Think Like a Doctor: Red Herrings Solved!

By LISA SANDERS, M.D.

On Thursday we challenged Well readers to take the case of a 29-year-old woman with an injured groin, a swollen foot and other abnormalities. Many of you found it as challenging as the doctors who saw her. I asked for the right test as well as the right diagnosis. More than 200 answers were posted.

The right test was…

The dexamethasone suppression test,though I counted those of you who suggested measuring the cortisol in the urine.

The right diagnosis was…

Cushing’s disease

More than a dozen of you got the right answer or the right test, but Dr. Davin Quinn, a consultant psychiatrist at the University of New Mexico Hospital, was the first to be right on both counts. As soon as he saw that the patient’s cortisol level was increased, he thought of Cushing’s. And he had treated a young patient like this one some years ago as a second year resident.

The Diagnosis:

Cushing’s disease is caused by having too much of the stress hormone cortisol in the body. Cortisol is made in the adrenal glands, little pyramid shaped organs that sit atop the kidneys. It is normally a very tightly regulated hormone that helps the body respond to physical stress.

Sometimes the excess comes from a tumor in the adrenal gland itself that causes the little organ to go into overdrive, making too much cortisol. More often the excess occurs when a tumor in the pituitary gland in the brain results in too much ACTH, the hormone that controls the adrenal gland.

In the body, cortisol’s most fundamental job is to make sure we have enough glucose around to get the body’s work done. To that end, the hormone drives appetite, so that enough fuel is taken in through the food we eat. When needed, it can break muscle down into glucose. This essential function accounts for the most common symptoms of cortisol excess: hyperglycemia, weight gain and muscle wasting. However, cortisol has many functions in the body, and so an excess of the hormone can manifest itself in many different ways.

Cushing’s was first described by Dr. Harvey Cushing, a surgeon often considered the father of modern neurosurgery. In a case report in 1912, he described a 23-year-old woman with sudden weight gain, mostly in the abdomen; stretch marks from skin too thin and delicate to accommodate the excess girth; easy bruising; high blood pressure and diabetes.

Dr. Cushing’s case was, it turns out, a classic presentation of the illness. It wasn’t until 20 years later that he recognized that the disease had two forms. When it is a primary problem of an adrenal gland gone wild and producing too much cortisol on its own, the disease is known as Cushing’s syndrome. When the problem results from an overgrown part of the pituitary making too much ACTH and causing the completely normal adrenal glands to overproduce the hormone, the illness is called Cushing’s disease.

It was an important distinction, since the treatment often requires a surgical resection of the body part where the problem originates. Cushing’s syndrome can also be caused by steroid-containing medications, which are frequently used to treat certain pulmonary and autoimmune diseases.

How the Diagnosis Was Made:

After the young woman got her lab results from Dr. Becky Miller, the hematologist she had been referred to after seeing several other specialists, the patient started reading up on the abnormalities that had been found. And based on what she found on the Internet, she had an idea of what was going on with her body.

“I think I have Cushing’s disease,” the patient told her endocrinologist when she saw him again a few weeks later.

The patient laid out her argument. In Cushing’s, the body puts out too much cortisol, one of the fight-or-flight stress hormones. That would explain her high blood pressure. Just about everyone with Cushing’s disease has high blood pressure.

She had other symptoms of Cushing’s, too. She bruised easily. And she’d been waking up crazy early in the morning for the past year or so – around 4:30 – and couldn’t get back to sleep. She’d heard that too much cortisol could cause that as well. She was losing muscle mass – she used to have well-defined muscles in her thighs and calves. Not any more. Her belly – it wasn’t huge, but it was a lot bigger than it had been. Cushing’s seemed the obvious diagnosis.

The doctor was skeptical. He had seen Cushing’s before, and this patient didn’t match the typical pattern. She was the right age for Cushing’s and she had high blood pressure, but nothing else seemed to fit. She wasn’t obese. Indeed, she was tall (5- foot-10) and slim (150 pounds) and athletic looking. She didn’t have stretch marks; she didn’t have diabetes. She said she bruised easily, but the endocrinologist saw no bruises on exam. Her ankle was still swollen, and Cushing’s can do that, but so can lots of other diseases.

The blood tests that Dr. Miller ordered measuring the patient’s ACTH and cortisol levels were suggestive of the disease, but many common problems — depression, alcohol use, eating disorders — can cause the same result. Still, it was worth taking the next step: a dexamethasone suppression test.

Testing, Then Treatment:

The dexamethasone suppression test depends on a natural negative feedback loop whereby high levels of cortisol suppress further secretion of the hormone. Dexamethasone is an artificial form of cortisol. Given in high doses, it will cause the level of naturally-occurring cortisol to drop dramatically.

The patient was told to take the dexamethasone pills the night before having her blood tested. The doctor called her the next day.

“Are you sure you took the pills I gave you last night?” the endocrinologist asked her over the phone. The doctor’s voice sounded a little sharp to the young woman, tinged with a hint of accusation.

“Of course I took them,” she responded, trying to keep her voice clear of any irritation.

“Well, the results are crazy,” he told her and proposed she take another test: a 24-hour urine test.

Because cortisol is eliminated through the kidneys, collecting a full day’s urine would show how much cortisol her body was making. So the patient carefully collected a day’s worth of urine.

A few days later, the endocrinologist called again: her cortisol level was shockingly high. She was right, the doctor conceded, she really did have Cushing’s.

An M.R.I. scan revealed a tiny tumor on her pituitary. A couple of months later, she had surgery to remove the affected part of the gland.

After recovering from the surgery, the patient’s blood pressure returned to normal, as did her red blood cell count and her persistently swollen ankle. And she was able to once again sleep through the night.

Red Herrings Everywhere:

As many readers noted, there were lots of findings that didn’t really add up in this case. Was this woman’s groin sprain part of the Cushing’s? What about the lower extremity swelling, and the excess red blood cell count?

In the medical literature, there is a single case report of high red blood cell counts as the presenting symptom in a patient with Cushing’s. And with this patient, the problem resolved after her surgery – so maybe they were linked.

And what about the weird bone marrow biopsy? The gastritis? The enlarged spleen? It’s hard to say for certain if any of these problems was a result of the excess cortisol or if she just happened to have other medical problems.

Why the patient didn’t have the typical symptoms of Cushing’s is easier to explain. She was very early in the course of the disease when she got her diagnosis. Most patients are diagnosed once symptoms have become more prominent

By the time this patient had her surgery, a couple of months later, the round face and belly characteristic of cortisol excess were present. Now, two years after her surgery, none of the symptoms remain.

From http://well.blogs.nytimes.com/2014/01/17/think-like-a-doctor-red-herrings-solved/?_php=true&_type=blogs&_r=0

No High-Quality Studies for Cushing’s Drugs

By Salynn Boyles, Contributing Writer, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

There is a paucity of clinical trial data supporting the efficacy of most drugs used to treat Cushing’s disease, researchers reported.

Just one drug — pasireotide — has been evaluated in a randomized, double-blind trial, but even it was judged by the researchers to have only a ‘moderate’ level of evidence supporting its effectiveness and safety.

The review of the literature evaluating drug treatments for Cushing’s disease, a rare pituitary disorder, is the first to employ a rigorous systematic approach with strict, predefined inclusion criteria and formal analysis of the quality of evidence using an established standard, researcher Monica Gadelha, MD, PhD, of Brazil’s Federal University of Rio de Janeiro, and colleagues wrote in the journal Clinical Endocrinology.

“This systematic review indicates that the majority of medical therapies currently used in the treatment of Cushing’s disease are supported by a low level of evidence,” the researchers wrote. “Further well-designed prospective studies of medications in Cushing’s disease would help to inform clinical practice further.”

Cushing’s disease is the most common form of endogenous Cushing’s syndrome, a hormonal disorder resulting from persistent exposure to abnormally high levels of the hormone cortisol. In the case of Cushing’s disease, the cortisol is secreted by a pituitary adenoma.

Prolonged exposure to high levels of cortisol raises the risk for diabetes mellitus, cardiovascular disease, osteoporosis and nephrolithiasis. Patients with persistent Cushing’s disease have a 3- to 5-fold higher mortality than the general population.

Surgery to remove the pituitary adenoma is the first-line treatment for Cushing’s disease in the U.S., and when the procedure is performed by an experienced surgeon, remission rates in patients with smaller tumors range from 65% to 90%. The long-term remission rate is lower, however, because many patients develop recurrent disease.

Several medical therapies are widely used to treat patients who are not candidates for surgery or who experience relapse following surgery.

Novartis Oncology’s somatostatin analog drug pasireotide (Signifor) became the only drug approved for this indication in December of last year. And the progesterone-blocking drug mifepristone, best known as the abortion pill once called RU-486, was approved in February of 2012 for the treatment of Cushing’s disease-associated hyperglycemia.

Other drugs — including metyrapone, mitotane, cabergoline, and ketoconazole — are also used off-label in the treatment of Cushing’s, and several have shown better response rates than pasireotide in small studies.

In their systematic review, Gadelha and colleagues identified 15 studies that included at least 10 adults with Cushing’s disease and reported treatment responses as the proportion of patients reaching a specified definition of response. Studies examining combinations of medications were excluded from the analysis, as were studies with indefinite diagnoses of Cushing’s disease.

For medications other than mifepristone, studies had to report the proportion of patients with normalized urinary free cortisol (UFC), midnight salivary cortisol or midnight serum cortisol.

The studies were scored according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system for rating quality of evidence.

Ten of the 15 included studies reported outcomes specifically for patients with Cushing’s disease and the remaining five included patients with other forms of Cushing’s syndrome.

The researchers reported that:

  • Pasireotide was the only treatment assessed in a randomized trial, and it was judged to have a ‘moderate’ level of evidence supporting its use. Response rates from three prospective studies of the drug ranged from 17% to 29%.
  • The remaining medications were supported by a ‘low’ or ‘very low’ level of evidence.
  • The highest response rates were reported in a small retrospective studies of metyrapone (75%, one study) and mitotane (72%, one study).
  • Response rates were 25% to 50% for cabergoline (four studies) and 45% for ketoconazole (one study).
  • Among studies that included patients with other forms of Cushing’s syndrome, response rates were 53% to 88% for ketoconazole (three studies), 70% for mitotane (one study), 57% for metyrapone (one study), and 38% to 60% for mifepristone (one study).

 

But the researchers urged caution in comparing the drugs, citing the variability in the study designs and patient selection endpoints, among other limitations in the research literature.

“The wide variation in the time-frames over which response to treatment was measured makes comparison a challenge,” they wrote. “Comparison of response rates reported in the included studies is also complicated by the variation in methodology used to assess response.”

They noted that well-designed clinical trials are needed to determine which drugs or drug combinations are most effective in the treatment of Cushing’s disease patients.

“Combinations of medical therapies with different modes of action might aid in optimizing the balance of efficacy and safety,” they wrote. “Investigational medications, such as bexarotene, LC1699 and retinoic acid, may help to expand the range of future therapeutic options.”

Maria Fleseriu, MD, who was not involved in the review, agreed that more drug treatments are needed. But she added that Cushing’s patients today have many more drug options than they did just a few years ago.

Fleseriu directs the Pituitary Center at Oregon Health & Science University, where she is an associate professor of medicine and endocrinology.

In a recently published analysis, Fleseriu wrote that pituitary-targeted medical therapies should soon play a more prominent role in treating Cushing’s disease, and may become first-line treatments when surgery fails or is contraindicated.

“We now have one drug approved for Cushing’s and another approved for diabetes symptoms associated with the disease,” she told MedPage Today. “We are moving forward, but we are not where we would like to be. Combination therapy is probably where we are heading, but further studies are needed.”

Financial support for this research was provided by Novartis Pharmaceuticals.

Researcher Monica Gadelha reports receiving speaker fees and participating on advisory boards for Novartis. Gadelha and co-author Leonardo Vieira Neto were investigators in Novartis’ clinical trials of pasireotide.

 

From http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/42043

NIH: An Open-Label Study of The Safety, Pharmacokinetics and Pharmacodynamics of Mifepristone in Children With Refractory Cushing’s Disease

This study is currently recruiting participants.

Summary

Number 13-CH-0170
Sponsoring Institute National Institute of Child Health and Human Development (NICHD)
Recruitment Detail Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 6
Max Age: 17
Referral Letter Required No
Population Exclusion(s) None
Special Instructions Currently Not Provided
Keywords Child;
Cushing Syndrome;
Metabolism;
Mifepristone;
Pharmacokinetic-Pharmacodynamic
Recruitment Keyword(s) None
Condition(s) Cushing’s Syndrome;
Cushing Syndrome
Investigational Drug(s) Mifepristone
Investigational Device(s) None
Intervention(s) Drug: mifepristone
Supporting Site National Institute of Child Health and Human Development

Background:

– There are currently no approved therapies for children with Cushing’s disease who are not cured by surgery alone. A drug called mifepristone has been approved to treat adults with Cushing’s syndrome and elevated blood glucose caused by Cushing’s. The drug is marketed under the name Korlym(Registered Trademark). The study drug may have a different effect on a child’s body than an adult’s, so researchers want to know how much of the drug to give children and what effect it will have. They want to learn if mifepristone improves Cushing’s disease in children as it does in adults. They also want to know about the drug’s side effects in children.

Objectives:

– To study the effect of a medication called mifepristone in children with Cushing’s disease that has not been helped by pituitary surgery.

Eligibility:

– Children ages 6 to 17 with active Cushing’s disease following pituitary surgery and who have a body weight higher than expected for their height and age.

Design:

– Participants will be screened for up to 8 weeks with a physical exam, medical history, and medical tests including blood tests and X-rays.

– Participants will take tablets of the study drug each day for 12 weeks.

– Participants will stay at the clinic for 4 nights at the beginning of the study. They will have three 1-day visits during the study. They will stay at the clinic the last 3 days of the study.

– At these visits, participants will be given several tests. In one test, a small wire is inserted under the skin of the belly and a small monitor is attached taped to the belly. In another, the participant drinks a liquid and blood samples are taken.

– Follow-up visits will occur 4 weeks and 12 weeks after the study ends.

–Back to Top–

Eligibility

INCLUSION CRITERIAPatients who are eligible for enrollment must meet the following eligibility criteria:

– Males and females 6-17 years at informed consent

– Active Cushing’s disease as demonstrated by the following:

–24 hour Urinary Free Cortisol greater than the upper limit of normal for age on two urine collections during screening and

— midnight serum cortisol > 4.4 mcg/dL (mean of two determinations on a single day at 2330 and 2400 during screening)

– Previous trans-sphenoidal surgery (TSS) for ACTH secreting pituitary tumor at least 3 months prior to screening

– Increased body weight defined by BMI Z-score of 1.5 or above

– Able to provide consent/assent

– Able to swallow study drug tablets (not crushed or split)

– Willing to use non-hormonal method of contraception in patients of reproductive potential

– Primary health care provider in home location

EXCLUSION CRITERIA:

– Hypercortisolism not due to Cushing’s disease.

– Type 1 diabetes mellitus

– HbA1c geater than or equal to 9.5% at Screening

– Body weight < 25 kg

– Use of certain medications that are CYP3A substrates with narrow therapeutic ranges, such as simvastatin, lovastatin, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus during the 4 weeks prior to starting study drug. Use of these medications is also prohibited until 2 weeks after end of dosing.

– Use of certain medications that are strong CYP3A inhibitors such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, mibefradil, posaconazole, saquinavir, telaprevir, telithromycin, and voriconazole during the 2 weeks prior to starting study drug.

Use of these medications is also prohibited until 2 weeks after end of dosing. Grapefruit and grapefruit juice are prohibited during this time frame.

– Use of certain medications that are strong inducers on CYP3A such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, St. John’s wort during the 2 weeks prior to starting study drug. Use of these medications is also prohibited until 2 weeks after end of dosing.

– Use of medications used to treat hypercortisolism from the duration indicated below prior to Day 1. Use of the medications is also prohibited until after the end of study 4 week follow up visit.

–steroidogenesis inhibitors such as ketoconazole, metyrapone: 4 weeks

–cabergoline, bromocriptine, somatostatin analogs such as octreotide, lanreotide, pasireotide long acting formulations: 8 weeks (immediate release formulations: 2 weeks)

–mitotane: 8 weeks

– Use of systemic glucocorticoid medications beginning 1 month prior to screening or anticipated use of these medications except for the treatment of adrenal insufficiency. Use of glucocorticoid medications is prohibited during the study until after the end of study 4 week study visit.

– Inflammatory, rheumatological, proliferative or other disorder(s) that would be anticipated to worsen with glucocorticoid blockade (e.g. inflammatory bowel disease, rheumatoid arthritis, psoriasis, etc.).

– Uncontrolled hypo- or hyperthyroidism.

– Uncorrected hypokalemia (< 3.5 mEq/L). The screening period may be used to correct hypokalemia prior to starting study drug. Use of potassium and/or mineralocorticoid antagonists is permitted during the study.

– QTc geater than or equal to 450 msec on Screening electrocardiogram

– Unexplained vaginal bleeding in females and/or any history of endometrial pathology.

– Positive pregnancy test in females.

From http://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2013-CH-0170.html

Cyclic Cushing’s syndrome: a clinical challenge

  1. J R Meinardi1,2,
  2. B H R Wolffenbuttel2 and
  3. R P F Dullaart2

+Author Affiliations


  1. 1Department of Internal Medicine, Canisius Wilhelmina Ziekenhuis, PO Box 9015, 6500 GS Nijmegen, The Netherlands and 2Department of Endocrinology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
  1. (Correspondence should be addressed to: R P F Dullaart; Email:r.p.f.dullaart@int.umcg.nl)

Abstract

Cyclic Cushing’s syndrome (CS) is a rare disorder, characterized by repeated episodes of cortisol excess interspersed by periods of normal cortisol secretion. The so-called cycles of hypercortisolism can occur regularly or irregularly with intercyclic phases ranging from days to years.

To formally diagnose cyclic CS, three peaks and two troughs of cortisol production should be demonstrated. Our review of 65 reported cases demonstrates that cyclic CS originates in 54% of cases from a pituitary corticotroph adenoma, in 26% from an ectopic ACTH-producing tumour and in about 11% from an adrenal tumour, the remainder being unclassified. The pathophysiology of cyclic CS is largely unknown.

The majority of patients with cyclic CS have clinical signs of CS, which can be either fluctuating or permanent. In a minority of patients, clinical signs of CS are absent. The fluctuating clinical picture and discrepant biochemical findings make cyclic CS extremely hard to diagnose. Clinicians should therefore be aware of this clinical entity and actively search for it in all patients with suspected CS but normal biochemistry or vice versa.

Frequent measurements of urinary cortisol or salivary cortisol levels are a reliable and convenient screening tool for suspected cyclic CS. Cortisol stimulation or suppression tests may give spurious results owing to spontaneous falls or rises in serum cortisol at the time of testing. When cyclic CS is biochemically confirmed, further imaging and laboratory studies are guided by the presence or absence of ACTH dependency. In cases of suspected ectopic ACTH production, specific biochemical testing for carcinoids or neuroendocrine tumours is required, including measurements of serotonin in platelets and/or urine, chromogranin A and calcitonin.

Read the entire article here:  http://www.scribd.com/doc/159503297/Cyclic-Cushing%E2%80%99s-syndrome-a-clinical-challenge

When to think Cushing’s syndrome in type 2 diabetes

ESTES PARK, COLO. – Diabetes mellitus, osteoporosis, and hypertension are conditions that should boost the index of suspicion that a patient with some cushingoid features may in fact have endogenous Cushing’s syndrome, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

An estimated 1 in 20 patients with type 2 diabetes has endogenous Cushing’s syndrome. The prevalence of this form of hypercortisolism is even greater – estimated at up to 11% – among individuals with osteoporosis. In hypertensive patients, the figure is 1%. And among patients with an incidentally detected adrenal mass, it’s 6%-9%, according to Dr. McDermott, professor of medicine and director of endocrinology and diabetes at the University of Colorado.

“Endogenous Cushing’s syndrome is not rare. I suspect I’ve seen more cases than I’ve diagnosed,” he observed. “I’ve probably missed a lot because I failed to screen people, not recognizing that they had cushingoid features. Not everyone looks classic.”

There are three screening tests for endogenous Cushing’s syndrome that all primary care physicians ought to be familiar with: the 24-hour urine cortisol test, the bedtime salivary cortisol test, and the overnight 1-mg dexamethasone suppression test.

“I think if you have moderate or mild suspicion, you should use one of these tests. If you have more than moderate suspicion – if a patient really looks like he or she has Cushing’s syndrome – then I would use at least two screening tests to rule out endogenous Cushing’s syndrome,” the endocrinologist continued.

The patient performs the bedtime salivary cortisol test at home, obtaining samples two nights in a row and mailing them to an outside laboratory. The overnight dexamethasone suppression test entails taking 1 mg of dexamethasone at bedtime, then measuring serum cortisol the next morning. A value greater than 1.8 mcg/dL is a positive result.

Pregnant women constitute a special population for whom the screening method recommended in Endocrine Society clinical practice guidelines (J. Clin. Endocrinol. Metab. 2008;93:1526-40) is the 24-hour urine cortisol test. That’s because pregnancy is a state featuring high levels of cortisol-binding globulins, which invalidates the other tests. In patients with renal failure, the recommended screening test is the 1-mg dexamethasone suppression test. In patients on antiepileptic drugs, the 24-hour urine cortisol or bedtime salivary cortisol test is advised, because antiseizure medications enhance the metabolism of dexamethasone.

Dr. McDermott said that “by far” the most discriminatory clinical features of endogenous Cushing’s syndrome are easy bruising, violaceous striae on the trunk, facial plethora, and proximal muscle weakness.

“They’re by no means specific. You’ll see these features in people who don’t have Cushing’s syndrome. But those are the four things that should make you really consider Cushing’s syndrome in your differential diagnosis,” he stressed.

More widely recognized yet actually less discriminatory clinical features include facial fullness and the “buffalo hump,” supraclavicular fullness, central obesity, hirsutism, reduced libido, edema, and thin or poorly healing skin.

Endogenous Cushing’s syndrome can have three causes. An adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma accounts for 80% of cases. A cortisol-secreting adrenal tumor is the cause of 10%. And another 10% are due to an ectopic ACTH-secreting tumor, most commonly a bronchial carcinoid tumor.

Once the primary care physician has a positive screening test in hand, it’s typical to refer the affected patient to an endocrinologist in order to differentiate which of the three causes is present. This is accomplished based upon the results of a large, 8-mg dexamethasone suppression test coupled with measurement of plasma ACTH levels.

Dr. McDermott recommended as a good read on the topic of evaluating a patient with endogenous Cushing’s syndrome a recent review article that included a useful algorithm (N. Engl. J. Med. 2013;368:2126-36).

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

From http://www.clinicalendocrinologynews.com

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