Morning ReportMorning Report

Rick HobbsRick Hobbs

PGY – 3.4ishPGY – 3.4ish

FrequencyFrequency

Endogenous Cushing syndrome –13 cases per Endogenous Cushing syndrome –13 cases per million individuals million individuals

70% to Cushing disease70% to Cushing disease 15% to ectopic ACTH15% to ectopic ACTH 15% to a primary adrenal tumor 15% to a primary adrenal tumor

Patient CharacteristicsPatient Characteristics

Female-to-male ratio 5:1 for Cushing Female-to-male ratio 5:1 for Cushing syndrome due to adrenal or pituitary tumor syndrome due to adrenal or pituitary tumor

Ectopic ACTH production is more frequent in Ectopic ACTH production is more frequent in men than in women because of the increased men than in women because of the increased incidence of lung tumors in this population incidence of lung tumors in this population

Clinical HistoryClinical History

Weight gain, skin changes, bruising, proximal Weight gain, skin changes, bruising, proximal muscle weakness, menstrual irregularities, muscle weakness, menstrual irregularities, decreased libido, depression, cognitive decreased libido, depression, cognitive dysfunction, emotional lability, HTN, diabetes, dysfunction, emotional lability, HTN, diabetes, impaired wound healing, infections, impaired wound healing, infections, osteoporotic fractures, headaches, vision osteoporotic fractures, headaches, vision changes, galactorrhea, virilizationchanges, galactorrhea, virilization

Physical Exam FindingsPhysical Exam Findings ObesityObesity

Increased adipose tissue w/Increased adipose tissue w/moon facies, moon facies, buffalo hump, and supraclavicular fat padsbuffalo hump, and supraclavicular fat pads

Central obesity w/ increased fat in mediastinum Central obesity w/ increased fat in mediastinum and peritoneum, and visceral fat on CT. and peritoneum, and visceral fat on CT.

Increased waist-to-hip ratio greater than 1 in men Increased waist-to-hip ratio greater than 1 in men and 0.8 in womenand 0.8 in women

SkinSkin Facial plethoraFacial plethora Violaceous striae on abdomen, buttocks, lower Violaceous striae on abdomen, buttocks, lower

back, upper thighs, upper arms, and breastsback, upper thighs, upper arms, and breasts EcchymosesEcchymoses Telangiectasias and purpura.Telangiectasias and purpura. Cutaneous atrophy with exposure of subcutaneous Cutaneous atrophy with exposure of subcutaneous

vasculature tissue and tenting of skinvasculature tissue and tenting of skin Increased lanugo facial hair.Increased lanugo facial hair. If glucocorticoid excess is accompanied by If glucocorticoid excess is accompanied by

androgen excess, as occurs in adrenocortical androgen excess, as occurs in adrenocortical carcinomas, hirsutism and male pattern balding carcinomas, hirsutism and male pattern balding may be present in women. Steroid acne over the may be present in women. Steroid acne over the face, chest, and back may be presentface, chest, and back may be present

Acanthosis nigricans, which is associated with Acanthosis nigricans, which is associated with insulin resistance and hyperinsulinism, may be insulin resistance and hyperinsulinism, may be present. Axilla, elbows, neck, and under breasts.present. Axilla, elbows, neck, and under breasts.

Cardiovascular and renalCardiovascular and renal Hypertension and possibly edema may be present Hypertension and possibly edema may be present

due to cortisol activation of the mineralocorticoid due to cortisol activation of the mineralocorticoid receptor leading to sodium and water retention.receptor leading to sodium and water retention.

GastroenterologicGastroenterologic Peptic ulceration particularly if patients are given Peptic ulceration particularly if patients are given

high doses of glucocorticoids (rare in endogenous high doses of glucocorticoids (rare in endogenous hypercortisolism).hypercortisolism).

EndocrineEndocrine Galactorrhea if anterior pituitary tumors compress Galactorrhea if anterior pituitary tumors compress

the pituitary stalk, leading to elevated prolactin the pituitary stalk, leading to elevated prolactin levels.levels.

Signs of hypothyroidism if anterior pituitary tumor Signs of hypothyroidism if anterior pituitary tumor whose size interferes with proper TRH and TSH whose size interferes with proper TRH and TSH functionfunction

Decreased testicular volume due to low Decreased testicular volume due to low testosterone levels from inhibition of LHRH and testosterone levels from inhibition of LHRH and LH/FSH functionLH/FSH function

Skeletal/muscularSkeletal/muscular Proximal muscle weaknessProximal muscle weakness Osteoporosis w/ fractures, kyphosis, height loss, Osteoporosis w/ fractures, kyphosis, height loss,

axial skeletal bone pain.axial skeletal bone pain. Avascular necrosis of the hip is also possible from Avascular necrosis of the hip is also possible from

glucocorticoid excess.glucocorticoid excess. NeuropsychologicalNeuropsychological

Emotional liability, fatigue, and depression.Emotional liability, fatigue, and depression. Visual-field defects, often bitemporal Visual-field defects, often bitemporal

hemianopsia, and blurred vision with large ACTH-hemianopsia, and blurred vision with large ACTH-producing pituitary tumors that impinge on the producing pituitary tumors that impinge on the optic chiasma.optic chiasma.

Adrenal crisisAdrenal crisis May occur in patients on steroids who stop taking May occur in patients on steroids who stop taking

their glucocorticoids or neglect to increase their their glucocorticoids or neglect to increase their steroids during an acute illness, or in patients who steroids during an acute illness, or in patients who have recently undergone resection of an ACTH-have recently undergone resection of an ACTH-producing or cortisol-producing tumor or who are producing or cortisol-producing tumor or who are taking adrenal steroid inhibitors.taking adrenal steroid inhibitors.

Hypotension, abdominal pain, vomiting, and Hypotension, abdominal pain, vomiting, and mental confusion (secondary to low serum sodium mental confusion (secondary to low serum sodium or hypotension). Hypoglycemia, hyperkalemia, or hypotension). Hypoglycemia, hyperkalemia, hyponatremia, and metabolic acidosis.hyponatremia, and metabolic acidosis.

Physical Physical FeaturesFeatures

LabsLabs

LeukocytosisLeukocytosis HyperglycemiaHyperglycemia Hypokalemic metabolic alkalosis due to Hypokalemic metabolic alkalosis due to

activation of the renal mineralocorticoid activation of the renal mineralocorticoid receptorreceptor

Okay, that’s my patient, Okay, that’s my patient, how do I find the source?how do I find the source?

Simplify.Simplify.

Step 1: Exogenous vs Endogenous Cortisol Step 1: Exogenous vs Endogenous Cortisol Excess?Excess?

Step 2: ACTH-dependent or ACTH-Step 2: ACTH-dependent or ACTH-independent?independent?

Step 3: ACTH from pituitary or ectopic?Step 3: ACTH from pituitary or ectopic?

Remember…Remember…

Exogenous corticosteroids are the leading Exogenous corticosteroids are the leading cause of Cushing’s Syndromecause of Cushing’s Syndrome

Exogenous steroids suppress the HPA axis, Exogenous steroids suppress the HPA axis, with full recovery taking as long as a year after with full recovery taking as long as a year after cessation of glucocorticoid administration. cessation of glucocorticoid administration.

ACTH-producing pituitary adenoma ACTH-producing pituitary adenoma

ACTH -> adrenal cortical hyperplasia -> ACTH -> adrenal cortical hyperplasia -> adrenal steroid overproductionadrenal steroid overproduction

Can also impair other anterior pituitary Can also impair other anterior pituitary hormones as well as vasopressin (galactorrhea hormones as well as vasopressin (galactorrhea not uncommonly)not uncommonly)

Bitemporal hemianopsiaBitemporal hemianopsia

Primary adrenal lesionsPrimary adrenal lesions

Adrenal adenoma, adrenal carcinoma, or Adrenal adenoma, adrenal carcinoma, or macronodular or micronodular adrenal macronodular or micronodular adrenal hyperplasiahyperplasia

Excess androgen secretion is suggestive of an Excess androgen secretion is suggestive of an adrenal carcinoma rather than an adrenal adrenal carcinoma rather than an adrenal adenomaadenoma

Ectopic ACTHEctopic ACTH

Ectopic ACTH is sometimes secreted by oat Ectopic ACTH is sometimes secreted by oat cell or small-cell lung tumors or by carcinoid cell or small-cell lung tumors or by carcinoid tumors tumors

Occurs later in lifeOccurs later in life

Question 1 – Endogenous?Question 1 – Endogenous? Endogenous overproduction of cortisol requires Endogenous overproduction of cortisol requires

the demonstration of inappropriately high serum the demonstration of inappropriately high serum or urine cortisol levels or urine cortisol levels

Four Methods:Four Methods: Urinary Free CortisolUrinary Free Cortisol Low Dose Dexamethasone Suppression TestLow Dose Dexamethasone Suppression Test Evening Serum and Salivary CortisolEvening Serum and Salivary Cortisol Dexamethasone-Corticotropin-Releasing hormone testDexamethasone-Corticotropin-Releasing hormone test

UFCUFC

3-4 times the upper limit of normal are highly 3-4 times the upper limit of normal are highly suggestive of Cushing syndrome suggestive of Cushing syndrome

3 negative UFC measurements excludes 3 negative UFC measurements excludes endogenous Cushing’s Syndromeendogenous Cushing’s Syndrome

Dexamethasone Suppression TestDexamethasone Suppression Test

Inhibit secretion of hypothalamic CRH and Inhibit secretion of hypothalamic CRH and pituitary ACTH but does not directly affect pituitary ACTH but does not directly affect adrenal cortisol production or ectopic adrenal cortisol production or ectopic productionproduction

Question 2 – ACTH Dependent?Question 2 – ACTH Dependent?

Undetectable plasma ACTH (<5pg/ml) with Undetectable plasma ACTH (<5pg/ml) with simultaneously elevated serum cortisol is simultaneously elevated serum cortisol is diagnostic of ACTH-independent Cushing diagnostic of ACTH-independent Cushing syndrome -> usually adrenal adenoma or syndrome -> usually adrenal adenoma or carcinomacarcinoma

Measurements of adrenal androgen Measurements of adrenal androgen production, DHEAS and 24-hour urinary 17-production, DHEAS and 24-hour urinary 17-ketosteroid can confirm adrenal tumorketosteroid can confirm adrenal tumor

Question 3- Okay, too much ACTH. Question 3- Okay, too much ACTH. But from where?But from where?

ACTH >10-20 = dependentACTH >10-20 = dependent 8mg overnight dex suppression test and 48hr 8mg overnight dex suppression test and 48hr

high-dose dex suppression test can high-dose dex suppression test can differentiate pituitary from ectopic ACTHdifferentiate pituitary from ectopic ACTH

CRH administration will increase pituitary-CRH administration will increase pituitary-driven ACTH and cortisol, but not affect driven ACTH and cortisol, but not affect ectopic sourcesectopic sources

ImagingImaging

Wait! Not until biochemical testing performed Wait! Not until biochemical testing performed given 10% prevalence of incidentalomas.given 10% prevalence of incidentalomas.

Abdominal CT to eval for primary adrenalAbdominal CT to eval for primary adrenal Pituitary MRIPituitary MRI Chest CT for lung CA w/ectopic secretionChest CT for lung CA w/ectopic secretion Octreotide scintigraphy can localize some Octreotide scintigraphy can localize some

ectopic ACTH tumorsectopic ACTH tumors

Inferior Petrosal Sinus SamplingInferior Petrosal Sinus Sampling

Can identify a pituitary source of ACTH not Can identify a pituitary source of ACTH not revealed by MRI by measuring ACTH revealed by MRI by measuring ACTH secretion in response to CRH in serum and secretion in response to CRH in serum and petrosal samples and comparing the valuespetrosal samples and comparing the values

Bilateral sampling can actually lateralize a Bilateral sampling can actually lateralize a microadenomamicroadenoma

TreatmentTreatment

Stop exogenous glucocorticoidStop exogenous glucocorticoid SurgerySurgery Medication to control hypercortisolismMedication to control hypercortisolism

Mitotane, ketoconazole, metyrapone, Mitotane, ketoconazole, metyrapone, aminoglutethimide, trilostane, and etomidate aminoglutethimide, trilostane, and etomidate

Often failOften fail Radiation if surgery not possibleRadiation if surgery not possible Must have stress-dose steroids pre-, intra-, Must have stress-dose steroids pre-, intra-,

post-oppost-op