Mild Cases of Cushing’s Syndrome Present Diagnostic Challenges

By Tori Rodriguez, MA, LPC

 

In the early 20th century, the term “pluriglandular syndrome” was coined by Harvey Cushing to describe the disorder that results from chronic tissue exposure to excessive levels of glucocorticoids.1 Now called Cushing’s syndrome, the condition affects an estimated 10-15 million people annually, most often women and individuals between the ages of 20 and 50 years.2 Risk factors and common comorbidities include hypertension, obesity, osteoporosis, uncontrolled diabetes, depression, and anxiety.3

Presentation

The clinical presentation of the disorder is heterogenous and varies by sex, age, and disease severity. Common signs and symptoms include central adiposity, roundness of the face or extra fat around the neck, thin skin, impaired short-term memory and concentration, irritability, hirsutism in women, fatigue, and menstrual irregularity.4 Because each of these features may be observed in a wide range of other conditions, it may be difficult to diagnose cases that are not severe.

“It can be challenging to differentiate the milder forms from pseudo-Cushing’s states,” which are characterized by altered cortisol production and many of the same clinical features as Cushing’s syndrome, according to Roberto Salvatori, MD, the medical director of the Johns Hopkins Pituitary Center, Baltimore, Maryland. These may include alcoholism, obesity, eating disorders, and depression. “Because Cushing’s can cause depression, for example, it is sometimes difficult to determine which came first,” he says. In these states, however, hypercortisolism is believed to be driven by increased secretion of hypothalamic corticotropin-releasing hormone, which is suppressed in Cushing’s syndrome.5

Causes and Diagnosis

If Cushing’s syndrome is suspected on the basis of the patient’s physical appearance, the diagnostic workup should include a thorough medical history, physical exam, and 1 or more of the following tests to establish hypercortisolism: the 24-hour urinary cortisol test, the low-dose dexamethasone suppression test, or the late-night salivary cortisol test. “We sometimes use 2 or 3 of these tests since 1 may not accurately reflect cortisol production in a particular patient,” Dr Salvatori notes. The next step is to determine the source of the hypercortisolism, which may involve the high-dose dexamethasone suppression test, magnetic resonance imaging, or petrosal sinus sampling.2

Medication is the most common cause of Cushing’s syndrome. These iatrogenic or exogenous cases typically result from corticosteroids administered for conditions such as asthma, allergies, and autoimmune disorders.6 More rarely, the disorder can be caused by the use of medroxyprogesterone. In these cases, corticosteroids should be reduced or discontinued under medical care, if possible.

Endogenous Cushing’s syndrome results from the presence of benign or malignant tumors on the adrenal or pituitary glands or elsewhere in the body. These tumors can interfere with the adrenal glands’ production of cortisol that is usually prompted by the adrenocorticotropic hormone (ACTH) released by the pituitary gland.6 There are 3 different mechanisms by which the process can occur.

  • Pituitary adenomas, which account for approximately 70% of endogenous cases of Cushing’s syndrome, secrete ACTH and stimulate additional cortisol production. Because of the large proportion of cases this condition represents, it is specifically referred to as Cushing’s disease. It is more common in women than men (with a ratio of 3 to 4:1), although in pediatric patients, it occurs more frequently in boys vs girls.5
  • Adrenal tumors (adenomas, malignant tumors, or micronodular hyperplasia) produce cortisol in their own tissue in addition to the amount produced by the adrenal glands. These tumors, which cause approximately 15% of endogenous Cushing’s syndrome cases, are more common in children vs adults and in women vs men.
  • Benign or malignant tumors elsewhere in the body, most often the lungs, thyroid, thymus, and pancreas, secrete ACTH and trigger the excessive release of cortisol. An estimated 15% of endogenous cases are attributed to these types of tumors.

Treatment

Surgery is the first-line treatment for Cushing’s syndrome. “We first want to try to figure out the cause of the disorder,” Dr Salvatori says. “Ideally, treatment involves surgery to remove the tumor that is causing it.”

When surgery is unsuccessful, contraindicated, or delayed, other treatment options include radiation or medications that inhibit cortisol, modulate the release of ACTH, or inhibit steroidogenesis.5 Bilateral adrenalectomy may be indicated for patients who do not respond to medication or other surgery.

If surgical resection of the tumor is successful, then “all of the comorbidities reverse, but if it is unsuccessful or must be delayed, you would treat each comorbidity” with the appropriate medication; for example, antihypertensives for high blood pressure and antidiabetic medications for diabetes, Dr Salvatori advises. In severe cases, prophylactic antibiotics may be indicated for the prevention of severe infections such as pneumonia.

It is also important to inquire about and address psychiatric symptoms related to Cushing’s syndrome, even in patients who are in remission. It has been proposed that the chronic hypercortisolism and dysfunction of the HPA axis may “lead to structural and functional changes in the central nervous system, developing brain atrophy, particularly in the hippocampus, which may determine the high prevalence of psychiatric disorders, such as affective and anxiety disorders or cognitive dysfunctions,” according to a recently published paper on the topic.7 Patients should be screened with self-report questionnaires such as the Beck Depression Inventory and the Hospital Anxiety and Depression Scale, and management of psychiatric symptoms may include patient education, psychotropic medications, and referral to a mental health professional.

Future Directions

Several trials are currently planned or underway, including a phase 2 randomized, double-blind, placebo-controlled study of an oral medication called ATR-101 by Millendo Therapeutics, Inc. (ClinicalTrials.gov identifier: NCT03053271). In addition to the need for novel medical therapies, refined imaging techniques could improve surgical success rates in patients with Cushing’s disease in particular, according to Dr Salvatori. “A significant portion of these patients have tumors too small to be detected by MRI, and the development of more sensitive MRI could improve detection and provide a surgical target” for neurosurgeons treating the patients, he says.

Summary

Milder cases of Cushing’s syndrome present diagnostic challenges are a result overlapping features with various other conditions. Diagnosis may require careful observation as well as biochemical and imaging tests.

References

  1. Loriaux DL. Diagnosis and differential diagnosis of Cushing’s syndromeN Engl J Med. 2017;376:1451-1459. doi:10.1056/NEJMra1505550
  2. American Association of Neurological Surgeons. Cushing’s syndrome/disease. http://www.aans.org/Patients/Neurosurgical-Conditions-and-Treatments/Cushings-Disease. Accessed August 1, 2017.
  3. León-Justel A, Madrazo-Atutxa A, Alvarez-Rios AI, et al. A probabilistic model for cushing’s syndrome screening in at-risk populations: a prospective multicenter studyJ Clin Endocrinol Metab. 2016;101:3747-3754. doi:10.1210/jc.2016-1673
  4. The Pituitary Society. Cushing’s syndrome and disease–symptoms. https://pituitarysociety.org/patient-education/pituitary-disorders/cushings/symptoms-of-cushings-disease-and-cushings-syndrome. Accessed August 1, 2017.
  5. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease managementClin Epidemiol. 2015;7:281-293. doi:10.2147/CLEP.S44336
  6. National Institutes of Health: Eunice Kennedy Shriver National Institute of Child Health and Human Development. What causes Cushing’s syndrome?https://www.nichd.nih.gov/health/topics/cushing/conditioninfo/pages/causes.aspx. Accessed August 1, 2017.
  7. Santos A, Resmini E, Pascual JC, Crespo I, Webb SM. Psychiatric symptoms in patients with Cushing’s syndrome: prevalence, diagnosis and management. Drugs. 2017;77:829-842. doi:10.1007/s40265-017-0735-z

From http://www.endocrinologyadvisor.com/adrenal/cushings-syndrome-diagnosis-treatment/article/682302/

Cataloging Cushing’s Patients

The Cushing/Whitney Medical Library is pleased to announce the completion of a grant funded to catalog 2,600 glass plate negatives from the Cushing Brain Tumor Registry.  The grant proposal, “Rethinking Early Neurosurgery: The Harvey Cushing Collection,” was funded through a National Network of Libraries of Medicine-New England Region Knowledge/Data Management Award.  From mid-February through April 30th 2017,  a team of graduate and undergraduate students carefully inputted information on over 3,000 glass plate negatives into the Cushing Center database, exceeding the estimated amount in the grant. The negatives depict Dr. Harvey Cushing’s patients, including histology.

Harvey Cushing, the pioneer and father of neurosurgery, was born on April 8, 1869 in Cleveland, Ohio. He graduated from Yale University in 1891, studied medicine at Harvard Medical School and received his medical degree in 1895. In 1896, he moved to Johns Hopkins Hospital where he trained to become a surgeon under the watchful eye of William S. Halstead, the father of American surgery. By 1899 Cushing became interested in surgery of the nervous system and began his career in neurosurgery. During his tenure at Johns Hopkins, there were countless discoveries in the field of neuroscience.

In 1913, Cushing relocated to Harvard as the surgeon-in-chief at the new Peter Bent Brigham Hospital. Cushing continued to operate on several hundred patients a year with remarkable results.  In addition he was relentless in his recording of patient histories and continued his careful attention to the details and documentation of each surgery.

In 1932 Harvey Cushing retired and in 1933 he agreed to join the staff at Yale University, his alma mater, as the Sterling Professor of Medicine in Neurology.  Cushing died in 1939.

The negatives are undergoing rehousing and digitization, and will be made available for research through the Cushing Center database, which brings multiple parts of Harvey Cushing’s work together in one place.  The database, still in development, will allow researchers to explore Cushing’s medical work and patients.  Please contact Terry Dagradi, Cushing Center Coordinator, for details.

 

From http://library.medicine.yale.edu/blog/cushing-center/cataloging-cushings-patients

Diagnosis and Differential Diagnosis of Cushing’s Syndrome

D. Lynn Loriaux, M.D., Ph.D.

N Engl J Med 2017; 376:1451-1459April 13, 2017DOI: 10.1056/NEJMra1505550

More than a century ago, Harvey Cushing introduced the term “pluriglandular syndrome” to describe a disorder characterized by rapid development of central obesity, arterial hypertension, proximal muscle weakness, diabetes mellitus, oligomenorrhea, hirsutism, thin skin, and ecchymoses.1 Cushing knew that this syndrome was associated with adrenal cancer,2 and he suspected that some cases might have a pituitary component.

On September 6, 1911, he performed a craniotomy on one of his patients (referred to as Case XLV) but found no pituitary tumor.3 In his description of the case, he goes on to say that “we may perchance be on the way toward the recognition of the consequences of hyperadrenalism.”2 With time, it became clear that the disorder could be caused by small basophilic adenomas of the pituitary gland,4 and the pluriglandular syndrome became known as Cushing’s syndrome.

Fuller Albright provided the next conceptual advance in an extraordinary report, published in the first volume of the Laurentian Hormone Conference, “The Effects of Hormones on Osteogenesis in Man”5:

It has been our concept that protoplasm in general, like the protoplasmic matrix of bone, is constantly being anabolized and catabolized at one and the same time; a factor which increases catabolism would lead to very much the same net result as a factor which inhibits anabolism, but there would be some differences; it is my belief that the “S” hormone [cortisol] is anti-anabolic rather than catabolic. . . . The anti-anabolism . . . is contrasted with the increased anabolism due to an excess of the “N” hormone [testosterone] in the adreno-genital syndrome. This anti-anabolism of protoplasm in Cushing’s syndrome accounts for not only the osteoporosis, but the muscular weakness, the thin skin, probably the easy bruisability, and possibly the atrophy of the lymphoid tissues and thymus.

Nonetheless, in the intervening years, the physical examination of patients suspected to have glucocorticoid excess focused on the anabolic changes, essentially to the exclusion of the antianabolic changes. With the rapid increase in the rate of obesity in the general population, Cushing’s syndrome can no longer be reliably separated from the metabolic syndrome of simple obesity on the basis of anabolic signs alone. However, the antianabolic changes in Cushing’s syndrome are very effective in making this distinction. This review focuses on the problems introduced into the diagnosis and differential diagnosis of Cushing’s syndrome by the obesity epidemic and on ways to alter the traditional approach, using the antianabolic changes of excess cortisol to separate patients with Cushing’s syndrome from obese patients with the insulin-resistant metabolic syndrome.

PHYSICAL EXAMINATION

Andreas Vesalius (1514–1564) published his transformational work on human anatomy, De Humani Corporis Fabrica Libri Septem, in 1543. It is the book that corrected many of Galen’s anatomical errors. The book was met with considerable hostility. As an example, Jacobus Sylvius (Jacques Dubois, 1478–1555), the world’s leading anatomist at the time and Vesalius’s former mentor, on being asked his opinion of the work, replied, “Galen is not wrong. It is man that has changed, and not for the better.”6 This was not true then, but it is true now.

Approximately one third of the U.S. population is obese. The worldwide prevalence of the metabolic syndrome among obese persons is conservatively estimated at 10%; that is, approximately 12 million people have the obesity-related metabolic syndrome.7,8 The clinical picture of this syndrome is almost the same as that of Cushing’s syndrome.9,10 The prevalence of undiagnosed Cushing’s syndrome is about 75 cases per 1 million population, or 24,000 affected persons. On the basis of these prevalence estimates, the chance that a person with obesity, hypertension, hirsutism, type 2 diabetes, and dyslipidemia has Cushing’s syndrome is about 1 in 500. In Harvey Cushing’s era, when obesity was rare, making the diagnosis of Cushing’s syndrome was the most certain aspect of the management of this disorder. Today, making the diagnosis is the least certain aspect in the care of patients with Cushing’s syndrome.

The metabolic syndrome caused by glucocorticoid hypersecretion can be differentiated from the obesity-associated metabolic syndrome with the use of a careful assessment of Albright’s antianabolic effects of cortisol. These effects — osteopenia, thin skin, and ecchymoses — are present in patients with Cushing’s syndrome but not in patients with simple obesity.

Patients in whom osteoporosis is diagnosed radiographically are more likely to have Cushing’s syndrome than those who do not have osteoporosis, with a positive likelihood ratio of 11.11-13 Today, a z score of −2 at the lumbar spine supports this criterion. Skinfold thickness is conveniently measured with an electrocardiographic caliper that has the points dulled with a sharpening stone and the screws tightened so that the gap is maintained when the caliper is removed from the skinfold. The skin over the proximal phalanx of the middle finger of the nondominant hand is commonly used for this measurement

 

(Figure 1 FIGURE 1Measurement of Skinfold Thickness.). A thickness of less than 2 mm is considered to be thin skin. Patients who have thin skin are more likely to have Cushing’s syndrome, with a positive likelihood ratio of 116

 

(Figure 2 FIGURE 2 Comparison of Skinfold Thickness in Patients with Cushing’s Syndrome and Those with Other Conditions Related to Insulin Resistance.).13-15 Finally, patients who have three or more ecchymoses that are larger than 1 cm in diameter and not associated with trauma such as venipuncture are more likely to have Cushing’s syndrome than are patients without such findings, with a positive likelihood ratio of 4.13,16

If we know the prevalence of undiagnosed Cushing’s syndrome in the population of persons with the obesity-related metabolic syndrome, we can begin to calculate the probability that a person has Cushing’s syndrome, using the likelihood ratios for the antianabolic features observed on physical examination. Likelihood ratios can be converted into probabilities with the use of Bayes’ theorem. This conversion is markedly facilitated by the Fagan nomogram for this purpose.17

The prevalence of undiagnosed Cushing’s syndrome is not known, but it can be estimated. Two persons per 1 million population die from adrenal cancer every year.18 The current life span for patients with adrenocortical carcinoma, after diagnosis, is between 2 and 4 years.19,20 Allowing 3 years to make the diagnosis, the prevalence of undiagnosed Cushing’s syndrome is 6 cases per million. In most case series of Cushing’s syndrome, an average of 8% of patients have adrenal carcinoma.21 If 6 per million is 8% of the group, the total Cushing’s syndrome group is 75 persons per million, or 24,000 persons. If all 24,000 patients are included in the metabolic syndrome group, comprising 12 million people, the prevalence of Cushing’s syndrome is 0.002, or 0.2%. With a probability of 0.2% and a likelihood ratio of 116 for thin skin, 18 for osteopenia, and 4 for ecchymoses, the probability that a patient with these three findings has Cushing’s syndrome is 95%.

URINARY FREE CORTISOL

The diagnosis of all endocrine diseases requires a clinical presentation that is compatible with the disease, as well as identification of the pathophysiological cause. An assessment for excess glucocorticoid effects can be made by measuring the 24-hour urinary free cortisol level.22 There are two kinds of free cortisol: plasma protein-unbound cortisol and cortisol unconjugated to sulfuric or hyaluronic acid. Protein-unbound cortisol is filtered in the glomerulus and then reabsorbed in the collecting system. About 3% of filtered cortisol ends up in the urine. This free cortisol in the urine is unconjugated. Thus, the urinary free cortisol level is a direct reflection of the free, bioactive cortisol level in plasma. The free cortisol level is quantified in a 24-hour urine sample by averaging the increased secretion of cortisol in the morning and the decreased secretion in the afternoon and at night. Urinary creatinine is also measured to determine whether the collection is complete. Creatinine levels of less than 1.5 g per day for men and less than 1 g per day for women indicate incomplete collection, and the test should be repeated in patients with these levels.

Unconjugated cortisol can be extracted directly from urine with a nonpolar lipid solvent. After extraction, the cortisol is purified by means of high-pressure liquid chromatography and then quantified with a binding assay, usually radioimmunoassay. Free cortisol also can be quantitated directly by means of mass spectroscopy. The urinary free cortisol assay of choice uses high-pressure liquid chromatographic separation followed by mass spectrometric quantitation.23 With the use of this assay, the urinary free cortisol level in healthy adults ranges from 8 to 51 μg per 24 hours (mean [±SD], 23±8). Clinical depression increases urinary free cortisol excretion, and most studies show that the level of urinary free cortisol ranges from 10 to 60 μg per day in patients with typical clinical signs and symptoms of depression. If we use 60 μg per day as the cutoff between normal values (<60 μg per day) and elevated values (≥60 μg per day), urinary free cortisol excretion of 62 μg per day or more has a positive likelihood ratio of 11.24 Thus, in a patient presenting with obesity, hypertension, type 2 diabetes, and hirsutism who has thin skin, osteopenia, ecchymoses, and an elevated urinary free cortisol level, the probability of Cushing’s syndrome is 1 (100%). For such patients, the clinician should move directly to a differential diagnostic evaluation.

DEXAMETHASONE-SUPPRESSION TEST

The dexamethasone-suppression test is commonly used in the diagnosis of Cushing’s syndrome. This test was developed by Grant Liddle in the early 1960s as a differential diagnostic test to separate corticotropin-dependent from corticotropin-independent Cushing’s syndrome. This is now done by measuring the plasma corticotropin level. Unfortunately, dexamethasone suppression has continued to be used as a screening test for Cushing’s syndrome.

The control group for this test comprises patients with obesity and depression in whom cortisol secretion is not suppressed in response to an oral dose of 1 mg of dexamethasone at midnight. Of the current U.S. population of 360 million people, approximately one third (120 million people) are obese. Of those who are obese, 10% (12 million people) have depression. In half these patients (6 million people), the plasma cortisol level will not be suppressed in response to a dexamethasone challenge. On the basis of my estimate of the current prevalence of undiagnosed Cushing’s syndrome (24,000 cases) and the estimate of the at-risk population (6 million persons), the positive predictive value of the dexamethasone-suppression test is only 0.4%. Thus, this test should not influence what the physician does next and should no longer be used for this purpose.

OUTLIERS

For patients with convincing evidence of Cushing’s syndrome on physical examination and an elevated 24-hour urinary free cortisol level, the differential diagnostic process outlined below should be initiated. However, a small group of patients will not meet these criteria.

Some patients have a strongly positive physical examination but low or zero urinary free cortisol excretion. Plasma corticotropin levels are suppressed in these patients. These patients are receiving exogenous glucocorticoids. The glucocorticoid must be identified, and a plan must be made for its discontinuation. Sometimes the glucocorticoid is being given by proxy (e.g., by a parent to a child), and no history of glucocorticoid administration can be found. Nevertheless, the glucocorticoid must be identified and discontinued.

Other patients have few or no clinical signs of Cushing’s syndrome but do have elevated urinary free cortisol excretion. Plasma corticotropin is measurable in these patients. They are usually identified during an evaluation for arterial hypertension. All such patients should undergo inferior petrosal sinus sampling to determine the source of corticotropin secretion. Ectopic sources are almost always neoplastic and are usually in the chest.25 Patients with eutopic secretion usually have the syndrome of generalized glucocorticoid resistance.26

Finally, a few patients have convincing findings on physical examination coupled with a normal urinary free cortisol level. In such cases, the clinician should make sure that urinary free cortisol is being measured with high-performance liquid chromatography and mass spectrometry, that renal function is normal, and that the collections are complete. “Periodic” Cushing’s syndrome must be ruled out by measuring urinary free cortisol frequently over the course of a month.27 If these efforts fail, the patient should be followed for a year, with urinary free cortisol measurements performed frequently. No additional tests should be performed until the situation is sorted out. More tests would be likely to lead to an unnecessary surgical procedure.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of Cushing’s syndrome is shown in Figure 3

FIGURE 3Differential Diagnosis of Cushing’s Syndrome.. If plasma corticotropin is measurable, the disease process is corticotropin-dependent. If corticotropin is not measurable, the process is corticotropin-independent.

Corticotropin-dependent causes of Cushing’s syndrome are divided into those in which the corticotropin comes from the pituitary (eutopic causes) and those in which the corticotropin comes from elsewhere (ectopic causes). This differentiation is made with the measurement of corticotropin in inferior petrosal sinus plasma and the simultaneous measurement of corticotropin in peripheral (antecubital) plasma immediately after corticotropin-releasing hormone stimulation of pituitary corticotropin secretion. In samples obtained 4, 6, and 15 minutes after stimulation with corticotropin-releasing hormone, eutopic corticotropin secretion is associated with a ratio of the central-plasma corticotropin level to the peripheral-plasma corticotropin level of 3 or more. Ectopic corticotropin secretion is associated with a central-to-peripheral corticotropin ratio of less than 3. The positive predictive value of this test is 1 (Figure 4

FIGURE 4Maximal Ratio of Corticotropin in Inferior Petrosal Sinus Plasma to Corticotropin in Peripheral Plasma in Patients with Cushing’s Syndrome, Ectopic Corticotropin Secretion, or Adrenal Disease.).28

Although some authorities suggest that inferior petrosal sinus sampling can safely be bypassed in patients with corticotropin-dependent Cushing’s syndrome and a well-defined pituitary adenoma, I disagree. The incidence of nonfunctioning pituitary microadenomas is between 15% and 40%.29 This means that up to 40% of patients with ectopic secretion of corticotropin have an incidental pituitary abnormality. If it is assumed that the pituitary abnormality is responsible for corticotropin secretion, 15 to 40% of patients with ectopic secretion of corticotropin will be misdiagnosed and submitted to a transsphenoidal exploration of the sella turcica and pituitary gland. The prevalence of ectopic corticotropin secretion in the population of patients with undiagnosed Cushing’s syndrome is about 10%, accounting for 2400 patients. Up to 40% of these patients, or 960, have an incidental pituitary tumor. The mortality associated with transsphenoidal microadenomectomy is 1%.30 If all 360 to 960 patients undergo this procedure, there will be up to 10 deaths from an operation that can have no benefit. For this reason alone, all patients with corticotropin-dependent Cushing’s syndrome should undergo inferior petrosal sinus sampling to confirm the source of corticotropin secretion before any surgical intervention is contemplated.

Patients with eutopic corticotropin secretion are almost certain to have a corticotropin-secreting pituitary microadenoma. An occasional patient will have alcohol-induced pseudo–Cushing’s syndrome. The slightest suggestion of alcoholism should lead to a 3-week abstinence period before any surgery is considered.31

Patients with ectopic corticotropin secretion are first evaluated with computed tomography (CT) or magnetic resonance imaging (MRI) of the chest. In two thirds of these patients, a tumor will be found.25 If nothing is found in the chest, MRI of the abdominal and pelvic organs is performed. If these additional imaging studies are also negative, there are two options: bilateral adrenalectomy or blockade of cortisol synthesis. If blockade is chosen, the patient should undergo repeat scanning at 6-month intervals.32 If no source is found by the end of the second year, it is unlikely that the source will ever be found, and bilateral adrenalectomy should be performed for definitive treatment (Doppman JL: personal communication).

Corticotropin-independent Cushing’s syndrome is usually caused by an adrenal neoplasm. Benign tumors tend to be small (<5 cm in diameter) and secrete a single hormone, cortisol. The contralateral adrenal gland is suppressed by the cortisol secreted from the tumorous gland. If the value for Hounsfield units is less than 10 and the washout of contrast material is greater than 60% at 15 minutes, the tumor is almost certainly benign.33 Such tumors can be treated successfully with laparoscopic adrenalectomy.

The syndromes of micronodular and macronodular adrenal dysplasia usually affect both adrenal glands. The nodules secrete cortisol. Corticotropin is suppressed, as is the internodular tissue of the adrenal glands. Percutaneous bilateral adrenalectomy, followed by glucocorticoid and mineralocorticoid treatment, is curative.

Adrenal tumors secreting more than one hormone (i.e., cortisol and androgen or estrogen) are almost always malignant. Surgical removal of all detectable disease is indicated, as is a careful search for metastases. If metastases are found, they should be removed. This usually requires an open adrenalectomy. It goes without saying that adrenal tumors, nodules, and metastases should be treated by the most experienced endocrine cancer surgeon available.

If the plasma cortisol level on the morning after a transsphenoidal microadenomectomy is 0, the operation was a success. The patient should be treated with oral hydrocortisone, at a dose of 12 mg per square meter of body-surface area once a day in the morning, and a tetracosactide (Cortrosyn) stimulation test should be performed at 3-month intervals. When the tetracosactide-stimulated plasma cortisol level is higher than 20 μg per deciliter (551 μmol per liter), cortisol administration can be stopped. The same rule applies in the case of a unilateral adrenalectomy. If the adrenalectomy is bilateral, cortisol, at a dose of 12 to 15 mg per square meter per day, and fludrocortisone (Florinef), at a dose of 100 μg per day, should be prescribed as lifelong therapy.

SUMMARY

The obesity epidemic has led to necessary changes in the evaluation and treatment of patients with Cushing’s syndrome. The most dramatic change is the emphasis on the antianabolic alterations in Cushing’s syndrome, which can provide a strong basis for separating patients with Cushing’s syndrome from the more numerous patients with obesity and the metabolic syndrome. More can be done along these lines. Likelihood ratios are known for proximal muscle weakness and can be known for brain atrophy and growth failure in children.

The dexamethasone-suppression test, although still very popular, no longer has a role in the evaluation and treatment of patients with Cushing’s syndrome. Only three biochemical tests are needed: urinary free cortisol, plasma corticotropin, and plasma cortisol measurements. Urinary free cortisol excretion is the test that confirms the clinical diagnosis of Cushing’s syndrome. To be trustworthy, it must be performed in the most stringent way, with the use of high-pressure liquid chromatography followed by mass spectrometric quantitation of cortisol. Measurement of plasma corticotropin is used to separate corticotropin-dependent from corticotropin-independent causes of Cushing’s syndrome and to separate eutopic from ectopic secretion of corticotropin. Inferior petrosal sinus sampling should be performed in all patients with corticotropin-dependent Cushing’s syndrome because of the high prevalence of nonfunctioning incidental pituitary adenomas among such patients. Measurement of plasma cortisol has only one use: determining the success or failure of transsphenoidal microadenomectomy or adrenalectomy. If the plasma cortisol level is not measurable on the morning after the operation (<5 μg per deciliter [138 μmol per liter]), the procedure was a success; if it is measurable, the operation failed. The surgeon must not administer intraoperative or postoperative synthetic glucocorticoids until the plasma cortisol level has been measured.

Successful evaluation of a patient who is suspected of having Cushing’s syndrome requires an endocrinologist who is skilled in physical diagnosis. Also required is a laboratory that measures urinary free cortisol using high-performance liquid chromatography and mass spectrometry and that can measure plasma cortisol and plasma corticotropin by means of radioimmunoassay.

Inferior petrosal sinus sampling is performed by an interventional radiologist. The treatment for all causes of Cushing’s syndrome, other than exogenous glucocorticoids, is surgical, and neurosurgeons, endocrine surgeons, and cancer surgeons are needed. This level of multidisciplinary medical expertise is usually found only at academic medical centers. Thus, most, if not all, patients with Cushing’s syndrome should be referred to such a center for treatment.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

SOURCE INFORMATION

From the Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, Portland.

Address reprint requests to Dr. Loriaux at the Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., L607, Portland, OR 97239-3098, or at .

From http://www.nejm.org/doi/full/10.1056/NEJMra1505550

Straight Talk Cushing’s

awareness

 

On April 8th, people from around the world unite in support of Cushing’s Disease Awareness Day.

In this animated video, learn more about Cushing’s disease, including the mechanism of disease, clinical manifestations, symptoms and diagnosis challenges.

Day 8, Cushing’s Awareness Challenge 2016

It’s Here!

Dr. Cushing was born in Cleveland Ohio. The fourth generation in his family to become a physician, he showed great promise at Harvard Medical School and in his residency at Johns Hopkins Hospital (1896 to 1900), where he learned cerebral surgery under William S. Halsted.

After studying a year in Europe, he introduced the blood pressure sphygmomanometer to the U.S.A. He began a surgical practice in Baltimore while teaching at Johns Hopkins Hospital (1901 to 1911), and gained a national reputation for operations such as the removal of brain tumors. From 1912 until 1932 he was a professor of surgery at Harvard Medical School and surgeon in chief at Peter Bent Brigham Hospital in Boston, with time off during World War I to perform surgery for the U.S. forces in France; out of this experience came his major paper on wartime brain injuries (1918). In addition to his pioneering work in performing and teaching brain surgery, he was the reigning expert on the pituitary gland since his 1912 publication on the subject; later he discovered the condition of the pituitary now known as “Cushing’s disease“.

Read more about Dr. Cushing

Today, April 8th, is Cushing’s Awareness Day. Please wear your Cushing’s ribbons, t-shirts, awareness bracelets or Cushing’s colors (blue and yellow) and hand out Robin’s wonderful Awareness Cards to get a discussion going with anyone who will listen.

And don’t just raise awareness on April 8.  Any day is a good day to raise awareness.


harvey-book

I found this biography fascinating!

I found Dr. Cushing’s life to be most interesting. I had previously known of him mainly because his name is associated with a disease I had – Cushing’s. This book doesn’t talk nearly enough about how he came to discover the causes of Cushing’s disease, but I found it to be a valuable resource, anyway.
I was so surprised to learn of all the “firsts” Dr. Cushing brought to medicine and the improvements that came about because of him. Dr. Cushing introduced the blood pressure sphygmomanometer to America, and was a pioneer in the use of X-rays.

He even won a Pulitzer Prize. Not for medicine, but for writing the biography of another Doctor (Sir William Osler).

Before his day, nearly all brain tumor patients died. He was able to get the number down to only 5%, unheard of in the early 1900s.

This is a very good book to read if you want to learn more about this most interesting, influential and innovative brain surgeon.


What Would Harvey Say?

 

harvey-book

(BPT) – More than 80 years ago renowned neurosurgeon, Dr. Harvey Cushing, discovered a tumor on the pituitary gland as the cause of a serious, hormone disorder that leads to dramatic physical changes in the body in addition to life-threatening health concerns. The discovery was so profound it came to be known as Cushing’s disease. While much has been learned about Cushing’s disease since the 1930s, awareness of this rare pituitary condition is still low and people often struggle for years before finding the right diagnosis.

Read on to meet the man behind the discovery and get his perspective on the present state of Cushing’s disease.

* What would Harvey Cushing say about the time it takes for people with Cushing’s disease to receive an accurate diagnosis?

Cushing’s disease still takes too long to diagnose!

Despite advances in modern technology, the time to diagnosis for a person with Cushing’s disease is on average six years. This is partly due to the fact that symptoms, which may include facial rounding, thin skin and easy bruising, excess body and facial hair and central obesity, can be easily mistaken for other conditions. Further awareness of the disease is needed as early diagnosis has the potential to lead to a more favorable outcome for people with the condition.

* What would Harvey Cushing say about the advances made in how the disease is diagnosed?

Significant progress has been made as several options are now available for physicians to use in diagnosing Cushing’s disease.

In addition to routine blood work and urine testing, health care professionals are now also able to test for biochemical markers – molecules that are found in certain parts of the body including blood and urine and can help to identify the presence of a disease or condition.

* What would Harvey Cushing say about disease management for those with Cushing’s disease today?

Patients now have choices but more research is still needed.

There are a variety of disease management options for those living with Cushing’s disease today. The first line and most common management approach for Cushing’s disease is the surgical removal of the tumor. However, there are other management options, such as medication and radiation that may be considered for patients when surgery is not appropriate or effective.

* What would Harvey Cushing say about the importance of ongoing monitoring in patients with Cushing’s disease?

Routine check-ups and ongoing monitoring are key to successfully managing Cushing’s disease.

The same tests used in diagnosing Cushing’s disease, along with imaging tests and clinical suspicion, are used to assess patients’ hormone levels and monitor for signs and symptoms of a relapse. Unfortunately, more than a third of patients experience a relapse in the condition so even patients who have been surgically treated require careful long-term follow up.

* What would Harvey Cushing say about Cushing’s disease patient care?

Cushing’s disease is complex and the best approach for patients is a multidisciplinary team of health care professionals working together guiding patient care.

Whereas years ago patients may have only worked with a neurosurgeon, today patients are typically treated by a variety of health care professionals including endocrinologists, neurologists, radiologists, mental health professionals and nurses. We are much more aware of the psychosocial impact of Cushing’s disease and patients now have access to mental health professionals, literature, patient advocacy groups and support groups to help them manage the emotional aspects of the disease.

Learn More

Novartis is committed to helping transform the care of rare pituitary conditions and bringing meaningful solutions to people living with Cushing’s disease. Recognizing the need for increased awareness, Novartis developed the “What Would Harvey Cushing Say?” educational initiative that provides hypothetical responses from Dr. Cushing about various aspects of Cushing’s disease management based on the Endocrine Society’s Clinical Guidelines.

For more information about Cushing’s disease, visit www.CushingsDisease.com or watch educational Cushing’s disease videos on the Novartis YouTube channel at www.youtube.com/Novartis.

From http://www.jsonline.com/sponsoredarticles/health-wellness/what-would-harvey-cushing-say-about-cushings-disease-today8087390508-253383751.html

 

MaryO

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