Exogenous Cushing’s syndrome is an ACTH-independent endocrine disorder, characterized by specific signs resulting from excessive glucocorticoid intake. This is mainly the case in the course of management of corticotherapy-necessitating chronic diseases such as asthma. It may occasionally lead to secondary Adrenal insufficiency, which is the inability of the adrenal glands to produce hormones, precisely cortisol and aldosterone, due to lack of secretion of ACTH from a suppressed pituitary gland. The clinical presentation of adrenal insufficiency may be gradual and nonspecific, depending on the degree of insufficiency and precipitating stress event. Symptoms may include fatigue, nausea, muscle weakness, and headache. We here present the case of an asthmatic infant treated with glucocorticoids, who came presenting with some of the above symptoms after the interruption of his medication, with onset of exogenous Cushing’s syndrome. The particularity of this case report is the association of iatrogenic Cushing’s syndrome with secondary adrenal insufficiency in an asthmatic infant. This is rare and very less reported in the pediatric population. Yet, it was effectively managed with a salt restriction diet and the re-administration of hydrocortisone, which is a glucocorticoid too. As such, a disorder caused by the intake of glucocorticoid had definitely found its solution in a treatment with glucocorticoids. Somehow-“healing evil with evil” or a “hair of the dog that bit you”.
Keywords: Cushing’s syndrome; Adrenal insufficiency; Asthma
Asthma is the most common chronic disease of childhood, with an estimated prevalence ranging from 5% to 30% in some countries . Glucocorticoids are used in the management of moderate to severe cases of asthma. They are routinely administered as aerosols and offer control of the respiratory symptoms. Despite this advantage, exogenous administration of glucocorticoids might lead to the suppression of the hypothalamic-pituitary-adrenal axis for months . Up to 6.8% of adrenal insufficiency are found in asthmatic infants secondary to the use of corticosteroids . There are two types of adrenal insufficiency: primary and secondary, and these may be of acute or chronic onset. Chronic primary adrenal insufficiency has the highest prevalence in overall population . Therapeutic glucocorticoid administration is thought to be the most common cause of secondary adrenal insufficiency. In effect, the chronic administration exogenous glucocorticoids may induce atrophy of pituitary corticotrophic cells . As a matter of fact, it is estimated that induced linear growth impairment as a complication of hypothalamic–pituitary–adrenal axis suppression occurs with glucucorticoid doses ⩽400 μg/day on biochemical testing. In addition, a Cushingoid appearance with central obesity and fatigue has been reported with higher doses [5,6]. Apart from common symptoms such as fatigue, nausea, muscle weakness, and headache, other features of adrenal insufficiency including hypoglycemia and weight loss, may occur as well on withdrawal of an exogenous corticosteroid treatment . However, adrenal glands and corticosteroid hormones they produce (cortisol and aldosterone) are so vital that the mainstay of the treatment in adrenal insufficiency can only be a replacement therapy with another synthetic corticosteroid. This may last from months to a year before remission [2-5].
Cushing’s Syndrome (CS) is an endocrine disorder resulting from high glucocorticoid level in the blood. It is either categorized as ACTH-dependent CS (due to pituitary tumors or excess ACTH administration) or ACTH-independent CS (due to adrenal neoplasms or excessive glucocorticoid intake)  .Under normal circumstances, ACTH is secreted by the pituitary gland which in turn stimulates the secretion of cortisol by the adrenal glands . Prolonged exogenous corticosteroid administration can lead to a number adverse effects based on the potency and duration of the treatment. This include secondary adrenal insufficiency marked with the suppression of the hypothalamic-pituitary-adrenal axis, iatrogenic Cushing’s syndrome with metabolic disorders, severe infections with immunodeficiency, and failure to thrive due to epiphyseal fusion. Our case report further highlights the potential for the systemic activity of iatrogenic glucocorticoids to induce concomitant Cushing’s syndrome with adrenal insufficiency in an infant. In this patient, facio-troncular obesity with curly hairs were consistent with Cushing syndrome, while fatigue, nausea and vomiting characterized adrenal insufficiency. Moreover, this child had biochemical evidence of adrenal insufficiency with low blood ACTH and cortisol levels, even though further complementary work-up was not conducted with blood aldosterone.
The low ACTH blood level indicated exogenous pituitary gland inhibition from betamethasone, which was originally meant for treating the child’s asthma [6-8]. While decreased blood cortisol was a repercussion of the insufficiently stimulated adrenal glands from low ACTH. Given the context and the clinical findings, all these factors oriented the diagnosis towards exogenous Cushing’s syndrome with secondary adrenal insufficiency. However, blood electrolytes’ levels were normal, with normal kalemia and natremia. This seemed strange, as low cortisol and aldosterone blood levels in adrenal insufficiency is generally responsible for hyperkalemia and hyponatremia. Such a strange phenomenon had earlier been documented in secondary adrenal insufficiency and postulated to be the result of inappropriate vasopressin secretion .
Corticosteroids form a family of biochemically active substances, naturally synthesized in vivo as hormones and pharmaceutically reproduced in vitro as drugs. They have functions in the regulation of overall metabolism, hydro-electrolytic balance and various stress. They are also immunosuppressant with anti-inflammatory activity [6-11]. With respect to the predominance of their individual functions, they may be subdivided into glucocorticoids and mineralocorticoids. Hydrocortisone is the recommended replacement therapy in case of adrenal insufficiency [6-11]. Although from the family of glucocorticoids as betamethasone (the causative drug in this case report) and cortisol (the main lacking hormone), it has some mineralocorticoid action in addition, making it similar to aldosterone (another lacking hormone in adrenal insufficiency). It is however closest in function with cortisol, which makes it even more suitable as a
replacement therapy. Its use as sole replacement therapy is generally sufficient to restore carbohydrate, fat and amino-acids metabolism and prevent electrolyte imbalances that may occur as well in adrenal insufficiency [6-12].
Although growth suppression has been reported as being associated with chronic adrenal insufficiency in some studies, this was not a feature in our patient [10,13]. Perhaps the absence of this sign was indicative of acute adrenal insufficiency, meaning an onset induced by the withdrawal of betamethasone spray [6,10,11]. However, this may also imply that adrenal suppression may manifests differently, depending on patient susceptibility, glucocorticoid doses and duration.
Exogenous Cushing’s syndrome and secondary adrenal insufficiency can manifest conjointly in pediatric patients. Asthmatic children with moderate to severe symptoms are mostly at risk for developing these. The onset of Cushing’s syndrome and adrenal insufficiency which may lead to adrenal crisis in such children should perhaps encourage to investigate different algorithms for management of asthma. The insidious nature of adrenal insufficiency in infants is even more alarming as the imbalance can progress unnoticed if Cushingoid features are not present. A large number of patients with asthma might have adrenal insufficiency even with low- to medium-dose corticosteroids treatment when they are administered over a long period. Thus, it is essential that patients with asthma under this treatment be checked for adrenal insufficiency more frequently.
Acknowledgements: Hospitals authorities, all collaborators to this project.
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