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Investigation of endocrine Investigation of endocrine diseasedisease
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Endocrinology is EasyEndocrinology is Easy
Diseases are due to– TOO MUCH hormone– TOO LITTLE hormone
Hormone levels vary physiologicallyTesting needs to be dynamic
– If the hormone is too high SUPPRESS IT– If the hormone is too low STIMULATE IT
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Pituitary GlandPituitary Gland
Anterior: hormone secretion of thyroid, adrenal cortex, gonads Posterior: water balance, salt balance
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Two Major Divisions of Two Major Divisions of PituitaryPituitary
Each has a distinct role to play in hormone regulation
Anterior“Adenohypophysis”
Posterior“Neurohypophysis”
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Diagnosis of PD by PH Diagnosis of PD by PH stimulation teststimulation test
Hormone Test agent N response
G H I H test 0.1 uint
L-dopa 250-500
Arginine 0.5 gm
Clonidine test
Glucagon test
Serum GH > 10ng/ml at any time
Prl TRH 100-500
metoclopramide
Doubling of baseline
TSH TRH 500 ng Peak value >5 mu/ml
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Pituitary stimulation test 2Pituitary stimulation test 2hormone Test agent N response
LH @FSH GnRH 100mmg IV
Doubling of the base line LH@FSH
ACTH I H TEST
(short ACTH stimulation test cosyntropin test)
Metyrapone test 2-3 gm po
Peak serum cortisol >20 ng/dl
Serum 11-deoxycortisol level >8 ng/dl
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Laboratory finding in Laboratory finding in acromegalyacromegaly
Plasma glucose may be elevatedIncrease serum insulin Elevated serum phosphate HypercalciuriaElevated GH
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Diagnosis of acromegalyDiagnosis of acromegaly
Glucose suppression testIGF-1
Tumor localization
MRI
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Posterior pituitary hormone Posterior pituitary hormone (ADH vasopressin)(ADH vasopressin)
ADH acts through tow receptors V1 @ V2 V1 receptors mediate vascular smooth muscle
contraction @stimulate prostaglandin synthesis V2 receptors produce renal action by increase the
water permeability of the luminal membrane of collecting duct epithelium
In the absence of ADH permeability of the epithelium is decrease leading to polyuria
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Laboratory finding Laboratory finding
A large urinary volume >3 l /per day Urine osmolality less than 200 mosm/kgSlightly elevated plasma osmolalityLow serum ADH in CDI High or normal ADH in NDI
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Diagnosis of DIDiagnosis of DIWater deprivation test (method)Deprivation from water for 4-18 hrHourly measurements of urine osmolalityContinues until urine osmolality of 3
consecutive sample varies by less than 30 mosml/kg
5 unite of AVP or 1 mg of desmopression injected @ urine and plasma osml measure 30,60,120 m later
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Interpretation of WDT Interpretation of WDT CDI NDI psychogenic
Urine osmol after wdt
No change
<300
No change
<300
Increase
>750
Urine osmol after vasopressin
increase No change increase
Plasma ADH low Normal or high
low
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Thyroid glandThyroid gland
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ThyroidThyroid
Growth, development Metabolic rate
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Thyroid Function TestsThyroid Function Tests
Free serum thyroxine (T4)Free serum T3TSH
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Scans/UltrasoundScans/Ultrasound
Radioiodine uptake (RAIU)Thyroid ScanUltrasoundFine needle Aspiration
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Radioiodine UptakeRadioiodine Uptake
Useful in differentiating non-pituitary thyrotoxic states (i.e., low TSH, high free thyroxine)
No use in hypothyroidismA set dose of radioactive iodine (usually
I123) is given and 24hrs later a radiation detector is placed over the thyroid to determine % of dose taken up by thyroid
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RAIURAIU
RAIU is increased in– Graves Disease– Hot nodules
Multi-nodular goiters Toxic Solitary Nodule hCG secreting tumors
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RAIURAIU
RAIU is decreased in– Amiodarone– Factitious Thyroiditis– Self limited thyroiditis-induced thyrotoxic state
Painless chronic thyroiditis Postpartum thyroiditis Subacute thyroiditis
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Thyroid ScanThyroid Scan
Also called scintiscan or radionuclide scan A dose of radioiodine or Tc99m is given Scintillation scanner produces a rough picture
indicating how these isotopes localize in the thyroid
Thyroid scan is only used for nodular disease---useful for determining whether a nodule is hot or cold
Again---RAIU produces a number, scan produces a picture
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UltrasoundUltrasound
U/S can provide information about its size and texture
Used for determining whether a nodule is cystic or solid
Follow the size of a nodule or goiter over time.
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Parathyroid glandParathyroid gland
And calcium metabolisms
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CALCIUM HOMEOSTASISCALCIUM HOMEOSTASIS
DIETARY CALCIUM
INTESTINAL ABSORPTIONORGAN PHYSIOLOGY
ENDOCRINE PHYSIOLOGY
DIETARY HABITS,
SUPPLEMENTSBLOOD CALCIUM
BONE
KIDNEYS
URINE
THE ONLY “IN”
THE PRINCIPLE “OUT”
ORGAN PHYS.
ENDOCRINE PHYS.
ORGAN, ENDOCRINE
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VITAMIN D SYNTHESISVITAMIN D SYNTHESIS
SKIN LIVER KIDNEY
7-DEHYDROCHOLESTEROL
VITAMIN D3
VITAMIN D3
25(OH)VITAMIN D
h25-HYDROXYLASE
25(OH)VITAMIN D
1,25(OH)2 VITAMIN D
(ACTIVE METABOLITE)
1-HYDROXYLASE
TISSUE-SPECIFIC VITAMIN D RESPONSES
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CALCIUM, PTH, AND VITAMIN D CALCIUM, PTH, AND VITAMIN D FEEDBACK LOOPSFEEDBACK LOOPS
NORMAL BLOOD Ca
RISING BLOOD Ca
FALLING BLOOD Ca
SUPPRESS PTH
STIMULATE PTH
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
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Adrenal glandAdrenal gland
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Synthesis of Adrenocortical Synthesis of Adrenocortical HormonesHormones
Zona glomerulosa: aldosteroneZona fasciculata: glucocorticoids (cortisol)Zona reticularis: androgens (DHEA and
androstenedione)
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Regulation of Adrenocortical Regulation of Adrenocortical
HormonesHormones Hypothalamus
– CRH-containing neurons are stimulated
– CRH delivered to anterior pituitary
– CRH binds to receptors on corticotrophs, causing synthesis and secretion of ACTH
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Pathways of Steroid BiosynthesisPathways of Steroid Biosynthesis
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Cushing’s SyndromeCushing’s SyndromeDiagnosis of Cushing’s syndrome
– History Weight gain, fatigue Infertility, impotence, changes in menstruation Diabetes, polyuria, polydypsia Depression, headache Signs of underlying tumor (weight loss, appetite)
– Physical exam Obesity, fat distribution Proximal muscle weakness/wasting Palpation of abdominal mass
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Cushing’s SyndromeCushing’s SyndromeDiagnosis of Cushing’s syndrome
– Labs 24 hour urinary cortisol
– 2-3 consecutive days
– Verify with creatinine values
Spot AM/PM serum cortisol – Circadian variation
– AM ACTH surge causes increased cortisol
– PM should see at least 50% drop in cortisol level
Low-dose dexamethasone suppression test
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Cushing’s SyndromeCushing’s Syndrome
Diagnose cause of Cushing’s syndrome– History (steroid use?)– Serum ACTH
Elevated : Cushing’s disease, ectopic ACTH Suppressed: primary adrenal source Correlate with cortisol levels
– High-dose dexamethasone suppression test – Metyrapone test
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Cushing’s SyndromeCushing’s SyndromeDexmethasone suppression test
– Synthetic glucocorticoid (30x more potent as inhibitor)
– Low dose 0.5mg po q6 hours x48 hours Measure cortisol, 17-hydroxycorticosteroid, creatinine Fall in all steroid levels in pseudo-Cushing and normals Differentiates presence/absence of Cushing’s syndrome
– Alternative dosing 1mg po at midnight and measure 8am cortisol Much less sensitive
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Cushing’s SyndromeCushing’s Syndrome
Dexmethasone suppression test– High Dose
2mg po q6 hours x48 hours Measure cortisol and urinary free cortisol Ectopic ACTH and adrenal tumors- no suppression Cushing’s disease- suppress to <50% of baseline Usually only used if ACTH/Cortisol assays
unavailable or equivocal
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Cushing’s SyndromeCushing’s Syndrome
Metyrapone test– Inhibits 11-B-hydroxylase– Blocks conversion of 11-deoxycortisol to cortisol– Plasma cortisol levels fall and ACTH increases– Marked increase in 17-hydroxycorticosteroid levels and
11-deoxycortisol levels Cushing’s Disease- normal or supernormal increase in levels Ectopic ACTH or adrenal sources- no response
– Risks adrenal insufficiency
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Cushing’s SyndromeCushing’s Syndrome
Petrosal vein sampling– Measure petrosal venous sinus ACTH level and
correlate to plasma levels– Invasive with morbidity– Usually not used
Adrenal venous sampling– Measure cortisol and aldosterone– Not used anymore
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Cushing’s SyndromeCushing’s SyndromeRadiographic Localization
– CT of sella turcica Unenhanced and gadolinium enhanced MRI Radionuclide imaging for somatostatin receptors >60% sensitive 1st study if diagnosed with Cushing’s syndrome
– CT of chest/abdomen with 3mm cuts through adrenal
Adrenal hyperplasia– Thickening and elongation of adrenal rami bilaterally– Multinodularity of cortex bilaterally
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Cushing’s SyndromeCushing’s SyndromeRadiographic Localization
– CT of adrenal glands Adenomas- usually >2cm but <5cm
– Low attenuation (lipid content)
– Atrophy of opposite gland
Carcinoma- indistinguishable from adenomas– >5cm
– Necrosis, calcifications, irregularity, invasion
– MRI of adrenal- usually not needed Signal intensity much higher than in spleen = carcinoma Adjacent organ and/or vascular involvement
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Cushing’s SyndromeCushing’s SyndromeRadiographic Localization
– CT of adrenal glands Adenomas- usually >2cm but <5cm
– Low attenuation (lipid content)
– Atrophy of opposite gland
Carcinoma- indistinguishable from adenomas– >5cm
– Necrosis, calcifications, irregularity, invasion
– MRI of adrenal- usually not needed Signal intensity much higher than in spleen = carcinoma Adjacent organ and/or vascular involvement
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DIAGNOSISDIAGNOSIS
Basal Cortisol Level– Avoid random level: low sensitivity– Check morning cortisol
Greater than 18 µg/dL indicates an intact axis Less than 3 µg/dL strongly suggests insufficiency
– Intermediate values: perform cosyntropin stimulation test
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DIAGNOSISDIAGNOSIS
Low-Dose Cosyntropin Test– Cosyntropin doses as low as 0.5 to 1 ug will give a
maximal response within 15 to 30 mins– Possibly superior to high-dose test for diagnosing
secondary insufficiency because ACTH level closer to physiologic level
– Normal response: peak plasma cortisol level > 18 µg/dL– Like high-dose test, low sensitivity when ruling out
mild or recent secondary insufficiency; confirm with more sensitive tests (insulin tolerance, metyrapone)
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DIAGNOSISDIAGNOSIS
Insulin Tolerance Test– Hypoglycemia induced by the IV injection of reg insuli
n stimulates the entire HPA axis.
– Plasma glucose and cortisol are measured after injection of insulin.
Normal response: cortisol increases to at least 18ug per dL
– Expensive and contraindicated in patients with coronary heart disease or seizures
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DIAGNOSISDIAGNOSIS
Metyrapone Test– Metyrapone inhibits conversion of 11-deoxycortisol to
cortisol
– Give at midnight and measure the concentration of 11-deoxycortisol and cortisol at 8am
– In normal subjects, the plasma 11-deoxycortisol concentration increases to at least 7ug per dL. In patients with adrenal insufficiency, the increase is smaller and is related to the severity of the corticotropin deficiency
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HyperaldosteronismHyperaldosteronism
Causes– Adenoma (most common)
F>M 4th-5th decades of life
– Bilateral adrenal hyperplasia– Adrenocortical carcinoma (rare)– Glucocorticoid remedial aldosteronism
Aldosterone producing adenoma Responsive to renin
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HyperaldosteronismHyperaldosteronismDiagnosis
– History, HTN, symptoms– Laboratory
Serum K+ (<3.0) Serum aldosterone
– Salt load patients (suppresses aldosterone)
– Level >14 micrograms/d diagnostic of primary hyperaldosteronism
Serum renin– If >1.0 then unlikely primary hyperaldosteronism
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Pheochromocytoma, Pheochromocytoma, DiagnosisDiagnosis
24hr urinary catecholamines (NE, Epi, Dop) and metabolites (metanephrine, normetanephrine, VMA)
Plasma catecholamine or metabolites during episode
Elevated serum epinephrine suggests pheo in medulla or Organ of Zukerkandl
NO FNA! (can precipitate hypertensive crisis)
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Pheochromocytoma, Pheochromocytoma, DiagnosisDiagnosis
Localizing studies: CT, MRI, MIBG scan– Thin cut CT detects most lesions: 97%
intraabdominal– MRI: 90% pheos bright on T2 weighted scan– MIBG: used for extraadrenal, recurrent,
multifocal, malignant diseaseMalignant disease
– Local invasion, disease outside of adrenal/paraganglionic tissue
– No histological or clinical criteria can differentiate malignant disease