Master Professor Rounds

Master Professor: Madup Naim, MD

Division of Endocrinology

Presenter: S. Marty Pantz, MD

Date

Case Presentation

ID/CC:

HPI:

Case Presentation (cont’d)

PMH: HTN x 25 yrs DepressionDM x 18 yrs DyslipidemiaHypothyroidism x 18 yrs ArthritisHospitalizations x 2

1. January 2006—nausea/vomiting, given IVF and discharged later that day

2. January 2006—atypical chest pain, scheduled for outpatient ischemic work-up

h/o L CVA in January, with residual R-sided facial paresthesias

Menstrual/OB Hx: postmenopausal x 9 yrs, not on HRT

h/o regular menses, G1P1

Allergies: NKDA

Case Presentation (cont’d)

Meds: Lexapro 10 mcg daily Spironolactone 25 mg dailyNorvasc 10 mg daily Metoprolol 50 mg BIDSynthroid 75 mcg daily Benazepril 40 mg dailyMetformin 500 mg BID Zocor 40 mg qHSASA 81 mg daily

Family Hx: mother deceased from heart disease(+) DM

Social Hx: (+) tobacco use — 5 cigarettes/day x 10 yrsdenies EtOH, IVDAfrom Mexico

Physical ExamVital Signs: T 98.2 BP 139/74 HR 78 RR 20

0/10 pain

General: WDWN, dark in appearance, (+) truncal obesity, NAD, AAO x 3, slow to respond to questions, at times inattentive

HEENT: NC/AT, (+) moon facies, (+) hirsutism, PERRL, EOMI, mmm, no thyromegaly, no LAD, (+) dorsal fat pad

Chest: CTAB, no c/w/r CV: RRR, nl S1S2, no S3/S4, no m/c/r/g Ab: (+) BS, S/NT/ND, no HSM GU: no clitoromegalySkin/Extremities: (+) abdominal striae, (+) ecchymotic

areas over abdomen and antecubital fossa, (+) thinning of skin, decreased

subcutaneous fat, (+) bilateral muscle wasting, 1+ edema BLE

Neuro: AAO x 3, proximal muscle weakness, 2+ DTR

Differential Diagnosis

Differential Diagnosis

• Cushing’s Syndrome– ACTH-dependent vs. ACTH-independent

• Pseudo-Cushing’s Syndrome

• PCOS

• Uncontrolled Hypothyroidism

• Rheumatoid Arthritis

• Polymyalgia Rheumatica

• Myopathy

How would you

approach this patient?

Studies

Labs:

• BMP

• CBC w/diff

• TSH/free T4

• Additional Tests

• Screening Tests I

• Screening Tests II

Imaging studies:

• CXR

• MRI brain

Next

Basic Metabolic Panel

Return to Menu

135 101 17

4.0 22 0.6236

CBC w/differential

Return to Menu

7.712.7

37.5322

N80 L14 M6

TSH/Free T4

Return to Menu

TSH 1.81 uIU/ml

Free T4 1.34 ng/dl

Additional Tests

• random cortisol 37.8 mcg/dl (10:40)

26.5 mcg/dl (21:20)(normal AM: 5-25 mcg/dl, normal PM: 3-13 mcg/dl)

• ACTH 69 pg/ml (21:20)(normal 5-27 pg/ml)

• Estradiol 25 pg/ml • DHEA-S 227 μg/dl

• FSH 1.0 U/L • Testosterone 47 pg/dl

• LH < 1.0 U/L • Prolactin 15.8 ng/ml Return to Menu

5/25 21:25

ACTH

69 pg/ml

Cortisol

26.5 mcg/dl

5/31 23:00

Dexamethasone

1 mg

6/01 08:01

ACTH

56 pg/ml

Cortisol

14.1 mcg/dl

Initial Screening Tests

Return to Menu

24 hour urinary free cortisol 457 μg (4-50 μg)

Low dose Dexamethasone Suppression Test

High Dose DexamethasoneSuppression Test

7/12 10:46

ACTH

61 pg/ml

Cortisol

21.6 mcg/dl

7/12 PM

Dexamethasone

8 mg

7/13 07:34

ACTH

9 pg/ml

Cortisol

3.1 mcg/dl

Return to Menu

CXR

Return to Menuatherosclerotic vascular disease

MRIMRI Brain

MRI

Return to Menu

no identifiable masses

chronic non-specific white matter changes

MRI Brain

Working Diagnosis

Cushing’s SyndromeACTH-dependent

most likely pituitary in origin

A Quick Synopsis on Cushing’s Syndrome

• rare condition that results from chronic exposure to glucocorticoids, characterized by abnormally high levels of cortisol

• more common in females than male, although ectopic causes occur more frequently in males

• two broad categories– ACTH-dependent

(includes Cushing’s disease, ectopic ACTH syndrome, and ectopic CRH syndrome)

– ACTH-independent(adrenal adenoma, adrenal carcinoma, micronodular hyperplasia, macronodular hyperplasia)

ACTH-Dependent Cushing’s Syndrome

• characterized by high cortisol associated with normal/high ACTH levels with dexamethasone suppression

• Cushing’s disease (70% of cases)– pituitary source of excess ACTH production– females > males

• Ectopic ACTH syndrome (15%)– usually from small cell cancer or other ACTH-producing

tumors– males > females

• Ectopic CRH syndrome– very rare

ACTH-IndependentCushing’s Syndrome

• high cortisol, with low ACTH levels on dexamethasone suppression testing

• ~15% of cases

• usually adrenal in origin

Orth D. N Engl J Med 1995;332:791-803

Physiologic and Pathophysiologic Features of the Hypothalamic-Pituitary-Adrenal Axis in Normal Subjects and Patients with Cushing's Syndrome (Top Panels)

and the Effect of Dexamethasone (Bottom Panels)

*

*Erratum: thick purple lines should be dotted purple lines (denoting suppressed secretion)

ACTH-dependent Cushing’s SyndromeACTH-independent

Cushing’s Syndrome

Clinical Manifestations of Cushing’s Syndrome

• central obesity (>80%)• facial plethora (>50%)• glucose intolerance (>40%)• weakness/proximal myopathy*

(>75%)• hypertension• psychological changes• easy bruisability*• hirsutism• oligomenorrhea/amenorrhea• impotence• acne, oily skin• abdominal striae• moon facies

• ankle edema• backache, vertebral collapse,

fracture• polydipsia, polyuria• renal calculi• hyperpigmentation• headache• exophthalmos• fungal infection• abdominal pain• thinning of skin*• weight gain• dorsal/supraclavicular fat pad

*features that distinguish Cushing’s syndrome from Pseudo-Cushing’s syndrome

An Algorithmic Approach

to the Patient

with Cushing’s Syndrome

Tests Used for Work-Up

• 24 hour urine cortisol– used as initial screening to confirm diagnosis of Cushing’s

syndrome

– most direct way of measuring cortisol secretion

– must correlate with urine creatinine levels to confirm adequate sample collection

– preferably, should have 2 or 3 elevated values to confirm dx

• Low-dose dexamethasone suppression test– helps distinguish ACTH-dependent vs. ACTH-independent

– check evening ACTH/cortisol, give 1 mg dexamethasone between 11pm-MN, check ACTH/cortisol at 8am

– standard 2-day, 2 mg suppression test is used as initial screening or if overnight test equivocal

Tests Used for Work-Up (II)• High-dose dexamethasone suppression test

– delineates pituitary vs ectopic sources of ACTH production– same process as for low-dose suppression testing, but 8mg

dexamethasone used– alternative test is total 48 mg given over 8 doses

(2 mg every 6 hrs), checking ACTH/cortisol 6 hrs after last dose

• Octreotide Scan– useful in identifying ectopic ACTH production in tumors with

somatostatin receptors

• Inferior Petrosal Sinus Sampling (IPSS)– most direct way to identify excess pituitary ACTH production– simultaneous bilateral sinus & venous samples to measure ACTH– CRH or DDAVP given peripherally, with additional samples

drawn at 2-3 minutes & at 5-6 minutes– central:peripheral ratio before/after is compared; if >2-3pituitary– gold standard for detecting Cushing’s disease– $$$, invasive

Management of Cushing’s Syndrome• depends on source, but surgery is usually first-line tx• Cushing’s disease

– transsphenoidal surgery (70-80% cure rate)– pituitary irradiation as second line– consider total bilateral adrenalectomy as last resort

• Ectopic ACTH/CRH syndrome– surgical resection of underlying tumor (poor cure rate in malignancy)– adrenal enzyme inhibitors (i.e. ketoconazole)– medical/surgical adrenalectomy

• Adrenal tumors– surgical resection if deemed operable (usually bilateral

adrenalectomy)– mitotane as a palliative measure for recurrent/residual disease– surgical resection of recurrent disease– adrenal enzyme inhibitors

• Exogenous glucocorticoid use– wean off offending agent slowly

Summary

• 2 elevated random cortisol levels get an ACTH level

• if cortisol + ACTH are high and s/sx consistent with possible Cushing’s initial screening tests to confirm dx and distinguish etiology (24 hr urine cortisol & low-dose dexamethasone suppression test)

• depending on the ACTH level, work-up accordingly– if low ACTH on suppression think adrenal causes and

get a CT A/P– if high/normal ACTH high-dose dexamethasone

suppression test to delineate pituitary (suppressed ACTH) & ectopic sources, followed by appropriate imaging studies

• surgery is usually first-line therapy, if resectable

References

Special Thanksto

Chief Holmanfor his invaluable resources and insight during the preparation

of this case!