Best Practice & Research Clinical Endocrinology & Metabolism 23 Suppl.

1 (2009) S5S14

Contents lists available at

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Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Diagnosis/differential diagnosis of Cushings syndrome:

a review of best practice
John Newell-Price*
Academic Unit of Diabetes, Endocrinology & Metabolism, University of Sheffield Beech Hill Road, Sheffield S10 2RX, UK
Keywords:
Cushings syndrome
Cushings disease
adrenocorticotrophic hormone (ACTH)
pituitary

Endogenous Cushings syndrome is an uncommon endocrine

disorder that can often prove challenging, for both initial diagnosis
and subsequent differential diagnosis of the underlying cause.
Understanding the advantages and pitfalls of the diagnostic
methods used in Cushings syndrome is essential for accurate
diagnosis and differential diagnosis, and guidelines outlining the
most appropriate approaches have recently been published. We
examine how current practice guidelines can be used in a real casebased scenario, and review the recommended strategies to achieve
successful diagnosis and differential diagnosis.
2009 Elsevier Ltd. All rights reserved.

Introduction
Endogenous Cushings syndrome is an uncommon endocrine disorder characterized by prolonged
and inappropriately elevated levels of circulating cortisol, and is associated with insufficiencies in
the feedback mechanisms of the hypothalamopituitary-adrenal (HPA) axis and the circadian rhythm
of cortisol secretion.
1

Cushings syndrome can affect patients of any age, but is more prevalent in
females than males.
2

Exogenous sources of glucocorticoids (e.g. tablets, creams, inhalers or injections)

are the most common cause of a Cushingoid phenotype. Endogenous Cushings syndrome is most
commonly adrenocorticotrophic hormone (ACTH)-dependent (80% of cases), with ACTH secreted either
by a pituitary adenoma (80% of ACTH-dependent cases) or by a non-pituitary source ectopic ACTH
syndrome (20% of ACTH-dependent cases). The remaining 20% of cases are ACTH-independent, and
are caused by autonomous secretion of cortisol from the adrenal gland(s); 60% of these cases are
adenomas, 40% are carcinomas, and
<
2% are caused by the very rare conditions of massive adrenal
hyperplasia, primary pigmented nodular adrenal disease (PPNAD), or McCune-Albright syndrome.
3

Once Cushings syndrome is suspected, confirming hypercortisolism and establishing the source
of oversecretion can prove challenging. An initial diagnosis of Cushings syndrome should be clearly
established before any attempts are made at differential diagnosis, as inconclusive test results and
factors such as patient characteristics, use of concomitant medication, and poor assay specificity can
*Correspondence: John Newell-Price, MA, PhD, FRCP. Academic Unit of Diabetes, Endocrinology & Metabolism, University of
Sheffield, Beech Hill Road, Sheffield S10 2RX, UK. Tel.: +44(0)1142261409; fax: +44(0)1142711863.
E-mail address:
j.newellprice@sheffield.ac.uk (J. Newell-Price).
1521-690X/$ see front matter 2009 Elsevier Ltd. All rights reserved..
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J. Newell-Price/Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) S5

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hinder diagnosis and the need for subsequent patient care. In this review, we examine a case-based

diagnostic dilemma encountered in clinical practice, and provide an overview of current practice
strategies for the accurate diagnosis and differential diagnosis of Cushings syndrome/disease.
Case study: diagnostic complexity in Cushings syndrome
A 57-year-old man was referred to our neuroendocrine clinic. He had a history of iron-deficiency
anaemia. Endoscopy had shown an irregular gastric mucosa, and biopsy revealed a gastric carcinoid.
A computed tomography (CT) scan had shown abnormalities in the body and fundus of the stomach,
but a normal pancreas and liver. He had elevated corrected levels of serum calcium (2.9mmol/L) and
parathyroid hormone (PTH) (31.1pmol/L), consistent with primary hyperparathyroidism. He also had
a history of chronic renal impairment, hypertension, and controlled type II diabetes, and drank 23
large glasses of wine per night, with even more at weekends. He appeared generally well, but with
some truncal obesity, thin arms, and mild bruising. Medications being taken at the time included
lansoprazole, bendroflumethazide, atenolol, aspirin, ferrous sulphate, and simvastatin.
Initial investigations in the clinic again showed elevated calcium and PTH values of 2.97mmol/L
and 330ng/L, respectively. Impaired renal function was reflected by an elevated serum creatinine
of 165
m
mol/L (eGF 40mL/min/1.73m
2

). Considering his physical appearance, a 48-h 2mg/day lowdose dexamethasone suppression test (LDDST) was performed and showed no suppression, with basal
serum cortisol levels of 505nmol/L (2+0h) and 566nmol/L post dexamethasone (2+48h). The ACTH
concentration was 42.1ng/L (normal range
<
55ng/L). Based on these results, confirmation of Cushings
syndrome was still questionable, considering the patients history of excessive alcohol intake and
renal impairment.
Repeat LDDST testing after no alcohol intake for approximately 4 weeks yielded lower cortisol levels
at 2+0h (394nmol/L) and 2+48h (176nmol/L), indicating some suppression, but not below 50nmol/L.
A series of urinary free cortisol (UFC) tests were done as a secondary measure to confirm Cushings
syndrome. Initial UFC measurements were just above the normal range at 263 and 271nmol/24h.
Repeat UFC measurements showed levels that were still elevated at 276 and 295nmol/24h. As the
patient had no suppression on several LDDST evaluations and consistently elevated UFC, despite
significant renal impairment, a diagnosis of ACTH-dependent Cushings syndrome was confirmed,
although mild in clinical phenotype. In association with Cushings syndrome, diagnoses of primary
hyperparathyroidism and a gastric carcinoid were also established, raising the likelihood of multiple
endocrine neoplasia type 1 (MEN1).
In view of the diagnosis of a gastric carcinoid, gut peptides were investigated as part of the initial
step towards establishing the source of excessive cortisol secretion (i.e. pituitary or ectopic). Levels
of gastrin, pancreatic polypeptide, glucagon, and chromogranin A were all elevated (
>
400,
>
500, 104,
and 452pmol/L, respectively). Repeat gut peptide results remained highly elevated despite cessation
of protein-pump inhibitor (PPI) medication.
Bone mineral density (BMD) imaging revealed an extremely low T score of 5.8 for the spine; T score
values for the hip (3.0) and forearm (2.9) were consistent with the changes seen in cortisol excess
and hyperparathyroidism. Magnetic resonance imaging (MRI) of the pituitary gland revealed a possible
small abnormality (Fig. 1).
The patient then had a standard corticotrophin-releasing hormone (CRH) test of up to 60min with
no significant changes observed in ACTH (36.434.8ng/L) or serum cortisol (704744nmol/L). Bilateral
inferior petrosal sinus sampling (BIPSS) showed no gradient between the peripheral and left and right
inferior petrosal sinus, or after stimulation with 100mg human sequence CRH at 0min, suggesting a
non-pituitary source of ACTH hypersecretion (Table 1).
In investigations for an ectopic source of the ACTH, CT imaging showed no abnormality in the
thorax, although the hyperplastic parathyroid glands were clearly visible. CT imaging of the abdomen
showed profound gastric rugae consistent with hypergastrinaemia (Fig. 2), along with five or more
pancreatic neuroendocrine tumours, and hyperplasia of the left and right adrenal glands (Fig. 3). An
octreotide scan demonstrated uptake in various neuroendocrine tumours in the pancreas, with a small
metastasis in the fundus of the stomach further complicating confirmation of a pituitary or ectopic
source of hypersecretion.
J. Newell-Price/Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) S5

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Fig. 1.
Pituitary MRI showing a small abnormality consistent with a potential pituitary source of excessive cortisol production.
Table 1
Bilateral inferior petrosal sinus sampling test for the case study patient
Time (min) ACTH (ng/L)
Peripheral Left inferior petrosal Right inferior petrosal
0
39.4 39.5
39.2
5 53.2 61.9 53.3
10 50.0 75.2 61.4
15 52.5 61.1 60.4
ACTH, adrenocorticotrophic hormone.
Fig. 2.

CT scan of the stomach showing excessive gastric rugae.

The final diagnosis confirmed that the patient had ACTH-dependent Cushings syndrome with
gastric carcinoid, multiple pancreatic neuroendocrine tumours, primary hyperparathyroidism, severe
osteoporosis, gastrinoma with Zollinger-Ellison syndrome (controlled on PPI), and MEN1 confirmed
by genetic testing. The patients corrected serum calcium increased to 3.34mmol/L, requiring
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Fig. 3.
Abdominal CT showing five pancreatic neuroendocrine tumours and hyperplasia of both the left and right adrenal
glands.

urgent intervention, and he underwent 3.5-gland parathyroidectomy with cervical exploration and
autotransplant to the right sternocleidomastoid, which lowered serum calcium levels to 2.38nmol/L.
Histology also revealed parathyroid hyperplasia.
In view of the patients severe osteoporosis, hypertension, and diabetes mellitus, urgent attention
was also needed for his ACTH-dependent Cushings syndrome. Considering his diagnosis of MEN1,
the source of ACTH could either be from the pituitary or any of the neuroendocrine tumours in his
pancreas. Based on inconclusive biochemical data, combined with a lack of a central to peripheral
gradient on BIPSS and the patients reluctance to consider a total pancreatectomy, he underwent a
bilateral adrenalectomy, leading to improved truncal obesity, considerable weight loss, and a fasting
glucose of 4.4mmol/L. The patients osteoporosis was managed with calcium, vitamin D supplements,
and weekly bisphosphonate, resulting in an improvement in his BMD.
Causes of Cushings syndrome
Once exogenous glucocorticoid use has been excluded, the majority of cases of Cushings syndrome are
caused by ACTH-dependent tumours, and ~7080% of these are due to pituitary adenomas (Cushings
disease), with the remainder attributable to ectopic ACTH sources, which may be occult and difficult
to find.
3

Ectopic sources of ACTH are most frequently small-cell lung carcinomas (SCLC) and bronchial
carcinoid tumours, but can also arise from many other organs in the body.
46

When the ACTH source

develops from SCLC, the presentation may be rapid, with weight loss, weakness, and pigmentation,
rather than the classic Cushingoid phenotype. However, when a carcinoid tumour is the source of
ACTH, the phenotype and biochemistry can exactly mimic that of Cushings disease. ACTH-independent
Cushings syndrome generally arises from an adrenal adenoma or carcinoma, which consequently
suppresses pituitary ACTH,
7,8

although in very rare cases (12%), it can be caused by other sources,

e.g. PPNAD, the Carney complex, ACTH-independent macronodular adrenal hyperplasia (AIMAH), or
McCune-Albright syndrome.
3

Cushings syndrome: strategies for diagnosis

The biochemical hallmark of Cushings syndrome is inappropriate cortisol secretion not subject to
the normal negative feedback effects of circulating glucocorticoids. Diagnostic tests are based on
demonstration of excessive cortisol secretion, loss of its circadian rhythm, and abnormal feedback
regulation of the HPA axis. Patients with Cushings syndrome generally demonstrate resistance to
negative feedback during testing. In Cushings disease, adenomas hypersecreting ACTH retain some
negative feedback, whereas ectopic neoplasms are generally unresponsive.