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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