European Journal of Endocrinology (2010) In press
DOI: 10.1530 / EJE-10-0602
Copyright © 2010 by European Society of Endocrinology
Cristina Eller-Vainicher, Valentina Morelli, Antonio Stefano Salcuni, Claudia Battista, Massimo Torlontano, Francesca Coletti, Laura Iorio, Elisa Cairoli, Paolo Beck-Peccoz, Maura Arosio, Bruno Ambrosi, Alfredo Scillitani and Iacopo Chiodini
C Eller-Vainicher, Department of Medical Sciences, Endocrinology and Diabetology Unit, Fondazione Ospedale Maggiore Policlinico, I.R.C.C.S., Milan, Italy
V Morelli, Milan, 20122, Italy
A Salcuni, Endocrinology Unit, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
C Battista, Endocrinology Unit, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
M Torlontano, Endocrinology Unit, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
F Coletti, Endocrinology Unit, Ospedale San Giuseppe Multimedica, Milan, Italy
L Iorio, Policlinico San Donato Institute, I.R.C.C.S.Depertment of Medical and Surgical Sciences, University of Milan, san Donato Milanese, Milan, Italy
E Cairoli, Department of Medical Sciences, Endocrinology and Diabetology Unit, Fondazione Ospedale Maggiore Policlinico, I.R.C.C.S., Milan, Italy
P Beck-Peccoz, Department of Medical Sciences, Endocrinology and Diabetology Unit, Fondazione Ospedale Maggiore Policlinico, I.R.C.C.S., Milan, Italy
M Arosio, University of Milan, Milan, Italy
B Ambrosi, Policlinico San Donato Institute, I.R.C.C.S.Depertment of Medical and Surgical Sciences, University of Milan, san Donato Milanese, Milan, Italy
A Scillitani, Endocrinology Unit, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
I Chiodini, Department of Medical Sciences, Endocrinology and Diabetology Unit, Fondazione Ospedale Maggiore Policlinico, I.R.C.C.S., Milano, 20123, Italy
Correspondence: Iacopo Chiodini, Email: iacopo.chiodini@email.it
Context: It is unknown if the metabolic effects of the removal of an adrenal incidentalomas (AI) can be predicted by the assessment of cortisol hypersecretion before surgery.
Objective: To evaluate the accuracy of several criteria of hypothalamic-pituitary-adrenal axis activity in predicting the metabolic outcome after adrenalectomy.
Design: Retrospective longitudinal study.
Patients: In 55 surgically-treated AI patients (Group 1) before surgery and in 53 non-treated AI patients (Group 2) at baseline, urinary free cortisol (UFC), cortisol after 1mg-overnight dexamethasone-suppression test (1mg-DST), ACTH and midnight serum cortisol (MSC) were measured. In Group 1 and 2, metabolic parameters were evaluated before and 29.6±13.8 months after surgery and at baseline and after 35.2±10.9 months, respectively.
Main Outcome Measures: The improvement/worsening of weight, blood pressure, glucose and cholesterol levels (endpoints) was defined in the presence of a >5% weight decrease/increase and following the European Society of Cardiology or the ATPIII criteria, respectively. The accuracy of UFC, 1mg-DST, ACTH and MSC, singularly taken or in combination, in predicting the improvement/worsening of ≥2 endpoints was calculated.
Results: The presence of ≥2 among UFC>70 µg/24h (193 nmol/L), ACTH<10>3.0 µg/dL (83 nmol/L) (UFC-ACTH-DST criterion) had the best accuracy in predicting the endpoints’ improvement (sensitivity 65.2%, specificity 68.8%) after surgery. In the non-treated AI patients, this criterion predicted the worsening of ≥2 endpoints (sensitivity 55.6%, specificity 82.9%).
Conclusions: The UFC-ACTH-DST criterion seems the best for predicting the metabolic outcome in surgically-treated AI patients.
From http://www.eje.org/cgi/content/abstract/EJE-10-0602v1
HPA Axis: Accuracy of several parameters of hypothalamic–pituitary–adrenal axis activity in predicting before surgery the metabolic effects of the rem
Thomas M Barber, Emily Adams, Olaf Ansorge, James V Byrne, Niki Karavitaki and John Wass
T Barber, Department of Endocrinology, OCDEM, University of Oxford, Oxford, United Kingdom
E Adams, Department of Endocrinology, OCDEM, University of Oxford, Oxford, United Kingdom
O Ansorge, Department of Pathology, University of Oxford, Oxford, United Kingdom
J Byrne, Department of Radiology, University of Oxford, Oxford, United Kingdom
N Karavitaki, Department of Endocrinology, OCDEM, University of Oxford, Oxford, United Kingdom
J Wass, Endocrinology, Oxford University, Oxford, OX3 7LJ, United Kingdom
Correspondence: John Wass, Email: john.wass@noc.anglox.nhs.uk
Abstract
Nelson’s Syndrome is a potentially life-threatening condition that not infrequently develops following total bilateral adrenalectomy (TBA) for the treatment of Cushing’s Disease. In this review article, we discuss some controversial aspects of Nelson’s Syndrome including diagnosis, predicitve factors, aetiology, pathology and management based on data from the existing literature and the experience of our own tertiary centre.
Definitive diagnostic criteria for Nelsons’s Syndrome are lacking. We argue in favour of a new set of criteria. We propose that Nelson’s Syndrome should be diagnosed in any patient with prior TBA for Cushing’s Disease and at least one of the following criteria: i) an expanding pituitary mass lesion compared with pre-TBA images; ii) an elevated 0800hrs plasma level of ACTH (>500ng/l) in addition to progressive elevations of ACTH (a rise of >30%) on at least three consecutive occasions. Regarding predictive factors for the development of Nelson’s Syndrome post-TBA, current evidence favours: the presence of residual pituitary tumour on MRI post-TSA; an aggressive subtype of corticotrophinoma (based on MRI growth rapidity and histology of TSA samples); lack of prophylactic neo-adjuvant pituitary radiotherapy at the time of TBA, and; a rapid rise of ACTH levels in year one post-TBA. Finally, more studies are needed to assess the efficacy of therapeutic strategies in Nelson’s Syndrome, including the alkylating agent, temozolomide which holds promise as a novel and effective therapeutic agent in the treatment of associated aggresive corticotroph tumours. It is timely to review these controversies and to suggest guidelines for future audit.
Sexuality and Fertility in Women with Addison's Disease
Journal of Clinical Endocrinology and Metabolism, 07/12/10
Erichsen MM et al. – The aim was to determine peripheral androgen status, sexual functioning, and birth rates in Addison's disease females. Despite androgen depletion, females with Addison's disease do not report impaired sexuality. The fertility is reduced after the diagnosis is made; the reasons for this remain unknown.
Read the abstract at http://jcem.endojournals.org/cgi/content/abstract/jc.2010-0445v1
Raymon H. Grogan, MD, Elliot Mitmaker, MD, Menno R. Vriens, MD, PhD, Avital Harari, MD, Jessica E. Gosnell, MD, Wen T. Shen, MD, Orlo H. Clark, MD, Quan-Yang Duh, MD
Accepted 14 May 2010. published online 24 June 2010.
Corrected Proof
Background
Adrenal incidentaloma remains a diagnostic challenge. Despite well-established management guidelines, the long-term results of following these guidelines are unknown. We sought to determine how accurately these guidelines identify functioning incidentalomas and how often these guidelines result in adrenalectomy for benign tumors.
Methods
We catalogued adrenal incidentalomas from a retrospective review of 500 consecutive adrenalectomies at a single institution. The outcome measures studied were patient demographics, preoperative biochemical analysis, imaging characteristics, tumor size, type of operation performed, and postoperative histologic diagnosis.
Results
Eighty-one of the 500 adrenalectomies performed were for incidentalomas. Size was the only significant characteristic that distinguished cortical cancers from benign adenomas. Only 1 out of 26 functioning tumors was incorrectly identified on preoperative workup. We also found that 25% of cortisol-secreting incidentalomas were cystic, and that benign adenomas accounted for 42% of all tumors resected.
Conclusion
Current guidelines accurately predict the functional status of adrenal incidentalomas. Some cystic lesions may be functioning and should therefore be screened for hormonal hypersecretion. However, even with the most up-to-date diagnostic tools available, most adrenal incidentalomas resected are benign tumors.
Department of Endocrine Surgery, University of California San Francisco, San Francisco, CA
PII: S0039-6060(10)00261-8
doi:10.1016/j.surg.2010.05.001
© 2010 Mosby, Inc. All rights reserved.
From http://www.surgjournal.com/article/PIIS0039606010002618/abstract?rss=yes
The production of cortisol by the adrenal glands is stimulated by ACTH (Adrenal Cortical Tropic Hormone), which is produced by the pituitary gland in the brain. Thus, overproduction of cortisol can be caused by either a tumor in the pituitary gland (Cushing's disease), or in the adrenal glands (Cushing's syndrome). Less commonly, a tumor producing too much ACTH may be found outside of the pituitary gland. In patients with Cushing's disease, the blood levels of both ACTH and cortisol are elevated. In patients with Cushing's syndrome, the blood level of cortisol is increased in the setting of a low level of ACTH. Rarely, adrenocortical cancers may cause Cushing's syndrome.
Diagnosis
There is a great deal of variability throughout the day in the amounts of cortisol produced by the adrenal glands. For this reason, the most sensitive test measures the amount of cortisol excreted in the urine over a 24-hour period. A 24 hour free cortisol level greater than 100 µg is diagnostic of Cushing's syndrome. Patients suspected of having Cushing's syndrome will also undergo a dexamethasone suppression test which helps to determine the cause of the increased cortisol production. A CT or MRI scan is used to determine the location of the tumor.
Treatment
Patients with Cushing's disease typically have benign tumors of the pituitary gland in the brain. These patients are referred to a neurosurgeon for removal of the tumors. If removal of the pituitary tumor and medications fail to control Cushing's disease, removing both adrenal glands may be indicated. In patients with Cushing's syndrome, an adrenalectomy—surgical removal of the adrenal gland—is curative. This operation is usually performed laparoscopically, through several very small incisions.
From http://www.columbiasurgery.org/pat/adrenal/cushing.html
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What Are the Causes of Secondary Adrenal Insufficiency news, info, articles, and resources shared by health experts on OrganizedWisdom Health.
http://organizedwisdom.com/What-Are-the-Causes-of-Secondary-Adrenal-Insufficiency/wt/med
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MountainQueen posted this on the Cushing's Help Boards. She said:
I came across this article about the clinical use of Dex for CAH carriers. After reading this article I remembered that NO ONE asked me if I was pregnant before I took the Dex test. What would have happened if I had been?
Very interesting article for CAH gene carriers: From Time Magazine on line
Medical Ethics: Prenatal Dexamethasone Use Questioned
By CATHERINE ELTON Catherine Elton – Mon Jun 21, 11:45 pm ET
When Marisa Langford found out she was pregnant again, she called Dr. Maria New, a total stranger, before calling her own mother. New, a prominent pediatric endocrinologist and researcher at Mount Sinai Medical Center in New York City, is one of the world's foremost experts in congenital adrenal hyperplasia, or CAH, a group of inherited disorders of the adrenal gland.
Langford and her husband learned they were silent carriers of the genetic variation that causes CAH when their son was diagnosed with the condition after birth. Their son - like the 1 in 16,000 babies born with CAH each year in the U.S. - faces a lifetime of taking powerful steroid medications to compensate for his faulty adrenal glands. When Langford contacted New about her second pregnancy, New, who was not Langford's regular doctor, called a local pediatric endocrinologist. That doctor prescribed Langford a commonly used medication for CAH. "Dr. New told me I had to start taking dexamethasone immediately," says Langford, 30, who lives in Tampa. "We felt very confident in someone of her stature and that what she was telling us was the right thing to do."(See the most common hospital mishaps.)
The early prenatal use of dexamethasone, or dex, has been shown to prevent some of the symptoms of CAH in girls, namely ambiguous genitalia. Because the condition causes overproduction of male hormones in the womb, girls who are affected tend to have genitals that look more male than female, though internal sex organs are normal. (In boys, in contrast, the condition leads to early signs of puberty, such as deep voice, body hair and enlarged penis by age 2 or 3.) But while the prenatal treatment may address girls' physical symptoms, it does not prevent the underlying, medical condition, which in some severe cases can be life-threatening, nor does it preclude the need for medication throughout life.
Langford says also that neither New nor her prescribing physician mentioned that prenatal dexamethasone treatment is an off-label use of the drug (an application for which it was not specifically approved by the government) or that the medical community is sharply divided over whether dexamethasone should be used during pregnancy at all.
Is It Safe - or Even Necessary?
To date, there has been just one controlled, prospective, long-term trial of prenatal dexamethasone for the prevention of ambiguous genitalia, conducted in Sweden. The results, published in 2007 in the Journal of Clinical Endocrinology & Metabolism - more than two decades after doctors began using the medication in pregnant patients - found some mild behavioral and cognitive deficits in children whose mothers had been treated. But the study, with just 26 participants, was too small to be definitive. "We just don't know what we are doing to these kids," says Dr. Walter Miller, the chief of endocrinology at University of California, San Francisco. "It's not sufficient to say, The baby was born and had all fingers and toes, so it's fine."(See the top 10 medical breakthroughs of 2009.)
In animal studies, dexamethasone has been shown to cause birth defects, but proponents of the treatment note that no human birth defects have ever been associated with the treatment, and that it is uncertain whether findings in lab animals translate to humans. Meanwhile, the possible benefits are clear: the treatment can spare young girls the potential psychosocial problems associated with having ambiguous genitalia as well as the ordeal of surgery to correct deformities later. "I see potential for benefits and I don't see evidence there's any negatives to this. There are lots of risks associated with surgery, and if this can prevent surgery, then it's a good thing," says Dr. Ingrid Holm, a pediatric endocrinologist at Children's Hospital in Boston.
Research has also suggested that affected women who were treated with dex in the womb show more typical gender behavior than other women with CAH; the latter group tends to behave more tomboyishly and express little interest in having children. New told the Wall Street Journal in 2009 that the treatment further spares parents the "terrifying prospect" of not knowing whether their newborn is a boy or a girl. (Comment on this story.)
It is these very benefits, however, that lead some researchers to question what, exactly, doctors are treating - and whether it needs to be treated at all. Miller believes that prenatal dex is being used to alleviate "parental anxiety," rather than the child's condition. Other doctors and researchers have criticized New for introducing gender behavior into the medical prognosis - in two recent presentations on CAH at medical conferences, New offered medical outcome data on prenatal dex alongside data on typical gender behavior. "Maybe this gives clinicians the idea that the treatment goal is normalizing behavior. To say you want a girl to be less masculine is not a reasonable goal of clinical care," says David E. Sandberg, a University of Michigan pediatric psychologist who treats and conducts research on children with CAH.(Read how postpartum depression can strike fathers.)
Perhaps most controversially, prenatal dex must be given as soon as a woman learns she is pregnant, which is usually several weeks before genetic tests can determine if the fetus is in fact a female affected with CAH - the chance of which is 1 in 8 for parents who already have an affected child or know they are carriers of the genetic disorder. If the baby is healthy, treatment is stopped, but at that point, the fetus has been exposed to the steroid drug for weeks. There is no data on how many mothers receive prenatal dex, but according to the odds, 7 of 8 may be taking medication unnecessarily.
Concerns over Patient Consent
Some critics strongly oppose prenatal dex in large part because of the way it is presented to patients. Guidelines issued by pediatric endocrine societies in Europe and North America recommend that doctors obtain written informed consent from the patient as well as ethics-committee oversight for the treatment, but it is not known how many physicians adhere to these guidelines. Langford says she was not made aware of them. In addition, 2010 practice guidelines from the international Endocrine Society suggest that prenatal dex be administered as part of clinical research, which requires informed consent and ethics-committee oversight.
However, prenatal dex is routinely given outside the research setting, as an off-label treatment. It is common - and perfectly legal - for doctors to use their own discretion when prescribing drugs off-label. Antiseizure drugs like topiramate are commonly prescribed to treat migraine headache pain, for example. The practice allows patients to receive valuable treatment for which the drug may not have been expressly approved and may never be - it takes money and drug-company interest, which are hard to come by, to conduct the large randomized controlled trials required for a new-use the Food and Drug Administration (FDA) approval of a drug that is already on the market.
But as doctors share information about a drug's perceived off-label benefits and lack of harm, it gets even harder to take a step back and launch a formal randomized controlled trial - considered the gold standard in medical research - because patients demand the treatment, and doctors say it would be unethical to withhold it from them or from control groups in clinical trials. "It's a risky and dangerous way to innovate," says prominent University of Pennsylvania bioethicist Arthur Caplan. "There's no systematic collection of information. So, yes, things do get proven this way, and it is a way to innovate, but it also can come at a cost of unnecessary expense and, sometimes, bad side effects."
It also enables doctors to do human research without gaining proper approval. All participants in human medical research are, by law, entitled to the protective oversight of an institutional review board (IRB), a committee that safeguards the interests of research volunteers and ensures they have been fully informed about the potential risks and benefits of an experimental treatment. If doctors are simply treating a patient with an off-label drug, they are not required to obtain written informed consent from patients. But if doctors give treatment with the intent to gain knowledge, they are technically doing research, which must receive IRB approval.
Ethicists say physicians may sometimes treat patients off-label, then decide later to launch a follow-up study; or, they do follow-up research on patients who have been treated by other doctors. In the process, they have converted these patients into unwitting research volunteers. Some doctors game the system this way, Caplan says, to avoid battles with IRBs.
Critics suspect that Mount Sinai's New, who has long championed prenatal dex and bills it as safe on her foundation website, has gamed the system. In a letter dated Feb. 2, 2010, a group of 36 bioethicists, including Alice Dreger, a professor of bioethics at Northwestern University, asked the FDA and the federal Office for Human Research Protections to investigate New's practices; the authors contend that the doctor has conducted follow-up studies on prenatal dex patients without receiving IRB approval for treatment trials. Dreger says she has also asked Weill Cornell Medical College, where New previously worked, and Mount Sinai Medical Center to investigate the matter.
New, who declined to be interviewed for this article, does not administer the treatment in her current practice - according to Mount Sinai Medical Center, she has prescribed it only once since joining the hospital in 2004 - but ethical concerns remain, Dreger says, if the doctor consults with patients, resulting in their being prescribed dex elsewhere, then follows up with them for research purposes. At a medical conference in January, where New presented data from her research on prenatal dex, the doctor refused to answer a fellow researcher's questions regarding her process of informed consent.
Clinical Trials vs. Legal Trials
For Langford's part, she says she is grateful to New for her help, even though her daughter, now 4 and healthy, was found not to have CAH.
But Jenny Westphal, 24, who took dexamethasone throughout her pregnancy at the recommendation of another doctor, says she feels misled. Like Langford she was not asked to give informed consent. Unlike Langford, however, her daughter, now 3, who has CAH, has also had serious and mysterious health problems since birth, including feeding disorders, that are not commonly associated with her adrenal-gland disorder.
In April, Westphal, who lives in Wisconsin, started doing research online and discovered there was some controversy over the treatment. "I was outraged, frustrated and confused. Confused, because no one had ever warned me about this. I wasn't given the chance to decide for myself, based on the risks and benefits, if I wanted the treatment or not," she says.
Westphal may never know whether her daughter's problems were caused by dexamethasone, though she will likely always believe they were. That is why so many similar situations, in which experimental drugs are prescribed off-label without informed consent rather than in clinical trials, wind up becoming case studies - not in scientific journals, but exactly where Westphal and her husband are considering taking theirs: to court.
Originally from http://news.yahoo.com/s/time/20100622/hl_time/08599199645300
By Crystal Phend, Senior Staff Writer, MedPage Today
Published: April 29, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Action Points
- Explain to interested patients that long-term glucocorticoid treatment may be part of the therapy for asthma, ulcerative colitis, kidney diseases, and rheumatologic disorders.
Patients on chronic glucocorticoid therapy often develop osteonecrosis of the hip, but injections of adrenocorticotropic hormone (ACTH) might prevent that devastating complication, a preclinical study showed.
Rabbits treated with depot methylprednisolone acetate (Depo Medrol) showed half as much necrotic surface area on the femoral head when also given the synthetic cosyntropin (Cortrosyn) form of ACTH (P<0.05), Mone Zaidi, MD, PhD, of the Mount Sinai School of Medicine in New York City, and colleagues found.
The protective effect weakened for deeper bone, with all rabbits in both groups showing focal necrotic spots.
But these deeper areas of necrosis were smaller and generally not consolidated in ACTH-treated rabbits compared with prominent consolidated areas of necrosis in those that got only the glucocorticoid, Zaidi's group reported online in the Proceedings of the National Academy of Sciences.
These results provide a rationale for extended use of cosyntropin to decrease the risk of osteonecrosis for human patients who have to be on long-term glucocorticoid treatment, they suggested.
"The results are very promising because this is the first proof-of-concept of any medical therapy" in this setting, Zaidi said in an interview.
The only treatment for this debilitating, painful condition has been surgical debridement, the researchers explained.
The rate of osteonecrosis of the hip induced by long-term glucocorticoid use isn't clear, but it is thought to account for about 10% of hip replacements in the U.S. each year, Zaidi noted.
The mechanism appears to be different than with osteoporosis from long-term glucocorticoid treatment, which occurs largely due to osteocyte apoptosis, his group wrote.
The researchers started looking into the the role of ACTH after noting that ACTH-producing adenomas result in a profound glucocorticoid excess but not osteonecrosis.
They gave rabbits 10 mg/kg depot methylprednisolone acetate, which consistently produced damage to bone in the femoral head within 28 days.
Half the rabbits also received 0.2 μg/kg ACTH in the form of subcutaneous cosyntropin injections daily, which normalized ACTH serum levels for about three hours.
Bone scans showed a small effect of ACTH on density of the femoral head: it was 10% greater with the hormone.
There was a highly significant approximately 50% reduction in the necrotic surface area in femora from the rabbits treated with MPA plus ACTH compared with those given the glucocorticoid alone.
The explanation for this and the other morphological results appeared to be that ACTH supported osteoblast activity, the researchers wrote.
Quantitative PCR indicated significantly greater vascular endothelial growth factor (VEGF) mRNA expression in bone marrow of rabbits that got ACTH compared with those on methylprednisolone alone.
VEGF might maintain viability of components of the bone matrix given its central role in bone development and homeostasis, Zaidi's group noted.
"The femoral head is a site of high bone turnover, with formation and resorption occurring continuously over a large fraction of the total surface area," they explained in the paper. "This surface area is also embedded with an extensive capillary network; this means that the maintenance and regeneration of capillaries requires support by molecules such as VEGF."
Further testing suggested that ACTH stimulated production of VEGF in osteoblasts, not monocytes, and that the glucocorticoid dexamethasone profoundly inhibited monocyte-induced VEGF production, "probably as one of several mechanisms that initiate osteonecrosis," the researchers wrote.
The effect of ACTH appeared VEGF-dependent in cell line experiments with ACTH-stimulated VEGF production apparently through the ACTH receptor MC2R.
The investigators didn't look at whether this mechanism is a normal feature of bone mass regulation in the absence of glucocorticoid treatment. They noted, though, that results from patients with familial glucocorticoid deficiency and adrenal Cushing's syndrome support "at least a small anabolic effect of ACTH, which seemingly counteracts the bone loss due to cortisol."
Zaidi said that because synthetic ACTH would be dosed to restore the naturally occurring hormone levels and is already in clinical use for testing adrenal sufficiency there shouldn't be any safety concerns with long-term use in patients on glucocorticoids.
However, the protective effect wouldn't extend to patients who already have developed osteonecrosis, he told MedPage Today.
"The idea is to prevent," he said in the interview. "Once that part of the bone is dead, I can't see any logical way to bring it back to life again."
The study was supported by grants from the National Institutes of Health and by the American Federation for Aging Research.
Primary source: Proceedings of the National Academy of Sciences
Source reference:
Zaidi M, et al "ACTH protects against glucocorticoid-induced osteonecrosis of bone" Proc Natl Acad Sci 2010; DOI:10.1073/pnas.0912176107
From http://www.medpagetoday.com/Orthopedics/Orthopedics/19823
Laparoscopic Resection is Inappropriate in Patients with Known or Suspected Adrenocortical Carcinoma
Free PreviewB. S. Miller1 
| (1) | Division of Endocrine Surgery, University of Michigan, 2920F Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA |
| (2) | Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA |
| (3) | Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University, Nashville, TN, USA |
Published online: 7 April 2010
| B. S. Miller Email: barbram@umich.edu |
Fulltext Preview (Small, Large)
Clinical Background
Adrenal insufficiency is defined as hypofunction of the adrenal gland with decreased or absent cortisol secretion.
Epidemiology
- Incidence – estimated at 5/100,000
- Sex – M:F, equal
Classification
- Primary or secondary insufficiency
Etiology
- Causes of primary adrenal insufficiency
- Autoimmune (Addison disease)
- Frequent association with other endocrine diseases
- Autoimmune polyendocrine syndromes
- Epidemiology
- Incidence – 1-2/100,000
- Age – usually in 30s
- Sex – M<F, 1:3
- Most frequent endocrine abnormality is adrenal insufficiency
- Type 1
- Addison disease
- Chronic mucocutaneous candidiasis
- Hypoparathyroidism
- Type 2
- Diabetes mellitus type 1 (DM1)
- Addison disease with hypothyroidism – Schmidt syndrome
- Epidemiology
- Both types 1 and 2 may also include:
- DM1
- Other autoimmune disorders – vitiligo, chronic atrophic gastritis, alopecia
- Autoimmune polyendocrine syndromes
- Autoantibodies to 21-hydroxylase are frequently present
- Frequent association with other endocrine diseases
- Anatomic destruction of the gland
- Surgical removal
- Bilateral hemorrhage into the gland
- Associated with anticoagulant therapy
- Invasion of the gland
- Metastatic cancer is extremely rare
- Infection
- Bacterial
- Tuberculosis
- Meningococcus (Waterhouse-Friderichsen) – rare
- Pseudomonas – rare
- Fungal – histoplasmosis, coccidioidomycosis
- Viral – cytomegalovirus (CMV), AIDS
- Bacterial
- Congenital adrenal hyperplasia (CAH)
- Autoimmune (Addison disease)
- Causes of secondary adrenal insufficiency
- Hypopituitarism
- Postpartum hemorrhage – Sheehan syndrome
- Pituitary radiation
- Pituitary surgery
- Acute interruption of prolonged corticosteroids
- Pituitary infiltrative disease – tuberculosis, sarcoidosis, Wegener granulomatosis
- Exogenous glucocorticoid administration
- Lymphocytic hypophysitis – may be part of autoimmune polyendocrine syndrome
- Hypopituitarism
Pathophysiology
- Primary – glucocorticoid and mineralocorticoid deficiency
- Secondary – only glucocorticoid deficiency
Clinical Presentation
- Insidious onset of fatigue, weakness, anorexia, nausea and emesis
- Cutaneous hyperpigmentation – diffuse tan, brown or bronzing
- Does not occur in secondary insufficiency
- Orthostatic hypotension
- Diarrhea, abdominal pain
- Acute presentation may occur in patients with mild adrenal insufficiency who are stressed (eg, critical illness, surgery)
- Mainly attributable to mineralocorticoid deficiency
- Hypotension which is unresponsive to fluids
Treatment
- Primary – glucocorticoids and mineralocorticoids in primary
- Secondary – glucocorticoids only
- Increase glucocorticoid dosing during acute illness
Diagnosis
- Indications for testing – presence of disease process associated with adrenal insufficiency and other symptoms consistent with adrenal insufficiency
- Laboratory testing
- Initial testing
- First, measure early morning serum cortisol
- Cortisol ≥5 µg/dL makes primary adrenal insufficiency less likely; however, if serious consideration is given to this diagnosis, perform stimulation testing
- Follow with adrenocorticotropic hormone (ACTH) testing
- If ACTH >300 pg/dL – adrenal failure likely
- If ACTH <10 pg/dL – pituitary failure likely
- If ACTH between 10 pg/dL and 300 pg/dL – administer ACHT (cosyntropin) stimulation test
- First, measure early morning serum cortisol
- Stimulation
- ACTH stimulation test – cortisol response to cosyntropin (250 µg followed by serial cortisol measures at 30 and 60 minutes)
- Cortisol <5 µg/dL – adrenal failure
- Cortisol >20 µg/dL – normal
- Cortisol ≤20 µg/dL but ≥5 µg/dL – evaluate for pituitary failure
- Pituitary failure stimulation testing
- Insulin tolerance testing (ITT)
- Metyrapone overnight testing
- CT/MRI anatomic location based on cortisol ratios (see Adrenal Insufficiency Testing Algorithm)
- ACTH stimulation test – cortisol response to cosyntropin (250 µg followed by serial cortisol measures at 30 and 60 minutes)
- Initial testing
- Imaging studies
- MRI/CT based on stimulation testing
- If stimulation testing or absolute cortisol suggests adrenal failure – MRI/CT of adrenal glands
- If stimulation testing suggests pituitary failure – MRI/CT of pituitary
Differential Diagnosis
- Bronchogenic carcinoma
- Hemochromatosis
- Peutz-Jeghers syndrome
- Tuberculosis
- Congenital adrenal hyperplasia
- Malnutrition
More at http://ow.ly/1wcRu