Downloaded from www.jama.com at Johns Hopkins University, on November 23, 2005 GRAND ROUNDS CLINICIAN’S CORNER AT THE JOHNS HOPKINS BAYVIEW MEDICAL CENTER Adrenal Insufficiency Roberto Salvatori, MD A 44-year-old woman reported several weeks of fatigue, somnolence, pain CASE PRESENTATION in the large joints, nausea, and decreased appetite. She had also noted an A 44-year-old woman whose medical unintentional 11-kg weight loss over a period of 6 months. She had a re- history was remarkable only for chon- mote history of amenorrhea, but she was presently menstruating regularly. drocalcinosis of the knees was referred She was taking no medications, with the exception of acetaminophen as needed to the endocrinology department to for knee pain. The diagnosis of adrenal insufficiency (AI) was considered. exclude a metabolic or hormonal prob- Serum cortisol level after adrenocorticotropin hormone (ACTH) stimulation lem. The patient complained of several was abnormal. Because her plasma ACTH level was not increased, a diag- weeks of fatigue, somnolence, pain in the large joints, nausea, and decreased nosis of secondary AI (due to deficiency in ACTH) was made. Magnetic reso- appetite. Her symptoms had appeared nance imaging of the brain performed to exclude the presence of a sellar or gradually, without a clear precipitating suprasellar mass showed reduction in size of the pituitary gland and an in- event. She had also noted an uninten- creased cerebrospinal fluid content within the sella, consistent with a par- tional 11-kg weight loss over a period tially empty sella. The patient’s symptoms improved rapidly with hydrocor- of 6 months, associated with reduced tisone therapy but during follow-up, the dose of hydrocortisone was found appetite and occasional nausea. Her to be excessive. Important differences exist between primary and secondary past medical history was remarkable AI, and the diagnosis of secondary AI may be challenging. The therapy of AI for the fact that in her early 30s she had had a period of amenorrhea lasting should be carefully tailored to the requirements of the individual patient. approximately 1 year. After blood work, JAMA. 2005;294:2481-2488 www.jama.com a physician had told her that “my pitu- itary was not working and that I would not be able to become pregnant.” Sub- with a body mass index (BMI, calcu- Upon examination of her labora- sequently, however, her periods returned lated as weight in kilograms divided by tory studies, the electrolytes were nor- spontaneously, and she had 4 natural the square of height in meters) of 25.2. mal (sodium 141 mEq/L, potassium 3.6 pregnancies. Her recumbent blood pressure was mEq/L), as were her creatinine and On the review of systems, the pa- 115/80 mm Hg, her heart rate 74/min, blood urea nitrogen levels. Blood he- tient denied any change in her skin her respiratory rate 12/min, and her moglobin was normal (13 g/dL). At color or texture, in bowel habits, diz- temperature 36.5°C. The patient had no 10 AM, serum cortisol and plasma ad- ziness, chest pain, shortness of breath, significant blood pressure or heart rate renocorticotropin hormone (ACTH) polyuria, polydypsia, headaches, or vi- change after 1 minute in the upright po- levels were 4.0 µg/dL (normal range, sual changes. Her periods were com- sition. The skin and buccal mucosa had 5-20 µg/dL) and 9 pg/mL (normal ing monthly, with normal flow. She was no hyperpigmentation or hypopigmen- range, 6-60 pg/mL), respectively. The taking no medications, with the excep- tation. The thyroid gland was pal- serum level of free thyroxine (T4) was tion of acetaminophen as needed for pable but without abnormalities. There 1.2 ng/dL (15.4 pmol/L) (normal range, knee pain. Physical examination was no cervical or axillary adenopa- thy. Examination of the heart showed Author Affiliation: Department of Medicine, Divi- showed a well-appearing woman who sion of Endocrinology, Johns Hopkins University School weighed 69.5 kg and stood 166 cm tall, a regular rate and rhythm with nor- of Medicine, Baltimore, Md. mal cardiac sounds and no murmurs. Corresponding Author: Roberto Salvatori, MD, De- partment of Medicine, Division of Endocrinology, Johns See also Patient Page. The lungs were clear to auscultation and Hopkins University School of Medicine, 1830 E Monu- the abdomen was benign. Visual fields ment St, Suite 333, Baltimore, MD 21287 (salvator CME available online at were full by confrontation, and the neu- @jhmi.edu). www.jama.com Grand Rounds Section Editor: David S. Cooper, MD, rological examination was nonfocal. Contributing Editor, JAMA. ©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, November 16, 2005—Vol 294, No. 19 2481 Downloaded from www.jama.com at Johns Hopkins University, on November 23, 2005 ADRENAL INSUFFICIENCY 0.18-1.6 ng/dL [2.32-20.59 pmol/L]), adenoma that infarcted, leaving ids in the adrenal glands and in the cen- with a thyroid-stimulating hormone of an “empty sella.”1 Although ACTH tral nervous system. Therefore, the 3.3 mIU/mL (normal range, 0.5-4.5 deficiency with normal thyroid- clinician should perform a careful neu- mIU/mL). An ACTH stimulation test stimulating hormone and gonadotro- rological examination in young males was performed. Sixty minutes after the pin secretion (judged by the resump- with primary AI, keeping in mind that intravenous injection of 1 to 24 syn- tion and continuation of normal AI can appear long before neurologi- thetic ACTH (250-µg intravenous), the menses) is rare, it has been described cal symptoms.6 Several infectious pro- serum cortisol was 7 µg/dL (normal, before in a similar setting.2 The low cesses known to be associated with Ͼ18 µg/dL). serum insulin-like growth factor 1 AIDS, particularly Cytomegalovirus, My- Magnetic resonance imaging of the in a patient with hypopituitarism cobacterium tuberculosis, Cryptococcus brain, performed to exclude the pres- strongly suggests growth hormone neoformans, Toxoplasma gondii, Myco- ence of a sellar or suprasellar mass, deficiency.3 bacterium avium intracellulare, Pneu- showed reduction in size of the pitu- The etiology, diagnosis, and therapy mocystis jiroveci, and Histoplasma cap- itary gland, mild leftward deviation of of primary and secondary AI, as well as sulatum, may lead to adrenal gland the pituitary stalk, and an increased ce- the differences between these 2 dis- destruction. Among medications, ke- rebrospinal fluid content within the ease states, are reviewed herein. The toconazole (an antifungal) and etomi- sella, consistent with a partially empty major hormones of the hypothalamic- date (a general anesthetic) can cause sella, but no tumor mass or cyst. pituitary-adrenal (HPA) axis are shown AI.7 The patient started taking hydrocor- in the FIGURE. Secondary AI. The most common tisone (20 mg in the morning and cause of secondary AI is the abrupt dis- 10 mg in the afternoon). Two months Classification of AI continuation of long-term administra- later, she reported significant improve- Adrenal insufficiency develops when a tion of glucocorticoids. There is a great ment of all her symptoms and a large part of the function of the adre- individual variability in susceptibility 6-kg weight gain. Six months later she nal glands is lost. Primary AI is caused to suppression of the HPA axis by ex- was feeling well, but her weight had by processes that damage the adrenal ogenous glucocorticoids; therefore, the increased to 94 kg (24.5 kg in 9 glands or by drugs that block cortisol presence of AI cannot be predicted re- months of therapy; BMI, 34.1), with synthesis. In contrast, secondary AI re- liably by the dose and duration of glu- preferential accumulation of adipose sults from processes that reduce the se- cocorticoid use.8 Several weeks of ex- tissue in her abdomen. Her hydrocor- cretion of ACTH by the pituitary gland ogenous glucocorticoid administration tisone dose was reduced to 10 mg in due to a pituitary or hypothalamic pa- are required for the development of AI.9 morning and 5 mg in afternoon, with- thology; although the latter, due to defi- Intramuscular, intra-articular, and even out any relapse of her symptoms. cit of corticotrophin-releasing hor- inhaled or topical glucocorticoids can Three and half years later, she was still mone (CRH), is sometimes called cause significant suppression of the HPA doing well with the same hydrocorti- tertiary AI. In this review, both forms axis.10,11 Similarly, megestrol acetate, a sone dose and her weight was 87 kg are included in the secondary AI group. synthetic progestational agent used to (BMI, 31.5). She was still having regu- Both primary and secondary AI can de- increase appetite in a variety of ca- lar periods. The insulin-like growth velop either slowly, over several weeks chexia-inducing illnesses, can sup- factor 1 was low at 71 ng/mL (normal or months, or acutely, with cata- press ACTH secretion at doses of more range, 90-360 ng/mL). strophic consequences that may lead to than 160 mg/d, leading to secondary cardiovascular collapse and death. The AI.12 DISCUSSION classification and common etiologies of Secondary AI can be caused by pi- This patient has symptoms and bio- primary and secondary AI are shown tuitary adenomas, craniopharyngio- chemical evidence of adrenal insuffi- in the Figure. mas, pituitary surgery,lymphocytic hy- ciency (AI), as shown by her abnormal Primary AI. In developed coun- pophysitis, and a wide variety of other cortisol response to ACTH (the inter- tries, the most frequent cause of pri- neoplastic, inflammatory, and infec- pretation criteria of the ACTH stimu- mary AI is autoimmune adrenalitis. In tious processes involving the sellar or lation test will be discussed below).