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The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

DanL. Longo, M.D., Editor

Diagnosis and Differential Diagnosis


of Cushings Syndrome
D.Lynn Loriaux, M.D., Ph.D.

M
ore than a century ago, Harvey Cushing introduced the term From the Division of Endocrinology, Dia-
pluriglandular syndrome to describe a disorder characterized by rapid betes, and Clinical Nutrition, Oregon
Health and Science University, Portland.
development of central obesity, arterial hypertension, proximal muscle Address reprint requests to Dr. Loriaux at
weakness, diabetes mellitus, oligomenorrhea, hirsutism, thin skin, and ecchymoses.1 the Division of Endocrinology, Diabetes,
Cushing knew that this syndrome was associated with adrenal cancer,2 and he and Clinical Nutrition, Oregon Health
and Science University, 3181 SW Sam
suspected that some cases might have a pituitary component. On September 6, Jackson Park Rd., L607, Portland, OR
1911, he performed a craniotomy on one of his patients (referred to as Case XLV) 97239-3098, or at loriauxl@ohsu.edu.
but found no pituitary tumor.3 In his description of the case, he goes on to say N Engl J Med 2017;376:1451-9.
that we may perchance be on the way toward the recognition of the consequences DOI: 10.1056/NEJMra1505550
of hyperadrenalism.2 With time, it became clear that the disorder could be caused Copyright 2017 Massachusetts Medical Society.

by small basophilic adenomas of the pituitary gland,4 and the pluriglandular syn-
drome became known as Cushings 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 Man5:

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 Cushings
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 sus-


pected 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, Cushings 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 Cushings syndrome are very
effective in making this distinction. This review focuses on the problems intro-
duced into the diagnosis and differential diagnosis of Cushings syndrome by the
obesity epidemic and on ways to alter the traditional approach, using the antiana-
bolic changes of excess cortisol to separate patients with Cushings syndrome
from obese patients with the insulin-resistant metabolic syndrome.

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The n e w e ng l a n d j o u r na l of m e dic i n e

Ph ysic a l E x a minat ion from the skinfold. The skin over the proximal
phalanx of the middle finger of the nondominant
Andreas Vesalius (15141564) published his trans- hand is commonly used for this measurement
formational work on human anatomy, De Humani (Fig.1). A thickness of less than 2 mm is con-
Corporis Fabrica Libri Septem, in 1543. It is the book sidered to be thin skin. Patients who have thin
that corrected many of Galens anatomical errors. skin are more likely to have Cushings syndrome,
The book was met with considerable hostility. As with a positive likelihood ratio of 116 (Fig.2).1315
an example, Jacobus Sylvius (Jacques Dubois, Finally, patients who have three or more ecchy-
14781555), the worlds leading anatomist at the moses that are larger than 1 cm in diameter and
time and Vesaliuss former mentor, on being not associated with trauma such as venipuncture
asked his opinion of the work, replied, Galen is are more likely to have Cushings syndrome than
not wrong. It is man that has changed, and not are patients without such findings, with a posi-
for the better.6 This was not true then, but it is tive likelihood ratio of 4.13,16
true now. If we know the prevalence of undiagnosed
Approximately one third of the U.S. population Cushings syndrome in the population of persons
is obese. The worldwide prevalence of the meta- with the obesity-related metabolic syndrome, we
bolic syndrome among obese persons is conser- can begin to calculate the probability that a per-
vatively estimated at 10%; that is, approximately son has Cushings syndrome, using the likelihood
12 million people have the obesity-related meta- ratios for the antianabolic features observed on
bolic syndrome.7,8 The clinical picture of this physical examination. Likelihood ratios can be
syndrome is almost the same as that of Cush- converted into probabilities with the use of Bayes
ings syndrome.9,10 The prevalence of undiagnosed theorem. This conversion is markedly facilitated
Cushings syndrome is about 75 cases per 1 mil- by the Fagan nomogram for this purpose.17
lion population, or 24,000 affected persons. On The prevalence of undiagnosed Cushings
the basis of these prevalence estimates, the chance syndrome is not known, but it can be estimated.
that a person with obesity, hypertension, hirsut- Two persons per 1 million population die from
ism, type 2 diabetes, and dyslipidemia has Cush- adrenal cancer every year.18 The current life span
ings syndrome is about 1 in 500. In Harvey for patients with adrenocortical carcinoma, after
Cushings era, when obesity was rare, making the diagnosis, is between 2 and 4 years.19,20 Allowing
diagnosis of Cushings syndrome was the most 3 years to make the diagnosis, the prevalence of
certain aspect of the management of this disor- undiagnosed Cushings syndrome is 6 cases per
der. Today, making the diagnosis is the least cer- million. In most case series of Cushings syn-
tain aspect in the care of patients with Cushings drome, an average of 8% of patients have adrenal
syndrome. carcinoma.21 If 6 per million is 8% of the group,
The metabolic syndrome caused by glucocor- the total Cushings syndrome group is 75 per-
ticoid hypersecretion can be differentiated from sons per million, or 24,000 persons. If all 24,000
the obesity-associated metabolic syndrome with patients are included in the metabolic syndrome
the use of a careful assessment of Albrights group, comprising 12 million people, the preva-
antianabolic effects of cortisol. These effects lence of Cushings syndrome is 0.002, or 0.2%.
osteopenia, thin skin, and ecchymoses are With a probability of 0.2% and a likelihood ratio
present in patients with Cushings syndrome but of 116 for thin skin, 18 for osteopenia, and 4 for
not in patients with simple obesity. ecchymoses, the probability that a patient with
Patients in whom osteoporosis is diagnosed these three findings has Cushings syndrome
radiographically are more likely to have Cushings is95%.
syndrome than those who do not have osteopo-
rosis, with a positive likelihood ratio of 11.11-13
Ur ina r y Fr ee C or t isol
Today, a z score of 2 at the lumbar spine sup-
ports this criterion. Skinfold thickness is conve- The diagnosis of all endocrine diseases requires
niently measured with an electrocardiographic a clinical presentation that is compatible with the
caliper that has the points dulled with a sharp- disease, as well as identification of the patho-
ening stone and the screws tightened so that the physiological cause. An assessment for excess
gap is maintained when the caliper is removed glucocorticoid effects can be made by measuring

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Diagnosis of Cushings Syndrome

A B

C D

Figure 1. Measurement of Skinfold Thickness.


Skinfold thickness is measured with a caliper and a micrometer or millimeter ruler (Panel A). A skinfold is created
(Panel B) and measured with the caliper (Panel C). The thickness of the skinfold is read on the ruler; the thickness
is 3 mm in this case (Panel D).

the 24-hour urinary free cortisol level.22 There Unconjugated cortisol can be extracted directly
are two kinds of free cortisol: plasma protein- from urine with a nonpolar lipid solvent. After
unbound cortisol and cortisol unconjugated to extraction, the cortisol is purified by means of
sulfuric or hyaluronic acid. Protein-unbound cor- high-pressure liquid chromatography and then
tisol is filtered in the glomerulus and then re- quantified with a binding assay, usually radio-
absorbed in the collecting system. About 3% of immunoassay. Free cortisol also can be quanti-
filtered cortisol ends up in the urine. This free tated directly by means of mass spectroscopy. The
cortisol in the urine is unconjugated. Thus, the urinary free cortisol assay of choice uses high-
urinary free cortisol level is a direct reflection of pressure liquid chromatographic separation fol-
the free, bioactive cortisol level in plasma. The lowed by mass spectrometric quantitation.23 With
free cortisol level is quantified in a 24-hour urine the use of this assay, the urinary free cortisol
sample by averaging the increased secretion of level in healthy adults ranges from 8 to 51 g
cortisol in the morning and the decreased secre- per 24 hours (mean [SD], 238). Clinical depres-
tion in the afternoon and at night. Urinary cre- sion increases urinary free cortisol excretion, and
atinine is also measured to determine whether most studies show that the level of urinary free
the collection is complete. Creatinine levels of less cortisol ranges from 10 to 60 g per day in pa-
than 1.5 g per day for men and less than 1 g per tients with typical clinical signs and symptoms
day for women indicate incomplete collection, of depression. If we use 60 g per day as the
and the test should be repeated in patients with cutoff between normal values (<60 g per day)
these levels. and elevated values (60 g per day), urinary free

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The n e w e ng l a n d j o u r na l of m e dic i n e

patients (6 million people), the plasma cortisol


5.5
level will not be suppressed in response to a
5.0 dexamethasone challenge. On the basis of my
4.5 estimate of the current prevalence of undiag-
Skinfold Thickness (mm)

4.0 nosed Cushings syndrome (24,000 cases) and


3.5
the estimate of the at-risk population (6 million
persons), the positive predictive value of the
3.0
dexamethasone-suppression test is only 0.4%.
2.5
Thus, this test should not influence what the
2.0 physician does next and should no longer be used
1.5 for this purpose.
1.0
0.5 Ou tl ier s
Normal Cushings Idiopathic Obesity, Obesity, Polycystic HAIR-AN
Disease Hirsutism Hirsutism No Ovary
Hirsutism
For patients with convincing evidence of Cush-
ings syndrome on physical examination and an
Figure 2. Comparison of Skinfold Thickness in Patients with Cushings elevated 24-hour urinary free cortisol level, the
Syndrome and Those with Other Conditions Related to Insulin Resistance. differential diagnostic process outlined below
HAIR-AN denotes hyperandrogenism, insulin resistance, and acanthosis ni- should be initiated. However, a small group of
gricans. Vertical bars indicate means 2 SD. Data are from Corenblum et al.14 patients will not meet these criteria.
Some patients have a strongly positive physical
examination but low or zero urinary free cortisol
cortisol excretion of 62 g per day or more has excretion. Plasma corticotropin levels are sup-
a positive likelihood ratio of 11.24 Thus, in a pa- pressed in these patients. These patients are re-
tient presenting with obesity, hypertension, type 2 ceiving exogenous glucocorticoids. The glucocor-
diabetes, and hirsutism who has thin skin, osteo- ticoid must be identified, and a plan must be
penia, ecchymoses, and an elevated urinary free made for its discontinuation. Sometimes the
cortisol level, the probability of Cushings syn- glucocorticoid is being given by proxy (e.g., by a
drome is 1 (100%). For such patients, the clini- parent to a child), and no history of glucocorti-
cian should move directly to a differential diag- coid administration can be found. Nevertheless,
nostic evaluation. the glucocorticoid must be identified and dis-
continued.
Other patients have few or no clinical signs
De x a me th a sone-Suppr ession Tes t
of Cushings syndrome but do have elevated uri-
The dexamethasone-suppression test is common- nary free cortisol excretion. Plasma corticotropin
ly used in the diagnosis of Cushings syndrome. is measurable in these patients. They are usually
This test was developed by Grant Liddle in the identified during an evaluation for arterial hyper-
early 1960s as a differential diagnostic test to tension. All such patients should undergo infe-
separate corticotropin-dependent from cortico- rior petrosal sinus sampling to determine the
tropin-independent Cushings syndrome. This is source of corticotropin secretion. Ectopic sources
now done by measuring the plasma corticotropin are almost always neoplastic and are usually in the
level. Unfortunately, dexamethasone suppression chest.25 Patients with eutopic secretion usually
has continued to be used as a screening test for have the syndrome of generalized glucocorticoid
Cushings syndrome. resistance.26
The control group for this test comprises Finally, a few patients have convincing find-
patients with obesity and depression in whom ings on physical examination coupled with a nor-
cortisol secretion is not suppressed in response to mal urinary free cortisol level. In such cases, the
an oral dose of 1 mg of dexamethasone at mid- clinician should make sure that urinary free
night. Of the current U.S. population of 360 mil- cortisol is being measured with high-performance
lion people, approximately one third (120 million liquid chromatography and mass spectrometry,
people) are obese. Of those who are obese, 10% that renal function is normal, and that the col-
(12 million people) have depression. In half these lections are complete. Periodic Cushings syn-

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Diagnosis of Cushings Syndrome

drome must be ruled out by measuring urinary with undiagnosed Cushings syndrome is about
free cortisol frequently over the course of a 10%, accounting for 2400 patients. Up to 40% of
month.27 If these efforts fail, the patient should these patients, or 960, have an incidental pitu-
be followed for a year, with urinary free cortisol itary tumor. The mortality associated with trans-
measurements performed frequently. No addi- sphenoidal microadenomectomy is 1%.30 If all
tional tests should be performed until the situa- 360 to 960 patients undergo this procedure,
tion is sorted out. More tests would be likely to there will be up to 10 deaths from an operation
lead to an unnecessary surgical procedure. that can have no benefit. For this reason alone,
all patients with corticotropin-dependent Cush-
ings syndrome should undergo inferior petrosal
Differ en t i a l Di agnosis
sinus sampling to confirm the source of cortico-
The differential diagnosis of Cushings syndrome tropin secretion before any surgical intervention
is shown in Figure3. If plasma corticotropin is is contemplated.
measurable, the disease process is corticotropin- Patients with eutopic corticotropin secretion
dependent. If corticotropin is not measurable, are almost certain to have a corticotropin-secret-
the process is corticotropin-independent. ing pituitary microadenoma. An occasional patient
Corticotropin-dependent causes of Cushings will have alcohol-induced pseudoCushings syn-
syndrome are divided into those in which the drome. The slightest suggestion of alcoholism
corticotropin comes from the pituitary (eutopic should lead to a 3-week abstinence period before
causes) and those in which the corticotropin any surgery is considered.31
comes from elsewhere (ectopic causes). This dif- Patients with ectopic corticotropin secretion
ferentiation is made with the measurement of are first evaluated with computed tomography
corticotropin in inferior petrosal sinus plasma (CT) or magnetic resonance imaging (MRI) of
and the simultaneous measurement of cortico- the chest. In two thirds of these patients, a tu-
tropin in peripheral (antecubital) plasma im- mor will be found.25 If nothing is found in the
mediately after corticotropin-releasing hormone chest, MRI of the abdominal and pelvic organs
stimulation of pituitary corticotropin secretion. is performed. If these additional imaging studies
In samples obtained 4, 6, and 15 minutes after are also negative, there are two options: bilat-
stimulation with corticotropin-releasing hormone, eral adrenalectomy or blockade of cortisol syn-
eutopic corticotropin secretion is associated with thesis. If blockade is chosen, the patient should
a ratio of the central-plasma corticotropin level to undergo repeat scanning at 6-month intervals.32
the peripheral-plasma corticotropin level of 3 or If no source is found by the end of the second
more. Ectopic corticotropin secretion is associ- year, it is unlikely that the source will ever be
ated with a central-to-peripheral corticotropin found, and bilateral adrenalectomy should be
ratio of less than 3. The positive predictive value performed for definitive treatment (Doppman
of this test is 1 (Fig.4).28 JL: personal communication).
Although some authorities suggest that infe- Corticotropin-independent Cushings syndrome
rior petrosal sinus sampling can safely be by- is usually caused by an adrenal neoplasm. Benign
passed in patients with corticotropin-dependent tumors tend to be small (<5 cm in diameter) and
Cushings syndrome and a well-defined pituitary secrete a single hormone, cortisol. The contra-
adenoma, I disagree. The incidence of nonfunc- lateral adrenal gland is suppressed by the corti-
tioning pituitary microadenomas is between 15% sol secreted from the tumorous gland. If the
and 40%.29 This means that up to 40% of pa- value for Hounsfield units is less than 10 and
tients with ectopic secretion of corticotropin the washout of contrast material is greater than
have an incidental pituitary abnormality. If it is 60% at 15 minutes, the tumor is almost certainly
assumed that the pituitary abnormality is respon- benign.33 Such tumors can be treated successfully
sible for corticotropin secretion, 15 to 40% of with laparoscopic adrenalectomy.
patients with ectopic secretion of corticotropin The syndromes of micronodular and macro
will be misdiagnosed and submitted to a trans- nodular adrenal dysplasia usually affect both ad-
sphenoidal exploration of the sella turcica and renal glands. The nodules secrete cortisol. Corti-
pituitary gland. The prevalence of ectopic corti- cotropin is suppressed, as is the internodular
cotropin secretion in the population of patients tissue of the adrenal glands. Percutaneous bilat-

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The n e w e ng l a n d j o u r na l of m e dic i n e

Measure plasma corticotropin

Measurable Not measurable

Corticotropin-dependent Corticotropin-independent

Determine ratio of central-plasma to Perform CT or MRI


peripheral-plasma corticotropin of adrenal glands

Ratio 3 Ratio <3 Unilateral disease Bilateral disease

Eutopic Ectopic Contrast-enhanced Bilateral


washout study adrenalectomy

Perform CT or MRI Perform CT or MRI


of pituitary and of chest
hypothalamus 60% at 15 min >60% at 15 min

Laparoscopic
Open surgery
Likely to Unlikely to Positive for Negative for surgery
be curable be curable Cushings Cushings
syndrome syndrome

Pituitary micro- Bilateral Perform CT or MRI


Surgery
adenomectomy adrenalectomy of abdomen
and pelvis

Positive for Negative for


Cushings Cushings
syndrome syndrome

Cortisol synthesis
Surgery
blockade

Figure 3. Differential Diagnosis of Cushings Syndrome.


Every branch point is associated with a test that will govern what the physician does next. No test should be deleted from the evaluation,
and no test should be added to the evaluation.

eral adrenalectomy, followed by glucocorticoid almost always malignant. Surgical removal of all
and mineralocorticoid treatment, is curative. detectable disease is indicated, as is a careful
Adrenal tumors secreting more than one hor- search for metastases. If metastases are found,
mone (i.e., cortisol and androgen or estrogen) are they should be removed. This usually requires an

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Diagnosis of Cushings Syndrome

A Basal Sampling B Sampling after CRH Administration


1000.0 1000.0

Maximal Central-to-Peripheral Corticotropin Ratio

Maximal Central-to-Peripheral Corticotropin Ratio


100.0 100.0

10.0 10.0

3.0
2.0
1.0 1.0

* *
0.1 0.1
)

0)

1)

7)

1)
15

03
=2

=1

=1

=1
=2

=2
(N

(N

(N

(N
(N

(N
e

e
m

as

as
e

e
om

om
ro

ro
ise

ise
nd

nd
dr

dr
lD

lD
yn

yn
Sy

Sy
na

na
sS

sS
n

n
re

re
pi

pi
g

g
Ad

Ad
ro

ro
in

in
ot

ot
sh

sh
tic

tic
Cu

Cu
or

or
cC

cC
pi

pi
to

to
Ec

Ec

Figure 4. Maximal Ratio of Corticotropin in Inferior Petrosal Sinus Plasma to Corticotropin in Peripheral Plasma
in Patients with Cushings Syndrome, Ectopic Corticotropin Secretion, or Adrenal Disease.
Panel A shows the results of corticotropin measurement in basal samples, and Panel B shows the results in samples
obtained after the administration of corticotropin-releasing hormone (CRH). Corticotropin measurement after CRH
administration is superior to basal measurement for differentiating Cushings syndrome from ectopic corticotropin
secretion and primary adrenal disease. Five patients with primary adrenal disease had undetectable corticotropin in
peripheral plasma before and after CRH administration (asterisks in Panels A and B). The positive predictive value
of this test is 1. Data are from Oldfield et al.28

open adrenalectomy. It goes without saying that and fludrocortisone (Florinef), at a dose of 100 g
adrenal tumors, nodules, and metastases should per day, should be prescribed as lifelong therapy.
be treated by the most experienced endocrine
cancer surgeon available. Sum m a r y
If the plasma cortisol level on the morning
after a transsphenoidal microadenomectomy is 0, The obesity epidemic has led to necessary chang-
the operation was a success. The patient should es in the evaluation and treatment of patients
be treated with oral hydrocortisone, at a dose of with Cushings syndrome. The most dramatic
12 mg per square meter of body-surface area change is the emphasis on the antianabolic altera-
once a day in the morning, and a tetracosactide tions in Cushings syndrome, which can provide
(Cortrosyn) stimulation test should be performed a strong basis for separating patients with Cush-
at 3-month intervals. When the tetracosactide- ings syndrome from the more numerous patients
stimulated plasma cortisol level is higher than with obesity and the metabolic syndrome. More
20 g per deciliter (551 mol per liter), cortisol can be done along these lines. Likelihood ratios
administration can be stopped. The same rule are known for proximal muscle weakness and
applies in the case of a unilateral adrenalectomy. can be known for brain atrophy and growth fail-
If the adrenalectomy is bilateral, cortisol, at a ure in children.
dose of 12 to 15 mg per square meter per day, The dexamethasone-suppression test, although

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The n e w e ng l a n d j o u r na l of m e dic i n e

still very popular, no longer has a role in the measurable, the operation failed. The surgeon
evaluation and treatment of patients with Cush- must not administer intraoperative or postopera-
ings syndrome. Only three biochemical tests are tive synthetic glucocorticoids until the plasma
needed: urinary free cortisol, plasma corticotro- cortisol level has been measured.
pin, and plasma cortisol measurements. Urinary Successful evaluation of a patient who is sus-
free cortisol excretion is the test that confirms pected of having Cushings syndrome requires an
the clinical diagnosis of Cushings syndrome. To endocrinologist who is skilled in physical diagno-
be trustworthy, it must be performed in the most sis. Also required is a laboratory that measures
stringent way, with the use of high-pressure urinary free cortisol using high-performance
liquid chromatography followed by mass spectro- liquid chromatography and mass spectrometry
metric quantitation of cortisol. Measurement of and that can measure plasma cortisol and plasma
plasma corticotropin is used to separate cortico- corticotropin by means of radioimmunoassay.
tropin-dependent from corticotropin-independent Inferior petrosal sinus sampling is performed
causes of Cushings syndrome and to separate by an interventional radiologist. The treatment
eutopic from ectopic secretion of corticotropin. for all causes of Cushings syndrome, other than
Inferior petrosal sinus sampling should be per- exogenous glucocorticoids, is surgical, and neuro-
formed in all patients with corticotropin-depen- surgeons, endocrine surgeons, and cancer sur-
dent Cushings syndrome because of the high geons are needed. This level of multidisciplinary
prevalence of nonfunctioning incidental pituitary medical expertise is usually found only at aca-
adenomas among such patients. Measurement of demic medical centers. Thus, most, if not all,
plasma cortisol has only one use: determining patients with Cushings syndrome should be re-
the success or failure of transsphenoidal micro- ferred to such a center for treatment.
adenomectomy or adrenalectomy. If the plasma
cortisol level is not measurable on the morning No potential conflict of interest relevant to this article was
reported.
after the operation (<5 g per deciliter [138 mol Disclosure forms provided by the author are available with the
per liter]), the procedure was a success; if it is full text of this article at NEJM.org.

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