Cushing Syndrome - Clinical Round Presented by Usama Ragab Youssif For 5th-year Medical students - Zagazig University

1. Usama Ragab Youssif (MD)
Lecturer of Internal Medicine
Zagazig University
Email: usamaragab@medicine.zu.edu.eg
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Cushing Syndrome
Clinical Implications & Summaries

2. Part I
Theoritical

5. Addison
Disease
ACTH Def.
Adrenal
Cushing
Cushing
Disease
(ACTH)

6. ACTH manner of secretion
 ACTH secretion is pulsatile
 Amplitude of each pulse varies in
circadian fashion
Highest at time of awakening
Lowest in late evening

8. The secreted steroids are:
1. From ZG (under control of RAAS ± ACTH):
 Aldosterone
 Deoxycorticosterone (DOCA)
2. From ZF (under control of ACTH):
 Cortisol (GC)
3. From ZR (under control of ACTH):
 Dehydroepiandrosteron (DHEA)
 Dehydroepiandrosterons(DHEAS)
 +/- glucocorticoids

9. Renin Angitensin Aldosteron System

10. Steroidogenesis
ACTH
Only source in females
Cortisone
G
G: 11 B-hydroxysteroid dehydrogenase 2

12. Cortisol action
 Metabolic= anti-insulin + lipogenesis
 Water= Inhibit vasopressin + K loss +/- Na retention
 Blood= ↓ eosinophil & lymphocytes

13. Aldosterone action
 Act on DCT and CD
 Na reabsorption & K loss

14. DHEA action
 In males= very little effect, responsible of first appearance of
axillary & pubic hair
 In females= it is the only androgen, adrenarche & pubarche +
sense of well being + libido

15. Arterial supply
3

16. Venous drainage
1

17. 3 arteries & 1 vein

18. Adrenal Hyperfunction

19. Case vignette
 A 35-year-old woman has hypertension of recent onset.
 Review of systems reveals several months of weight gain and
menstrual irregularity.
 On examination, she is obese, with a plethoric appearance. The
blood pressure is 165/98 mm Hg. There are prominent purplish
striae over the abdomen and multiple bruises over both lower legs.

20. Dr. Harvey Cushing

21. Definition
 Cushing syndrome (CS) comprises the symptoms and signs
associated with prolonged exposure to inappropriately elevated
levels of free plasma glucocorticoids.
 Cushing disease and ectopic ACTH syndrome are associated with
excess cortisol secretion caused by ACTH from the pituitary or a
non-pituitary tumor, respectively.
 ACTH-secreting pituitary adenoma is the most common cause of
endogenous Cushing syndrome (CS) (60%) with the rest being
adrenal (25%) or ectopic (15%) in origin.

22. Etiology of CS
 True Cushing versus pseudo-Cushing.
 Exclude exogenous intake.
 ACTH-dependent or independent.
 If ACTH dependent = pituitary > ectopic.

23. Etiology of CS (cont.)
 The etiology of CS can be classified into ACTH-dependent or
ACTH-independent.
 If CS due to exogenous glucocorticoids is excluded, primary ACTH-
independent adrenal etiologies account for 15–20% of endogenous
CS in adults, of which approximately 90% are unilateral tumors

24. Causes of Cushing’s syndrome
Pseudo-Cushing’s syndrome
•Alcoholism <1%.
•Severe depression 1%
Exogenous steroids, including creams
ACTH-dependent Cushing
•Pituitary adenoma 68% (Cushing’s disease).
•Ectopic ACTH syndrome 12%.
•Ectopic CRH secretion <1%
ACTH-independent Cushing (Adrenal CS)
Unilateral
•Benign adrenal adenoma
•Adrenocortical carcinoma
•Unilateral adrenocortical hyperplasia
Bilateral
•Bilateral macronodular hyperplasia (BMNH)
•Primary pigmented nodular adrenocortical disease (PPNAD) and Carney’s complex

26. Other classification
 According to source
1. Exogenous: Prolong steroid therapy (ACTH independent).
2. Endogenous:
 Pituitary cause (85%, ACTH dependent)
 Adrenal tumor (ACTH independent)
 Ectopic production of ACTH (ACTH dependent).

27. Cushing’s Syndrome Epidemiology
 Relatively even distribution between men and women
Men more common ACTH secreting lung tumors
Women more commonly have Cushing’s Disease
 Age at presentation varies depending on etiology
Cushing’s Disease: 25-45 years old
Adrenal Tumors: 40-50 years old
Ectopic ACTH secretion: Age > 50

28. Rationale of pituitary Cushing
 Increased ACTH
 Increased cortisol in turn
 Effect of excess cortisol + excess ACTH

29. Rationale of Adrenal Cushing
 Excess cortisol
 Low ACTH
 Effect of excess cortisol onyly

30. Adrenal
Cushing
Cushing
Disease
(ACTH)

31. Clinical features suggestive of Cushing syndrome
 Facial plethora, hirsuitism, acne
 Central obesity
 Wide purplish striae (>1 cm)
 Proximal myopathy, muscle wasting
 Changes in serial photographs
 Spontaneous bruising, Liddle’s sigh = cigarette paper skin.
 Osteopenia/Osteoporosis

34. Growth retardation in children

44. CLINICAL PRESENTATION (cont.)
 Hypokalemic hypertension
 Abnormal glucose tolerance
 Menstrual irregularities, ↓ libido, ED in men.
 Psychiatric disturbances including depression.
 Supraclavicular and dorsocervical fat pads (buffalo hump) are
nonspecific findings and may be seen in most patients presenting to
obesity clinics? Some advocate that those are specific findings

47. Delayed diagnosis
 3 – 6 years delay.
 In ACTH dependent Cushing, degree of scar
pigmentation may give clue to date of CD.

48. Subclinical CS (SCS)
 5 – 20%
 Adrenal incidentaloma + autonomus GC secretion but no
clinical features of CS
 Normal urinary free cortisol
 Failure to supress LDDST
 ACTH may be low or suppressed

49. Subclinical CS (SCS) (cont.)
 ↑ risk of DM, osteoporosis, HTN
 Controversial whether to treat or not to treat
 If removed, contralateral adrenal is suppressed → wait
for recovery + give GC coverage + revaluate

50. Hint on ectopic ACTH
 SCLC >50%
 Thymic carcinoid 15%
 Islet cell tumors 10%
 Bronchial carcinoid 10%
 Other carcinoids 5%
 Pheochromocytomas 2%

51. Hint on ectopic ACTH (cont.)
All the previous symptoms but…..
 Ectopic dominated by :
Hypokalemic alkalosis (dominant feature)
HTN, glucose intolerance
Steroid psychosis, myopathy
Intense pigmentation
Failure of suppression by HDDST.
Failure to increase with CRH test.
 Absence of other features may be explained by more sudden
onset by acquired ACTH from tumor.

53. Source of morbidity in CS
 Diabetes
 HTN
 Osteoporotic fractures and avascular necrosis
 Infections
 Nephrolithiasis
 Psychosis
 VTE: DVT, pulmonary embolism = hypercoagulable state

54. Diagnosis
 Once CS due to exogenous administration of glucocorticoids is
excluded, the evaluation of a patient with suspected CS should
take place in two stages:
1. Is it Cushing?
2. Where is the lesion?

55. Think again
 True Cushing versus pseudo-Cushing.
 Exclude exogenous intake.
 ACTH-dependent or independent.
 If ACTH dependent = pituitary > ectopic.

57. Diagnosis (cont.)
1. 24 h. urinary free cortisol (repeat or not alone).
Random serum cortisol has no role
2. A 1 mg overnight dexamethasone suppression test with an
morning cortisol level below 1.8 μg/dL virtually rules out the
disease (40% false-positive rate).
3. Serial salivary cortisol.

59. How to start
 Outpatient tests
 2–3x 24h urinary free cortisol.
 Overnight dexamethasone suppression test.
 2 x Late-night salivary cortisol
 If both the above tests are normal, Cushing’s syndrome is unlikely.
 Inpatient tests
 2 x Midnight cortisol
 Low-dose dexamethasone suppression test.
 Need 2/3 tests to be positive to establish diagnosis of Cushing’s
Syndrome
 Further testing indicated for patients with slightly abnormal or discordant
results

60. Types of Low Dose Dexamethasone Suppression
Test
 Overnight 1 mg test
1 mg dexa 11 PM → cortisol next 8 AM
Normal value < 1.8 mcg/dL
 Two-day 2 mg test
0.5 mg q6h for 2 days
Serum cortisol at 2 and 6 hours after LAST dexa.
Normal value < 1.8 mcg/dL

61. Where is the lesion
If screening is positive: go for ACTH
 If ACTH is undetectable, an adrenal tumour is likely →
1. CT/MRI adrenal glands.
2. If no mass, proceed to adrenal vein sampling.
 If ACTH is detectable, distinguish a pituitary cause from ectopic
ACTH production by
1. high-dose suppression test or
2. corticotropin-releasing hormone (CRH) test: 100mcg ovine or
human CRH IV.

62. Where is the lesion (cont.)
 If ACTH is changeable i.e. responder i.e. maleable
1. Image the pituitary (MRI) and
2. consider bilateral inferior petrosal sinus blood sampling.
 If tests indicate that cortisol does not respond to manipulation, think
ectopic
1. IV contrast CT of chest, abdomen, and pelvis ± MRI of neck,
thorax, and abdomen, e.g. for small ACTH secreting carcinoid
tumours.

63. ACTH dependent CS
 ACTH is undetectable in adrenal CS, high in pituitary Cushing and
higher in ectopic Cushing
 CRH stimulation test and HDDST are used for differentiation
between the two.
 Cortisol levels are not suppressed with the high-dose (8 mg)
dexamethasone test in patients with ectopic ACTH syndrome and
CRH stimulation may not lead to a further rise in ACTH.

64. Plasma ACTH levels (9 a.m.) in patients with pituitary-dependent Cushing’s disease, adrenal tumours, and
ectopic ACTH secretion.

65. HDDST
High-dose dexamethasone suppression test
 HDDST is performed in an identical way to the low-dose test
but with 2mg doses of dexamethasone (120
micrograms/kg/day).
 In Cushing’s disease, the cortisol falls by >50% of the basal
value.
 In ectopic disease, there is no suppression.

66. CRH stimulation test
 CRH stimulation test is used for differentiation between the two.

67. LDDST vs HDDST
 Low dose
 Utilized to establish diagnosis of Cushing’s Syndrome = screening
 High Dose
 Utilized to differentiate Cushing’s Disease from patients with ectopic
ACTH syndrome

68. Diagnosis (cont.)
 The gold standard test to differentiate pituitary Cushing from an
ectopic ACTH-producing tumor is inferior petrosal sinus sampling.
 This test should be performed by experienced neuroradiologist and
it is essential to note that it cannot be used to make the diagnosis
of Cushing’s syndrome.

69. Inferior petrosal sinus sampling
 Bilateral inferior petrosal sinus sampling (BIPSS) with concurrent
blood sampling for ACTH in the right and left inferior petrosal sinus
and a peripheral vein.
 An increased central/peripheral plasma ACTH ratio >2 at baseline
and >3 after CRH injection is indicative of Cushing's disease, with
very high sensitivity and specificity.

73. Diagnosis of ectopic ACTH
 Ectopic ACTH: typically resistant to dexamethasone suppression and
unresponsive to CRH.
1. CT/MRI neck, chest, abdomen & pelvis.
2. Octreotide scintigraphy can be helpful in some cases as ectopic
ACTH-producing tumors often express somatostatin receptors.
3. Do not stop if you found pituitary lesion in context of difficult to
suppress ACTH → remember pituitary incidentaloma.

74. Diagnosis of adrenal CS
 Once the diagnosis of ACTH-independent CS has been
established, the adrenals need to be imaged by noncontrast CT
scan.
 In patients with unilateral hyperfunctioning adrenal tumor, the
contralateral adrenal gland is usually atrophic.
 If suspect carcinoma: MRI may better delineate the tumor & assess
spread

75. Adrenal vein sampling (AVS)
 AVS is a safe and valuable tool for differentiation between unilateral
and bilateral cortisol secretion
 It may not correlate with CT findings
 It could detect unvisualized adrenal mass
 It should be considered when operative treatment will be utilized

79. Cyclical Cushing’s
 A small group of patients with CS have alternating normal and
abnormal cortisol levels on an irregular basis.
 All causes of CS may be associated with cyclical secretion of
cortisol.
 Clearly, the results of dynamic testing can only be interpreted when
the disease is shown to be active (e.g. elevated urinary cortisol
secretion and loss of normal circadian rhythm and suppressibility
on dexamethasone).

82. Differential Diagnosis (Pseudocushing)
 A pseudo-Cushing's state can be defined as some or all of the
clinical features of CS together with some evidence for
hypercortisolism.
 Alcoholism, sleep apnea, depression, obesity, uncontrolled T2D,
and anorexia.
 Resolution of the underlying cause results in disappearance of the
cushingoid state.

84. Management of CD

85. Management of CD (pituitary CS)
 Surgical (trans-sphenoidal) removal of the ACTH-secreting pituitary
tumor is the treatment of choice.
 An undetectable cortisol level postoperatively off steroid is
considered to be an excellent marker for long-term cure.
 For those not cured by the surgery, other options include a second
operation and radiation therapy.
 Patients whose tumor is unresponsive to these therapies may then
be offered medical or surgical adrenalectomy.

86. Management of ectopic CS
 Ectopic ACTH-producing tumors should be resected if possible.
 Octreotide may inhibit ectopic ACTH secretion.
 Mitotane is perhaps the most effective adrenolytic agent.
 Other medications, such as aminoglutethimide, ketoconazole, or
metyrapone, are useful as temporizing agents only.
 Mifepristone is promising.

87. Management of adrenal CS
 Normalization of cortisol levels, eradication of the tumor, and
avoidance of permanent hormonal deficiency.
 Hormone-secreting adrenal adenomas should be surgically
removed.
 Surgical resection of the adrenocortical carcinoma at an early stage
is the only therapy that may offer potential for cure.

88. Treatment summary
 Cushing’s Disease: Transphenoidal resection of pituitary adenoma
 Adrenal neoplasms: resection
 Ectopic ACTH: resection if possible
 Bilateral adrenal hyperplasia: may need adrenalectomies (lifelong
glucocorticoid and mineralcorticoid replacement)

89. ‘Medical’ Adrenalectomy
Medications that inhibit steroidogenesis
 Ketoconazole (600 to 1200 mg/day)
 metyrapone (exacerbates female virilization) (2-3 g/day)
 Mitotane(2-3 g/day)- slow onset
 Aminoglutethinide (1g/day)
 Ocreotide can work in 1/3 of patients: major side affect is adrenal
insufficiency, therefore start at lowest dose and titrate.
Steroidogenesis inhibitors
(inhibit cortisol synthesis)
Pituitary directed
(inhibit ACTH secretion)
Glucocorticoid receptor
antagonist
(inhibit cortisol action)
Ketoconazole
Metyrapone
Mitotane
Etomidate
Pasireotide
Cabergoline
Mifepristone

90. Nelson’s Syndrome
 Occurs in patients with CD, following adrenalectomy ≈ 50% at 10
years.
 Hyperpigmentation and an enlarging (often invasive) pituitary
tumour, associated with markedly elevated ACTH levels.
 MRI and ACTH: start 6 mo after adrenalectomy, yearly for at least 6
years

91. Prognosis
 Benign adrenal adenoma- 95% 5 year survival, 90% 10 year
 Cushing’s disease (pituitary adenoma) same survival, but 10-
20% transphenoidal resection failure rate over 10 years.
 Ectopic ACTH survival depends on malignancy
 Adrenal carcinoma- median survival 7 months

92. Part II
Clinical Wise

93. Adrenal Hyperfunction

94. Personal History
NAS OMRHH
 Age group
 Sex
 Marital status
 Habits = alchohol = pseudocushing
= smoking = lung cancer = ectopic CS

95. Chief complaints
 Excessive weight gain for … months
 Weakness for … months
 Backache and generalized body ache for months
 Skin changes, pigmentation, bleeding spots
 Hypertension

96. Chief complaints (cont.)
 Psychiatric abnormalities e.g. depression
 Pathologic fracture (not related to trauma)
 Sexual dysfunctions: ED, menstrual irregularities,
decreased libido

97. Present history
 According to the statement of the patient, she was reasonably well
months back. Since then, she is gaining weight which is
progressively increasing inspite of normal food intake. She also
feels extremely weak and lethargic. The patient also complains of
backache and generalized bodyache for the last … months. The
pain is more marked with activity and the patient feels comfortable
by taking rest.

98. Present history (cont.)
 Sometimes, she feels difficulty in standing from sitting position. For
the last … months, she noticed multiple bleeding spots on the skin,
involving mostly the forearms and legs. There is no history of
headache, visual problem, cough or chest pain.
 Her bowel and bladder habits are normal.
 There is no history of intolerance to cold, or increased sleepiness.

99. Past history
 Nothing significant
 We need to exclude drug history
 Diseases treated with GC?
 Alcohol = ? Pseudo-Cushing

100. Menstrual history
 She gives history of oligomenorrhea (or amenorrhea) for …
months, previously it was regular.

101. Family history
 Irrelevant
 Ask for similar conditions
 Ask for obesity, hirsuitism
 Ask for autoimmune diseases

102. General appearance
General overview:
 Appearance
 Built: overbuilt… or stunted growth in children
 Color
 Decubitus:
 Exposure (Back, breast, genitalia)
 Facial expression: moon facies, plethoric…
 Gait: waddling in myopathy…

103. General appearance (cont.)
 Vitals
 BP: HTN
 P
 Temp: fever = 2ry infection
 RR
 O2
 RBS
 UOP

104. General appearance (cont.)
 Upper limbs: thin
 Lower limbs: thin, bruises, thin skin
 HEENT
 Trunk: stria

105. Systemic examination
 CNS:
 Examine higher psychiatric function e.g. psychosis
 Examine motor system: myopathy
 Examine sensory system: diabetic PN
 CVS
 HTN complications
= LVE + LVF

106. Systemic examination
 Chest
 As a cause e.g. BA on GC, lung cancer
 As a sequel e.g. TB (cavity, bronchial breath)
 Abdomen
 Skin changes
 Protruded abdomen
 Abdominal mass
 Examine genitalia

107. Systemic examination
 Joint
 Tender spine or bone = osteoporosis
 Stunted growth
 Deformity
 Osteoarthritis
 AVN of femur neck

108. General appearance (cont.)
 The patient is obese. There is more truncal obesity with relatively
lean and thin limbs (lemon on a match stick appearance)
 Face is moonlike, puffy and plethoric with acne, hirsutism and
frontal baldness

109. General appearance (cont.)
 There is buffalo hump at the root of the neck and increased fat
above both the supraclavicular fossa
 There are multiple pink striae on abdomen, back and axilla
 Skin is thin, with multiple purpura and bruise

110. General appearance (cont.)
 Pulse—90/min, regular
 BP—155/90 mm Hg
 Temperature—37.2ºc
 Respiration—16/min.

111. Systemic examination
 Abdomen
 The abdomen looks distended and flanks are full
 There are multiple pink striae of variable size and shape
 No organomegaly
 Ascites—absent (as evidenced by absent fluid thrill and shifting
dullness)

112. Systemic examination (cont.)
 CVS
 Pulse—90/min
 BP—155/90 mm Hg
 Precordium—normal (look for complication of HTN e.g. LVE, LVF)

113. Systemic examination (cont.)
 Chest
 TB: apical crackles, bronchial breathing
 Bronchogenic carcinoma: non resolving pneumonia

114. Systemic examination (cont.)
 Nervous system
 Higher psychic functions—normal
 Cranial nerves—intact
 Motor system—proximal muscular weakness of both upper and
lower limbs.
 Reflexes are normal
 Sensory system– normal may be affected in DM.

115. Systemic examination (cont.)
 Musculoskeletal System
 Proximal myopathy is present more marked in the lower limb than
upper limb
 There is slight kyphosis (osteoporosis)
 Spine is tender at lumbar region (due to osteoporosis)
 Stunted growth in children & adolescence

116. Salient features
 Female
 Middle age
 Weight gain
 Fatigue
 Proximal weakness
 Menstrual irregularity
 Physical findings in examination

117. Different faces of Cushing
 Obesity mostly Cushing mostly pituitary
 Obesity + DM + HTN mostly Cushing mostly treatment
complications

120. What are the causes of puffy face?
 Cushing’s syndrome (plethoric
moon face, with hirsutism, acne)
 Myxedema (puffy with baggy
eyelids, fall of lateral eyebrows,
malar flush)
 Nephrotic syndrome and acute
glomerulonephritis (puffy with
periorbital oedema)
 SVC obstruction (engorged and
non pulsatile veins, plethoric face
with subconjunctival effusion)
 Angioedema (localized, swollen
lip or face)
 Chronic alcoholism (plethoric,
puffy face)
 Simple obesity
 Surgical emphysema (history of
trauma, also swelling is extended
upto the neck and chest. There
are multiple crepitations on
palpation).

121. What are the causes of periorbital edema
 Nephrotic syndrome
 Acute glomerulonephritis
 Myxedema
 Angioedema
 Dermatomyositis
 Orbital cellulitis
 Malignant exophthalmos
 Primary amyloidosis

132. What is the difference between Cushing’s disease and
Cushing’s syndrome?
 CD= pituitary ACTH-dependent
 CS= syndrome of hypercortisolemia

133. Other causes of stria?
 Striae gravidarum = stria nigra
 Cushing’s syndrome = stria rubra (wide lines, pink or purple or red,
mostly horizontal or oblique. Pink or red color is due to increased
vascularity).

134. How to differentiate clinically different types of
Cushing’s syndrome?
1. In Cushing’s syndrome due to adrenal cause:
 In adrenal adenoma—clinical features of glucocorticoid excess
are present but androgenic effect like hirsutism and virilisation
are absent and no pigmentation.
 In adrenal carcinoma—clinical features of glucocorticoid excess
are present and androgenic effect like hirsutism and virilisation
are rapidly progressive.

135. How to differentiate clinically different types of
Cushing’s syndrome? (cont.)
2. In ectopic ACTH syndrome—usually there is short history,
excess pigmentation due to high ACTH level, weight loss (rather
than obesity) and severe hypokalemic alkalosis. Hypertension
and edema are more common. Classical features of Cushing’s
syndrome are usually absent. Features of the primary lesion are
present.
Marked hypoklemia suggests ectopic ACTH syndrome.

136. How to differentiate clinically different types of
Cushing’s syndrome? (cont.)
3. In Cushing’s disease—classic features of Cushing’s syndrome
are present. If there is pituitary macroadenoma, visual
disturbance and features of hypopituitarism may be present.
There may be features of raised intracranial pressure like
headache.
4. History of alcoholism and depression or simple obesity suggests
pseudo-Cushing’s syndrome.

137. Final Look

139. Email: usamaragab@medicine.zu.edu.eg
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