Health Care Expenditure Burden High in Adrenal Insufficiency

Patients with adrenal insufficiency may accrue substantial health care costs and have more hospital stays and outpatient visits compared with healthy controls, according to findings published in the Journal of the Endocrine Society.

Candace Gunnarsson, PhD, vice president of health economics and outcomes research at CTI Clinical Trial and Consulting in Cincinnati, and colleagues evaluated data from a U.S.-based payer database on 10,383 patients with adrenal insufficiency to determine the estimated annual health care burden among them.

Participants were divided into groups based on their type of adrenal insufficiency: primary adrenal insufficiency (n = 1,014), adrenal insufficiency secondary to pituitary disease (n = 8,818) or congenital adrenal hyperplasia (n = 551). A group of matched controls was also evaluated for comparison.

Total annual health care expenditures were significantly higher in the primary adrenal insufficiency group ($18,624 vs. $4,320), adrenal insufficiency secondary to pituitary disease group ($32,218 vs. $6,956) and the congenital adrenal hyperplasia group ($7,677 vs. $4,203) compared with controls. The adrenal insufficiency secondary to pituitary disease group had the highest health care expenditure estimated with an incremental health care burden of $25,262, followed by the primary adrenal insufficiency group ($14,304) and the congenital adrenal hyperplasia group ($3,474).

Compared with controls, participants with adrenal insufficiency spent eight to 10 times more days in the hospital and had up to twice as many outpatient visits per year.

“When comparing [adrenal insufficiency] patients within each cohort based on their drug regimen, patients receiving prednisone therapy vs. hydrocortisone therapy had significantly higher total annual expenditures in the [primary adrenal insufficiency] and [congenital adrenal hyperplasia] and significantly lower total expenditures in the [pituitary disease] cohort,” the researchers wrote. “Patients taking only hydrocortisone and meeting the threshold of 50% adherence were found to have lower expenditures when medication adherence was 75% or higher.” – by Amber Cox

Disclosure: Gunnarsson reports being an employee of CTI Clinical Trial and Consulting. Please see the full study for a list of all other authors’ relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B8f92bd0c-0c72-4902-beb5-663c356a61cb%7D/health-care-expenditure-burden-high-in-adrenal-insufficiency

Lower health-related quality of life observed in patients with Addison’s disease, Cushing’s syndrome

Patients with hypothalamic-pituitary-adrenal axis dysregulations report health-related quality of life that is far lower than that of the general population, according to findings of a prospective study.

“In most centers, both patients with adrenal deficiency and patients with Cushing’s syndrome are managed by the same team,” Charlotte DeBucy, of the Center for Rare Adrenal Diseases at Cochin Hospital in Paris, and colleagues wrote. “Despite the usual perception that both types of diseases alter quality of life, few studies have similarly investigated the impact of cortisol dysregulations on [health-related quality of life]. Such studies are important, however, to identify meaningful differences that would be important to consider to improve management and outcome.”

De Bucy and colleagues analyzed data from 343 patients with Addison’s disease or Cushing’s syndrome followed in routine practice at a single center in France between September 2007 and April 2014 (78% women; mean age, 48 years; mean length of time since diagnosis, 7.8 years; 61% married). All participants completed the short-form health survey (SF-36), a survey of health-related quality-of-life measures and the 12-item general health questionnaire (GHQ-12), a measure of psychological well-being or distress. Questionnaires were completed at baseline and at 6, 12, 24 and 36 months. Patients with Cushing’s syndrome were also assessed for cortisol status at baseline and at follow-up evaluations.

Within the cohort, 206 had Cushing’s syndrome of pituitary origin, 91 had Cushing’s syndrome of adrenal origin and 46 patients had Addison’s disease; 16% were included in the study before any treatment was initiated.

Researchers found that mean standard deviation scores for psychological and physical dimensions of the SF-36 were “well below” those of the general population, but diagnosis, cortisol status and time since treatment initiation all influenced individual scores. Cushing’s syndrome of pituitary origin was associated with worse health-related quality of life, especially for physical functioning, social functioning and mental health. In Cushing’s syndrome, health-related quality of life was generally worse during periods of hypercortisolism, but scores for these patients were lower than those of patients with Addison’s disease even during periods of hypocortisolism or eucortisolism, according to the researchers.

“The differences were particularly large for physical functioning and role-physical subscales,” the researchers wrote.

They also found that mental health scores for patients with Cushing’s syndrome decreased during periods of hypocortisolism, whereas other adrenal conditions were associated with higher mental health scores.

More than half of patients, regardless of diagnosis and cortisol status, had psychological distress requiring attention, according to the GHQ-12 survey.

“Our findings are important for clinical practice,” the researchers wrote. “The consequences of cortisol dysregulation on [health-related quality of life] should be considered in the management of adrenal insufficiency and even more (in) Cushing’s syndrome patients, and these consequences can be long term, affecting apparently cured patients. Early information on these consequences might be helpful for patients who often perceive a poor quality of life as the result of inadequate disease control or treatment. Even if this possibility exists, knowing that adrenal diseases have long-lasting effects on [health-related quality of life] may be helpful for patients to cope with them.” – by Regina Schaffer

Disclosure: L’association Surrénales supported this study. The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B842655ce-e710-4476-a3c2-2909b06434ed%7D/lower-health-related-quality-of-life-observed-in-patients-with-addisons-disease-cushings-syndrome

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

History of Cortisone’s Discovery

It was Christmas Day in 1914 when the Mayo Clinic chemist Edward C. Kendall, PhD, first succeeded in isolating pure crystalline thyroxin using 6,500 pounds of hog thyroid glands, a success that would set him on the course for making one of the greatest discoveries in medicine in the last century.

His pivotal discovery, according to William F. Young, Jr., MD, MSc, chair of the division of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic College of Medicine, would lead Kendall, a self-described “hormone hunter,” to conduct adrenal experiments that would eventually change the course of medicine in ways he couldn’t have imagined. Kendall and his team’s discovery of cortisone would lead not only to a breakthrough treatment, Young said, but a Nobel Prize and international acclaim.

In an interview prior to presenting the Clark T. Swain Memorial History of Endocrinology Lecture at ENDO 2017, Young said that understanding the history behind such a monumental discovery can help endocrinologists see how hormone research has evolved, and provides insight into how to make advances in basic science and improve patient care. In preparing to tell Kendall’s story, Young completed archival research at Mayo and uncovered information that has not previously been published, he said.

“The cortisone story originated at Mayo Clinic, where I have been on staff for 33 years,” Young told Endocrine Today. “Although much of this story is not new information, it is not familiar to the current generations of endocrine scientists and clinical endocrinologists. It is a story of discovery science, clinical intuition, persistence, team science, patient volunteerism and sacrifice, hopes, and dreams.”

‘A big oak tree’

When Kendall first took on the project of preparing better adrenal extracts to potentially treat Addison’s disease in 1930, he was already thinking bigger, Young said.

“He once said, ‘I want to grow a great big oak tree … I am not interested in a bunch of blackberry bushes,’” Young said.

During his experiments at Mayo Clinic, the cost of bovine adrenals rose from 0.20 cents a pound to $3 per pound, equivalent to $42 per pound today. In 1934, Kendall struck a deal with Parke Davis Co., were he would extract “adrenalin” at no cost for the company if it would, in turn, deliver to him 600 pounds of bovine adrenals each week, Young said. He would then use the adrenal cortex for his studies.

In addition, Kendall struck a side deal with Wilson Labs, Young said, for an additional 300 pounds of bovine adrenals per week, to produce a cortical extract for them. He would in turn use the adrenal medullas to boost his production of adrenalin for the Park Davis deal.

“From 1934 to 1949, virtually all of the adrenaline used in North America was manufactured at Mayo Clinic in the small town of in Rochester, Minnesota,” Young said. “This lab ran 24 hours a day, in three shifts. By 1949, over 150 tons of adrenal glands had been processed at Mayo Clinic … $12.4 million in research supply dollars.”

A new discovery

In 1934, Kendall recognized through his work that the adrenal cortex produced more than one hormone, Young said. Over the next year, Kendall’s group isolated five crystalline compounds, naming them compounds “A” through “E” based on their order of identification. Compound “E” — what would later be named cortisone — was found to be biologically active, Young said.

Interest in synthesizing the active hormone from the adrenal cortex grew as part of the American war effort in the 1940s, Young said, and the U.S. National Research Council made it a priority. By 1948, 9,000 mg of “compound E” had been synthesized for clinical study; 2,000 mg were given to each of three investigators at Mayo Clinic for studies in patients with Addison’s disease and the remaining 3,000 mg were saved for future study.

In 1948, a patient known as H.G., a 28-year-old women with progressive inflammatory arthritis, presented to the clinic, Young said. After an unsuccessful treatment with the Swedish hepatoxin lactophenin — a therapy used at the time that induced jaundice in some patients, leading to remission — her physician, Philip Hench, went to Kendall for help. Kendall agreed to give Hench some of the remaining 3,000 mg of “compound E,” if Hench could convince Merck to grant permission.

The clinicians did get permission, and H.G. began treatment. Within days, Young said, the improvement was remarkable. Reading from the original, handwritten notes of Hench and his colleagues in rheumatology, , Young detailed the patient’s progress:

“Rolled over and turned off the radio with ease for the first time in weeks,” the notes said from “day 3.” “No more trembling of knees when moving.”

The clinicians were so amazed, Young said, that they filmed H.G’s progress. Young, who obtained the original films from the Mayo Clinic archives, showed footage of a crippled H.G. struggling to stand, only to be walking normally.

“They started taking videos because they realized no one would believe them,” Young said as the video played. “That they actually had something that could affect, up until this point, a crippling disorder.”

Hench came up with the acronym “cortisone,” adapted from corticosterone.

The discovery became international news. In December 1950, Kendall, Hench along with Tadeus Reichstein, received the 1950 Nobel Prize in Physiology and Medicine — just 27 months after H.G. received her first dose of “compound E.”

The future of corticosteroids

Today, Young said, corticosteroids are used for their anti-inflammatory and immunosuppressive properties across the field of medicine. Natural and synthetic glucocorticoids are used to treat a wide variety of non-adrenal diseases, from allergies, to gastrointestinal disorders and infectious diseases.

The important story of patient H.G. — and the scientific journey of Kendall and his colleagues — still resonates, Young said.

“My hope is that this story will remind us of our endocrine heritage and give us an opportunity to recognize the unlimited potential for discovery, research and clinical investigation that is taking place in research laboratories and clinical endocrine centers across the globe,” Young said in an interview. “In the current environment in the U.S., where federal research funds are being cut back, it is important to recall where the major advances in research and public health have come from.”

“There are many other messages in the presentation,” Young said. “For example, the importance of ‘team science’— a phrase only recently coined — has been in place for decades. It is team science that has led to many of the major advances in medicine, including the therapeutic use of corticosteroids.” – by Regina Schaffer

Reference:

Young WF. A Chemist, a Patient and the 1950 Nobel Prize in Physiology and Medicine: The Stories Behind the Stories on Cortisone. Presented at: The Endocrine Society Annual Meeting; April 1-4, 2017; Orlando, Fla.

Disclosures: Young reports no relevant financial disclosures.

 

From http://www.healio.com/endocrinology/adrenal/news/online/%7Bd8d71bcc-a981-418e-9d41-af4b2dcaa48f%7D/history-of-cortisones-discovery-offers-lessons-in-team-science-persistence

Prednisolone May Raise Cholesterol in Adrenal Insufficiency

Prednisolone treatment of patients with adrenal insufficiency is associated with significantly elevated total-and low-density-lipoprotein (LDL) cholesterol levels compared with use of an alternative glucocorticoid, hydrocortisone, new data suggest.

Real-world data from the European Adrenal Insufficiency Registry (EU-AIR) were presented on April 2 here at ENDO 2017: The Endocrine Society Annual Meeting by Robert D Murray, MBBS, consultant endocrinologist and honorary associate professor at Leeds Teaching Hospitals NHS Trust, United Kingdom.

In an interview, Dr Murray told Medscape Medical News, “In addition to previous data showing that prednisolone can cause lower bone mass, we’ve now shown that it may raise cholesterol to a higher degree than hydrocortisone.”

Asked to comment, session moderator Constantine A Stratakis, MD, chief medical officer of the National Institute of Child Health & Human Development, Bethesda, Maryland, said: “These are significant findings. I think that the difference he’s seeing may be mostly due to the differences in how glucocorticoids are metabolized locally in the liver and fat tissues.”

Regarding clinical implications, Dr Stratakis said, “These data point to the need for using hydrocortisone. Clearly, at these doses anyway, you have increases in LDL and cholesterol with prednisolone.”

Indeed, the new findings support recent recommendations from the Endocrine Society to use hydrocortisone as first-line glucocorticoid replacement therapy for primary adrenal insufficiency.

But the huge cost difference between the two generic medications has led some to suggest otherwise. In 2014, the BMJ published editorials arguing both for and against the preferred use of prednisolone.

During his presentation, Dr Murray reported that in the United Kingdom, an annual supply of 5-mg prednisolone (one tablet a day) costs about £16 and 3 mg (three 1-mg tablets a day) about £48, compared with £1910 for a year’s supply of twice-daily 10-mg hydrocortisone.

(Hydrocortisone is also considerably more expensive than prednisolone in the United States, although the differential isn’t quite as dramatic.)

Dr Murray pointed out that about 75% of the patients in the database were taking 5 mg/day of prednisolone and that although that’s within the recommended range (3–5 mg/day), it might be too much. “I suspect this isn’t related to the steroid use, but that we may actually have gotten the doses wrong, and we may need a smaller dose of prednisolone. I think probably in reality the ideal dose is probably nearer to 3.5 to 4 mg. Therefore, I think we may be slightly overtreating these people and both the bone mass and the cholesterol may be a reflection of that.

“I think for now we have to stay with hydrocortisone as our mainstay of treating adrenal insufficiency, but I think more studies need to be done in patients taking 3.5 to 4.0 mg to then look at the effects on cholesterol, bone mass, and other markers….It would be quite a significant saving if we were able to move patients to prednisolone,” he added.

Dr Stratakis commented, “I have to say the price difference to me is amazing.” Asked about Dr Murray’s dose hypothesis, he responded, “It is possible we may be giving more prednisolone than we should. Also, there might be important differences in the handling of glucocorticoids at the tissue level, in fat and liver, specifically, that we don’t account for.”

Hydrocortisone vs Prednisolone

Beginning his presentation, Dr Murray noted that data on risk factors for cardiovascular disease in patients with adrenal insufficiency treated with prednisolone are scarce, despite this condition being the predominant cause of excess mortality, and so in this analysis he and his colleagues aimed to address this gap in the literature.

EU-AIR is a prospective, observational study, initiated in August 2012 to monitor the long-term safety of glucocorticoids in patients with adrenal insufficiency, and of 946 enrolled — in Germany, the Netherlands, Sweden, and the United Kingdom — 91.8% were using hydrocortisone for glucocorticoid replacement therapy compared to just 6.8% using prednisone, with marked heterogeneity in doses and frequency and timing of dosing (Endocrine Abstracts. 2015: DOI:10.1530/endoabs.37.EP39).

Other previous studies have found lower bone mass at the hip and spine with prednisolone compared with hydrocortisone-treated patients, but no quality-of-life difference between the two treatments, Dr Murray said.

The current study is the first patient-matched analysis of cardiovascular-risk-factor differences for the two glucocorticoid therapies. Patients were excluded if they were receiving more than one glucocorticoid, had congenital adrenal hyperplasia, were receiving modified-release hydrocortisone, or were receiving prednisolone or hydrocortisone doses outside the Endocrine Society’s recommended ranges.

Prior to matching, the 909 hydrocortisone patients were significantly more likely to be female, to have primary adrenal insufficiency, to be older, and to have longer disease duration. After matching three hydrocortisone patients for every one taking prednisolone, the 141 hydrocortisone and 47 prednisolone patients were similar for those factors: 62% were female, 40% had primary adrenal insufficiency, average age was around 59 years, and disease duration 23 years.

Both total cholesterol and LDL levels were significantly higher, at 6.3 and 3.9 mmol/L, respectively, in the prednisolone group compared with 5.4 and 3.2 mmol/L for hydrocortisone (both P < .05). However, there were no significant differences in rates of hypertension, diabetes (of either type), blood pressure, triglycerides, or HDL cholesterol.

In subgroup analysis, both total and LDL cholesterol were elevated among patients with primary adrenal insufficiency taking prednisolone, but among those with only secondary adrenal insufficiency, just total cholesterol was elevated with prednisolone.

Dr Stratakis told Medscape Medical News, “It is peculiar for me to see that the only difference he found from all the parameters he measured were in lipids, and specifically total cholesterol and LDL. I think the difference is tissue-specific.”

Dr Murray said it’s certainly plausible that the current prednisolone dosing is too high for two reasons: First, in the United Kingdom prednisolone comes in 1-mg and 5-mg tablets, so taking 5 mg/day is simpler than taking the lower end of the recommended range.

Second, “hydrocortisone is cortisol, so you know what the body produces and about what your levels should be, but you can’t do that with prednisone because it’s an analog. So, we’re guessing, and I think we’ve guessed too high.”

Dr Murray is a speaker and consultant to Shire. Disclosures for the coauthors are listed in the abstract. Dr Stratakis has no relevant financial relationships.   

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ENDO 2017. April 2, 2017; Orlando, Florida. Abstract OR03-5

 

From http://www.medscape.com/viewarticle/878097

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