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Tamara Spaic, R4. Testing in Cushing’s Syndrome and pheochromocytoma. Adrenal cortex and HPA axis Testing in Cushing’s syndrome Review of the Endocrine Society Clinical Practice Guidelines (JCEM, May 2008) Assessment of adrenal medullary function and disorders Which test is the best?.

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Testing in Cushing’s Syndrome and pheochromocytoma

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Tamara Spaic, R4

Testing in Cushing’s Syndrome and pheochromocytoma


  • Adrenal cortex and HPA axis

  • Testing in Cushing’s syndrome

  • Review of the Endocrine Society Clinical Practice Guidelines (JCEM, May 2008)

  • Assessment of adrenal medullary function and disorders

  • Which test is the best?

Objectives


4 g weight

2x5x1 cm

Posteromedial surface of the kidney

Retroperitoneal

Adrenal Gland


Cross sectional anatomy


L adrenal metastasis

Unenhanced CT

PET scan


Figure 28.   Adrenal lymphoma in a 74-year-old woman with biopsy-proved non-Hodgkin lymphoma. Contrast-enhanced CT scan demonstrates bilateral adrenal masses (straight arrows). The patient also has a destructive lesion from the lymphoma in the right rib (curved arrow)


Bilateral adrenal hyperplasia


Nodular hyperplasia


Adrenal Cortex


Histology


zona glomerulosa lacks

Only zona glomerulosa


Steroid synthesis


  • 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)

ACTH


POMC (proopiomelanocortin) - precursor

ACTH biosynthesis


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

ACTH secretion


Circadian rhythm


Episodic secretion and circadian rhythm of ACTH

Stress responsivness of the HPA

Feedback inhibition by cortisol of ACTH secretion

Neuroendocrine Control


  • 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

Rhythm changes


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

Stress responsivness


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

Feedback Inhibition


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

ACTH measurement


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)

Cortisol secretion


  • 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%)

Cortisol circulation


Produced by the liver

Progesterone in late pregnancy

Synthetic steroids – do not significantly bind (except prednisolone)

CBG


High estrogen states (pregnancy, OCP)

↑T4

Diabetes

Hematologic d/s

Chronic active hepatitis

↑CBG


Familial CBG deficiency

↓ T4

Protein deficiency states (nephrotic syndrome, liver failure)

↓CBG


Metabolism – liver (conjugation)

Excretion – kidney (<1% in urine unchanged – “free”)

11β-hydroxysteriod dehydrogenase (inhibited by IGF-1)

Cortisol metabolism


↓ clearance in starvation/anorexia nervosa and pregnancy (↑CBG)

↓ metabolism and excretion – hypoT4

↑metabolism – OCP, liver disease

Also drugs : dilantin, barbiturates, mitotane, rifampin

Altered metabolism


ACTH Dependent

ACTH Independent

Pseudo-Cushing’s Syndrome

Cushing’s Syndrome


Etiology

Pseudo-Cushing’s Syndrome

Etoh

Obesity

Depression


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).

Sign and symptoms


  • Answer 2 questions:

  • Does this patient have Cushing’s Syndrome?

  • Having confirmed Cushing’s syndrome clinically and biochemically – What is the cause?

Investigations


Options for investigation

  • Diagnosis

  • UFC

  • Circadian Rhythm of plasma cortisol

  • Low dose dexamethasone

  • Salivary cortisol

  • Differential Diagnosis

  • Plasma ACTH

  • Plasma K, HCO3

  • High dose dexamathasone suppression

  • Metyrapone test

  • CRH

  • IPSS

  • CT/MRI pituitary, adrenals

  • 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

Accuracy


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

Suspicion


  • To reduce FP rate (high pretest probability)

  • Pts with unusual features for age (osteoporosis, HTN)

  • Pts with multiple and progressive features 9especially those predictive of Cushing’s

  • Children with decreasing height ‰ and increasing wt

  • Adrenal incidentaloma compatible with adenoma

Who should be tested?


<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

UFC


  • 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

Issues UFC


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

Late-night salivary cortisol


  • 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

Late- night salivary cortisol


11 β hydroxysteriod dehydrogenase type 2

Cortisol → cortisone (inhibits)

Answer


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 DST


  • 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)

LDS


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

48 hrs low DST


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)

RAtional


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)

LDDST CRH


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

Special consideration


Plasma ACTH

High dose dexamethasone suppression test

CRH

IPSS

What is the cause ?


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

ACTH (9 am)


  • 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

HDDST (High Dose Dexamethasone Suppression Test)


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%

HDDST


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

HDDST


Sn 81%

Sp 66.7%

There was no cut off point that would yield 100% specificity

Diagnostic accuracy only

70%

HDDST


  • Gold standard

  • Function

  • Confirmation of pituitary ACTH secreting tumor

  • Localization

IPSS


Anatomy


  • 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)

IPSS


Technically demanding!!!

Proficient center

Complications : referred auricular pain, thrombosis, hemorrhage

Central location

Issues


MRI

CT

Imaging


Adrenal Medulla


Specialized part of autonomic nervous system

Sympathoadrenal system

System of “fight or flight”

Actions best characterized by the appearance of patient in shock

Adrenal Medulla


  • Chromaffin cells (endocrine cells of adrenal medulla)- contain granules important in storage and secretion of catecholamines

  • In humans 85% of catecholamine store is epinephrine

Anatomy


  • 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

Catecholamine Synthesis and Metabolism


Synthesis

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

Cont’d


  • 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 preganglionicfibers

  • In circulation bound to albumin mostly

Storage, secretion, transport


  • Once NE released in the synapse :

    1. Reacts with α1 postsynaptic receptor

    2. Reacts with presynapticα2 receptor (down regulates its own synthesis and release)

    3. Taken up into the cell by “uptake 1” (blocked by TCA, cocaine) – main mode of removal

    4. Diffuse out and undergo degradation

    Note: NE can also be removed by extraneuronal uptake by “uptake 2” (inhibited by corticosteroids)

Neuroadrenergic junction


Metabolism and Inactivation


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

Cont’d


Receptor Agonists and Antagonists


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)

Pheochromocytoma


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 painPolydipsia, polyuria   ConstipationAcrocyanosis, cold extremities   FlushingDyspnea   Dizziness, syncope   ConvulsionsBradycardia   Fever

Clinical Presentation Werbel SS, Ober KP. Pheochromocytoma. Update on diagnosis, localization, and management. Med Clin NA 1995; 79:131–153


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

Pheochromocytoma


  • 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

Secretion of CCH in pheochromocytoma


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)

Biochemical Diagnosis


  • 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)

Factors that affect test accuracy


  • 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

Medications that may increase measured levels of catecholamines and metanephrines


  • 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

24-hour urine CCH and metanephrines


  • 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

Fractionated plasma free metanephrines


  • 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

Clonidine Suppression Test


  • 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

Chromogranin A


  • 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

Which test is the best?


  • 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 pheodx 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

Lenders et al. Bichemical Diagnosis of Pheochromocytoma. Which Test Is Best? JAMA. 2002, 287:1427-34


Results


  • 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.

Conclusion


Single center, retrospective study, over 1 year

349 patients, 8(?) hereditary

Objective as above

Results:

Sawka, et al: A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J ClinEndocrinolMetab 2003; 88:553.


  • +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

Likelihood ratios


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.

Conclusion


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.

Sawka et al: A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma. BMC Endocrine Disorders 2004; 4:2


Evaluation and treatment of catecholamine-producing tumors


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