Anesthetic Implications of Pheochromocytoma & Cushing syndrome &Addison’s disease
Testing in Cushing’s Syndrome and pheochromocytoma
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Transcript of Testing in Cushing’s Syndrome and pheochromocytoma
Tamara Spaic, R4
1. Adrenal cortex and HPA axis
2. Testing in Cushing’s syndrome
3. Review of the Endocrine Society Clinical Practice Guidelines (JCEM, May 2008)
4. Assessment of adrenal medullary function and disorders
5. Which test is the best?
4 g weight 2x5x1 cm Posteromedial surface of the kidney Retroperitoneal
Unenhanced CT PET scan
zona glomerulosa lacks
Only zona glomerulosa
Trophic hormone of zonae fasciculata and reticularis
Major regulator of adrenal androgen and cortisol production
Regulated by CRH (whose action is also potentiated by AVP -arginine vasopressin, and β adrenergic catecholamines)
Rapid synthesis and secretion of steroids (hormone levels rise within minutes)
POMC (proopiomelanocortin) - precursor
ACTH circadian rhythm generated in suprachiasmatic nc (signals CRH release)
Secreted with both circadian periodicity and ultradian pulsatility
Periodic secretory bursts at frequency of ~ 40 pulses/day Entrained by visual cues, light –dark cycle Continuous CRH administration desensitizes the ACTH
response Prolonged pulsatile CRH administration restores cortisol
secretion Corticosteroids directly suppress basal or stimulated
ACTH pulse amplitude
1. Episodic secretion and circadian rhythm of ACTH
2. Stress responsivness of the HPA
3. Feedback inhibition by cortisol of ACTH secretion
Physical stresses (major illness, surgery, trauma, starvation)
Psychological stress (anxiety, depression, manic-depressive psychosis)
CNS and pituitary d/s Cushing’s syndrome Liver d/s CRF Alcoholism
ACTH and cortisol secreted within minutes (Sx, hypoglycemia)
Abolish circadian periodicity (prolonged stress)
Stress →↑CHR → ↑ACTH Stress response abolished by proior high
dose glucocorticoids/Cushing’s syndrome Enhanced following adrenalectomy
FAST feedback inhibition – depends on the rate of increase of GC (not the dose)
Rapid (within minutes) and transient (up to 10 minutes)
DELAYED feedback inhibition is both time and dose dependent
Ideally nonstressed resting subject should have venous sample drawn 6-9 am
Unstable on room temperature (must immediately go on ice, -20° C)
Siliconized glass tube containing EDTARandom ACTH values do not on their own provide an accurate assessment of HPA function
Under basal (non stressed) conditions 8-25 mg/day (22-69 μmol/day) Mean 9.2 mg/day (25 μmol/day) – less than
thought before (?20 mg/day)
Circulate bound to plasma proteins (bound – biologically inactive
t½ (60-90 minutes) is determined
extend of plasma binding and
rate of metabolic inactivation 10% - free 75-90% - CBG (corticosteriod binding globulin) 15% - albumin (dexamethasone -75%)
Produced by the liver Progesterone in late pregnancy Synthetic steroids – do not significantly bind
(except prednisolone)
High estrogen states (pregnancy, OCP) ↑T4 Diabetes Hematologic d/s Chronic active hepatitis
Familial CBG deficiency ↓ T4 Protein deficiency states (nephrotic
syndrome, liver failure)
Metabolism – liver (conjugation) Excretion – kidney (<1% in urine unchanged
– “free”) 11β-hydroxysteriod dehydrogenase (inhibited
by IGF-1)
↓ clearance in starvation/anorexia nervosa and pregnancy (↑CBG)
↓ metabolism and excretion – hypoT4 ↑metabolism – OCP, liver disease Also drugs : dilantin, barbiturates, mitotane,
rifampin
ACTH Dependent ACTH Independent Pseudo-Cushing’s Syndrome
Pseudo-Cushing’s SyndromeEtohObesityDepression
Sign/symptom Frequency (%) Truncal obesity 96 Facial fullness 82 Diabetes or glucose intolerance 80 Gonadal dysfunction 74 Hirsutism, acne 72 Hypertension 68 Muscle weakness 64 Skin atrophy and bruising 62 Mood disorders 58 Osteoporosis 38 Oedema 18 Polydipsia, polyuria 10 Fungal infections 6
The mean age of the 239 female and 63 male patients was 38·4 years (SD 13·5; range 8–75).
• Answer 2 questions:
1. Does this patient have Cushing’s Syndrome?
2. Having confirmed Cushing’s syndrome clinically and biochemically – What is the cause?
• Diagnosis
1. UFC
2. Circadian Rhythm of plasma cortisol
3. Low dose dexamethasone
4. Salivary cortisol
• Differential Diagnosis
1. Plasma ACTH
2. Plasma K, HCO3
3. High dose dexamathasone suppression
4. Metyrapone test
5. CRH
6. IPSS
7. CT/MRI pituitary, adrenals
8. Scintigraphy
Obesity epidemics Aging population Suspicion - common Rare diagnosis (5-10 cases/million
population/year) – Cushing’s disease – (70% of all cases)
0.5% of lung cancer patients have ectopic ACTH syndrome
False positive tests
2-5% prevalence of unsuspected Cushing’s syndrome in pts with poorly controlled DM
0.5-1% in HTN 10.8% of pts with osteoporosis/vertebral # 3% in osteoporosis Overlap with PCOS (5.8%) 9% pts with incidental adreanal nodules (>2
cm) have evidence of hypercortisolism
• To reduce FP rate (high pretest probability)1. Pts with unusual features for age
(osteoporosis, HTN)2. Pts with multiple and progressive features
9especially those predictive of Cushing’s3. Children with decreasing height ‰ and
increasing wt4. Adrenal incidentaloma compatible with
adenoma
<1% of secreted cortisol unchanged in urine Cushing’s – CBG binding capacity exceeded, so plasma
free cortisol ↑ - ↑UFC N range 50-250 nmol/24 h (80-120) Not affected by conditions and meds that alter CBG Use the upper limit of normal as cut-off point Should do 2 or 3 complete consecutive collections (with 24
hr Cr) Can not do in RF (falsely low) False + if fluid intake >5 L /day
Am cortisol often not elevated in Cushing’s syndrome
(late night usually increased) Small increases in cortisol at circadian nadir may
not be detected as ↑ UFC Sn 45-71% (although most studies show
excellent sn, sp is the problem) Pseudo vs Cushing’s – ? Useful (also anxiety,
starvation, AN) To avoid overlap 4-fold increase Levels elevated during stress
Abnormal circadian rhythm (absence of late night nadir) Same as in midnight serum cortisol (but impractical) Sn 100%, Sp 77% CBG absent in plasma (measures free, not dependent on
CBG) Not affected on saliva amount or composition Stable on room temperature Can be sampled at home by the pt At least 2 measurements
N (bedtime or 2300-2400) <4 nmol/L Sn 92-100% Sp 93-100% (highly accurate for differentiating from
pseudocushing’s) Circadian rhythm is blunted in depression, shift workers May be absent in critically ill Chewing tobacco or licorice may have falsely elevated
result (inhibits which enzyme?) ?Smokers Different time zones
11 β hydroxysteriod dehydrogenase type 2
Cortisol → cortisone (inhibits)
Assessing feedback inhibition of HPA axis Suppresses pituitary ACTH ↓plasma and urinary cortisol Cushing’s – fails to suppress Dexamethasone does not interfere with the
measurment of cortisol Measure simultaneously daxamethasone
level (to assess compliance, etc)
1 mg po dexamethasone at 23 00 Am cortisol If cortisol <50 nmol/L – excluded (Sn 95%) FP 12.5% (dilantin, rifampin, chronically ill, etoh, uremia,
estrogen, pseudocushing’s) FN <2% (slow dex metabolizers)
Plasma cortisol at day 0 and 48 hours (9:00 am)
Dexamethasone 0.5 mg q6h x 48 hours FP <1% TP 97-100% (increased specificity) 2 weeks absence from etoh and 6 weeks of
OCP ?Pseudocushing’s r/o
Cushing’s syndrome (CS) - may adequately suppress serum cortisol (sn 98% if 50 nmol/L used) (? Impaired clerance)
Pseudocushings (PC) - ↑CRH secretion, yet cortisol continues to exert negative feedback on HPA (allowing suppression by exogenous GC)
CS – HPA axis more responsive to CRH and less to dex
CRH test (CS vs PCS)
O.5 mg dex q6h for 48 hrs In standard LDDST 6hrs post serum cortisol CRH – 2 hrs after the last dose – serum
cortisol, than iv 100 μg human rCRH (bw before and 15 min after)
LDDST – cut off 50 nmol/L LDDST CRH - <38 nmol/L (excluded CS)
Addition of CRH to LDDST does not improve the diagnostic accuracy. By adding CRH can not improve Sn beyond 100%, while sp went down to 67%
Pregnancy : UFC Epilepsy : UFC or late night salivary RF: 1 mg DST Cyclic Cushing’s syndrome : UFC Adrenal incidentaloma : 1 mg DST
1. Plasma ACTH
2. High dose dexamethasone suppression test
3. CRH
4. IPSS
ACTH dependent vs independent Adrenal tumors < 1 pmol/L CS : N (inappropriately) or elevated Problem in differentiating CD and Ectopic
ACTH syndrome (30% overlap) Higer in EAS ( >20 pmol/L ) Normal range 2-11 pmol/L
Rational : resetting of the negative feedback control to ACTH at higher level in CD
DDx of Cushings Disease vs Ectopic ACTH syndrome
Originally described by Liddle in 1960 2 mg q6h x 48 hours Original to demonstrate >50% drop in urinary 17
OH CS Liddle used only for adrenal dependent vs pituitary
(at that time EAS not even described
Plasma and urinary free cortisol (0 and 48 hrs)
>50% suppression Problem : 20-30% EAS will suppress ~20 – 30 % of CD will not suppress But 90% of pts will have CD Diagnostic accuracy of test only 76%
You want very specific test (to identified rare/few cases of EAS)
Improve sp by changing cut off 100% sp with suppression of >90% of UFC
Sn 81% Sp 66.7% There was no cut off point that would yield
100% specificity Diagnostic accuracy only
70%
Gold standard Function
1. Confirmation of pituitary ACTH secreting tumor
2. Localization
Simultaneous IPS and peripheral ACTH measuring
Before and after CRH 5 time points (0,2,3,5,10 minutes) Each petrosal sinus and peripheral vein IPS/peripheral ACTH > 2 → CD Absent gradient – EAS Sn 97%, sp 100% (if ratio pf 3 used)
Technically demanding!!! Proficient center Complications : referred auricular pain,
thrombosis, hemorrhage Central location
MRI CT
Specialized part of autonomic nervous system Sympathoadrenal system System of “fight or flight” Actions best characterized by the appearance of patient
in shock
Chromaffin cells (endocrine cells of adrenal medulla)- contain granules important in storage and secretion of catecholamines
In humans 85% of catecholamine store is epinephrine
Catecholamines : dopamine, norepinephrine, and epinephrine
Chromogranin A (CgA) – peptide stored and released with catecholamines by exocytosis (higher in HTN patients)
Catestatin – fragment of prohormone that inhibits further catecholamine release (antagonist at neuronal cholinergic receptor), low level may increase the risk of EHTN
Abbreviations: TH, tyrosine hydroxylase; AAD, amino acid decarboxylase; DβH, dopamine β-hydroxylase; PNMT, phenylethanolamine-N-methyltransferase.
Tyrosine – derived from ingested food or synthesized from phenylalanine in the liver
First step – rate limiting TH (expressed only in tissues that synthesize CCH) inhibited by
dopa, dopamine, NE, ?alpha-methyltyrosine (Rx of pheo) AADC – found in non-neuronal tissues (liver, kidney), methyldopa is
competitive inhibitor Dopamine taken up into chromaffin garnules DHB – only in vesicles of cells synthesizing CCH In the adrenal medulla NE returns to cytosol to be methylated by
phenylethanolamine-N-methyl transferase (PNMT) to form epinephrine PNMT – nonspecific (lung, kidney, pancreas, RBC), inducible by high
dose corticosteroids, ?angiotensin II
Stored in the chromaffin granules with several neuropeptides (neuropeptide Y, substance P, VIP, chromogranins, ACTH)
Released by exocytosis Response to many stressful stimuli (pain,
exercise, hemorrhage, anesthesia, hypoglycemia, anoxia..)
Secretion mediated by release of Acetylcholine from the terminals of preganglionic fibers
In circulation bound to albumin mostly
Once NE released in the synapse : 1. Reacts with α1 postsynaptic receptor 2. Reacts with presynaptic α2 receptor (down
regulates its own synthesis and release)3. Taken up into the cell by “uptake 1” (blocked
by TCA, cocaine) – main mode of removal4. Diffuse out and undergo degradationNote: NE can also be removed by extraneuronal
uptake by “uptake 2” (inhibited by corticosteroids)
MOA – regulates the CCH content of neurons, levels ↑progesteron, ↓estrogen
Peripheral circulating NE metabolized largely by COMT (catechol-O-methyltransferase)
COMT – found in most tissues (blood cells, liver, kidney, vascular smooth muscle)
Conjugation with sulfate or glucuronide
Rare and often unrecognized adrenal medulla tumor
Derived from chromaffin cells (paraganglioma if from extra-adrenal chromaffin cells: 10-15%)
Wide range of clinical presentation Associated with different familial disorders
(vHL, MEN2a, 2b, NF-1)
COMMON (>33% OF PATIENTS)LESS COMMON (<33% OF PATIENTS)
Hypertension (probably >90%) Paroxysmal (50%) Sustained (30%) Paroxysms superimposed (about 50%) Hypotension, orthostatic (10%-50%) Headache (40%-80%) Sweating (40%-70%) Palpitations and tachycardia (45%-70%) Pallor (40%-45%) Anxiety and nervousness (20%-40%) Nausea and vomiting (20%-40%) Funduscopic changes (50%-70%) Weight loss (60%-80%)
Tremor Abdominal pain Chest pain Polydipsia, polyuria Constipation Acrocyanosis, cold extremities Flushing Dyspnea Dizziness, syncope Convulsions Bradycardia Fever
Paroxysm (or pheo crisis) is the consequence of CCH release
CCH synthesis at increased rate likely due to lack of feedback inhibition of tyrosine hydroxylase
CCH produced in quantities that exceed the vesicular storage capacity – accumulate in cytoplasm – diffuse into the circulation
Most contain more NE than Epinephrine (unlike normal medulla)
May secrete other peptides
Not innervated (unlike adrenal medulla) so catecholamine release is not initiated by neural impulses
Precipitated by any movement that displaces abdominal content, vigorous palpation of abdomen, spontaneous hemorrhage within tumor, surgical manipulation
Drugs – opioids (fentanyl), amphetamines, decongestants, histamine, TCA, dopamine antagonists (metoclopromide), glucagon, ACTH, intraarterial radiographic contrast
24 hour urine catecholamines and metanephrines
Fractionated plasma free metanephrines Other tests (clonidine suppression test,
chromogranin A) No role (plasma catecholamines, 24- hour
urinary VMA, histamine, glucagon, tyramine stim tests)
Foods: coffee/decaffeinated drinks – inhibits adenosine – inhibits release of CCH (false elevated results); bananas – tyrosine, peppers (may cause confounding peaks on HPLC)
Drugs – long list Conditions: ALS, carcinoid, eclampsia, exercise,
GBS, hypoglycemia, Pb poisoning, AMI, pain, porphyria, acute psychosis, RF (decreases excretion)
Tricyclic antidepressants Levodopa Drugs containing adrenergic receptor agonists (eg, decongestants) Amphetamines Buspirone and most psychoactive agents Prochlorperazine Reserpine Withdrawal from clonidine and other drugs Ethanol Acetaminophen (may increase measured levels of fractionated
plasma metanephrines in some assays) Captopril (may cause confounding peak) Codeine
Fractionated metanephrines (normetanephrine, metanephrine), total metanephrines, urinary vanillylmandelic acid (VMA)
Should include urinary Cr to verify adequate collection
Ability to follow instructions and cost Should not be on TCA Diagnostic cutoffs based on normotensive
volunteers – may result in excessive FALSE POSITIVE testing
Plasma free normetanephrine and metanephrine
Requires overnight fast and intravenous cannula
Patient should be supine at least 20 minutes before collection
No tylenol for 5 days prior and avoid caffeinated beverages overnight
As CCH are metabolized within tumor cells, plasma levels of free metanephrines are very sensitive
Centrally acting α2 adrenergic agonist Suppresses the release of CCH from neurons but it does not
affect secretion for pheochromocytoma Confirmatory test – distinguish between pheo and false positive
increase in CCH (when ↑CCH but not diagnostic) Administered orally (0.3 mg) Plasma catecholamines or metanephrines measured before and
3 hrs post dose In essential HTN – plasma CCH and normetanephrine
concentrations decrease, while in pheo – remain increased Patient should not take diuretics (euvolemic), β-blockers, TCA
Released from the secretory granules Increased in 80% of patients with pheo Have circardian rhythm (lowest at 8:00 am,
highest 11:00 pm) Also secreted from extra-adrenal sympathetic
nerves Renal clearance Sensitivity 98% and Specificity 97% PPV 97% and NPV 98% (sporadic)Herbomez et al. An analysis of biochemical diagnosis of 66 Pheochromocytomas. European Journal of Endocrinology 2007,
156:569-75
Ideal test has 100% sensitivity and specificity Sensitivity =TP/TP+FN (negative test r/o diagnosis) Specificity =TN/TN+FP (positive test r/i diagnosis) PPV = TP/ TP+FP NPV = TN/TN+FN
For any biochemical test - Sn low and Sp high for hereditary (high suspicion) vs sporadic case
If the disease has low prevalence - ↑false positive
Multicenter cohort study, over 5 years Objective – to determine the biochemical test or
combination of tests that provide the best method of diagnosing pheochromocytoma
1003 pt tested, 858 included (85%) 443 sporadic, 415 hereditary Conformation of pheo dx required +path examination
of surgical resection, biopsy, or inoperable malignant pheochromocytoma based on imaging.
Excluded if lack of tumor in CT/MRI, - path examination of Sx or bx, and lack of disease on 2 years patient follow up
Since measurements of urinary fractionated metanephrines and plasma free metanephrines offer similar high sensitivity, a negative result for either test is equally effective for excluding pheo.
However, because urinary fractionated metanephrines have low specificity, test of plasma free metanephrines exclude pheo in many more patients without tumor.
Plasma free MN provide the best test for excluding or confirming pheo and should be the test of choice for diagnosis.
Single center, retrospective study, over 1 year
349 patients, 8(?) hereditary Objective as above
Results:
+LR 6.3 (plasma free MN) + LR 58.9 (24 hrs urine total MN and CCH) If prevalence of pheo is- 0.5% (screened HTN pt) –post test probability:
3% vs 23% - 5.1% (incidentaloma) : 25% vs 76%- 42 % (MEN2a) : 82% vs 98% In addition specificity of plasma free MN falls to
77% in pt above age 60
Suggested that measurement of fractionated plasma metanephrines may be the biochemical test of choice in high-risk patients (those with a familial syndrome or vascular adrenal mass).
However, in the more common clinical setting when sporadic pheochromocytoma is sought, particularly older hypertensive patients, measurement of 24-h urinary metanephrines and catecholamines may provide adequate sensitivity, with a lower rate of false positive tests.
Included 3 studies 56 pt with pheo and 445 without pheo Sensitivity 97-100% Specificities 82-100% Pooled +LR 5.77, -LR 0.02 (sporadic cases) Post-test probabilities : 2.8%, 23.7% and 0.01%,
0.11% Conclusion : useful to r/o pheo, but a positive
test only slightly increases suspicion when screening for sporadic pheochromocytoma.