores were identified based on sensitivity and specificity. We identified one cut-off point with high sensitivity for ruling out AI and another cut-off point with high specificity for ruling in AI. The positive predictive value for each score category with its corresponding confidence interval were presented. A sample size of at least 25 patients with at least 5 patients with AI was estimated to give 80% power at the 5% significance level.4 There was no missing data in this study.

Results

Baseline characteristics and biochemical investigations are shown in Table 1. Forty-two patients with dermatological diseases were included in this study. Of these, 17 patients (40.5%) had AI of whom 5 (29.4%) were female. The mean age of the group was 56.5 ±15.4 years, the mean duration of treatment was 10.1 ± 6 years, and the majority of patients had psoriasis (n = 14, 82.4%). There was no significant difference in sex, age, duration of treatment, potency dose-time, comorbidities, or underlying skin disease between the AI and non-AI groups. The average body surface area of corticosteroids use was significantly higher in patients with AI than in the non-AI group (27.5 ±18.7 m2 and 10.7 ±11.7 m2, p < 0.001, respectively). Basal serum cortisol levels were significantly lower in the AI group (6.52 ± 4.04 ”g/dL) than in the non-AI group (10.48 ± 3.45 ”g/dL, p 0.003). Although lower serum morning cortisol levels were observed in the AI group, the difference was not statistically significant (5.24 ± 4.65 ”g/dL vs 13.39 ± 15.68 ”g/dL, p = 0.069). Three patients were identified as having Cushingoid features. All patients with Cushingoid features had AI.

Table 1 Comparison of Clinical Characteristics Between Patients with a History of Topical Corticosteroids Use for at Least 12 Months Who Were Diagnosed with Adrenal Insufficiency and Those without Adrenal Insufficiency (n = 42)

 

Based on the multivariate logistic regression analysis (shown in Table 2), the significant predictive factors for AI in patients who used topical corticosteroids for more than 12 months were body surface area of corticosteroids use of 10–30% and >30% (POR 18.9, p =0.042, and POR 59.2, p = 0.035, respectively), age less than 60 years (POR 13.8, p = 0.04), and basal serum cortisol of <7 ”g/dL (POR 131.5, p = 0.003). Only serum basal cortisol was included in the final multivariable model as there was clinical collinearity among serum morning cortisol and basal cortisol as well as 20- and 40-minute cortisol measurements.

Table 2 Multivariable Model for Prediction of Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38)

 

Predictive risk score was created to determine the probability of patients having AI using the aforementioned three significant predictive factors from the multivariable analysis (Table 2). As previous studies have demonstrated that duration of treatment is a strong predictive factor for AI in corticosteroid users,4,18 this factor was also incorporated in the model. The transformed score for body surface area, age and basal serum cortisol had a range of 0 to 30. For treatment duration, the transformed score was based on cumulative years of treatment. The total score was categorized into three groups: low, intermediate, and high risk (Table 3).

Table 3 Accuracy of the Score to Rule in and Rule Out Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38)

 

The cut-off point of ≄50 suggests high risk for developing AI with a sensitivity of 46.2% and a specificity of 100%, a score of <25 suggests a low risk with a sensitivity of 100% and a specificity of 52%, and a score between 25 and 49 indicates an intermediate risk of having AI. The ROC curve for the model assessing predictive performance which included all significant factors had an AuROC of 0.92 (Figure 1). The Hosmer-Lemeshow goodness-of-fit test revealed non-statistically significant results (p = 0.599), indicating that our newly derived scoring system fits the data well.

Figure 1 Model discrimination via receiver operating characteristic curve in patients with a history of topical corticosteroids use for at least 12 months (n = 42).

 

Discussion

The present study proposes an easy-to-use predictive model for AI following topical corticosteroids use in dermatological patients based on demographic and biochemical factors. The accuracy of the model shows an excellent diagnostic accuracy of 92% based on AuROC. Currently, the diagnosis of AI in dermatological patients with topical corticosteroids use involves multiple steps including screening for serum morning cortisol followed by dynamic ACTH stimulation testing. The proposed simple predictive model, which requires only three demographic data items (age, body surface area of corticosteroids use, duration of use) and one biochemical test (serum basal cortisol), could potentially reduce the number of dynamic ACTH stimulation tests performed, resulting in cost- and time-saving for both patients and health-care facilities.

Based on the proposed cut-off points, we suggest screening of individuals at high risk for having AI, including serum morning cortisol and the ACTH stimulation tests to confirm a diagnosis of AI. If there is evidence of AI, the patient should begin to receive treatment for AI to reduce future complications. For those in the low-risk group, only clinical follow-up should be carried out. In the intermediate-risk group, we recommend regular and close biochemical follow-up including serum morning cortisol and clinical follow-up for signs and symptoms of AI. Signs and symptoms that should raise a high index of suspicion for AI include significant weight loss, nausea and/or vomiting, orthostatic hypotension and lethargy. However, this proposed predictive model was studied in adults and cannot simply be generalized and extrapolated to children or infants.

In our study, 40.5% of the patients were determined to have AI. A previous meta-analysis by Broersen et al reported the percentage of patients with AI secondary to all potencies of topical corticosteroids based on a review of 15 studies was 4.7%, 95% CI (1.1–18.5%).19 The higher prevalence of AI in our study could be a result of differences in patients’ baseline characteristics, eg, duration of treatment, corticosteroids potency and body surface area involvement.

In the predictive model, we incorporated both clinical and biochemical factors which are easy to obtain in actual clinical practice. Some of those predictive factors have been previously reported to be linked to AI. Body surface area of corticosteroids use larger than 10% found to be significantly related to AI, especially in patients with a lesion area of over 30%. This finding is consistent with a study by Kerner et al which suggests the extent of surface area to which the corticosteroids are applied may influence absorption of the drug.20 Regarding the age of the patients, our study found that individuals over 60 years old tended to be at high risk of AI following topical corticosteroids therapy. The underlying explanation is that the stratum corneum acts as a rate-limiting barrier to percutaneous absorption as the stratum corneum in younger individuals is thinner than in older people. Diminished effectiveness of topical corticosteroid treatment in older people was demonstrated in a study by Malzfeldt et al.21 Even though serum basal cortisol is not recommended as a standard test to diagnose AI, a prior study reported that it can be considered as an alternative choice to diagnose AI when serum morning cortisol results are not available. In fact, it has been reported that there is no difference in diagnostic accuracy between serum morning cortisol and basal cortisol22 which supports our finding that serum basal cortisol <7 ”g/dL is one of the significant factors related to AI.

The final model found no statistically significant relationship between the incidence of AI and the duration of corticosteroids treatment. However, we decided to include this factor in the final model since previous publications have reported that the duration of treatment is a relevant risk factor for developing AI following continuous topical corticosteroids use. The duration of AI events has been reported to vary between 2 weeks to 18 months.4,18 Additionally, a case report of AI demonstrated that 5 years of topical corticosteroids use can cause AI.6 Together, this suggests that patients with a longer duration of topical corticosteroids use are at increased risk of AI, especially those who also have other risk factors. Although both potency and dosage of topical corticosteroids have been reported to be significantly linked to HPA axis suppression, the present study found only a non-significance link. This could be the result of the small sample size as well as of other factors, eg, body surface area involvement and serum cortisol levels, which could have masked the association between potency and dosage of topical corticosteroids with HPA suppression.

To the best of our knowledge, this study is the first to use these novel predictive factors to develop a predictive model for AI in patients using topical corticosteroids. This model has multiple potential implications. First, the model uses clinical and biochemical factors which are obtainable in many institutes. Second, the model’s risk score provides good diagnostic accuracy in terms of both sensitivity and specificity. Finally, each of the predictive factors in the model has an underlying pathophysiological explanation and is not due simply to chance.

There are some limitations in this study. First, the sample size is relatively small, although it does offer sufficient statistical power for each of the predictive factors. Second, further external validation is needed to validate the predictive performance of the model. Third, the cut-off level of serum cortisol after ACTH stimulation test was based on the older generation of ECLIA assay. There was a study proposed that the cut-off for serum cortisol in the newer generation of cortisol assay should be lower (~14–15 ”g/dL) than the previous one (18 ”g/dL).23 However, this proposed cut-off has not yet been established in the current guideline for AI. In the future, if the newer cut-off for serum cortisol will have been employed in the standard guideline, our predictive model may lead to overdiagnosis of AI.

Conclusions

The proposed predictive model uses both demographic and biochemical factors to determine the risk of AI in dermatological patients following topical corticosteroids use with a high level of diagnostic accuracy. This model has advantages in terms of a reduction in the number of dynamic ACTH stimulation tests needed, thus saving time and resources. Additionally, it can provide guidance to clinical practitioners regarding which patients should be closely followed up for development of AI. Future external validation of this predictive model is warranted.

Acknowledgments

The authors are grateful to Lamar G. Robert, PhD and Chongchit S. Robert, PhD for editing the manuscript.

Disclosure

The authors report no conflict of interest in this work.

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8. Böckle BC, Jara D, Nindl W, Aberer W, Sepp NT. Adrenal insufficiency as a result of long-term misuse of topical corticosteroids. Dermatology. 2014;228(4):289–293. doi:10.1159/000358427

9. Ospina NS, Al Nofal A, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427–434. doi:10.1210/jc.2015-1700

10. Curtis JR, Westfall AO, Allison J, et al. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum. 2006;55(3):420–426. doi:10.1002/art.21984

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12. Dhar S, Seth J, Parikh D. Systemic side-effects of topical corticosteroids. Indian J Dermatol. 2014;59(5):460–464. doi:10.4103/0019-5154.139874

13. Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufficiency: clinical implications. Am J Clin Dermatol. 2002;3(3):141–147. doi:10.2165/00128071-200203030-00001

14. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389. doi:10.1210/jc.2015-1710

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Identified: the gene behind an unusual form of Cushing’s Syndrome

A team of scientists in Montreal and Paris has succeeded in identifying the gene responsible for the development of a food-dependent form of Cushing’s Syndrome, a rare disease affecting both adrenal glands.

In their study published in The Lancet Diabetes & Endocrinology, Dr. Isabelle Bourdeau and Dr. Peter Kamenicky identify in the gene KDM1A the mutations responsible for the development of this unusual form of the disease.

The scientists also show, for the first time, that the disease is genetically transmitted.

Bourdeau is a researcher and a UniversitĂ© de MontrĂ©al medical professor practising at the CHUM Research Centre (CRCHUM), while Kamenicky works at the HĂŽpital de BicĂȘtre, part of the Assistance publique-hĂŽpitaux de Paris network in France.

Cushing’s Syndrome is caused by the overproduction of cortisol, a steroid hormone, by the two adrenal glands located above the kidneys.

“When the tissues of the human body are exposed to this excess of cortisol, the effects for those with the disease are serious: weight gain, high blood pressure, depression, osteoporosis, and heart complications, for example,” said Bourdeau, co-lead author of the study with Dr. Fanny Chasseloup, a colleague from the French team.

This discovery comes nearly 30 years after food-induced Cushing’s Syndrome was first described in 1992 by a research group led by Dr. AndrĂ© Lacroix at the CRCHUM and his colleagues Drs. Johanne Tremblay and Pavel Hamet.

The form of the disease being studied by Bourdeau and her colleagues is caused specifically by the abnormal expression of the receptors of a hormone named GIP (glucose-dependent insulinotropic peptide), in both adrenal glands of patients. This hormone is produced by the small intestine in response to food intake. For people with the disease, cortisol concentrations increase abnormally every time they ingest food.

The discovery of the genetic mechanism by the French and Quebec teams was made possible through the use of recent cutting-edge genetic techniques on tissues of patients including those investigated by Dr Lacroix at CHUM. Bourdeau was aided by CRCHUM researcher Martine TĂ©treault during the computer analyses related to the research project.

Earlier diagnosis thanks to genetic analysis

“In general, rare diseases are generally underdiagnosed in clinics,” said Bourdeau, the medical director of the adrenal tumors multidisciplinary team at the CHUM.

“By identifying this new gene, we now have a way of diagnosing our patients and their families earlier and thus offer more personalized medicine. At the CHUM, genetic analysis is already offered in our Genetic Medicine Division.”

In a remarkable demonstration of scientific cooperation, the Quebec and French teams were able to collect and study tissue specimens available in local and international biobanks in Canada, France, Italy, Greece, Belgium and the Netherlands.

Blood and adrenal gland tissue samples of 17 patients—mostly women—diagnosed with GIP-dependent Cushing’s Syndrome were compared genetically with those of 29 others with non-GIP-dependent bilateral adrenal Cushing’s Syndrome.

This was quite an accomplishment, given the rarity of the disease in the general population. It allowed the researchers to identify the genetic mutations of the KDM1A gene and to determine that the disease is genetically transmitted.

Since 2009, the CHUM has been designated as the adrenal tumors quaternary care centre of the Quebec Cancer Program.

About this study

“Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing’s syndrome: a multicenter retrospective cohort study,” by Drs. Fanny Chasseloup, Isabelle Bourdeau and their colleagues, was published Oct. 13, 2021, in The Lancet Diabetes & Endocrinology. Funding was provided by the Agence nationale de la recherche, the Fondation du Grand dĂ©fi Pierre Lavoie, the Institut national du cancer, the Fonds de recherche du QuĂ©bec-SantĂ©, INSERM and Assistance publique-hĂŽpitaux de Paris.

About the CRCHUM

The University of Montreal Hospital Research Centre (CRCHUM) is one of North America’s leading hospital research centres. It strives to improve adult health through a research continuum covering such disciplines as the fundamental sciences, clinical research and public health. Over 1,850 people work at the CRCHUM, including more than 550 researchers and more than 460 graduate students

Media contact

  • Jeff HeinrichUniversitĂ© de MontrĂ©alTel: 514 343-7593
  • Lucie DufresneCentre hospitalier de l’UniversitĂ© de MontrĂ©alTel: 514 890-8000 p. 15380

From https://nouvelles.umontreal.ca/en/article/2021/10/15/identified-the-gene-behind-an-unusual-form-of-cushing-s-syndrome/

ACTH-independent Cushing’s syndrome due to bilateral adrenocortical adenoma

https://doi.org/10.1016/j.radcr.2021.07.093

 

Abstract

The chronic excess of glucocorticoids results in Cushing’s syndrome. Cushing’s syndrome presents with a variety of signs and symptoms including: central obesity, proximal muscle weakness, fatigue striae, poor wound healing, amenorrhea, and others.

ACTH independent Cushing’s syndrome is usually due to unilateral adenoma. A rare cause of it is bilateral adrenal adenomas.

In this paper we report a case of a 43-year-old woman with Cushing’s syndrome due to bilateral adrenal adenoma.

Read the case report at https://www.sciencedirect.com/science/article/pii/S1930043321005690

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