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Cushing Syndrome - Clinical Round

The document discusses Cushing's syndrome, detailing its clinical implications, classifications, and various causes. It provides a comprehensive overview of diagnostic approaches, management strategies, and potential treatment options for different types of Cushing's syndrome, including pituitary, adrenal, and ectopic ACTH-producing tumors. The document emphasizes the importance of distinguishing between true Cushing's and pseudo-Cushing's states, alongside the significance of patient history and specific diagnostic tests in establishing a correct diagnosis.

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Usama Ragab Youssif (MD) Lecturer of Internal Medicine Zagazig University Email: usamaragab@medicine.zu.edu.eg Slideshare: https://www.slideshare.net/dr4spring/ Mobile: 00201000035863 Cushing Syndrome Clinical Implications & Summaries
Part I Theoritical
Addison Disease ACTH Def. Adrenal Cushing Cushing Disease (ACTH)
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
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
Renin Angitensin Aldosteron System
Steroidogenesis ACTH Only source in females Cortisone G G: 11 B-hydroxysteroid dehydrogenase 2
Cortisol action  Metabolic= anti-insulin + lipogenesis  Water= Inhibit vasopressin + K loss +/- Na retention  Blood= ↓ eosinophil & lymphocytes
Aldosterone action  Act on DCT and CD  Na reabsorption & K loss
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
Arterial supply 3
Venous drainage 1
3 arteries & 1 vein
Adrenal Hyperfunction
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.
Dr. Harvey Cushing
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.
Etiology of CS  True Cushing versus pseudo-Cushing.  Exclude exogenous intake.  ACTH-dependent or independent.  If ACTH dependent = pituitary > ectopic.
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
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
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).
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
Rationale of pituitary Cushing  Increased ACTH  Increased cortisol in turn  Effect of excess cortisol + excess ACTH
Rationale of Adrenal Cushing  Excess cortisol  Low ACTH  Effect of excess cortisol onyly
Adrenal Cushing Cushing Disease (ACTH)
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
Growth retardation in children
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
Delayed diagnosis  3 – 6 years delay.  In ACTH dependent Cushing, degree of scar pigmentation may give clue to date of CD.
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
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
Hint on ectopic ACTH  SCLC >50%  Thymic carcinoid 15%  Islet cell tumors 10%  Bronchial carcinoid 10%  Other carcinoids 5%  Pheochromocytomas 2%
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.
Source of morbidity in CS  Diabetes  HTN  Osteoporotic fractures and avascular necrosis  Infections  Nephrolithiasis  Psychosis  VTE: DVT, pulmonary embolism = hypercoagulable state
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?
Think again  True Cushing versus pseudo-Cushing.  Exclude exogenous intake.  ACTH-dependent or independent.  If ACTH dependent = pituitary > ectopic.
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.
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
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
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.
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.
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.
Plasma ACTH levels (9 a.m.) in patients with pituitary-dependent Cushing’s disease, adrenal tumours, and ectopic ACTH secretion.
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.
CRH stimulation test  CRH stimulation test is used for differentiation between the two.
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
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.
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.
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.
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
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
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).
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.
Management of CD
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.
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.
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.
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)
‘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
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
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
Part II Clinical Wise
Adrenal Hyperfunction
Personal History NAS OMRHH  Age group  Sex  Marital status  Habits = alchohol = pseudocushing = smoking = lung cancer = ectopic CS
Chief complaints  Excessive weight gain for … months  Weakness for … months  Backache and generalized body ache for months  Skin changes, pigmentation, bleeding spots  Hypertension
Chief complaints (cont.)  Psychiatric abnormalities e.g. depression  Pathologic fracture (not related to trauma)  Sexual dysfunctions: ED, menstrual irregularities, decreased libido
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.
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.
Past history  Nothing significant  We need to exclude drug history  Diseases treated with GC?  Alcohol = ? Pseudo-Cushing
Menstrual history  She gives history of oligomenorrhea (or amenorrhea) for … months, previously it was regular.
Family history  Irrelevant  Ask for similar conditions  Ask for obesity, hirsuitism  Ask for autoimmune diseases
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…
General appearance (cont.)  Vitals  BP: HTN  P  Temp: fever = 2ry infection  RR  O2  RBS  UOP
General appearance (cont.)  Upper limbs: thin  Lower limbs: thin, bruises, thin skin  HEENT  Trunk: stria
Systemic examination  CNS:  Examine higher psychiatric function e.g. psychosis  Examine motor system: myopathy  Examine sensory system: diabetic PN  CVS  HTN complications = LVE + LVF
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
Systemic examination  Joint  Tender spine or bone = osteoporosis  Stunted growth  Deformity  Osteoarthritis  AVN of femur neck
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
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
General appearance (cont.)  Pulse—90/min, regular  BP—155/90 mm Hg  Temperature—37.2ºc  Respiration—16/min.
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)
Systemic examination (cont.)  CVS  Pulse—90/min  BP—155/90 mm Hg  Precordium—normal (look for complication of HTN e.g. LVE, LVF)
Systemic examination (cont.)  Chest  TB: apical crackles, bronchial breathing  Bronchogenic carcinoma: non resolving pneumonia
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.
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
Salient features  Female  Middle age  Weight gain  Fatigue  Proximal weakness  Menstrual irregularity  Physical findings in examination
Different faces of Cushing  Obesity mostly Cushing mostly pituitary  Obesity + DM + HTN mostly Cushing mostly treatment complications
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).
What are the causes of periorbital edema  Nephrotic syndrome  Acute glomerulonephritis  Myxedema  Angioedema  Dermatomyositis  Orbital cellulitis  Malignant exophthalmos  Primary amyloidosis
What is the difference between Cushing’s disease and Cushing’s syndrome?  CD= pituitary ACTH-dependent  CS= syndrome of hypercortisolemia
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).
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.
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.
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.
Final Look
Email: usamaragab@medicine.zu.edu.eg Slideshare: https://www.slideshare.net/dr4spring/ Mobile: 00201000035863

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Cushing Syndrome - Clinical Round

  • 1.
    Usama Ragab Youssif(MD) Lecturer of Internal Medicine Zagazig University Email: usamaragab@medicine.zu.edu.eg Slideshare: https://www.slideshare.net/dr4spring/ Mobile: 00201000035863 Cushing Syndrome Clinical Implications & Summaries
  • 2.
  • 5.
  • 6.
    ACTH manner ofsecretion  ACTH secretion is pulsatile  Amplitude of each pulse varies in circadian fashion Highest at time of awakening Lowest in late evening
  • 8.
    The secreted steroidsare: 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.
  • 10.
    Steroidogenesis ACTH Only source infemales 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  Acton DCT and CD  Na reabsorption & K loss
  • 14.
    DHEA action  Inmales= 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.
  • 16.
  • 17.
  • 18.
  • 19.
    Case vignette  A35-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.
  • 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’ssyndrome 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  Accordingto 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 pituitaryCushing  Increased ACTH  Increased cortisol in turn  Effect of excess cortisol + excess ACTH
  • 29.
    Rationale of AdrenalCushing  Excess cortisol  Low ACTH  Effect of excess cortisol onyly
  • 30.
  • 31.
    Clinical features suggestiveof 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.
  • 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 ectopicACTH  SCLC >50%  Thymic carcinoid 15%  Islet cell tumors 10%  Bronchial carcinoid 10%  Other carcinoids 5%  Pheochromocytomas 2%
  • 51.
    Hint on ectopicACTH (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 morbidityin CS  Diabetes  HTN  Osteoporotic fractures and avascular necrosis  Infections  Nephrolithiasis  Psychosis  VTE: DVT, pulmonary embolism = hypercoagulable state
  • 54.
    Diagnosis  Once CSdue 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  TrueCushing versus pseudo-Cushing.  Exclude exogenous intake.  ACTH-dependent or independent.  If ACTH dependent = pituitary > ectopic.
  • 57.
    Diagnosis (cont.) 1. 24h. 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 LowDose 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 thelesion 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 thelesion (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 suppressiontest  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.)  Thegold 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 sinussampling  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 ectopicACTH  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 adrenalCS  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  Asmall 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.
  • 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 ectopicCS  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 adrenalCS  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’sDisease: 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 thatinhibit 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  Occursin 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 adrenaladenoma- 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.
  • 93.
  • 94.
    Personal History NAS OMRHH Age group  Sex  Marital status  Habits = alchohol = pseudocushing = smoking = lung cancer = ectopic CS
  • 95.
    Chief complaints  Excessiveweight 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  Accordingto 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  Nothingsignificant  We need to exclude drug history  Diseases treated with GC?  Alcohol = ? Pseudo-Cushing
  • 100.
    Menstrual history  Shegives 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 ofCushing  Obesity mostly Cushing mostly pituitary  Obesity + DM + HTN mostly Cushing mostly treatment complications
  • 120.
    What are thecauses 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 thecauses of periorbital edema  Nephrotic syndrome  Acute glomerulonephritis  Myxedema  Angioedema  Dermatomyositis  Orbital cellulitis  Malignant exophthalmos  Primary amyloidosis
  • 132.
    What is thedifference between Cushing’s disease and Cushing’s syndrome?  CD= pituitary ACTH-dependent  CS= syndrome of hypercortisolemia
  • 133.
    Other causes ofstria?  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 differentiateclinically 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 differentiateclinically 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 differentiateclinically 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.
  • 139.

Editor's Notes

  • #6 We put here an example for increased ACTH and cortisol We are not discussing resistance syndromes
  • #7 Pulsatile manner = random samples are not OK with measurement Variation makes measuring ACTH to diagnose Cushing’s syndrome or disease inaccurate
  • #9 The zona glomerulosa is deficient in 17α-hydroxylase and, as a result, it cannot produce cortisol or androgens.
  • #10 The secretion of mineralocorticoids from zona glomerulosa is regulated primarily by angiotensin 2, serum potassium levels and ACTH. Atrial natriureitc peptide and dopamine can also influence the secretion of mineralocorticoids. ACTH plays a key part in regulation of glucocorticoids secretion from zona fasciculata.
  • #11 First step in steroids synthesis is primed with ACTH Plasma lipoproteins are the major source of cholesterol to the adrenal glands. The conversion of cholesterol to pregnenolone is the major site of action of ACTH. The zona glomerulosa is deficient in 17α-hydroxylase and, as a result, it cannot produce cortisol or androgens
  • #18 3 arteries and 1 vien 3 taps and 1 pipe
  • #21 Harvey Williams Cushing (April 8, 1869 – October 7, 1939) was an American neurosurgeon, pathologist, writer, and draftsman. A pioneer of brain surgery, he was the first exclusive neurosurgeon and the first person to describe Cushing's disease. He wrote a biography of William Osler in three volumes.
  • #22 Pituitary Cushing is mostly microadenoma, rarely macroadenoma. The tumours typically maintain some responsiveness to the usual feedback control factors that influence the normal corticotroph (e.g. high doses of glucocorticoids and CRH). However, this may be lost, and the tumours become fully autonomous, particularly in Nelson’s syndrome.
  • #23 It is important to decide whether the patient has true Cushing’s syndrome rather than pseudo-Cushing’s associated with depression or alcoholism. First exclude exogenous ingestion as source of hypercortisolemia. Secondly, ACTH-dependent Cushing’s must be differentiated from ACTH-independent disease (usually due to an adrenal adenoma or, rarely, carcinoma). Once a diagnosis of ACTH-dependent disease has been established, it is important to differentiate between pituitary-dependent (Cushing’s disease) and ectopic secretion.
  • #25 Adrenocortical carcinomas (ACC) are usually >6cm in diameter, although they may be smaller, and are not infrequently associated with local invasion and metastases at the time of diagnosis. Adrenal carcinomas are characteristically associated with the excess secretion of several hormones; most frequently found is the combination of cortisol and androgen (precursors); occasionally, they may be associated with mineralocorticoid or oestrogen secretion.
  • #26 Adrenal cortical adenoma associated with Cushing syndrome: a well encapsulated 3.6 cm yellow-tan intra-adrenal mass with focal hemorrhage. Normal adrenal tissue is seen to the right (arrow).
  • #31 We put here an example for increased ACTH and cortisol We are not discussing resistance syndromes
  • #32 The onset of clinical features is usually gradual in patients with adrenal adenomas but often rapid in adrenocortical carcinomas. ----- It is important to note that, in patients with adrenal carcinoma, there may also be features related to excessive androgen production in ♀ and also a relatively more rapid time course of development of the syndrome. ----- The features of Cushing’s syndrome are progressive and may be present for several years prior to diagnosis. A particular difficulty may occur in a patient with cyclical Cushing’s where the features and biochemical manifestations appear and disappear with a variable periodicity.
  • #36 The striae in CS are red-purple in color and usually greater than 1 cm in width , (in contrast to silver, healed post-partum striae)
  • #38 Thin skin; compare dorsum of the patient hand to that of examiner Skin bruising
  • #39 Hirsuitism Male pattern baldness
  • #44 Serial photographs of a patient with Cushing syndrome demonstrating gradual development of moon face, acne, and facial plethora. The patient underwent surgery in 2003. Note the dramatic improvement in the facial appearance 9 months after surgery. A = 1995;B = 1996;C = 1998; D = 1999;E = 2000;F = 2001;G = 2002;H = 2003; I = 2004. (Not taken as clinical pictures)
  • #45 Hypertension and hypokalemia may be seen in patients with CS and are mainly due to the binding of excess cortisol to the nonspecific type 1 aldosterone receptors. Excess glucocorticoid secretion overcomes the ability of 11-HSD2 to rapidly inactivate cortisol to cortisone in the kidney, thereby exerting mineralocorticoid actions, manifest as : diastolic hypertension Hypokalemia edema ----- Hypertension (>50%) due to mineralocorticoid effects of cortisol (cortisol overwhelms the renal 11B-hydroxysteroid dehydrogenase enzyme protecting the mineralocorticoid receptor from cortisol). Cortisol may also increase angiotensinogen levels. ----- Virilization may be a part of the clinical picture in patients with adrenocortical carcinoma cosecreting androgens. ----- Hyperglycemia—Due to: −− Increased hepatic neoglucogenesis −− Insulin resistance −− Hypokalemia-related decreased insulin production. -----
  • #46 The mineralocorticoid receptor has an equal affinity for cortisol and aldosterone, but there is a 100-fold excess of circulating cortisol over aldosterone. The mineralocorticoid receptor is usually protected from the effects of stimulation by cortisol by the 11B-hydroxysteroid type 2 dehydrogenase enzyme, which converts cortisol to cortisone. Hypertension (>50%) due to mineralocorticoid effects of cortisol (cortisol overwhelms the renal 11B-hydroxysteroid dehydrogenase enzyme protecting the mineralocorticoid receptor from cortisol). Cortisol may also increase angiotensinogen levels.
  • #48 POMC (proopiomelanocortin gene) which codes for ACTH, MSH (melanocyte stimulating hormone), Beta lipotropin, Beta endorphin, metenkephalin.
  • #52 Hypokalaemia <3.2mmol/L is found in almost 100% of patients with ectopic secretion of ACTH but in <10% of patients with pituitary-dependent disease. ----- High-dose dexamethasone suppression test The high-dose dexamethasone suppression test 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. However, approximately 10% of cases of ectopic disease, particularly those due to carcinoid tumours, show >50% suppression, and 10% of patients with Cushing’s disease do not suppress. ----
  • #54 There is a high incidence of venous thromboembolism (careful during surgery). Overall mortality greater than of general population (by a factor of 6).
  • #55 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) establishing hypercortisolemia confirm presence of CS), and (2) establishing the etiology of CS.
  • #58 Urinary cortisol: This test can be useful for outpatient screening—however, the false –ve rate of 5–10% means that it should not be used alone. (Fenofibrate, carbamazepine, and digoxin may lead to false +ves, depending on assay, and reduced GFR <30mL/min may lead to false –ves.) In children: correct for body surface area. Mild elevation occurs in pseudo-Cushing’s and normal pregnancy. ----- This test may have a significant value in establishing the diagnosis in those with pseudo-Cushing and elevated 24 hr urinary free cortisol. ----- Why dexamethasone? Because, dexamethasone does not cross react in radioimmunoassay for cortisol. But other steroids can cross react. --------------------- A combination of low-dose dexamethasone suppression test and CRH stimulation test has been shown to have 100% diagnostic accuracy
  • #60 Late-night salivary cortisol may be promising, particularly in those with possible cyclical Cushing’s Morning serum or salivary cortisol concentrations have no diagnostic value Normal evening cortisol nadir preserved in obese and depressed patients Nadir not present in patients with Cushing’s Benefits Easy: can be done at home Non-invasive Cortisol stable in saliva for days permitting testing days after collection Normal ranges vary depending on commercial assay
  • #61 Both tests have similar sensitivity and specificity
  • #62 Measure cortisol at 120min. Cortisol rises with pituitary disease but not with ectopic ACTH production. If tests indicate that cortisol responds to manipulation, Cushing’s disease is likely.
  • #63 High-dose dexamethasone suppression test The high-dose dexamethasone suppression test 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. However, approximately 10% of cases of ectopic disease, particularly those due to carcinoid tumours, show >50% suppression, and 10% of patients with Cushing’s disease do not suppress. ----- For ACTH-dependent cortisol excess an MRI of the pituitary is the investigation of choice, however: it may not show an abnormality in up to 40% of cases because small tumors are below the sensitivity of detection. Characteristically, pituitary corticotrope adenomas fail to enhance following gadolinium administration on T1-weighted MRI images
  • #64 ACTH may not be fully suppressed in some adrenal causes of Cushing’s; however, ACTH >4pmol/L is suggestive of an ACTH-dependent aetiology. ----- As regard pituitary imaging, should it be first line investigation in suspected CD: MRI, following gadolinium enhancement which significantly increases the pickup rate, localizes corticotroph adenomas in up to 80% of cases. However, it should be remembered that at least 10% of the normal population harbour microadenomas and, therefore, the biochemical investigation of these patients is essential, as a patient with an ectopic source to Cushing’s syndrome may have a pituitary ‘incidentaloma’. -----
  • #66 However, approximately 10% of cases of ectopic disease, particularly those due to carcinoid tumours, show >50% suppression, and 10% of patients with Cushing’s disease do not suppress.
  • #67 ACTH may not be fully suppressed in some adrenal causes of Cushing’s; however, ACTH >4pmol/L is suggestive of an ACTH-dependent aetiology. CRH test in pituitary-dependent and ectopic disease. In the patient with pituitary-dependent disease, the characteristic marked plasma cortisol rise after an IV bolus of 100 micrograms of CRH is seen. Serum cortisol levels are unaltered in the patient with ectopic ACTH secretion. ----- As regard pituitary imaging, should it be first line investigation in suspected CD: MRI, following gadolinium enhancement which significantly increases the pickup rate, localizes corticotroph adenomas in up to 80% of cases. However, it should be remembered that at least 10% of the normal population harbour microadenomas and, therefore, the biochemical investigation of these patients is essential, as a patient with an ectopic source to Cushing’s syndrome may have a pituitary ‘incidentaloma’. -----
  • #71 Bilateral simultaneous inferior petrosal sinus sampling with measurement of ACTH centrally and in the periphery in the basal state and following stimulation with IV CRH (100 micrograms) allows differentiation between pituitary-dependent and ectopic disease. A central to peripheral ratio of >2 prior to CRH is very suggestive of pituitary-dependent disease, and >3 following CRH gives a diagnostic accuracy approaching 90–95% for pituitary-dependent disease. The test should be performed when cortisol levels are elevated. The accurate lateralization of a tumour using the results from inferior petrosal sinus sampling (IPSS) is difficult, as differences in blood flow and catheter placement, etc. will affect the results. Brainstem vascular events and deep vein thrombosis are rare complications.
  • #73 Simultaneous bilateral inferior petrosal sinus and peripheral vein sampling for ACTH. The ratio of >3 between the left central and peripheral vein confirm a diagnosis of Cushing’s disease.
  • #74 In all cases of confirmed ACTH-dependent Cushing's, further tests are required for the differential diagnosis of pituitary Cushing's disease and ectopic ACTH syndrome. Most pituitary corticotrope adenomas still display regulatory features, including residual ACTH suppression by high-dose glucocorticoids and CRH responsiveness. Ectopic sources of ACTH are typically resistant to dexamethasone suppression and unresponsive to CRH. ----- Some benign tumors, such as carcinoids or islet cell tumors, have been shown to cause ectopic ACTH syndrome and are difficult to differentiate from pituitary causes of Cushing's syndrome. This difficulty is exaggerated by radiologic investigations of the sella that are often negative or shows a microadenoma, which is seen in up to 20% of autopsy series in normal individuals.
  • #75 Non contrast CT is good: it allows assessment of : adrenal morphology determination of tumor density in Hounsfield Units (HU), which helps to distinguish between benign and malignant adrenal lesions ----- MRI has a similar diagnostic value as CT in differentiating benign and malignant adrenal masses. However, in patients with suspected adrenocortical carcinoma, MRI provides more information about vascular invasion, particularly the inferior vena cava and the adrenal and renal veins.
  • #83 Differential Diagnosis of Cushing syndrome Chronic alcoholism (alcoholic pseudo-Cushing syndrome) Diabetes mellitus Depression (may have hypercortisolism) Osteoporosis or obesity due to other cause Primary hyperaldosteronism Anorexia nervosa (high urine free cortisol) Striae distensae (“stress marks”) seen in adolescence and in pregnancy Lipodystrophy from antiretroviral agents
  • #84 First patient is man with simple obesity and depression
  • #85 The facial appearance will generally revert upon treatment
  • #86 Availability of an experienced surgeon is crucial with an 80–90% remission rate following surgery. ----- There is a period of temporary adrenal insufficiency following successful surgery, usually of 6–8 months, but may be as long as 2 years in duration. ----- Nelson’s syndrome: skin pigmentation due to ACTH from an enlarging pituitary tumour, as adrenalectomy removes Ωve feedback; responds to pituitary radiation).
  • #88 Compared to the open adrenalectomy, the laparoscopic approach is associated with decreased postoperative pain, reduced time to return of bowel function, and decreased length of hospital stay.
  • #90 Purpose of medical treatment Correct metabolic abnormalities before attempted surgical cure Palliate surgically noncurable disease Achieve remission in patients for whom surgery is unlikely to achieve satisfactory long term results ------------ Inhibit ACTH release Somatostatin receptor analogues D2 receptor analogues (cabergoline) Block cortisol synthesis Ketaconozole, Metyrapone, Mitotane Block the cortisol receptor Mifepristone
  • #91 Usually within 2 years of adrenalectomy. Overall incidence is 50% at 10 years. However, if pituitary adenoma visible at time of adrenalectomy, incidence is 80% at 3 years.
  • #92 Unknown cause of elevated ACTH- 65% 5 year survival, 55% 10 year survival
  • #123 The striae in CS are red-purple in color and usually greater than 1 cm in width , (in contrast to silver, healed post-partum striae)
  • #131 Serial photographs of a patient with Cushing syndrome demonstrating gradual development of moon face, acne, and facial plethora. The patient underwent surgery in 2003. Note the dramatic improvement in the facial appearance 9 months after surgery. A = 1995;B = 1996;C = 1998; D = 1999;E = 2000;F = 2001;G = 2002;H = 2003; I = 2004. (Not taken as clinical pictures)