Download ADRENAL GLAND Medulla

ADRENAL GLAND
Medulla
Objectives:
• Adrenal medulla anatomy and Embryology.
• Gross structures, histology, and innervations.
• Adrenal medulla hormones:
– Synthesis, release, and uptake.
– Regulation.
– Actions.
• Diagnosis of Pheochromocytoma.
Embryology of the Adrenal Gland
•
•
•
The cortex develops before the medulla.
Cortexes develop from coelomic epithelium. (appear in
the 6th week)
Neural crest cells migrate into the centre of the
cortexes to develop the medulla. The cells differentiate
in to sympathetic nerve cells.
– By the 10th week of fetal life, the adrenal glands
show evidence of catecholamine production.
– During fetal life, the chromaffine cells secrete only
nor-epinephrine but just before birth, some cells
begin to synthesize epinephrine.
ADRENAL
CORTEX
Innervations
• The principal hormones of the adrenal
medulla are catecholamine:
– 80 % Epinephrine
– 20 % Norepinephrine
• Sympathetic nerve (nervous system)
endings produce only Norepinephrine.
• Each Chromaffine cell is innervated by
cholinergic pre-sympathetic neurone,
which release acetylcholine.
• Synapses are the termination of fibers
whose cells bodies lie mainly between T3
and L3 in the spinal cord.
Hormonal Synthesis
Regulation of synthesis:
•First step: through tyrosine hydroxlase (rate-limiting ).
–Regulation is under negative feedback by NEpi and Epi.
•Last step: conversion from NorEpi to Epi through (Phenylthanolamine
N-methyltransferase)
–Requires high concentration of glucocorticoids in the central vein of the medulla.
Hormonal Release and
Regulation.
Hormonal Actions.
• Alpha 1 (eye, vessels of
skeletal muscles, heart )
– Epinephrine, Norepinephrine
– Increased free calcium
• Vasoconstriction, medriasis,
increase bladder sphincter
tone
• Alpha 2 (CNS, platelets,
pancreas and fat cell )
– Epinephrine, Norepinephrine
– Decreased cyclic AMP
• Inhabit NE. release, and insulin
release, increase lipolysis.
• Beta 2 (lung, vessels of skeletal
muscles, liver )
– Epinephrine
– Increase cyclic AMP
• Vasodilatation, bronchodilatation,
increase glycogenolysis and
increase glucagon release. uterine
relaxation.
• Beta 1 (heart)
– Epinephrine, Norepinephrine
– Increased cyclic AMP
• Tachycardia, and increase
myocardial contractility
•
About 70% of the norepinephrine and epinephrine are
conjugated to sulfate (inactive) ?? function.
•
Normal plasma level of free norepinephrine is about
300 pg/mL (1.8 nmol/L). On standing, the level
increases 50-100%. free epinephrine level, is normally
about 30 pg/mL (0.16 nmol/L).
•
The catecholamines half-life is about 2 minutes in the
circulation.
levels in human venous blood in various physiologic and pathologic states. In each case, the vertical
dashed line identifies the threshold plasma concentration at which detectable physiologic changes are
observed. (Modified and reproduced, with permission, from Cryer PE: Physiology and
pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med 1980;303:436.)
Circulatory changes produced in humans by the slow intravenous infusion
Hormonal Uptake
Fate of Catecholamine
• Uptake-1 “mainly Norepinephrine”
– (post-ganglionic sympathetic nerve terminals)
– De-aminated by monoamine oxidase in mitochondria then enters
to the vesicle (store).
– Become available for re-use.
– Sites of drug action (e.g.. cocaine and antidepressants)
• Uptake-2 “Mainly Epinephrine”
– (non-neuronal tissues)
– Inactivated by O-methylation by catechol-O- methyl transferase
(COMT)
– Metpolised to inactive end-products mainly metanephrine
and normetanephrine and VMA.
Secreted Catecholamines (urine)
• 50% appear in the urine as free or conjugated
metanephrine and normetanephrine.
• 35% as VMA.
• Small amounts of free norepinephrine and
epinephrine.
• After adrenalectomy
– The plasma norepinephrine level is generally
unchanged.
– Free epinephrine level, falls to essentially
zero.
• Adrenal medulla failure:
– Hypoglycemia and hypotension.
– Hormones of the cortex are way more important in
this regard.
– No need to replace adrenal medulla hormones.
PHEOCHROMOCYTOMA
DIAGNOSIS
Clinical presentation Pheochromocytoma
• Usually suggested by:
– Symptoms:
• Classic triad episodic headache (90%), sweating (60%), and
tachycardia, paroxysmal hypertension (50%).
– Incidental adrenal mass:
– Family history in a patient with familial disease:
• MEN 2A: pheo. (B/L), medullary carcinoma of the thyroid (MTC),
primary parathyroid hyperplasia.
• MEN 2B: pheo. (B/L), MTC, mucosal neuromas, thickened
corneal nerves, intestinal ganglio-neuromatosis, and marfanoid
body.
• von Hippel-Lindau disease: pheo.(B/L) paraganglioma, retinal
angiomas, cerebellar hemangioblastoma, epididymal
cystadenoma, renal and pancreatic cysts, and renal cell
carcinoma.
Diagnosis of Pheochromocytoma
•
Among patients suspected to have
Pheochromocytoma, the diagnosis is rarely
confirmed.
– Diagnosis confirmed in 1 of 300 patients
evaluated for pheochromocytoma
•
Fogarty, J, Engel, C, Russo, J, et al. Hypertension and
pheochromocytoma testing: The association with anxiety
disorders. Arch Fam Med 1994; 3:55.
• Methods of evaluation:
1. Biochemical evaluation.
2. Radiological evaluation.
Biochemical evaluation
• Interferences with plasma/urine catecholamine measurements
– False increase:
• Alpha1 blocker, beta-blocker, vasodilators “Hydralazine, Nitro,
Minoxidile”, CCB (short term), Methyldopa. Phenothiazin.
• Tricyclic antidepressants, psychoactive agents, nicotine,
Amphetamine.
• Theophylline & Aminophylline, Epinephrine & epinephrine like
drugs “nasal drops, cough and sinus medications.
• Ampicillin, Quinidine, Tetracycline.
• Vit. B complex, withdrawal (Etoh and clonidine).
– False decrease:
• ASA, alpha 2 agonist, bromocriptine, CCB (long term), cimetidine,
clonidine, delay in the separation of RBCs from plasma(5 min)
Avoid medications for at least 2 weeks before the test
Multi-center cohort study in Netherlands that included 214 patients with
confirmed pheochromocytoma and 644 patients who were not .
Test performed
Sensitivity
Specificity
Fractionated plasma free 99 %
metanephrines
89 %
Urinary fractionated
metanephrines
97 %
69 %
Urinary catecholamines
86 %
88 %
Plasma catecholamines
84 %
81 %
Urinary total
metanephrines
77 %
93 %
Urinary VMA
64 %
95 %
Lenders JW; Pacak K; Walther MM; Linehan WM; Mannelli M; Friberg P; Keiser HR; Goldstein DS;
Eisenhofer G SOJAMA 2002 Mar 20;287(11):1427-34.
349 patients tested for pheochromocytoma at Mayo Clinic Rochester from
January 1, 1999, until November 27, 2000. “tumors were histologically
proven ”
Fractionated plasma
metanephrine
24-hr urinary metanephrines
(metanephrine+normetanephri
ne) in combination with urinary
catecholamines
Sensitivity
97 %
90 %
Specificity
85 %
96 %
likelihood ratio for a
positive test
6.3
58.9
likelihood ratios for a
negative test
0.04
0.10
Sawka AM; Jaeschke R; Singh RJ; Young WF Jr SOJ Clin Endocrinol Metab 2003
Feb;88(2):553-8
Systematic review and meta-analysis from Hamilton, Ontario, of
Fractionated plasma free metanephrines including 3 studies of 56 patients
with and 445 subjects without pheochromocytoma
Sensitivity
97 to 100 %
Specificity
82 to 100 %
Positive likelihood ratio
5.77
Negative likelihood ratio
0.02
Very useful to rule out pheochromocytoma
Sawka AM; Prebtani AP; Thabane L; Gafni A; Levine M; Young WF Jr SOBMC Endocr
Disord. 2004 Jun 29;4(1):2.
Normal values
•
Urine Catecholamines (measured by HPLC)
– Norepinephrine (15-80 micrograms/day)
– Epinephrine (0-20 micrograms/day)
•
Urine Deconjugated Fractionated Metanephrines (measured by HPLC)
– Normetanephrine-sulfate (44-540 micrograms/day)
– Metanephrine-sulfate (26-230 micrograms/day)
•
•
•
Urine Deconjugated Total Metanephrines (measured by
Spectrofluorimetry) (0-1.2 milligrams/day) (Sum of free plus sulfate
conjugated metanephrine & normetanephrine)
Urine VMA (measured by Spectrofluorimetry) (0-7.9 milligrams/day)
Plasma Catecholamines (measured by HPLC)
– Norepinephrine (80-498 picograms/milliliter)
– Epinephrine (4-83 picograms/milliliter)
•
Plasma Free Metanephrines (measured by HPLC)
– Normetanephrine (18-112 picograms/milliliter)
– Metanephrine (12-61 picograms/milliliter)
•
Plasma Deconjugated Metanephrines (measured by HPLC)
– Normetanephrine-sulfate (610-3170 picograms/milliliter)
– Metanephrine-sulfate (316-1706 picograms/milliliter)
• Clonidine suppression test :
– Suppresses the release of catecholamines from neurons but not
from pheochromocytoma tissues.
– 0.3 mg PO, then plasma catecholamines or/and metanephrines
are measured before and 3 hours after .
• Plasma catecholamine concentrations decrease by >50 %.
• Plasma normetanephrine decrease by >40 %.
Suggest Essential HTN.
• If remain increased suggest pheochromocytoma.
– The test is 92 % accurate
• Sjoberg RJ; Simcic KJ; Kidd GS Arch Intern Med 1992 Jun;152(6):1193-7.
• Eisenhofer G; Goldstein DS; Walther MM; Friberg P; Lenders JW; Keiser
HR; Pacak K J Clin Endocrinol Metab 2003 Jun;88(6):2656-66.
What I am going to order
• Fractionated plasma free metanephrines.
• 24-hr urinary metanephrines, urinary
catecholamines and Urinary VMA.
Radiological evaluation
• About 10 percent of the tumors
are extra-adrenal, and 95 % are
within the abdomen and pelvis.
– Bravo EL Endocr Rev 1994
Jun;15(3):356-68.
• Abdominal paraaortic areas (75
%), the urinary bladder (10 %),
the thorax (10 %), and the head,
neck, and pelvis (5 %)
– Whalen RK; Althausen AF; Daniels
GH J Urol 1992 Jan;147(1):1-10.
CT Scan
MRI
Radiation exposure
High
None
risk of exacerbate HTN
due to contrast agent
High “can be prevented
by pretreatment with
alpha-adrenergic
blockade”
None
Expense
less
more
Distinguish
Unable to differentiate
pheochromocytoma from
other adrenal masses
1.
2.
pheochromocytomas
appear hyperintense and
other adrenal tumors
isointense, as compared
with the liver
Both have high sensitivity (98 to 100 %), but are only about 70 percent
Low specificity (70%) ?adrenal "incidentalomas."
Radiological evaluation
• 123-I-metaiodobenzylguanidine “MIBG” scan:
– If CT or MRI is negative in the presence of clinical and
biochemical evidence of pheochromocytoma,
– Multiple tumors when CT or MRI is positive.
• Octreoscan, total body MRI, and PET scanning:
– Detect a tumor in an unusual location (heart) when
the other techniques have failed.
• Positron emission tomography (PET) scan:
– Identifying sites of metastatic disease.
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