Beyond the adrenals: Organ manifestations in inherited primary adrenal insufficiency in children.

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients.

Determinants of altered sleep-wake rhythmicity in patients treated for nonfunctioning pituitary macroadenomas.

CONTEXT AND OBJECTIVE: In a cohort of 17 patients treated for nonfunctioning pituitary macroadenoma (NFMA), we observed alterations in polysomnographic sleep characteristics and actigraphic sleep-wake rhythmicity, and subjective fatigue, daytime somnolence, and low sleep quality. We aimed to confirm the actigraphic data in a larger scale cohort of NFMA patients, powered to address risk factors for altered rhythmicity, including the effects of hydrocortisone replacement. METHODS: Sleep-wake rhythmicity in treated NFMA patients was measured using actigraphy for 7 days, and subjective sleep quality and quality of life (QoL) with validated questionnaires. To assess the influence of hydrocortisone dependency, we additionally studied patients with Addison's disease (AD). The results were compared with matched healthy controls. RESULTS: We included 69 NFMA patients in long-term remission after trans-sphenoidal surgery on stable replacement therapy for hypopituitarism, 21 AD patients, and 58 controls. NFMA patients reported severely impaired QoL, sleep quality, and increased daytime sleepiness. The day-night dichotomy of activity was fragmented, with decreased daytime activity and a tendency for increased nighttime activity. Preoperative visual field defects (VFD) were associated with this fragmentation, and vasopressin deficiency with decreased sleep efficiency, independent of age, hypopituitarism, or radiotherapy. AD patients showed similar decreases in daytime functioning, but normal subjective and objective sleep, and no daytime sleepiness. CONCLUSION: NFMA patients suffer from altered sleep-wake rhythmicity. Hydrocortisone dependency may explain part of the decreased daytime functioning, but the independent influence of VFD and differences between AD and NFMA patients point towards a role for dysfunction of the adjacent suprachiasmatic nucleus (SCN).

Adrenal diseases during pregnancy: pathophysiology, diagnosis and management strategies.

: Adrenal diseases--including disorders such as Cushing's syndrome, Addison's disease, pheochromocytoma, primary hyperaldosteronism and congenital adrenal hyperplasia--are relatively rare in pregnancy, but a timely diagnosis and proper treatment are critical because these disorders can cause maternal and fetal morbidity and mortality. Making the diagnosis of adrenal disorders in pregnancy is challenging as symptoms associated with pregnancy are also seen in adrenal diseases. In addition, pregnancy is marked by several endocrine changes, including activation of the renin-angiotensin-aldosterone system and the hypothalamic-pituitary-adrenal axis. The aim of this article was to review the pathophysiology, clinical manifestation, diagnosis and management of various adrenal disorders during pregnancy.

Drug prescription patterns in patients with Addison's disease: a Swedish population-based cohort study.

CONTEXT: There are no published data on drug prescription in patients with Addison's disease (AD). OBJECTIVE: Our objective was to describe the drug prescription patterns in Swedish AD patients before and after diagnosis compared with population controls. DESIGN AND SETTING: We conducted a population-based cohort study in Sweden. PATIENTS: Through the Swedish National Patient Register and the Swedish Prescribed Drug Register, we identified 1305 patients with both a diagnosis of AD and on combination treatment with hydrocortisone/cortisone acetate and fludrocortisone. Direct evidence of the AD diagnosis from patient charts was not available. We identified 11 996 matched controls by the Register of Population. MAIN OUTCOME MEASURE: We determined the ratio of observed to expected number of patients treated with prescribed drugs. RESULTS: Overall, Swedish AD patients received more prescribed drugs than controls, and 59.3% of the AD patients had medications indicating concomitant autoimmune disease. Interestingly, both before and after the diagnosis of AD, patients used more gastrointestinal medications, antianemic preparations, lipid-modifying agents, antibiotics for systemic use, hypnotics and sedatives, and drugs for obstructive airway disease (all P values < .05). Notably, an increased prescription of several antihypertensive drugs and high-ceiling diuretics was observed after the diagnosis of AD. CONCLUSION: Gastrointestinal symptoms and anemia, especially in conjunction with autoimmune disorders, should alert the physician about the possibility of AD. The higher use of drugs for cardiovascular disorders after diagnosis in patients with AD raises concerns about the replacement therapy.

[Subclinical adrenal diseases: silent pheochromocytoma and subclinical Addison's disease]. / Maladies surrénaliennes infracliniques: cas du phéochromocytome silencieux et de la maladie d'Addison infra-clinique.

The silent pheochromocytoma, a hidden form of pheochromocytoma, exposes the patient to an increased risk of mortality if the diagnosis is not established on time. Biological diagnosis of pheochromocytoma can be difficult. Catecholamine secretion is dependent on tumor size and a large number of physiological, pharmacological, lifestyle modifications and sampling conditions influence the measurement of urinary and plasma metanephrines. The prevalence of pheochromocytoma is 2% among adrenal incidentaloma smaller than 3 cm (2/3 of tumors). Recent studies suggest the almost zero risk of pheochromocytoma among these tumors if they are hypodense (<10 housefield units) on adrenal tomography. Addison's disease is a pathology affecting about 1 in 8000. Immunopathology is still unknown, but some elements advocated the hypothesis of a predominant cell-mediated immunity in particular Interferon-gamma production by CD4 T lymphocytes in the presence of an epitope from the 21-hydroxylase, as well as IgG1 subtype produced by activated B lymphocytes, autoantibodies do appear to be a simple marker of the disease. Subclinical Addison's disease is defined by the presence of anti-21-hydroxylase autoantibodies, without clinical symptoms. It evolves faster to the clinical phase in young subjects, male, having high levels of autoantibodies and with an initially impaired adrenal function. Dosage of ACTH, plasma renin active, and basal cortisol and after Synacthen allow to discriminate the subjects with low or high risk of evolution and establish an appropriate monitoring.

[Perioperative Addisonian crisis]. / Perioperative Addison-Krise.

An Addisonian crisis marks an acute adrenocortical failure which can be caused by decompensation of a chronic insufficiency due to stress, an infarct or bleeding of the adrenal cortex and also abrupt termination of a long-term glucocorticoid medication. This article reports the case of a 25-year-old patient with Crohn's disease who suffered an Addisonian crisis with hypotension, hyponatriemia and hypoglycemia during an emergency laparotomy after he had terminated prednisolone medication on his own authority. This necessitated an aggressive volume therapy in addition to an initial therapy with 100 mg hydrocortisone, 8 g glucose and a continuous administration of catecholamines. Under this treatment regimen hemodynamic stabilization was achieved. Reduction of the administration of hydrocortisone after 3 days resulted in cardiovascular insufficiency which required an escalation of the hydrocortisone substitution.

Musculoskeletal symptoms and neurological investigations in adrenocortical insufficiency: a case report and literature review.

OBJECTIVES: Various forms of adrenocortical insufficiency can cause musculoskeletal symptoms such as muscle pain, tautness of the limbs, arthralgia, and flexion contractures. However, the findings of neurological investigations are inconclusive and have not been well summarized. METHODS: We report the case of a 61-year-old man with isolated adrenocorticotropic hormone deficiency who presented with musculoskeletal symptoms, including flexion contractures. We performed three neurological investigations: nerve conduction studies, electromyography, and muscle biopsy analysis. Further, we reviewed reports of 16 patients with various forms of adrenocortical insufficiency and musculoskeletal symptoms by considering the findings of these three investigations. RESULTS: From the literature review, we found that (a) analysis of muscle biopsy is the most sensitive technique, followed by electromyography and then nerve conduction studies; and (b) the longer the duration of the musculoskeletal symptoms, the greater the incidence of abnormal findings with all three techniques. CONCLUSIONS: Physicians may prioritize neurological investigations, depending on these findings.

Myasthenia gravis and autoimmune Addison disease in a patient with thymoma.

The association of thymoma with myasthenia gravis has been well documented. However, the relationship between these two syndromes and Addison disease are very rarely encountered in clinical practice. We report on a 32-year-old man who underwent a resection for thymoma 48 months ago. The diagnosis of Addison disease was made followed by a diagnosis of myasthenia gravis on the basis of a high titer of acetylcholine receptor levels. The treatment of oral prednisolone 7.5 mg/day and oral prostigmine 180 mg/day was initiated. His symptoms and physical signs were improved after this treatment. To our knowledge, this is the fourth reported case of thymoma synchronously associated with myasthenia gravis and Addison disease.

Metabolic and cardiovascular profile in patients with Addison's disease under conventional glucocorticoid replacement.

OBJECTIVE: Although two studies have shown that Addison's disease (AD) is still a potentially lethal condition for cardiovascular, malignant, and infectious diseases, a recent retrospective study showed a normal overall mortality rate. Differently from secondary hypoadrenalism, scanty data exist on the role of conventional glucocorticoid replacement on metabolic and cardiovascular outcome in AD. SUBJECTS AND METHODS: In 38 AD under conventional glucocorticoid replacement (hydrocortisone 30 mg/day or cortisone 37.5 mg/day) ACTH, plasma renin activity (PRA), DHEAS, fasting glucose and insulin, 2-h glucose after oral glucose tolerance test, serum lipids, 24-h blood pressure and intima-media thickness (IMT) were evaluated and compared with 38 age-, sex- and body mass index (BMI)-matched controls (CS). RESULTS: AD had ACTH and PRA higher and DHEAS lower (p<0.0005) than CS. Mean waist was higher (p<0.05) in AD than in CS. Although no differences were found for mean gluco-lipids levels, a higher percentage of AD compared to CS were IGT (8 vs 0%), hypercholesterolemic (18 vs 8%), and hypertriglyceridemic (18 vs 8%); none of the AD and CS showed either HDL<40 mg/dl or LDL>190 mg/dl. At the multiple regression analysis, in both AD and CS, BMI was the best predictor of 2-h glucose and age of total and LDL cholesterol; in AD, no significant correlation was found between the above mentioned metabolic parameters and either hormone levels or disease duration. In both AD and CS 24-h blood pressure and IMT were normal. CONCLUSIONS: Our study shows a higher prevalence of central adiposity, impaired glucose tolerance and dyslipidemia in AD patients.

Exaggerated postsurgical inflammation in a patient with insufficiently treated Addison disease.

A patient with Addison disease developed fever, pain, and marked orbital inflammation 3 days after evisceration in the setting of perforated corneal ulcer. He was treated for presumed orbital cellulitis without improvement. Increasing the corticosteroid dose for his Addison disease resulted in complete resolution of the inflammation.

Focal segmental glomerular sclerosis in two patients with Addison's disease: any more than fortuitous development of glomerular disease?

Adjustment of the mineralocorticoid activity under substitution therapy is of primary importance in Addison's disease. We report the clinical and biological conditions of 2 patients with Addison's disease who developed nephrotic proteinuria during their deficient mineralocorticoid state. Renal biopsy was performed and the specimens processed using conventional histochemistry, Congo red staining, and indirect immunofluorescence. The renal biopsy specimens showed focal segmental glomerular sclerosis and nodular deposits of IgM and C3. Negative for Congo red staining. Serum complement, circulating immune complexes, and anti-DNA and hepatitis B and C and human immunodeficiency virus antibodies were all normal or negative. Absence of vesicoureteral reflux was assessed by X-ray studies. Our observations suggest that deficiency in mineralocorticoid substitution therapy inducing a status of hyperreninemia could play a role in the development of focal segmental glomerulosclerosis in patients with Addison's disease.

[Severe perioperative hypotension after nephrectomy with adrenalectomy]. / Hipotensión perioperatoria grave tras nefrectomía con suprarrenalectomía.

A 70-year-old obese, hypertensive woman taking angiotensin converting enzyme (ACE) inhibitors and chlorthalidone but with no history of corticosteroid treatment or hypothalamus-hypophyseal-adrenal disease, underwent nephrectomy and adrenalectomy under combined general and epidural anesthesia. Severe hypotension with oliguria developed during surgery and persisted during postoperative recovery, with anuria, metabolic acidosis, hyponatremia and hyperpotassemia. Although the symptoms were initially attributed to prior treatment with ACE inhibitors and diuretics together with combined anesthesia, the patient's lack of response to crystalloid, colloid and inotropic catecholamine therapy in the context of anuria, metabolic acidosis, hyponatremia and hyperpotassemia led us to consider a diagnosis of Addisonian crisis. Blood samples were taken to determine adrenocorticotropic hormone levels, and hydrocortisone treatment was started. The patient responded to treatment and cortisol levels fell, confirming the diagnosis of adrenal insufficiency. Compensatory endrocrine secretion of cortisol by the contralateral adrenal gland has been observed in patients undergoing nephrectomy and adrenalectomy for excision of a hypernephroma, and replacement therapy is therefore not recommended. Perioperative Addisonian crises have also been described in patients suffering great surgical stress, and severe hypotension has been observed in patients on long-term treatment with ACE inhibitors after induction of general anesthesia and after epidural anesthesia with local anesthetics. The combination of these factors made rapid diagnosis and start of appropriate therapy difficult.

Corticosteroids and pregnancy.

Pregnancy results in major changes in the hypothalamo-pituitary-adrenal (HPA) axis, which in turn influence fetal growth and the timing of labor. From the beginning of the second trimester maternal cortisol secretion increases, and in late pregnancy the placenta, in large part mediated through corticotroph-releasing hormone, plays a crucial role in the regulation of the fetal HPA axis to ensure the synchronization of the various processes involved in parturition. Exposure of the fetus to excess glucocorticoid results in intrauterine growth failure and possibly "programs" the development of cardiovascular disease in adult life. Biochemical assessment of the HPA axis is complicated by the estrogen-induced elevation of circulating cortisol-binding globulin, resulting in misleadingly high circulating cortisol levels The hypercortisolemia of Cushing's syndrome causes infertility, but if pregnancy does occur it can result in increased morbidity and mortality in mother and fetus. However, the prospects of a successful pregnancy are greatly improved with control of hypercortisolemia by surgery and medical therapy with metyrapone. Hypoadrenalism can be difficult to diagnose during pregnancy but, once the diagnosis is made, with careful monitoring, dose adjustment as indicated, and parenteral cover for labor, a successful pregnancy should result.