Download Investigation of endocrine disease

Investigation of endocrine
disease
Endocrinology is Easy

Diseases are due to
– TOO MUCH
– TOO LITTLE
hormone
hormone

Hormone levels vary physiologically
 Testing needs to be dynamic
– If the hormone is too high SUPPRESS IT
– If the hormone is too low STIMULATE IT
Pituitary Gland


Anterior: hormone secretion of thyroid, adrenal cortex,
gonads
Posterior: water balance, salt balance
Two Major Divisions of
Pituitary
Anterior
“Adenohypophysis”
Posterior
“Neurohypophysis”

Each has a distinct role to play in hormone regulation
Diagnosis of PD by PH
stimulation test
Hormone
GH
Prl
TSH
Test agent
I H test 0.1 uint
L-dopa 250-500
Arginine 0.5 gm
Clonidine test
Glucagon test
TRH 100-500
metoclopramide
TRH 500 ng
N response
Serum GH >
10ng/ml at any
time
Doubling of
baseline
Peak value >5
mu/ml
Pituitary stimulation test 2
hormone
Test agent
LH @FSH
GnRH 100mmg Doubling of the
IV
base line
LH@FSH
I H TEST
Peak serum
cortisol >20
(short ACTH
stimulation test ng/dl
cosyntropin test)
Metyrapone test Serum 112-3 gm po
deoxycortisol
level >8 ng/dl
ACTH
N response
Laboratory finding in
acromegaly

Plasma glucose may be elevated
 Increase serum insulin
 Elevated serum phosphate
 Hypercalciuria
 Elevated GH
Diagnosis of acromegaly

Glucose suppression test
 IGF-1

Tumor localization
MRI
Posterior pituitary hormone
(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
Laboratory finding

A large urinary volume >3 l /per day
 Urine osmolality less than 200 mosm/kg
 Slightly elevated plasma osmolality
 Low serum ADH in CDI
 High or normal ADH in NDI
Diagnosis of DI

Water deprivation test (method)
 Deprivation from water for 4-18 hr
 Hourly measurements of urine osmolality
 Continues 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
Interpretation of WDT
CDI
NDI
psychogenic
Urine osmol
after wdt
No change No change Increase
<300
<300
>750
Urine osmol
after
vasopressin
Plasma ADH
increase
No change increase
low
Normal or low
high
Thyroid gland
Thyroid

Growth, development
 Metabolic rate
Thyroid Function Tests

Free serum thyroxine (T4)
 Free serum T3
 TSH
Scans/Ultrasound

Radioiodine uptake (RAIU)
 Thyroid Scan
 Ultrasound
 Fine needle Aspiration
Radioiodine Uptake

Useful in differentiating non-pituitary
thyrotoxic states (i.e., low TSH, high free
thyroxine)
 No use in hypothyroidism
 A 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
RAIU

RAIU is increased in
– Graves Disease
– Hot nodules
 Multi-nodular goiters
 Toxic Solitary Nodule
 hCG secreting tumors
RAIU

RAIU is decreased in
– Amiodarone
– Factitious Thyroiditis
– Self limited thyroiditis-induced thyrotoxic state
 Painless chronic thyroiditis
 Postpartum thyroiditis
 Subacute thyroiditis
Thyroid 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
Ultrasound

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.
Parathyroid gland
And calcium metabolisms
CALCIUM HOMEOSTASIS
DIETARY CALCIUM
THE ONLY “IN”
BONE
DIETARY HABITS,
SUPPLEMENTS
ORGAN,
ENDOCRINE
BLOOD CALCIUM
INTESTINAL ABSORPTION
ORGAN PHYSIOLOGY
KIDNEYS
ENDOCRINE PHYSIOLOGY
ORGAN PHYS.
ENDOCRINE PHYS.
URINE
THE PRINCIPLE “OUT”
VITAMIN D SYNTHESIS
SKIN
LIVER
7-DEHYDROCHOLESTEROL
h
VITAMIN D3
VITAMIN D3
KIDNEY
25(OH)VITAMIN D
25-HYDROXYLASE
25(OH)VITAMIN D
1a-HYDROXYLASE
1,25(OH)2 VITAMIN D
(ACTIVE METABOLITE)
TISSUE-SPECIFIC VITAMIN D RESPONSES
CALCIUM, PTH, AND VITAMIN D
FEEDBACK LOOPS
BONE RESORPTION
URINARY LOSS
SUPPRESS PTH
1,25(OH)2 D PRODUCTION
RISING BLOOD Ca
NORMAL BLOOD Ca
FALLING BLOOD Ca
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
STIMULATE PTH
Adrenal gland
Synthesis of Adrenocortical
Hormones

Zona glomerulosa: aldosterone
 Zona fasciculata: glucocorticoids (cortisol)
 Zona reticularis: androgens (DHEA and
androstenedione)
Regulation of Adrenocortical
Hormones

Hypothalamus
– CRH-containing
neurons are stimulated
– CRH delivered to
anterior pituitary
– CRH binds to receptors
on corticotrophs,
causing synthesis and
secretion of ACTH
Pathways of Steroid Biosynthesis
Cushing’s Syndrome

Diagnosis 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
Cushing’s Syndrome

Diagnosis 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
Cushing’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
Cushing’s Syndrome

Dexmethasone 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
Cushing’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
Cushing’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
Cushing’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
Cushing’s Syndrome

Radiographic 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
Cushing’s Syndrome

Radiographic 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
Cushing’s Syndrome

Radiographic 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
DIAGNOSIS

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
DIAGNOSIS

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)
DIAGNOSIS

Insulin Tolerance Test
– Hypoglycemia induced by the IV injection of reg
insulin 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
DIAGNOSIS

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
Hyperaldosteronism

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
Hyperaldosteronism

Diagnosis
– 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
Pheochromocytoma,
Diagnosis

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)
Pheochromocytoma,
Diagnosis

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 disease

Malignant disease
– Local invasion, disease outside of
adrenal/paraganglionic tissue
– No histological or clinical criteria can
differentiate malignant disease