Case Report
ACUTE SEVERE CUSHING SYNDROME:
NOT ALWAYS ECTOPIC ACTH SYNDROME
Carlos Tavares Bello, MD1; Inês Gil, MD2; Filipa Alves Serra, MD3; João Sequeira Duarte1
ABSTRACT
Objective: Cushing syndrome (CS) is a rare disease
that results from prolonged supraphysiologic tissue action
of glucocorticoids. Cushing disease is the most frequent
cause of endogenous CS and is associated with increased
morbidity and mortality. Disease onset and severity reflects
the magnitude of cortisol excess, and ectopic adrenocorti-
cotropic hormone (ACTH) syndrome is the most frequent
cause of acute, severe CS. Cushing disease tends to have a
slower onset with gradual appearance of the typical pheno-
type and associated metabolic consequences.
Methods: Case report and review of the literature.
Results: A 62-year-old man was admitted for altered
mental status, severe hyperglycemia, and refractory
hypokalemia. Despite clinical and biochemical presen-
tation being suggestive of ectopic ACTH secretion, an
ACTH-secreting pituitary adenoma was the underlying
cause. Endoscopic transsphenoidal tumor excision led to
disease remission.
Submitted for publication April 9, 2017
Accepted for publication May 9, 2017
From the 1Department of Endocrinology Hospital de Egas Moniz,
Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal, 2Department of
Neuroradiology, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal,
and 3Department of Endocrinology, Hospital das Forças Armadas, Lisboa,
Portugal.
Address correspondence to Dr. Carlos Tavares Bello, Hospital de Egas
Moniz, Centro Hospitalar de Lisboa Ocidental, Rua Da Junqueira 126, 1349-
019, Lisboa, Portugal.
E-mail: bello.carlos04@gmail.com.
DOI: 10.4158/EP171905.CR
To purchase reprints of this article, please visit: www.aace.com/reprints.
Copyright © 2018 AACE.
Copyright © 2018 AACE AACE CLINICAL CASE REPORTS Vol 4 No. 1 January/February 2018 e45
Conclusion: The case is noteworthy for the atypical
clinical presentation, severity of the hypokalemia, and
excellent treatment outcome. The biochemical testing has
limitations, and these should be kept in mind in the inves-
tigation of hypercortisolism. (AACE Clinical Case Rep.
2018;4:e45-e50)
Abbreviations:
ACTH = adrenocorticotropic hormone; CD = Cushing
disease; CS = Cushing syndrome; CT = computed
tomography; EAS = ectopic ACTH secretion; MRI =
magnetic resonance imaging
INTRODUCTION
Cushing disease (CD) is the most frequent cause of
endogenous Cushing syndrome (CS). It is characterized by
an autonomous secretion of cortisol secondary to an under-
lying pituitary adenoma. Pituitary adenomas are thought
to affect 10.6% of the population, mostly undiagnosed
and asymptomatic, and among these, up to 13.8% may be
adrenocorticotropic hormone (ACTH)-secreting (1,2). CD
is more common in female patients and has the highest
incidence during the fourth decade of life. Lesions smaller
than 1 cm (microadenomas) are more frequent than inva-
sive lesions at the time of diagnosis.
Patients with CD often exhibit numerous clinical and
laboratory abnormalities. The prolonged supraphysiologic
tissue action of glucocorticoids is believed to underlie the
majority of the consequences of CS. As glucocorticoids
are major contraregulatory hormones in carbohydrate
metabolism, glucose intolerance and diabetes mellitus are,
as expected, common features, affecting up to 50% of CS
patients. Some authors consider this to be an underestima-
tion, as no standardized strategies to screen hyperglycemia
e46 Nonectopic Severe Cushing, AACE Clinical Case Rep. 2018;4(No. 1)
in CS have been established (3). Diabetes screening by
means of fasting blood glucose levels fails to diagnose a
significant portion of patients that have predominant post-
prandial hyperglycemia. For screening purposes, either the
oral glucose tolerance test and/or glycated hemoglobin are
considered far more sensitive (4). Furthermore, hypoka-
lemic metabolic alkalosis is not so frequent in CS, being
present in up to 15% of cases (5).
Although CD remains the most frequent cause of
endogenous hypercortisolism, acute, severe clinical
presentations are more typical of ectopic ACTH secretion.
This presentation may be explained by the fact that disease
onset and severity reflect on how high and how fast corti-
sol levels have risen; in ectopic ACTH secretion, cortisol
secretion is far more extreme than in any other CS subtype
(6). The authors report on a case of a patient that presented
with severe hyperglycemia and refractory hypokalemic
metabolic alkalosis that upon investigation was compatible
with CD. In the case reports that have described a simi-
lar presenting clinical picture, the underlying cause was
always ectopic ACTH secretion (7-10). The diagnosis of
CD was unexpected; therefore, we believe that this case
report is noteworthy.
CASE REPORT
A 62-year-old man with a past medical history of
obesity and hypertension, without any previous medica-
tion, was admitted to the emergency department with
altered mental status, polyuria, polydipsia, irritability,
easy bruising, and proximal muscle weakness of sudden
onset. Complaints were progressive and had begun 1
month prior to hospital admission. On admission, physical
examination was remarkable for normal blood pressure,
slight dehydration, obesity (body mass index 31.2 kg/m2),
moon face, echymoses on the upper limbs, and proximal
muscle weakness. There was no peripheral edema, striae,
or evidence of congestive heart failure. Neurologically, the
patient was disoriented in time and space, and he also had
slurred speech.
At admission, plasma glucose was 452 mg/dL (25
mmol/L), serum potassium 2.7 mmol/L, arterial pH 7.6,
and bicarbonate 50 mmol/L, without evidence of under-
lying infection (unremarkable complete blood count and
C-reactive protein levels). Electrocardiogram revealed no
changes typical of hypokalemia. A head computed tomog-
raphy (CT) showed no evidence of cerebral ischemia or
hemorrhage but did reveal an ill-defined sellar mass. The
patient was admitted to the medical ward, where intrave-
nous fluids were administered, and a subcutaneous, inten-
sive insulin regimen with glargine and lispro was started.
After a transient clinical improvement, the patient
developed peripheral edema, orthopnea, and fatigue,
along with pulmonary rales, jugular venous distension,
arterial hypertension, and an elevated brain natriuretic
Copyright © 2018 AACE
peptide. Echocardiogram showed left ventricular concen-
tric hypertrophy, diastolic dysfunction, without regional
wall motion abnormalities suggestive of ischemia. Acute
congestive heart failure was diagnosed, and intravenous
diuretics (furosemide 60 mg/day) were administered.
Diuretic dose was soon downtitrated due to rapid clinical
improvement; however, on the third day of diuretic thera-
py, laboratory tests documented severe hypokalemia (1.5
mmol/L). Furosemide was stopped, and intravenous potas-
sium supplementation was given. High doses of potassium
supplements were needed for correction of the hypokale-
mia and maintenance of normokalemia. An average main-
tenance dose of 100 mEq/day of potassium chloride was
required even after the introduction of spironolactone.
When his clinical status stabilized, further investi-
gation revealed ACTH-dependent hypercortisolism and
hypercortisolism-induced suppression of thyroid-stimu-
lating hormone, follicle-stimulating hormone, luteinizing
hormone, and growth hormone (Table 1).
Despite biochemical evidence of ACTH-dependent
hypercortisolism and the identification of a sellar mass, the
severity of the clinical picture led to further investigations
aiming to exclude ectopic ACTH syndrome. A 48-hour,
8-mg dexamethasone suppression test documented a rise
in plasma cortisol values (20.3 to 38.3 µg/dL), and inferior
petrosal venous sinus sampling revealed baseline and stim-
ulated inferior petrosal sinus to peripheral ACTH ratios of
1.46 and 1.5, respectively. Due to clinical and biochemi-
cal suggestion of ectopic ACTH syndrome, Octreoscan
followed by CT of the chest, abdomen, and pelvis were
performed, both evidencing no relevant changes. Due to
the initial CT suggestion of a sellar mass, cranial magnet-
ic resonance imaging (MRI) was performed, revealing a
right-sided sellar expansive lesion with suprasellar and
right cavernous sinus extension measuring 22 mm maxi-
mum diameter. It had a heterogeneous texture with multi-
focal hypersignaling areas in T1-weighted images (Fig. 1).
Despite biochemical evidence suggestive of ectopic
ACTH syndrome, the only positive imaging finding was
the invasive pituitary adenoma. The patient underwent
endoscopic transsphenoidal tumor excision, with pre-oper-
ative preparation with metyrapone. Postoperatively, the
patient developed transient diabetes insipidus. Intra- and
postoperative hormone supplementation with glucocorti-
coids was prescribed. Potassium supplements were tapered
over 7 days after surgery, with rapid potassium level
normalization. Hydrocortisone dose was also progressive-
ly tapered, and clinical benefits regarding mental status,
hyperglycemia, and hypertension were rapidly evident
over a 4-week period. Blood and urinary free cortisol and
plasma ACTH soon normalized after surgery (postopera-
tive day 7, plasma cortisol 11.1 µg/dL; ACTH, 10.4 pg/
mL) while on oral hydrocortisone replacement therapy.
Histology report was a pituitary adenoma without cellular
atypia or mitosis. Immunohistochemistry was positive for
Copyright © 2018 AACE Nonectopic Severe Cushing, AACE Clinical Case Rep. 2018;4(No. 1) e47

Table 1
Patient’s Laboratory Investigation
Parameter Value Reference range
Morning plasma cortisol 26.4 10-20 µg/dL
24-h urinary free cortisol 12,112.8 29-214 µg/day
ACTH 121 <46 pg/mL
Renin activity 0.5 0.5-1.9 ng/mL/hour
Aldosterone <1.1 <22 ng/dL
Spot urinary potassium 105.7 20-40 mg/dL
Concomitant serum potassium 3.8 3.5-5.2 mmol/L
Baseline values
TSH 0.22 0.5-4.68 µU/L
Free T4 13.4 12-22.8 pmol/L
Prolactin 9.1 <19 ng/mL
FSH <0.66 1.5-12.4 U/L
LH <0.22 1.7-8.6 U/L
Total testosterone 41 193-740 ng/dL
IGF-1 49.3 91-282 ng/mL
1 mg dexamethasone
Cortisol after DST 18.6 <1.8 µg/dL
suppression test (DST)
Suggestive of ectopic
48-hour 8 mg DST Cortisol: basal→post DST ↑100%a
ACTH syndrome
Abbreviations: ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone;
IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; T4 = thyroxine; TSH = thyroid-
stimulating hormone.
aCortisol levels increased from 18.9 to 38.5 µg/dL after the 48-hour 8 mg DST.

Fig. 1. Magnetic resonance imaging presurgery. There is a lesion that
expands mainly the right side of the sella turcica with invasion of the
posterior region of the right cavernous sinus (red arrow).
Fig. 2. Magnetic resonance imaging presurgery showing lesion that
expands mainly the right side of sella turcica with invasion of posterior
region of right cavernous sinus (red arrow) and spontaneous high signal
in T1-weighted images (white arrowheads) demonstrating recent hemor-
rhagic component.
e48 Nonectopic Severe Cushing, AACE Clinical Case Rep. 2018;4(No. 1)
ACTH, and the Ki67 index was 1%. Postoperative MRI (6
months) showed a residual lesion of 10 mm that was stable
1 year after the operation (Figs. 3 and 4).
Eighteen months after surgery, the patient has no
complaints, his Cushingoid phenotype has ameliorated,
and he remains on physiologic doses of hydrocortisone
(15 mg/day) and metformin monotherapy, with adequate
glycemic control.
DISCUSSION
CS is characterized by a constellation of signs and
symptoms that develop due to excessive, prolonged tissue
exposure to inappropriate high glucocorticoid levels. The
majority of cases are attributable to exogenous cortico-
steroid use (iatrogenic CS). Endogenous Cushing is far
less common, with an estimated incidence of 0.7 to 2.4
per million population. It may be etiologically divided
into ACTH-dependent (80 to 85% of cases) and ACTH-
independent disease (3).
CD accounts for 75 to 80% of ACTH-dependent CS
cases, is more prevalent in females, and has the highest
incidence in the fourth decade. The source of excessive
circulating cortisol is usually an ACTH-secreting pituitary
microadenoma (<1 cm). Ectopic ACTH syndrome (EAS)
is less common, being responsible for 15 to 20% of endog-
enous CS cases. It is more frequent in males and occurs
later than CD. Excessive ACTH tends to be produced by an
extrapituitary tumor such as pulmonary (45% of all EAS
cases: bronchial carcinoid, pulmonary small cell or adeno-
Fig. 3. Magnetic resonance imaging 6 months after surgery. There is
lesion reduction, being substituted by multiple cysts with high signal in
T2-weighted images (white arrow). The lesion has lobulated borders and
peripheral contrast enhancement. The supra-sellar cistern (asterisk) is
more permeable due to the reduction of the pituitary adenoma. Left devia-
tion of pituitary stalk (red arrow) persists. These features may correspond
to postsurgical changes or presence of residual lesion.
Copyright © 2018 AACE
carcinoma), thymic (11%), and gastrointestinal neuroen-
docrine tumors (5%), islet cell tumors (8%), medullary
thyroid carcinomas (6%), and pheochromocytomas (5%).
Epithelial neoplasms may also be associated with EAS;
however, they are far less frequent (6). Adrenal CS, on the
other hand, is the most frequent cause of CS in the pedi-
atric age group. Rare causes of CS include corticotropin-
releasing hormone–secreting neoplasms and cyclic CS (3).
Clinical presentation of CS will vary according to
gender, age, underlying cause, duration and severity of
hypercortisolism, and the rapidity of biochemical gluco-
corticoid rise. Men usually present at a younger age with
a more severe clinical manifestations, such as violaceous
striae, muscle weakness, osteoporosis, and urolithiasis
(3). Obesity, hypogonadism, and psychiatric and cogni-
tive dysfunction are highly prevalent in both genders (3).
Metabolic complications are also common, namely, hyper-
tension in 70 to 80%, glucose intolerance in 45 to 70%,
hypercholesterolemia in 70%, and osteoporosis in 50 to
80%. Hypokalemic metabolic alkalosis affects mostly
EAS patients (90% vs. 10 to 15% in CD) (3). According
to etiology, circulating cortisol levels are usually higher
in patients with EAS, explaining the rapid onset (over 1
month) and severity of the clinical picture in these cases.
EAS secondary to more indolent tumors may be clini-
cally indistinguishable from CD, in which the classical
clinical and metabolic abnormalities of CS are of grad-
ual onset (over months to years) (9). Diagnosis relies on
confirmation of autonomous cortisol secretion with differ-
ent tests: 1 mg and low-dose dexamethasone suppression
Fig. 4. Magnetic resonance imaging 6 months after surgery. There is
lesion reduction (9 × 10 mm), with peripheral enhancement (white
arrowheads) in T1-weighted images and lobulated margins. The supra-
sellar cistern (asterisk) is more permeable due to the reduction of the
pituitary adenoma. Left deviation of pituitary stalk (red arrow) persists.
These features may correspond to postsurgical changes or presence of
residual lesion.
Copyright © 2018 AACE Nonectopic Severe Cushing, AACE Clinical Case Rep. 2018;4(No. 1) e49
test, midnight salivary cortisol, 24-hour urinary free corti-
sol, and cortisol rhythm. After establishing the diagnosis,
establishing the cause is the next step and includes ACTH
measurement. If ACTH is elevated, additional tests are
needed to distinguish CD from EAS (8 mg dexamethasone
suppression test [overnight or 48-hour] and inferior petro-
sal sinus sampling), and according to the findings, cranial
MRI or nuclear imaging (Octreoscan, 68Ga-DOTATATE),
respectively, may be warranted. ACTH levels below 5 pg/
mL warrant adrenal imaging, and if needed, genetic testing
(Carney complex, PRKAR1A, ARM5) (10).
First-line therapy is almost always surgical.
Transsphenoidal surgery in CD is associated with relapse
in 20% of patients, while adrenal causes are often curable,
with an excellent prognosis in benign disease. EAS, on
the other hand, is difficult to manage, since most of the
ACTH-secreting neoplasms are already metastasized
at the time of diagnosis and may require either medical
therapy or bilateral adrenalectomy. Corticosteroid cover
is required during and for some time after surgery, since
long-term hypercortisolism suppresses both nonadenoma
corticotrophes (ACTH-dependent cases) and the “healthy”
adrenal (unilateral ACTH-independent causes). This long-
term suppression leads to a temporary adrenal ‘stunning’
that requires time to full functional recovery. Physiologic
glucocorticoid replacement may be required for more than
1 year after surgery. Pituitary radiotherapy may be an
option if there is residual tumor after surgery. Its effects
are delayed for years and usually require medical thera-
py until the radiotherapy has an effect. Medical therapy
is only indicated as pre-operative preparation in patients
with contra-indications to surgery, relapsed and occult
disease cases, and as a bridge to the effects of radiotherapy.
Pharmacologic options include ketoconazole, metyrapone,
mitotane, etomidate, mifepristone, pasireotide, and caber-
goline. Most of the agents have a poor side effect profile,
and since some are adrenolytic, may warrant concomitant
glucocorticoid supplementation (3).
The reported case illustrates an acute, severe presen-
tation of CS, which would usually be suggestive of an
ectopic ACTH source; however, the absence of an iden-
tifiable extrapituitary tumor along with the presence of a
pituitary macroadenoma led to a clinical dilemma. On the
one hand, the adenoma appeared to be invasive and was
the probable cause the hypopituitarism, therefore favoring
a surgical indication. On the other hand, incidental pitu-
itary adenomas are present in 10.6% of the population, and
the macroadenoma could have been just an incidentaloma,
if not for the concomitant hypopituitarism, since the clini-
cal and biochemical picture were both highly suggestive of
EAS. From this case, it is clear that pituitary adenomas can
also give rise to florid CS presentations.
The reason behind the acute presentation is not clear.
The large tumor size, along with the low mitotic index, could
suggest that the adenoma was not rapidly growing. No typi-
cal clinical data of long-term ‘subclinical’ Cushing suggest
a previously undiagnosed CD that suddenly progressed.
The tumor was probably an inefficient secreting neoplasm
that for unknown reasons suddenly became hormonally
active. The authors speculate that beyond tumor mass and
mitotic index, other mechanisms might be at play, namely,
proopiomelanocortin processing and/or ACTH packag-
ing defects. A few case reports (mostly affecting women
before the seventh decade) have described silent macroad-
enoma progression to florid CS; however, clinical evidence
data are still scarce for this seemingly distinct clinical
entity (11).
After establishing the diagnosis of CS, the etiologic
diagnostic strategies also have some limitations. The 8
mg dexamethasone suppression test relies on the prin-
ciple that pituitary adenoma ACTH secretion is sensitive
to prolonged extremely high doses of exogenous gluco-
corticoids. However, the failure to suppress cortisol secre-
tion after high-dose dexamethasone (to less than 50% of
baseline cortisol concentration) has been shown to have
poor accuracy, sensitivity, and specificity (76.5, 79.3, and
66.7%, respectively) in the differentiation between CD and
EAS. Furthermore, pituitary ACTH-secreting macroad-
enomas, compared with microadenomas, are often less
suppressible in dynamic testing, possibly explaining some
of the unexpected biochemical results (12). Inferior petro-
sal sinus sampling also has limitations, most of which are
of technical character. This approach requires the expertise
of a high-volume center, as the imprecise placement of the
central catheters may be a significant source of error (13).
In the reported case, the clinical and biochemical
response to pituitary surgery are highly suggestive of under-
lying CD. If clinical or biochemical evidence of relapse CS
is documented, repeated full diagnostic approach should
be done. The case is noteworthy for the severe and rapidly
progressive clinical course of CS, that despite biochemi-
cally being compatible with ectopic ACTH secretion,
the underlying cause was an ACTH-secreting pituitary
macroadenoma. Not all acute CS cases are due to ectopic
ACTH, and even well-recognized diagnostic strategies
have caveats, as was the case here.
CONCLUSION
CD often presents with the gradual onset of a constel-
lation of signs and symptoms of prolonged supraphysi-
ologic cortisol levels. Sudden and dramatic onset of CS
often suggests an ectopic ACTH-secreting tumor. These
cases are more frequently accompanied by altered mental
status, hyperglycemic emergencies, and hypokalemia.
The described case illustrates an atypical presentation of
a severe case of CD with new, marked hyperglycemia and
severe refractory hypokalemia. It is noteworthy to empha-
size the importance in the suspicion of a secondary cause
of diabetes mellitus in the presence of hyperglycemia
e50 Nonectopic Severe Cushing, AACE Clinical Case Rep. 2018;4(No. 1)
emergencies. Furthermore, the biochemical investigation
of ACTH-dependent CS is complex and subject to inac-
curacy, justifying a holistic approach and goal-oriented
therapy in all cases.
DISCLOSURE
The authors have no multiplicity of interest to disclose.
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