Transcript The Buffalo Hump April 11, 2006

The Buffalo Hump
April 11, 2006
Robert R. Zaid D.O
James Walter M.D
Chief complaint
First visit – April 2005
• 55 year old Caucasian female presents
with
– Low back pain
– Fatigue
– 45 pound weight gain in two years
History and physical
First visit – April 2005
History
• Hypothyroidism
• Uncontrolled
hypertension with
multiple medications
• Previously diagnosed
with Cushing’s
syndrome
• All other history noncontributory
Physical
• Moon facies
• Buffalo hump
• Supraclavicular filling
• Obesity
• What would you order?
• What would you do?
Office visit
One month later
• MRI – Pituitary microadenoma on R side
• Sent to U of M for surgery consult
Office visit
November 2005
•
•
•
•
Rapid weight gain of 25 lbs
Round plethora in face
No skin changes
Supraclavicular filling
Office visit
June 27th – U of M
• Proximal muscle weakness of lower
extremity
• Labs –
– Endocrine clinic
• Cushing
• MRI- performed (no result back)
Office visit
August 10, 2006
• Seen at U of M
– 24 hour urine cortisol showed cushings
– Transphenoidal surgery was performed
without complications
– Glucose 171, Electrolytes normal
– Pt sent home
Office Visit
Late August
• Pituitary tumor biopsy
– Adenohypothesis shows ACTH cells
predominately
Office Visit
9/5/6
• Fall fx R distal radius, pt placed in long
arm cast
• No visual symptoms
• U of M – May need repeat transsphenoidal resection
• BP better, fatigue better since resection
Office Visit
9/12/6
• Neuro surgery
– Not in remission
Office Visit
9/13/6
• Endocrine clinic
– Persistent hypercortisolemia
– Pt was sent home with ketoconazole
– Physical
• Wt gain 51 lbs., depressed
• Lanugo hirsuitism, LE edema, Liver and spleen not
palpable
– Labs
• Glucose 154, cortisol 53.2
Office Visit
9/13/6
• Endocrine clinic
– Assesment/ Plan
• ACTH dependent cushing syndrome following
surgery
• Not improved with ketoconazole
• No distinct microadenoma
• Recommend b/l adrenalectomy
• 6 x 5 mm non enhancement of post pituitary
– May be a false finding
• What would you do?
• What about 5X6 non-enhancing lesion?
• Location of ACTH excess?
Office Visit
9/28/6
• Pt confused about recommendations
– No adrenalectomy
• Spirinolactone prescribed; BP normal
• Toprol QD
Office Visit
10/18/6 Ann arbor ER
• Vomitting; non-billous, non-bloody
• Ketoconazole causing metallic taste in
mouth
• No diarrhea/constipation
• CBC normal
• Creat 2.1; K 5.6, NA 131, Calcium normal
• BP improves with fluids
Office Visit
11/2/6
• Renal ultrasound was normal
• ACTH 61; cortisol 416
• MRI
– Post surgical scars
– Small residual microadenoma still possible
– Cut out adrenals
• What would you like to know?
Differential
• ACTH dependent causes
– ACTH – secreting pituitary tumor
– Nonpituitary ACTH secreting neoplasm
(ectopic)
• ACTH independent causes
– Adrenal adenoma
– Adrenal carcinoma
– Micronodular adrenal disease
– Factitious glucocorticoid administration
Differential
• Ectopic production of
ACTH
–
–
–
–
–
–
Small cell lung cancer
Pulmonary carcinoid
Medullary thyroid cancer
Islet cell tumor
Pheochromocytoma
Ganglioneuroma
• CRH
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–
Medullary thyroid cancer
Paraganglioma
Prostate cancer
Islet cell tumor
Intrasellar gangliocytoma
• MEN 2a?
• ACTH independent
– Adrenal adenoma
– Adrenal carcinoma
– Micronodular adrenal
disease
– Factitious glucocorticoid
administration
Goldman, Ausiello, Cecils textbook of medicine, 22nd edition, pgs 1379-1381
• Pituitary source of ACTH or ectopic ACTH
– How would you know?
– Should she undergo another pituitary
surgery?
– What about 5x6mm non-enhancement of
posterior pituitary?
• Bilateral inferior petrosal sinus sampling
– Done by radiologist
– Catheterization of left and right sinus and
periphery
• Blood samples taken and a ratio of central to
peripheral ACTH is made
• If ratio favors pituitary by >1.5 then it is likely to be
central
• BIPSS procedure showed peripheral
source
• Evidence points to ectopic production
Differential
• Ectopic production of
ACTH
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–
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Small cell lung cancer
Pulmonary carcinoid
Medullary thyroid cancer
Islet cell tumor
Pheochromocytoma
Ganglioneuroma
• CRH
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Medullary thyroid cancer
Paraganglioma
Prostate cancer
Islet cell tumor
Intrasellar gangliocytoma
• MEN 2a?
• ACTH independent
– Adrenal adenoma
– Adrenal carcinoma
– Micronodular adrenal
disease
– Factitious glucocorticoid
administration
Goldman, Ausiello, Cecils textbook of medicine, 22nd edition, pgs 1379-1381
• What do you want to rule out?
Thyroid
• Ultrasound
– Globally enlarged
Thyroid
• Fine needle aspirate
– Benign findings
– Cysts most likely
colloid
CT
• Normal adrenals
• Normal pancreas
• Small 1x1cm mass in right lower lobe
– No calcifications, ground glass appearance
– Pet imaging was negative
– Octeotride testing negative
• Most likely etiology?
• Test to confirm?
• Bronchial carcinoid?
• Small cell carcinoma?
– How do we differentiate?
– How do we diagnose?
Ectopic ACTH
Lung etiology
Description
Carcinoid
Small Cell
Age
40-50
27-66
Mortality
Slow growing
6-10 months
Symptoms
Neuroendocrine
Cough, hemoptysis
symptoms usually first
Diagnosis
CT, MRI, PET
CT, MRI, PET
Confirmed
Histology/
Bronchoscopy
Histology/
Bronchoscopy
500
• What is bronchial
carcinoid?
Cushings and ectopic ACTH
ETIOLOGY AND PATHOGENESIS
• Cushing's disease (60-70%)
– Pituitary adenoma
• Causes excess production of ACTH
– Only 15% of tumors secrete ACTH
• Women : Men , 8: 1
• Cushing's syndrome (glucocorticoid excess)
– Adrenal causes of cortisol excess
– Ectopic production of ACTH and CRH
– Physiologic states
• Overproduction of cortisol
Cecils, online Copyright 2004. WB Saunders, an Elsevier imprint. All rights reserved.
Cushings and ectopic ACTH
ETIOLOGY AND PATHOGENESIS
• Cushing's disease
– Likely a primary defect
• At the level of the pituitary
– Rare cases caused by
• Hypothalamic dysregulation
• Corticotroph hyperplasia
– CRH production
» Intrasellar gangliocytomas
» Ectopic CRH-producing cancer
Cushings and ectopic ACTH
ETIOLOGY AND PATHOGENESIS
ACTH-secreting tumors
– Microadenomas (80-90%)
– Clinical features of cortisol excess may allow
detection of corticotroph adenomas before
they have grown to a larger size.
Cushings and ectopic ACTH
CLINICAL MANIFESTATIONS
• Clinical features
– Caused by
• Excess glucocorticoids
• Hypersecretion
– ACTH
– POMC peptide products
– Severity
• Reflects
– Level of free cortisol
– Duration of the disease
– Sensitivity to glucocorticoid
action
• Early in the disease or in mild
cases
– Can be extremely
challenging diagnosis
– Clinical suspicion is
important
Cushings and ectopic ACTH
CLINICAL MANIFESTATIONS
• Clinical features
– Centripetal distribution of fat
• Characteristic
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“Buffalo hump"
“Moon facies"
Supraclavicular area
Minimal fat in the extremities
– Striae (>1cm)
• Purple
– Reflect steroid-induced thinning of the dermis
– Spontaneous ecchymoses
• Thinning of the skin
• Capillary fragility
– Proximal muscle weakness
• Manifestation of glucocorticoid excess
Cushings and ectopic ACTH
CLINICAL MANIFESTATIONS
• Clinical features
– Findings consistent with ACTH excess
• Osteopenia
• Hypokalemia
– Results from effects of ACTH on mineralocorticoid
production
– Cortisol can "spill over" and act on mineralocorticoid
receptors in the distal tubule.
Cushings and ectopic ACTH
CLINICAL MANIFESTATIONS
• Clinical features
– Hyperpigmentation
• Also found with addisons
– Hirsutism and acne
• Increased production of adrenal androgens
• Prominent in patients with Cushing's disease
– Not as common with adrenal adenomas
– Oligo/amenorrhea
– Hypertension and glucose intolerance
• Caused by glucocorticoid excess
– Immunosuppression
– Neuropsychiatric symptoms
• Depression
Cushings and ectopic ACTH
DIAGNOSIS
• Screening tests and differential diagnosis
– One of the greatest diagnostic challenges in
endocrinology
• First step
– Determine cortisol excess
• Must distinguish among
– (1) Adrenal causes of cortisol excess
– (2) Pituitary causes of ACTH excess (Cushing's
disease)
– (3) Ectopic sources of ACTH
– (4) Ectopic CRH
Cushings and ectopic ACTH
DIAGNOSIS
• Hypercortisolism
– Random cortisol levels
• Not useful
– Diurnal variation
– Overnight dexamethasone test
• Most widely used screening test
• A normal result of the dexamethasone test
– Excludes Cushing's
• Abnormal overnight dexamethasone suppression
– Can be seen in up to 30% of hospitalized patients
– During alcohol withdrawal
Cushings and ectopic ACTH
DIAGNOSIS
• 24-hour urine free cortisol
– Provides an alternative
– Reduces day to day variations
• Once cortisol excess is present
– Determine the source
• ACTH or cortisol
– Classic approach
• Dexamethasone suppression test
– Low-dose, followed by a high-dose,
– Cushing’s patients are not suppressed
Cushings and ectopic ACTH
DIAGNOSIS
• High-dose dexamethasone test can be used to
differentiate
– ACTH independent
• Adrenal sources of cortisol
• Plasma and urinary cortisol levels are not affected
• ACTH levels are low (HP axis is suppressed)
– ACTH dependent
• Pituitary adenomas
– Partial ability to respond to high-dose dexamethasone
– Criteria debated
• Ectopic
Cushings and ectopic ACTH
DIAGNOSIS
• Ectopic ACTH syndrome
– Suspected in patients
• Known malignancies
– Small cell carcinoma of
the lung
– Carcinoids
» Bronchial
» Thymic
» Gastrointestinal
carcinoids
» Islet cell tumors
» Medullary
carcinoma of the
thyroid
Plasma ACTH levels
• Very high (>200 pg/mL)
• Hyperpigmentation
• Clinical features
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Rapid onset
Tumor cachexia
Pronounced weakness
Fluid retention
Glucose intolerance
Hypokalemia
Poor skin integrity
Cushings and ectopic ACTH
DIAGNOSIS
• Ectopic ACTH (Carcinoids)
– Can sometimes be detected by CT or MRI
• Many are too small to be seen
– Exhibit dexamethasone suppression similar to
pituitary adenomas
• High-dose dexamethasone test
– Unreliable
Cushings and ectopic ACTH
DIAGNOSIS Ectopic ACTH (Carcinoids)
•
Variety of procedures have been
developed
– Metyrapone test
• Inhibition of 11β-hydroxylase
• Blocks cortisol production
• Subset of ectopic tumors that
respond atypically to
dexamethasone are most likely to
give a positive response in the
metyrapone test.
•
Inferior petrosal sinus sampling
– Distinguish pituitary and ectopic
sources
• Experienced radiologist
• Catheterization of the petrosal
sinuses
• Blood samples are taken
simultaneously from the left and
right petrosal sinuses and from
the periphery
– ACTH-producing pituitary
adenomas
• Gradient in ACTH levels between
the central and peripheral
• Administration of CRH stimulates
ACTH and tends to enhance the
gradient
– 2 : 1 (central:peripheral) basally
or
– 3 : 1 after CRH on either the left
or the right
– Consistent with a pituitary source
of ACTH
Cushings and ectopic ACTH
Treatment
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•
Transphenoidal surgery
Removal of ectopic source
Post-surgical hypocortisolemia
Adrenalectomy
Ketoconazole
Thank you
Questions, comments, concerns…