1. Dr. M. SOFI MD; FRCP (London); FRCPEdin; FRCSEdin
CUSHING’S SYNDROME
Dr. M. SOFI MD; FRCP (London); FRCPEdin; FRCSEdin

2. CUSHING’S SYNDROME A metabolic disorder caused by overproduction of
corticosteroid hormones by the adrenal cortex and often
involving obesity and high blood pressure.
Diagnosis is often difficult because none of the symptoms or
signs are pathognomonic of the syndrome.
There is a large spectrum of manifestations from subclinical to
overt syndrome, depending on duration and intensity of
excess steroid production.
Patients with obesity, hypertension, and glucose intolerance
are common who do not have adrenal hyperfunction.
An important clinical clue to the presence of glucocorticoid
excess is the simultaneous development and increasing
severity of several of these symptoms.

3. CUSHING’S SYNDROME
Symptoms most suggestive of the hypercortisolism include supraclavicular fat pads, skin atrophy, wide purplish striae, and proximal muscle weakness.
Some of the most common manifestations of Cushing’s syndrome, such as obesity, hypertension, and glucose intolerance, are less suggestive of the presence of hypercortisolism as they are also common in individuals who do not have adrenal hyperfunction.
Iatrogenic CS is likely the most common cause
Ectopic corticotropin (ACTH) secretion associated with small-cell Ca lung, hypercortisolism may not be recognized because of weight loss and paraneoplastic syndromes.
Pituitary ACTH-dependent Cushing's syndrome is five to six times more common than Cushing's syndrome caused by benign and malignant adrenal tumors combined.

4. Symptoms and signs of Cushing's syndrome
Symptom or sign
Reported incidence, percent
Centripetal obesity
79 to 97
Facial plethora
50 to 94
Glucose intolerance
39 to 90
Weakness, proximal myopathy
29 to 90
Hypertension
74 to 87
Psychological changes
31 to 86
Easy bruisability
Hirsutism
64 to 81
Impotence
55 to 80
Acne, oily skin
26 to 80
Symptom or sign
Reported incidence, percent
Abdominal striae
51 to 71
Ankle edema
28 to 60
Backache, vertebral collapse, fracture
40 to 50
Polydipsia, polyuria
25 to 44
Renal calculi
15 to 19
Hyperpigmentation
4 to 16
Headache
0 to 47
Exophthalmos
0 to 33
Tinea versicolor infection
0 to 30
Abdominal pain
0 to 21

5. History & Physical Examination
Patients with Cushing syndrome may complain of weight gain.
Changes in their skin, including purple stretch marks, easy bruising, and signs of skin thinning.
May have difficulty climbing stairs, getting out of a low chair, and raising their arms.
Menstrual irregularities, amenorrhea, infertility, and decreased libido may occur in women due to inhibition of pulsatile secretion of (LH) and (FSH).
In men, inhibition of LHRH and FSH/LH function may lead to decreased libido and impotence.
Psychological problems such as depression, cognitive dysfunction, and emotional labiality may develop.

6. New-onset or worsening of hypertension and DM,
History & Physical Examination
Patients with Cushing disease may develop headaches, polyuria and nocturia, visual problems, or galactorrhea.
Rapid onset of symptoms of glucocorticoid excess in conjunction with virilization in women or feminization in men suggests an adrenal carcinoma as the underlying cause of the Cushing syndrome.
New-onset or worsening of hypertension and DM,
Difficulty with wound healing, increased infections,
If sufficient mass effect from the tumor is present on the anterior pituitary, hyposomatotropism, hypothyroidism, hyper-prolactinemia or hypoprolactinemia, and hypogonadism may develop.

7. Physical Examination Obesity
Patients may have increased adipose tissue in the face (moon facies), upper back at the base of neck (buffalo hump), and above the clavicles (supraclavicular fat pads).
Central obesity with increased adipose tissue in the mediastinum and peritoneum; increased waist-to-hip ratio greater than 1 in men and 0.8 in women; and, upon CT scan of the abdomen, increased visceral fat is evident.
Cardiovascular and renal
Hypertension and possibly edema may be present due to cortisol activation of the mineralocorticoid receptor leading to sodium and water retention.
Gastroenterologic
Peptic ulceration may occur with or without symptoms Particularly at risk are patients given high doses of glucocorticoids (rare in endogenous hypercortisolism).

8. Physical Examination Obesity
Patients may have increased adipose tissue in the face (moon facies), upper back at the base of neck (buffalo hump), and above the clavicles (supraclavicular fat pads).
Central obesity with increased adipose tissue in the mediastinum and peritoneum; increased waist-to-hip ratio greater than 1 in men and 0.8 in women; and, upon CT scan of the abdomen, increased visceral fat is evident.
Cardiovascular and renal
Hypertension and possibly edema may be present due to cortisol activation of the mineralocorticoid receptor leading to sodium and water retention.
Gastroenterologic
Peptic ulceration may occur with or without symptoms Particularly at risk are patients given high doses of glucocorticoids (rare in endogenous hypercortisolism).

9. Skin Glucocorticoid excess may cause increased lanugo facial hair.
Physical Examination
Skin
Facial plethora may be present, especially over the cheeks.
Violaceous striae, often wider than 0.5 cm, are observed most commonly over the abdomen, buttocks, lower back, upper thighs, upper arms, and breasts.
Patients may have telangiectasias and purpura.
Cutaneous atrophy with exposure of subcutaneous vasculature tissue and tenting of skin may be evident.
Glucocorticoid excess may cause increased lanugo facial hair.
Ecchymoses may be present.
Acanthosis nigricans, which is associated with insulin resistance and hyperinsulinism, may be present. The most common sites are axilla and areas of frequent rubbing, such as over elbows, around the neck, and under the breasts.

10. Proximal muscle weakness may be evident.
Physical Examination
Endocrine
Galactorrhea may occur when anterior pituitary tumors compress the pituitary stalk, leading to elevated prolactin levels.
Signs of hypothyroidism, such as slow reflex relaxation, may occur from an anterior pituitary tumor whose size interferes with proper thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) function. Similarly, other pituitary function may be interrupted.
Low testosterone levels in men may lead to decreased testicular volume from inhibition of LHRH and LH/FSH function.
Skeletal/muscular
Proximal muscle weakness may be evident.
Osteoporosis may lead to incident fractures and kyphosis, height loss, and axial skeletal bone pain. Avascular necrosis of the hip is also possible from glucocorticoid excess.
Neuropsychological
Patients may experience emotional liability, fatigue, and depression.
Visual-field defects, often bitemporal, and blurred vision may occur in individuals with large ACTH-producing pituitary tumors that impinge on the optic chiasma.

11. Moon face causes the face to become round, full, or puffy
Moon face causes the face to become round, full, or puffy. The sides of the face become so round from the fat that the ears can't be seen from the front of face. Fat deposits in the sides of the skull can also make the face look rounder.
A high release of hormones, especially cortisol, is a cause of moon face called hypercortisolism.

12. Easy bruisability in Cushing's disease
Forearm of a 42-year-old man with Cushing's disease showing multiple ecchymosis due to minimal trauma.

13. Buffalo hump in Cushing's syndrome
Side view of a patient with Cushing's syndrome showing a dorsocervical fat pad ("buffalo hump").

14. Buccal hyperpigmentation due to ACTH excess
Lips and gums of a 32-year-old man demonstrating hyperpigmentation of the buccal mucosa
The high plasma ACTH concentrations responsible for the hyperpigmentation were due in this case to primary adrenal insufficiency; similar changes can be seen in patients with ACTH-dependent Cushing's syndrome or Nelson's syndrome.

15. Right hand of a 16-year-old woman with Nelson's syndrome (right) next to that of a woman without endocrine disease (left), demonstrating skin hyperpigmentation that is accentuated over the knuckles (which are areas of repeated trauma). Similar hyperpigmentation occurs in patients with other causes of chronic ACTH excess such as Cushing's disease or primary adrenal insufficiency.

16. Premature puberty in Cushing's syndrome
A 2.5 year-old boy with an adrenocortical carcinoma that secreted excess cortisol and androgens. He presented with signs of Cushing's syndrome (moon face, obesity) and premature puberty (Tanner III pubic hair and penis enlargement, with prepubertal testicular volume).

17. Proximal muscle wasting and
weakness are common in
Cushing's syndrome, being
induced by the catabolic
effects of excess glucocorticoid
on skeletal muscle .
As a result, many patients
cannot rise from a squatting
position without assistance.
patients with more severe
disease may be unable to
climb stairs or get up from a
deep chair.
Muscle wasting and weakness
are rare in patients with
pseudo-Cushing's syndrome.

19. Who should be tested? — Patients in whom a diagnosis is most likely, include:
Unusual findings for their age (osteoporosis or
hypertension in young adults)
Multiple progressive features of Cushing’s syndrome
(CS), particularly those that are predictive of CS such as:
facial plethora,
proximal myopathy
striae (>1 cm wide and red/purple)
easy bruising
Unexplained severe features (resistant hypertension,
osteoporosis) at any age
Adrenal incidentalomas

20. Exclude exogenous glucocorticoids — 
The most common cause of hypercortisolism is ingestion
of prescribed glucocorticoid.
All glucocorticoids, including potent inhaled and topical
glucocorticoids such as beclomethasone and fluocinolone,
and especially inhaled fluticasone, inhibit corticotropin
(ACTH) secretion if given in sufficient doses
Surreptitious intake of glucocorticoids is known as
factitious Cushing's syndrome, a rare disorder that may
be seen in individuals who are close to the health
professions.
Factitious CS is responsible for less than 1 percent of
patients with CS, but even a careful history may fail to
detect this disorder and it may be difficult to exclude with
laboratory tests.

21. Initial testing — 
The initial diagnostic tests for hypercortisolism should be
highly sensitive
The diagnosis of CS is established when at least two
different first-line tests are unequivocally abnormal.
Once the diagnosis is established, additional evaluation is
done to identify the cause of the hypercortisolism.
Low index of suspicion:
late-night salivary cortisol (two measurements),
24-hour urinary free cortisol (UFC) excretion (two
measurements), or the
overnight 1 mg dexamethasone suppression test (DST).

22. High index of suspicion:
If UFC is chosen as the initial screening test, the result
should be unequivocally increased (threefold above
the upper limit of normal for the assay) or the diagnosis
of CS is uncertain and other tests should be performed.
Some centers use the longer low-dose DST (2 mg/day
for 48 hours) as an initial test.
UFC and late-night salivary cortisol measurements are
each obtained at least twice because the hypercortisolism
in CS may be variable.
Two measurements must be abnormal for the test to be considered abnormal; for patients with mild or fluctuating disease, this may require collecting a number of salivary cortisols or UFCs over weeks.

23. Normal results — 
If initial testing is normal with a low index of suspicion
for CS, it is unlikely that the patient has CS.
If initial testing is abnormal with a high index of
suspicion for CS (clinical features suggestive of CS), refer
to an endocrinologist.
Any abnormal result — 
In patients with at least one abnormal test result
additional evaluation includes excluding physiologic
hypercortisolism.
Exclude physiologic hypercortisolism — 
Physiologic hypercortisolism or pseudo-CS. Clinically,
patients with these physiologic forms of hypercortisolism
seldom have the cutaneous (i.e., easy bruising, thinning,
and friability) or muscle (i.e., proximal muscle atrophy
and weakness) signs of CS.

24. Physiologic hypercortisolism that may have some clinical features of CS include
Pregnancy
Patients with severe obesity, especially those with visceral obesity or PCOS
Patients with psychological stress, especially patients with a severe major depressive disorder and melancholic symptoms
Poorly controlled diabetes mellitus
Rarely, chronic alcoholism
Physical stress (illness, hospitalization/surgery, pain)
Malnutrition, anorexia nervosa
Intense chronic exercise
Hypothalamic amenorrhea
High corticosteroid-binding globulin (CBG) (increased serum cortisol but not UFC)
Glucocorticoid resistance

25. Diagnostic Testing for Cushing’s Syndrome
Low-Dose Dexamethasone Suppression Testing
A small dose dexamethasone (1 mg) at 11:00 p.m. followed by a measurement of serum cortisol early next morning.
Normal subjects should suppress their cortisol level to a very low level (<1.8 µg/dl)
95-97% sensitivity in the diagnosis of Cushing’s syndrome; however, there are many things that may cause false-positive testing.
Urine Free Cortisol
A 24 hour urine free cortisol level does reflect the cortisol secretion throughout an entire day.
Majority of patients with Cushing’s have elevated levels of urine free cortisol
It is estimated that 20-25% of patients with Cushing’s syndrome may have a normal urine cortisol.
Depression, chronic alcoholism, and eating disorders may increase urine free cortisol.

26. Differential Diagnostic Testing
The majority of patients with Cushing’s syndrome have an
ACTH-secreting tumor usually from the pituitary gland (Cushing’s disease).
Ectopic ACTH syndrome.
Solitary or multiple tumors in their adrenal glands secreting excessive cortisol.
ACTH Levels
The first step is the measurement of morning ACTH.
Patients with ACTH-secreting tumors will either have a normal or elevated level of ACTH.
In contrast, patients with adrenal Cushing’s will have a subnormal level.
Late-Night Salivary Cortisol
Late-night salivary cortisol is one of the most sensitive diagnostic tests (sensitivity % ) for CS.
Elevated cortisol between 11:00 p.m. and midnight appears to be the earliest detectable abnormality in CS
Normal levels of late-night salivary cortisol usually exclude the diagnosis of Cushing’s syndrome due to an ACTH secreting tumor.
Some patients with Cushing’s caused by an adrenal tumor will have normal late-night salivary cortisol levels.

28. Cushing’s syndrome etiology
ACTH-dependent
(Pseudo-CS)
Pituitary (CD) (70%)
Microadenomas (95%)
Macroadenomas (5%)
Ectopic ACTH or CRH (10%)
Small cell lung ca
Carcinoids: lung, pancreas, thymus
ACTH-independent
(Factitious)
Unilateral
Adrenal adenoma (10%)
Adrenal carcinoma (5%)
Bilateral
Macronodular Hyperplasia (AIMAH) (<2%)
Primary pigmented Micronodular Adrenal disease (PPNAD) (<2%)
McCune Albright Syndrome (<2%)

29. Cushing’s syndrome: Establishing cause
Clinical features may provide a clue. First step is to measure plasma ACTH to differentiate ACTH-dependent from ACTH independent CS
If ACTH <1 pmol/L---adrenal CS
If ACTH >3.3 pmol/L—ACTH-dependent
If ACTH 1-3CRH stim

30. Treatment
The goal of treatment of all patients with Cushing's syndrome is to achieve normalization of hypothalamic-pituitary-adrenal function and subsequent reversal of Cushingoid signs/symptoms and co-morbidities
Optimal treatment involves localization and complete removal of a corticotropin (ACTH)-secreting pituitary or ectopic tumor or cortisol-secreting adrenal tumor(s).
In patients with Cushing’s disease who were not cured by pituitary surgery, medical therapy targeting the corticotrophin tumor such as cabergoline or pasireotide can result in normalization of 24-hour urinary free cortisol in 20 to 40 percent of them, especially if they have only mild hypercortisolism.
Pituitary irradiation is another second-line treatment for persistent or recurrent Cushing's disease.
Adrenal enzyme inhibitors must be used to control hypercortisolism until it is effective in approximately 85 percent of them.
Bilateral adrenalectomy is a definitive treatment for ACTH-secreting pituitary or ectopic tumors.

31. Trans-sphenoidal surgery
5 – 20 % recurrence Adults
% final cure
75 – 90 %
initial cure
75 – 90 %
initial cure
Pituitary irradiation ±
Mitotane
Pituitary irradiation ± Mitotane
% cure
Total bilateral adrenelectomy
100% cure

32. Treatment
Metastatic or occult ectopic ACTH-secreting tumors may respond to somatostatin analog treatment, adrenal enzyme inhibitors or mitotane.
The physical symptoms and signs of Cushing's syndrome resolve gradually over a period of two to 12 months after effective cure of Cushing syndrome. Hypertension, osteoporosis and glucose intolerance improve but may not disappear
Patients may have impaired quality of life for many years despite remission of hypercortisolism. However the long-term prognosis of cured patients who had benign disease is excellent. The prognosis of patients with malignancy is variable and relates to the ability to control hypercortisolism and treat the cancer.

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