Pituitary Dysfunction Flashcards
Pituitary Hormones
The Hypothalamus/Pituitary Gland-Master Gland, whose hormones affects, directly or indirectly, virtually every organ or tissue
a. Anterior Pituitary:
i. Thyroid Stimulating Hormone (TSH)
ii. Adrenocorticotropic hormone (ACTH)
iii. Growth Hormone
iv. Follicle Stimulating hormone (FSH) and Luteinizing hormone (LSH)
v. Prolactin
b. Posterior Pituitary
i. Oxytocin
ii. Anti-diuretic Hormone (ADH)
Pituitary Gland Regulation
Complex Integration Of Signals:
a. Higher CNS Centers
i. Thalamus
ii. Limbic System
iii. RAS
iv. Retina
b. Nutritional Status
c. Hormone Cross-Talk
Growth Hormone Regulation
a. Somatotropin (GH); most abundant pituitary hormone
i. 91 aa , 21kDa protein, Structurally similar to prolactin
ii. Half-life 20-25 minutes
iii. Multiple (6-8) discrete pulses/day
b. In youth, most pronounced with onset of sleep (children: 50-75% during phase 3-4 NREM sleep)
c. Stimulation
- Sleep
- Low glucose
- Exercise
- Stress
- Puberty
- High aa/protein
- GHRH
- Glucagon
- Alpha-adrenergic
d. Suppression
- Somatostatin
- High glucose
- Aging
- FFA
Excess and Deficiency of Pituitary Hormones
- GH
Excess: Acromegaly
Deficiency: GH Deficiency - PRL
Excess: Hypogonadism
Deficiency: Failed Lactation - FSH/LH
Excess: Rarely Clinically Evident
Deficiency: Hypogonadism - ACTH
Excess: Cushing’s Disease
Deficiency: Adrenal Insufficiency - TSH
Excess: Hyperthyroidism
Deficiency: Hypothyroidism - ADH
Excess: SIADH
Deficiency: Diabetes Insipidus
Assessment of Pituitary Hormones
a. Biochemical Evaluation requires assessment of Pituitary (Trophic) Hormones and their Target Gland Hormones
Pituitary Hormone and their Target Organ-Hormone
- TSH
i. Thyroid-T4 (+/- T3) - ACTH
i. Adrenal Gland-Cortisol and DHEA-S - Growth hormone (GH)
i. Liver-IGF - PRL
i. Breast - LH and FSH
i. Gonads-Testosterone (♂)
ii. Estradiol (♀)
Level of the Hypothalamic-PituitaryTarget
Organ Defect
a. Deficiencies are categorized as either central or Peripheral
b. Central Defect—> The hypothalamus or the Pituitary gland
i. If its the hypothalamus–> tertiary disorder (type of central disorder)
ii. If the disorder is the Pituitary–> Secondary disorder (type of central disorder/defect)
c. Peripheral defect—> mean that there is a primary disorder involving the target organ
Disorders of Pituitary Hormones
and their Target Glands
a. If the target organ has the disorder, it is a primary defect
b. If it is the hypothalamus (tertiary) or the pituitary gland (secondary) it is a central disorder
Dynamic Pituitary Testing
a. Utilizes Known Physiologic Stimulators and Suppressors of Pituitary Hormone Release.
b. Hormone Excess is assessed by a
Suppression Test (e.g., Oral glucose
tolerance test for GH suppression to
confirm acromegaly).
c. Hormone Deficiency is assessed by a
Stimulation Test (e.g., insulin tolerance
test to evaluate pituitary (ACTH and
GH) reserves.
Growth Hormone Regulation
a. Negative feedback regulation of Growth Hormone and IGF
b. GH and IGF will feedback onto the hypothalamus, this will cause there to be a decrease in GHRH release
Actions of Growth Hormone
a. Growth Hormone will increase the amount Insulin like growth factor to be created
i. requires high insulin for IGF to be created
ii. IGF will increase growing in bones, cell mass, protein synthesis
b. GH will also cause increased protein synthesis and fat breakdown (increase hormone sensitive lipase activity for higher serum FFA)
Problems of Growth Hormone Excess
a. GIGANTISM-Growth hormone excess before puberty (before closure of the growth plates).
b. ACROMEGALY-GH excess after puberty (after completion of linear growth).
Clinical Presentation of Acromegaly
GH excess after puberty
Clinical Features of Acromegaly
1. Acral/Facial Changes +++ (>60%)
- Headaches +++
- Hyperhidrosis (increased sweating) +++
- Oligo/Amenorrhea +++
- Obstructive Sleep Apnea +++
- Hypertension ++ (20-50%)
- Dyslipidemia ++
- Paresthesias/Carpal Tunnel Syndrome ++
- Impaired Glucose Tolerance /Diabetes Mellitus ++
Growth Hormone Excess
Diagnosis
a. Clinical Features of GH excess (old pictures are helpful)
AND
b. Elevated IGF-1 level (age and gender
matched)-best screening test. Integrated
24 h secretion.
i. Long-half life.
c. GH levels fluctuate widely over 24 hrs and normal values can overlap with GH secreting tumors.
c. Check OGTT/GH levels for equivocal cases
d. Pituitary MRI-macroadenomas are detected in >80% of acromegaly
What is one of the most critical parts of diagnosing Growth Hormone Excess?
Elevated IGF-1 level (age and gender
matched)-best screening test. Integrated
24 h secretion.
i. Long-half life.
Acromegaly Treatment
a. A multi-modal and disciplinary approach from among a dedicated team of: Neurosurgeons, Endocrinologists,
Neuropathologists, Radiologists and Radiation/Oncologists.
b. Treatment Approach
i. Surgery
ii. Medical Therapies
iii. Somatostatin Analogs
iv. Growth Hormone Receptor Antagonist
v. Radiation Therapies
Growth Hormone Deficiency
a. GH/IGF-1 Levels Change with Age
i. Highest during puberty
ii. will naturally decrease each decade with adult life
b. Progressive Decline (14% per Decade) during Adult Lifetime
Wiki:
Growth hormone deficiency (GHD) is a medical condition, caused by problems arising in the pituitary gland, in which the body does not produce enough growth hormone (GH). Growth hormone, also called somatropin, is a polypeptide hormone which stimulates growth and cell reproduction.
Growth hormone deficiency has a variety of different negative effects at different ages; for example, in newborn infants, the primary manifestations may be hypoglycemia or micropenis, while in later infancy and childhood, growth failure is more likely. Deficiency in adults is rare, but may feature diminished lean body mass, poor bone density, and a number of physical and psychological symptoms. on.
The most common cause of GHD (representing two-thirds of cases) are pituitary and parasellar tumors. The origin of adult GHD may be congenital or acquired. Of those adult GHD that are acquired, roughly 15% are idiopathic, 50% are from pituitary tumors, 20% from extrapituitary tumors, and 5% from infiltrative or inflammatory lesions.
GH deficiency can be treated through growth hormone replacement, injections of growth hormone, or radiation or surgical treatment of tumors.
Manifestations of Adult Growth Hormone
Deficiency (GHD)
a. Body Composition
i. Increased Fat Deposition
ii. Decreased Muscle Mass, Strength and Exercise Capacity
b. Bone Strength
i. Increased Bone Loss and Fracture Risk
c. Metabolic and Cardiovascular Effects
i. Increased Cholesterol Levels
ii. Increased Inflammatory and Prothrombotic Markers (Creactive
protein) .
d. Psychological Well-Being
i. Impaired Energy and Mood
ii. Quality of Life (QoL)
Uses and Abuses of GH Therapy
a. Multi-Billion Dollar Industry
b. Numerous Web-Sites
- Ineffective (oral) Formulations
- Fraudulent Claims
c. Not FDA-Approved Uses
- Anti-Aging
- Obesity
- Chronic Fatigue Syndrome
Adult-Onset Growth Hormone
Deficiency (AoGHD)
a. GH replacement deficiency approved for use in Children-1985, Adults-1996
b. GH therapy-still somewhat controversial in adults regarding cost/benefit ratio
c. Studies in adult patients with severe GHD, albeit relatively short-term (<1 yr) have shown modest benefits in body composition, metabolic parameters
and QoL.
d. No hard end-points: reduced fracture, CV events or increased longevity.
Diagnosis of AoGHD
(Adult-Onset Growth Hormone
Deficiency)
a. Provocative Testing for GH Reserve
i. Limited Reagents
b. Insulin induced hypoglycemia (gold standard).
i. Contraindications: Elderly, h/o seizure disorder, coronary artery disease or cerebrovascular disease.
c. GHRH-Arginine (second best test), although no longer available in U.S
d. Available tests: Arginine and glucagon stimulation tests
e. IGF-1 Level -Low (in the setting of multiple other pituitary hormone deficiencies).
i. Must be age/gender-matched.
Two major diagnosing paths to know for Adult-Onset Growth Hormone
Deficiency (AoGHD)
- Insulin induced hypoglycemia (gold standard).
i. Contraindications: Elderly, h/o seizure disorder, coronary artery disease or cerebrovascular disease. - IGF-1 Level -Low (in the setting of multiple other pituitary hormone deficiencies).
i. Must be age/gender-matched.
Hyperprolactinemia
PRL Level usually <150 ng/d
a. Physiological
i. Pregnancy, suckling, sleep, stress
b. Pharmacological
i. Estrogens (OCPs)
ii. Antipsychotics, antidepressants (TCAs),
antiemetics (reglan), Opiates
c. Pathological
i. Pituitary Stalk Interruption
ii. Hypothyroidism, chronic renal/liver failure, seizure
iii. Prolactinoma
Prolactinomas-The Basics
a. Most Common Functional Pituitary adenoma (30-40%)
b. Female:Male Prevalence-10:1, median age of diagnosis-34 yrs
Prolactinoma Diagnosis
a. Random PRL level (gender-based normative ranges)
b. Levels usually correlate with tumor size
i. >100-150 ng/dl with microadenomas
ii. >200-250 ng/dl with macroadenomas
c. Pituitary MRI (with/without contrast)
Prolactin Deficiency
a. Etiology: Severe pituitary (lactotrope) destruction from any cause (e.g., pituitary tumors, infiltrative diseases, infectious diseases, infarction, neurosurgery or radiation).
b. Clinical Presentation: Failed lactation in postpartum females, no known effect in males.
c. Diagnosis: low basal PRL level
Cortisol Physiology
a. A Catabolic “Stress” Hormone
i. Essential for Life
b. Primary Functions:
i. Gluconeogenesis
ii. Metabolism of Fat and Protein
iii. Control Inflammatory Reactions
c. ACTH acts on adrenal cortex
i. ZF, stimulates glucocorticoid production
ii. ZG, usually inactivated by 11-beta HSD2
- but can activate mineralcorticoid receptor in marked excess (HTN, hypokalemia)
iii. ZR, stimulates steroid hormone synthesis
The Complications of Chronic Cortisol
Excess
a. Changes in Carbohydrate, Protein and Fat Metabolism
i. Peripheral Wasting of Fat/Muscle
ii. Central obesity, Moon facies, fat pads
iii. Osteoporosis
iv. Diabetes
v. Hypertriglyceridemia
b. Changes in Sex Hormones
i. Amenorrhea/Infertility
ii. Excess hair growth (♀)
iii. Impotence
c. Salt and Water Retention
i. HTN and Edema
d. Impaired Immunity
e. Neurocognitive Changes
Cortisol Excess (Hypercortisolism)
Causes:
a. ACTH Dependent
i. Corticotrope Adenoma
(Cushing’s Disease)
ii. Ectopic Cushing’s
(ACTH/CRH tumors)
b. ACTH Independent
i. Adrenal Adenomas
ii. Adrenal Carcinoma
iii. Nodular Hyperplasia
(micro or macro)
Clinical Aspects of Cushing’s Disease
a. Incidence: 2-3 cases per 1 million/year.
b. ~10-15% of Functional Pituitary adenomas
c. Female, Middle-aged predominance
Non-Specific Signs/Symptoms of
Cushing’s Syndrome
Obesity Fatigue Menstrual Irregularities Hirsutism HTN
Glucose Intolerance/DM Dyslipidemia Acne Anxiety/Depression Peripheral Edema Metabolic Syndrome
Screening Guidelines for Cushing’s Syndrome
Screening indicated in patients with
multiple and progressive “high discriminatory” features of Cushing’s
Syndrome.
Specific Signs of Cushing’s Syndrome 1. Plethoric/moon facies 2. Wide (>1 cm), violaceous striae (abdominal, axillary) 3. Spontaneous Ecchymoses 4. Proximal Muscle Weakness 5. Early/Atypical Osteoporosis (atraumatic rib fx)
Specific Signs of Cushing’s Syndrome
- Plethoric/moon facies
- Wide (>1 cm), violaceous striae (abdominal, axillary)
- Spontaneous Ecchymoses
- Proximal Muscle Weakness
- Early/Atypical Osteoporosis
(atraumatic rib fx)
Cortisol Rhythms
a. Episodic ACTH/cortisol secretions daily
b. Major ACTH/cortisol burst in the early morning (before
awakening) .
c. Cortisol Nadir 11-12 pm (assuming a normal sleep-wake cycle)
Cortisol Binding
a. Most cortisol is bound to transcortin (cortisol binding globulin-CBG).
b. 10-15% bound to albumin (less tightly)
c. 5% Unbound (Free cortisol)
Screening Tests for Cushing’s Syndrome
a. Disrupted Circadian Rhythm
i. Midnight Salivary or Serum Cortisol
b. Increased Filtered Cortisol Load
i. 24 hr Urine Free Cortisol
c. Attenuated Negative Feedback
i. Low Dose (1 mg) Dexamethasone
Suppression test (11-12 p.m.)
Confounding Issues in Cushing’s
Diagnosis
a. “Pseudo-Cushing’s Disease”
overactivation of the HPA axis, without
tumorous cortisol hypersecretion
b. Conditions that can give false negatives for Cushing’s (lead to high cortisol)
i. Severe Depression/Anxiety/OCD
ii. Severe Obesity
iii. ?Obstructive Sleep Apnea
iv. Alcoholism
v. Poorly-controlled DM/hypoglycemia
vi. Physical Stress (acute illness,
surgery, pain)
Cushing’s Disease Work-up
- ACTH LEVEL
• Plasma ACTH levels are usually high-normal to mildly elevated in Cushing’s disease - IMAGING
• Pituitary MRI (~80% microadenomas, 50% identified on MRI) - INFERIOR PETROSAL SINUS
SAMPLING
• For a negative/equivocal MRI
Central Adrenal Insufficiency (AI)
low cortisol
a. Etiologies of Primary AI-separate lecture
b. Etiologies of Secondary/Tertiary AI—> Suppression of the HPA axis
i. S/p tumor resection for Cushing’s Syndrome (pituitary, ectopic or adrenal)
ii. Supraphysiologic exogenous glucocorticoid use (most common) > 5-7.5 mg prednisone (or equivalent
glucocorticoid dose) for >1 month
iii. Drugs: Opioids and megace
c. Hypothalamus/Pituitary Diseases and/or their treatments.
d. Other-Isolated ACTH deficiency (very rare)
Central Adrenal Insufficiency
Clinical Presentation of secondary/tertiary
adrenal insufficiency (AI)
1. Fatigue
2. Anorexia, nausea/vomiting and weight loss
3. Generalized malaise/aches
4. Scant Axillary/Pubic hair (DHEA-S dependent in females)
5. Hyponatremia and Hypoglycemia
Central Adrenal Insufficiency
a. Basal Testing: Random a.m. cortisol level, <3 ug/dl (establishes AI diagnosis), >18 ug/dl (excludes AI diagnosis), additional provocative testing required for equivocal results.
b. Stimulation Tests
i. Insulin-induced hypoglycemia (gold standard)–assesses entire hypothalamic-pituitary-adrenal axis.
ii. Cosyntropin (synthetic ACTH 1-24) stimulation test-valid for assessing HPA axis only if prolonged (several weeks-months) loss of pituitary signaling and resulting adrenal atrophy.
Hypogonadism Differential Dz
Hypergonadotropic vs. Hypogonadotropic Hypogonadism
- Hypergonadotropic Hypogonadism–> High FSH/LH
i. Congenital Anorchia
ii. Klinefelter’s Syndrome
iii. Testicular Injury
iv. Autoimmune Testicular Dz
v. Glycoprotein Tumor (rarely) - Hypogonadotropic Hypogonadism
i. Hypothalamic/Pituitarydiseases- Macroadenomas, prolactinomas, XRT
- Isolated GnRH Deficiency (Kallman’s=anosmia vs. Idiopathic)
- Hemochromatosis
ii. “Functional” Deficiency-Critical Illness, OSA, starvation, Meds-opiates, glucocorticoids
Clinical Features of Hypogonadism
FEMALES a. Anovulatory cycles i. oligo/amenorrhea, infertility b. Vagina dryness, dyspareunia c. Hot Flashes d. Decreased libido e. Breast atrophy f. Reduced bone mineral density (BMD)
MALES a. Reduced libido, b. Erectile dysfunction c. Oligospermia or azoospermia, d. Infertility e. Decreased muscle mass, testicular atrophy and decreased BMD. f. Hot flashes with acute and severe onset of hypogonadism.
LH/FSH (Gonadotropin)Excess
a. Clinical Presentation of Gonadotrope Adenomas
i. The majority of FSH/LH tumors are clinically silent (?inefficient intact LH/FSH hormone synthesis or secretion).
ii. Rare presentation (from functionally-intact FSH/LH molecules) include: ovarian hyper-stimulation syndrome (females) or macro-orchidism (males).
b. Middle-aged patients (males >females) with macroadenomas and related mass effects (e.g., headaches, vision loss, cranial nerve palsies, and/or pituitary hormone deficiencies).
Thyrotropin (TSH) Elevation
Etiologies
a. Secondary
i. Thyrotropin secreting pituitary tumor-very rare
(<1% of pituitary tumors)
ii. Thyroid hormone resistance (generalized or pituitary-specific, rare conditions)
Central Hyperthyroidism
Clinical Presentation
a. Thyrotropinoma (TSHoma)-similar clinical presentation to primary hyperthyroidism (i.e., goitre, tremor, weight
loss, heat intolerance, hair loss, diarrhea, irregular menses) but also with associated mass effects (i.e., headaches, vision loss, loss of pituitary gland function) from macroadenoma.
b. Diagnosis
i. Elevated Free T4 and a non-suppressed TSH
ii. Pituitary MRI (>80% macroadenomas)
Central TSH Deficiency
a. Etiologies
1. Pituitary/Hypothalamic Diseases and/or their treatments
- Critical Illness/Starvation-Euthyroid Sick Syndrome
- Congenital defects (TSH-beta mutations, PROP1, POUF1 mutations)
- Drug induced-supraphysiologic steroids, dopamine, rexinoids.
b. Clinical presentation: similar to primary hypothyroidism (e.g., fatigue, weight gain, cold intolerance, constipation, hair loss, irregular menses).
i. Possible mass effects
c. Diagnosis: Low Free T4 levels in the setting of a low or normal TSH.
Hypopituitarism
a. Definition: Deficiency of 1 or more pituitary hormones.
i. Panhypopituitarism=loss of all pituitary hormones
b. Etiologies:
i. Congenital-Genetic Diseases (transcription factor mutations)
ii. Acquired-Pituitary Lesions and/or their treatments (75%)
- Macroadenomas/Pituitary Surgery/Radiation Therapy
- Infiltrative/Infectious/Granulomatous diseases
- Traumatic Brain Injury/Subarchnoid Hemorrhage
- Apoplexy
- Autoimmune Hypophysitis-Immune-tolerance disruptors (Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4, Ipilimumab)
Apoplexy
a. Apoplexy Definition: Clinical syndrome of headache, vision changes, ophthalmoplegia and altered mental status caused by the sudden hemorrhage or infarction of the pituitary gland.
b. Occurs in ~10-15% of pituitary adenomas; subclinical disease is more common
c. Diagnosis: Pituitary MRI or CT
d. Treatment
i. Emergent surgery is indicated for evidence of severe vision loss, rapid clinical deterioration, or mental status changes.
ii. Stress dose steroids for adrenal insufficiency.
Pituitary Hormone Deficiency
a. Predictable Loss of Anterior Pituitary Hormones
b. Anti-diuretic Hormone (ADH)-deficiency-common with metastatic tumors (i.e., breast, lung or GI) or craniopharyngiomas, but not pituitary adenomas.
Hypopituitarism
a. Clinical Presentation:
i. Depends on the severity of the pituitary hormone deficiencies and their rate of development.
ii. Generally similar presentation to target gland hormone deficiency, with some exceptions:
- Primary adrenal insufficiency also presents w/ hyperkalemia from mineralcorticoid deficiency and hyperpigmentation from ACTH
excess) .
b. Diagnosis: Basal and Dynamic Testing
Hypopituitarism
Management
Treatment of Anterior Pit. Hormone Deficiencies (End Organ Hormone Replacement):
1. Thyroid – Multiple L-thyroxine formulations available.
- Adrenal – Physiologic hydrocortisone or prednisone
i. Medic Alert Bracelet, Sick day rules for glucocorticoid replacement
ii. No mineralcorticoid replacement needed - Gonadal –
i. Various formulations-oral/transdermal E2, transdermal/IM Testosterone
ii. Gonadotropin or pulsatile GnRH therapy - Growth Hormone
i. Various Formulations of subcutaneous shots (not orally active).
Prolactin – SQ formulation, research purposes only.
“Bio-identical” Hormones
a. Media Misinformation
b. “Chemically-Identical” Hormones
c. “Custom-made, by compounding pharmacies, and individually-tailored
based on saliva tests.”
d. Exaggerated and unproven claims of
safety and efficacy relative to other
FDA-approved products.
Posterior Pituitary Gland
a. Clinical syndromes are primaril associated with disorders of AVP
i. AVP (arginine vasopressin) = ADH
(antidiuretic hormone).
b. Release Controlled Primarily
By-High osmolar states
i. via hypothalamic osmoreceptors
Volume Regulation of ADH
a. Release Controlled Primarily by–> High osmolar states
i. via hypothalamic osmoreceptors
b. Release Also Controlled By:
i. Hypovolemia via baroreceptors
Mechanism of ADH Action
V1 – Vascular Vasoconstriction, Platelet aggregation
V2 - Antidiuretic effects in kidney
Adenylate cyclase activation movement of
Aquaporin water channels to the cell
membrane water reabsorption
Regulation of ADH Release
a. Vasopressin is secreted from the posterior pituitary gland in response to reductions in plasma volume, in response to increases in the plasma osmolality, and in response to cholecystokinin (CCK) secreted by the small intestine:
b. Secretion in response to reduced plasma volume is activated by pressure receptors (baroreceptors) in the veins, atria, and carotid sinuses
i. Secretion in response to increases in plasma osmotic pressure is mediated by osmoreceptors in the hypothalamus.
c. Secretion in response to increases in plasma CCK is mediated by an unknown pathway.
d. The neurons that make AVP, in the hypothalamic supraoptic nuclei (SON) and paraventricular nuclei (PVN), are themselves osmoreceptors, but they also receive synaptic input from other osmoreceptors located in regions adjacent to the anterior wall of the third ventricle. These regions include the organum vasculosum of the lamina terminalis and the subfornical organ.
SIADH Basics
a. SIADH Definition: A syndrome of inappropriate AVP release/action in the absence of physiologic osmotic or hypovolemic stimulus.
b. Hallmark is the excretion of inappropriately concentrated urine in the setting of hypo-osmolality and hyponatremia.
c. SIADH is one of the most frequent causes of hyponatremia, and occurs in an estimated:
i. 15-22% of hospitalized patients
ii. 5-7% of ambulatory patients
SIADH Etiologies
Major Categories
1. Malignant Disease- Carcinoma, Lymphoma, Sarcomas
- Pulmonary Disorders-Infections, Asthma, Cystic Fibrosis, Positive Pressure Ventilation
- CNS Disorders-Infection, Tumors, Trauma, Bleeds
- Drugs-Stimulate/Potentiate AVP release/actions
i. Narcotics, Nicotine, Anti-psychotics, Carbamazepine, Vincristine
Misc.-Nausea, Stress and Pain
SIADH
Clinical Presentation
a. Depends on the severity of hyponatremia and the rapidity of
development (acute, <48 hr)
b. Manifests with neurological symptoms from osmotic fluid shifts and brain edema
c. Plasma Na+ Signs/Symptoms
130-135 mmol/L Usually Asymptomatic
125-130 mmol/L Anorexia, N/V, Headaches, Irritable
115-125 mmol/L Altered Sensorium, Gait disturbance
<115 mmol/L Seizure, Coma, Death
SIADH Diagnosis
Criteria
a. Hyponatremia (Na+ <135 mmol/L) and hypotonic plasma
(osmolality <275 mOsm/kg)
b. Inappropriate urine concentration (Urine Osm >100 mOSm/kg) with normal renal function
c. Euvolemic Status (no orthostatics hypotension)
d. Exclusion of other potential causes of euvolemic hypoosmolality
i. Hypothyroidism
ii. Hypocortisolism
SIADH Treatment
a. Identify and Reverse Underlying Disorder (when possible)
b. Treatment depends on the severity of hyponatremia, the rate of development and the patient’s symptomatology
- Mild-to-Moderate Hyponatremia (Na+ ~120-134 mmol/L)
i. Water Restriction (500-1000L/24hrs)
ii. V2 Receptor Antagonists ($$$)
iii. Salt tablets, Lasix, Urea (Europe) - Severe Hyponatremia (usually Na+ <120 mmol/L)
i. Hypertonic (3%) Saline-if patient is symptomatic (delirium/seizure/coma)
Reducing Risk of Hyponatremia
Complications
a. Limit Correction of Chronic Hyponatremia:
i. < 12 mmol in the first 24 hrs.
ii. Slower correction with other risk factors associated with osmotic demyelination syndrome
- Hypokalemia, alcoholism, poor nutritional status
b. NO LIMITATIONS with acute onset hyponatremia
i. (e.g., <48 hr onset, marathon runners)
Diabetes Insipidus (DI)
a. Definition-DI is a syndrome of hypotonic polyuria as a result of either:
i. Inadequate ADH secretion
ii. Inadequate renal response to ADH
b. Hallmark-Voluminous (Urine output > 40ml/kg/d) dilute urine
c. Main Causes:
i. Central Diabetes Insipidus
ii. Nephrogenic Diabetes Insipidus
iii. Pregnancy-increased ADH metabolism from placental vasopressinase,
but is generally not clinically relevant.
iv. Primary Polydipsia
d. Clinical Significance: Can lead to severe dehydration if thirst mechanisms are impaired, or if the patient has limited access to water
DI Etiologies
a. Nephrogenic DI
i. Congenital: X-linked recessive AVP V2 receptor gene mutation; autosomal recessive aquaporin-2 water channel gene mutation
ii. Drugs: demeclocycline, lithium,
amphotericin B
iii. Electrolyte abnormalities: hypokalemia and hypercalcemia
iv. Infiltrative kidney diseases: sarcoidosis and amyloidosis
v. Vascular disease: sickle cell
anemia
b. Neurogenic DI
i. Neoplasms: craniopharyngioma,
metastatic pituitary disease (e.g., colon,
breast, lung)
ii. Idiopathic:+AVP Ab
iiii. Congenital defects: autosomal dominant
AVP neurophysin gene mutation
iv. Inflammatory/Infectious/granuloma
pituitary diseases: lymphocytic
hypophysitis,histiocytosis, sarcoidosis
v. Trauma/Vascular event: neurosurgery,
TBI/deceleration injury
Post-Operative/Trauma-related DI
a. Classic Triphasic Response:
1° phase– DI-polyuric phase due to axonal
shock/decreased AVP release (days 1-5)
2° phase – SIADH from degenerating
neurons/excessive AVP release (days 6-11)
3° phase-Permanent DI after depleted ADH stores and if >80% AVP neuronal cell death
b. Permanent DI-uncommon complication with an experienced neurosurgeon (<1%)
c. Isolated Second (SIADH) Phase-More
Common (~25%)
Outpatient DI Diagnosis
a. Confirm polyuria with 24 hr urine volume collection (normalized to creatinine)
b. Exclude hyperglycemia (osmotic diuresis), renal insufficiency and electrolyte disturbances (K+/Ca 2+)
c. Assess Urine and Plasma Osmolalities
d. Consider Water Deprivation Test
e. Pituitary Imaging (for suspected neurogenic DI)
Water Deprivation Test
a. Fluid restriction to stimulate ADH release
b. Measure Uosm , Posm Serum Na+ and Urine output
c. Urine concentration Response to dDAVP
d. +/- ADH Level after mild dehydration
Central DI Treatment
a. Anti-Diuretic Hormone Replacements
1. First Line-dDAVP (nasal, oral or parenteral routes of administration)
i. Longer half-life than ADH
ii. No Vasopressor Effect
- Second-Line-ADH (IV, SQ or IM routes of administration).
b. Goals:
i. Resolution of Polyuria/Polydipsia
ii. Minimal disruption of sleep/daily routine
iii. Normal Serum Sodium
Anterior Pituitary
Anterior Pituitary-80% of the whole pituitary gland
o Five differentiated cell types that secrete six major hormones
o Complex integration of signals: Positive and negative influences on pituitary hormone secretion from the CNS, hypothalamus, target hormones and physiologic factors.
The loss of a target (peripheral) organ hormone
a. The loss of a target (peripheral) organ hormone may be due to a defect at the level of the target organ, the pituitary gland, or the hypothalamus, which are referred to as primary, secondary and tertiary endocrine disorders, respectively.
b. Secondary and tertiary disorders may be difficult to distinguish and are referred to as central disorders.
Basal Testing and Dynamic Testing of Pituitary Hormones
a. Basal Testing- TSH/Free T4, ACTH/a.m. cortisol, PRL, GH/IGF-1, LH, FSH, Testosterone (in males), estradiol (in females)-and timed within 5-7 days of starting menses (follicular phase).
i. Pituitary hormone deficiency is established by a low target hormone level in the setting of a low, or an inappropriately normal, pituitary hormone level.
ii. Pituitary hormone excess is established by a high target hormone level in the setting of an inappropriately normal or high pituitary hormone level.
b. Dynamic Testing is done if indicated by an equivocal basal test. It utilizes known physiologic stimulators and suppressors of pituitary hormone release.
i. Hormone deficiency is assessed by a stimulation test (e.g., insulin tolerance test for adrenal insufficiency).
ii. Hormone Excess is assessed by a suppression test (e.g., oral glucose tolerance test for GH suppression in acromegaly).
Growth Hormone Excess and Diagnosis
from Somatotrope cells
a. GH Excess
1. Gigantism (before epiphyseal plate closure)
2. Acromegaly (after epiphyseal plate closure)
o Etiologies: Pituitary tumors (95%), ectopic GH/GHRH tumors (5%)
b. Diagnosis
i. Clinical Features of GH excess (old pictures are helpful),
AND
ii. Elevated IGF-1 level (age and gender matched)-best screening test
iii. GH levels fluctuate widely over 24 hrs and normal values can overlap with GH-secreting tumors
iv. Confirmatory testing (for equivocal IGF-1 level)
-Oral glucose tolerance test-75 gm oral glucose load, followed by growth hormone testing q 30 minutes for 2 hrs (abnormal GH response >1 ug/L or >0.40 ng/ml with ultrasensitive GH assays).
v. Pituitary MRI-macroadenomas are detected in most cases of acromegaly (>80%).
Diagnosis for Growth Hormone Excess
a. Clinical Features of GH excess (old pictures are helpful),
AND
b. Elevated IGF-1 level (age and gender matched)-best screening test
i. best screen
c. GH levels fluctuate widely over 24 hrs and normal values can overlap with GH-secreting tumors
d. Confirmatory testing (for equivocal IGF-1 level)
- Oral glucose tolerance test-75 gm oral glucose load, followed by growth hormone testing q 30 minutes for 2 hrs (abnormal GH response >1 ug/L or >0.40 ng/ml with ultrasensitive GH assays).
e. Pituitary MRI-macroadenomas are detected in most cases of acromegaly (>80%).
GH Deficiency (GHD) in Adults:
a. Etiologies: Pituitary/hypothalamic diseases and/or their treatments (e.g., surgery, radiation therapy), childhood onset GHD and traumatic brain injury.
b. Clinical Presentation:
i. altered body composition (e.g., increased central obesity, reduced lean body mass)
ii. decreased bone mineral density
iii. increased insulin resistance/glucose intolerance, pro-atherogenic lipid profile/increased inflammatory markers (e.g., CRP, hypertriglycerides, IL-6)
iv. and impaired psychological well-being (e.g., fatigue and depression).
c. Diagnosis: Adult GH Deficiency is best established by
i. Low IGF-1 (in the setting of multiple other pituitary hormone deficiencies)
ii. Provocative testing for GH reserve 1. Insulin induced hypoglycemia (gold standard). Insulin (0.1U/kg) to induce hypoglycemia (blood sugar <40 mg/dl). Normal GH response: > 3-5 ug/dl. Contraindications: elderly, h/o seizure disorder, coronary artery disease or cerebrovascular disease. 2. GHRH-Arginine (second best test), although no longer available in U.S 3. Arginine and glucagon-currently available tests, but problematic.
Clinical Presentation and Diagnosis of Growth Hormone Deificency in adults
Clinical Presentation:
a. altered body composition (e.g., increased central obesity, reduced lean body mass)
b. decreased bone mineral density
c. increased insulin resistance/glucose intolerance, pro-atherogenic lipid profile/increased inflammatory markers (e.g., CRP, hypertriglycerides, IL-6)
d. and impaired psychological well-being (e.g., fatigue and depression).
Diagnosis: Adult GH Deficiency is best established by
a. Low IGF-1 (in the setting of multiple other pituitary hormone deficiencies)
i. Must be age/gender-matched
b. Provocative testing for GH reserve
1. Insulin induced hypoglycemia (gold standard). Insulin (0.1U/kg) to induce hypoglycemia (blood sugar <40 mg/dl). Normal GH response: > 3-5 ug/dl.
i. Contraindications: elderly, h/o seizure disorder, coronary artery disease or cerebrovascular disease.
- GHRH-Arginine (second best test), although no longer available in U.S
- Arginine and glucagon-currently available tests, but problematic.
Etiologies of Hyperprolactinemia
a. Physiological
i. Pregnancy, suckling, sleep, stress
b. Pharmacological
i. Estrogens
ii. Antipsychotics , antidepressants (tricyclics, MAO-I), anti-emetics (reglan), anti-HTN (verapamil)
iii. Opiates
c. Pathological
i. Prolactinoma
ii. Pituitary Stalk Interruption (from any cause)
iii. Hypothyroidism, chronic renal/liver failure, seizure
d. Idiopathic; macroprolactin (PRL:IgG complex)
Hyperprolactinemia Clinical Presentation and Diagnosis
a. Clinical Presentation
i. Hormone Effects-Galactorrhea (rarely in males), irregular menses/amenorrhea (♀), erectile dysfunction (♂), infertility, osteoporosis, decreased libido
ii. Mass Effects-Macroadenoma-related (♂ > ♀) and includes: headaches, vision disturbances, cranial nerve palsies and pituitary hormone deficiencies
b. Diagnosis
i. Random PRL level (use gender-based normative ranges)
ii. Levels usually >100-150 ng/mL with prolactinomas
iii. Pituitary MRI
PRL Deficiency
prolactin
a. Etiology: Severe lactotrope destruction from any cause (e.g., pituitary tumors, infiltrative diseases, infectious diseases, infarction, neurosurgery or radiation)
b. Clinical Presentation: Failed lactation in post-partum females, no effect in males.
c. Diagnosis: low random PRL level
Dopamine Agonists
For treating Hyperprolactinemia
a. Bromocriptine (Parlodel) 2.5 mg tab. “Start low and go slow”
i. Common Side Effects: GI upset, Nasal Congestion, Orthostatic Dizzyness.
ii. Preferred only if planned pregnancy
Hyperortisolism Etiology and Clinical presentation
a. Etiologies of Cortisol Excess (hypercortisolism)
• ACTH –Dependent (70-75%)-Corticotrope adenomas/Cushing’s Disease (CD), ectopic ACTH/CRH tumors
• ACTH-Independent (25-30%)-adrenal adenomas, adrenal carcinomas, nodular (micro or macro) adrenal hyperplasia
b. Clinical Presentation of Hypercortisolism
• Specific features of Cushing’s include: facial plethora, easy bruising, wide (>1 cm) violaceous striae and proximal muscle weakness
• General signs/symptoms (poor specificity): weight gain/obesity, diabetes, hypertension, irregular menses, dorsocervical hump, acne, low libido, depression or hirsutism
Diagnosis of Cushing’s Disease
a. Initial Screening Tests:
1) 24 hour urinary cortisol,
2) 11-12 p.m. salivary cortisol test,
or
3) 1 mg dexamethasone suppression test (1 mg dexamethasone given at 11-12 p.m., followed by ~8 am serum cortisol level. Normal cortisol suppression <1.8 ug/dl).
i. Caveat: “Pseudo-Cushing’s” disease: non-tumoral activation of hypothalamic-pituitary-adrenal (HPA) axis (e.g., severe depression, alcoholism, marked stressors)
can give a false-positive screening test.
b. Plasma ACTH level is normal to mildly elevated in Cushing’s disease
c. Pituitary MRI (~80% microadenomas, 50% identified)
d. Inferior petrosal sinus sampling (IPSS) for a negative or equivocal MRI.
e. Positive test for Cushing’s disease:
basal central/peripheral ACTH gradient (> 2), or >3 after CRH stimulation
Cortisol Deficiency
Large Summary
a. Primary (adrenal gland failure) (Will be covered in the Adrenal lecture)
b. Secondary/Tertiary
i. Suppression of the HPA axis
• Supraphysiologic exogenous glucocorticoid use (most common)
• S/p tumor resection for Cushing’s Syndrome (pituitary, ectopic or adrenal)
• Drugs: Opioids and megace
ii. Diseases of the Hypothalamus/Pituitary and/or their treatments
iii. Other-Isolated ACTH deficiency (congenital TPIT mutations). Very rare
c. Presentation of secondary/tertiary adrenal insufficiency (AI)
i. Fatigue, pallor, anorexia, weight loss, nausea, vomiting, abdominal pain, hyponatremia, hypoglycemia, orthostatic dizziness and scant axillary/pubic hair (DHEA-S dependent).
d. Diagnosis
i. Random a.m. cortisol level, <3 ug/dl (establishes AI diagnosis), >18 ug/dl (excludes AI diagnosis), 3-18 ug/dl equivocal result; requires additional provocative testing
ii. Stimulation tests to assess HPA axis
-Insulin-induced hypoglycemia (gold standard)–assesses entire axis.
-Cosyntropin (synthetic ACTH 1-24) stimulation test-valid for assessing HPA
axis only if prolonged (several weeks-months) interruption of pituitary
signaling. ACTH-250 ug IV, check serum cortisol level at 30 & 60 minutes.
Normal cortisol response >18 mg/dl
Gonadotropinoma Diagnosis
a. Blood tests: usually low FSH/LH, T/E2
b. Pituitary MRI
c. Immunohistochemical analyses
(+FSH, LH, or ASU staining) of the
resected tumor
Cortisol Deficiency Presentation and Diagnosis
a. Presentation of secondary/tertiary adrenal insufficiency (AI)
i. Fatigue, pallor, anorexia, weight loss, nausea, vomiting, abdominal pain, hyponatremia, hypoglycemia, orthostatic dizziness and scant axillary/pubic hair (DHEA-S dependent).
b. Diagnosis
i. Random a.m. cortisol level, <3 ug/dl (establishes AI diagnosis), >18 ug/dl (excludes AI diagnosis), 3-18 ug/dl equivocal result; requires additional provocative testing
ii. Stimulation tests to assess HPA axis
-Insulin-induced hypoglycemia (gold standard)–assesses entire axis.
-Cosyntropin (synthetic ACTH 1-24) stimulation test-valid for assessing HPA
axis only if prolonged (several weeks-months) interruption of pituitary
signaling. ACTH-250 ug IV, check serum cortisol level at 30 & 60 minutes.
Normal cortisol response >18 mg/dl
Clinical Presentation of Gonadotrope Adenomas and Diagnosis
a. The vast majority of FSH/LH tumors are clinically silent macroadenomas and present in middle-aged patients with mass effects (i.e., headaches, vision loss, cranial nerve palsies, or pituitary hormone deficiencies)
b. Hypogonadotropic Hypogonadism
i. Females: anovulatory cycles, oligo/amenorrhea, infertility, hot flashes, vaginal dryness/atrophy, dyspareunia, reduced bone mineral density (BMD)
ii. Males: Reduced libido, erectile dysfunction, oligospermia or azoospermia, testicular atrophy, infertility, decreased muscle mass and low BMD. Hot flashes with acute and severe onset of hypogonadism.
c. Rare presentation (from functionally-intact FSH/LH molecules) include:
ovarian hyperstimulation syndrome (females) or macro-orchidism (males).
d. Diagnosis
• FSH/LH, T and E2, alpha-subunit
• Pituitary MRI
• Immunohistochemical analyses (+FSH or LH staining of the resected tumor) establishes the diagnosis
Etiologies of TSH Excess and Deficiencies
Throid Stimulating Hormone
a. TSH Elevation (Will also be covered in a separate lecture)
1. Primary hypothyroidism from thyroid gland failure (Hashimoto’s disease most common)
2. Thyrotropin secreting pituitary tumor-very rare (<1% of pituitary tumors)
3. Other-Thyroid hormone resistance and recovery phase of euthyroid sick syndrome.
b. TSH Deficiency
1. Pituitary/Hypothalamic Diseases and/or their treatments
2. Congenital defects (TSH-beta mutations, PROP1, POU1F1 mutations)
3. Drug induced-supraphysiologic steroids, dopamine, rexinoids.
Clinical Presentation and Diagnosis of Thyroid Stimulating Hormone Disorder
a. Clinical Presentation
i. Thyrotropinoma (TSHoma)-similar clinical presentation to primary hyperthyroidism (i.e., goitre, tremor, weight loss, heat intolerance, hair loss, diarrhea, irregular menses) but also with associated mass effects (i.e., headaches, vision loss) from macroadenoma.
ii. Central Hypothyroidism-similar clinical presentation to primary hypothyroidism (e.g., fatigue, weight gain, cold intolerance, constipation, hair loss, irregular menses).
b. Diagnosis
o Thyrotropinoma: elevations of circulating thyroxine (T4) and triiodothyronine (T3) concentrations, and a non-suppressed (inappropriately normal or frankly elevated) TSH level.
o Central hypothyroidism: Low Free T4 levels in the setting of a low or normal TSH.
o Pituitary MRI
Hypopituitarism
Definition and Etiology
a. Definition: Deficiency of >1 pituitary hormone(s). Panhypopituitarism=deficiencies of all pituitary hormones.
b. Etiologies: Pituitary tumors and/or their treatment (75% of cases), parasellar tumors (e.g., craniopharyngiomas, meningiomas), pituitary infarction/apoplexy/Sheehan’s syndrome, infiltrative diseases (sarcoidosis, lymphocytic hypophysitis, hemochromatosis, Langerhan’s cell histiocytosis), infection (TB, abscess), traumatic brain injury/subarachnoid hemorrhage, or genetic defects.
c. Generally predictable order of pituitary hormones deficiencies:
i. GH≈FSH/LH > TSH ≈ACTH > PRL
ii. ADH deficiency- infrequent with pituitary adenomas, but common with metastatic diseases to the pituitary gland (e.g., lung, breast or colon) and craniopharyngiomas.
Apoplexy Summary
o Apoplexy
a. Definition: Clinical syndrome of headache, vision changes, ophthalmoplegia and altered mental status caused by the sudden hemorrhage or infarction of the pituitary gland.
b. Occurs in ~10-15% of pituitary adenomas; sub-clinical disease is more common
c. Diagnosis: Pituitary MRI or CT
d. Treatment
• Emergent surgery is indicated for evidence of severe vision loss, rapid clinical deterioration, or mental status changes.
• Stress dose steroids are indicated for presumptive adrenal insufficiency. Expectant management is indicated for thyroid hormone and sex steroids.
i. Residual pituitary hormone deficiencies are common.
Empty Sella Syndrome (ESS)
Empty Sella Syndrome (ESS)
a. Primary ESS-due to arachnoid herniation through a congenital diaghragmatic defect.
i. Hyperprolactinemia in ~10% of cases, but hypopituitarism is uncommon.
b. Secondary ESS- due to pituitary/parasellar disease and/or their treatment. Pituitary deficiencies are more common than in primary ESS.
Clinical Presentation, Diagnosis, and Treatment of Hypopituitarism
a. Clinical Presentation of Hypopituitarism
o Depends on the severity of the pituitary hormone deficiencies and their rate of development.
o Represents a continuum from partial to complete pituitary hormone deficiency.
o Similar presentation to target gland hormone deficiency as detailed above with some exceptions (e.g., primary adrenal insufficiency also presents w/hyperkalemia from mineralcorticoid deficiency and hyperpigmentation from ACTH excess).
b. Diagnosis
o Assessment of pituitary hormones and target hormones with basal and dynamic testing.
c. Treatment: Replacement of hormones as indicated by deficiencies
i. Glucocorticoids- Prednisone or hydrocortisone–first line therapies.
ii. Thyroid hormone-multiple T4 formulations available.
iii. Testosterone or estrogen
• Various formulations-oral/transdermal E2, transdermal/IM Testosterone
• Gonadotropin therapy is sometimes required for fertility treatment.
• Growth hormone-subcutaneous shots (controversial use in adults regarding cost-to- benefit ratio).
iv. dDAVP-oral or nasal formulations
Physiology of the Posterior Pituitary Gland
Neurohypophysis-20% of the pituitary gland
i. other name for posterior pituitary
a. AVP = arginine vasopressin = ADH = antidiuretic hormone
i. AVP release is stimulated by:
• High osmolar states (via hypothalamic osmoreceptors)
• Hypovolemia (via baroreceptors)
b. AVP causes free water retention (via V2 receptors in the kidney) and vasoconstriction (via V1 receptors of blood vessels)
c. Oxytocin-mediates milk let-down and uterine contractions
Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Large Summary
A syndrome of inappropriate AVP release in the absence of hyperosmotic or hypovolemic stimulus. The hallmark of SIADH is excretion of concentrated urine in the setting of serum hypoosmolality and hyponatremia.
Etiology of SIADH
• CNS disturbances (e.g., mass lesion, inflammatory diseases, degenerative/ demyelinative diseases, head injury, subarachnoid hemorrhage, hydrocephalus).
• Drugs:
o Stimulate AVP release: morphine, nicotine, phenothiazine, tricyclic antidepressants
o Direct renal effects and/or potentiates AVP effects- prostaglandin synthesis inhibitor
o Mixed or uncertain actions: carbamazepine, clofibrate, vincristine, cyclophosphamide, haloperidol.
• Pulmonary disease (e.g., infections, mechanical ventilation)
• Tumors (e.g., bronchogenic carcinoma, thymoma, leukemia, sarcoma, mesothelioma).
• Other: idiopathic, AIDS, prolonged physical exercise, nausea, pain
Clinical Presentation of SIADH
• Presentation depends on the severity and rate of hyponatremia development
• Manifests with neurological symptoms from osmotic fluid shifts and brain edema
• Symptoms range from mild → severe, and include: headaches, fatigue, anorexia, nausea, vomiting, altered sensorium, seizure, coma and death
Criteria for Diagnosis
• Hyponatremia (Na+ <135 mEq/L) and hypotonic plasma (osmolality <275 mOsm/kg)
• Inappropriate urine concentration (Urine Osm >100 mOSm/kg) with normal renal function
• Euvolemic Status
• Elevated urinary sodium excretion (with normal salt and water intake)
• Exclude other potential causes of euvolemic hypo-osmolality:
o Hypothyroidism
o Hypocortisolism
Treatment of SIADH
• Treat underlying etiology
• Water restriction to 500-1000 mL/24 h
• Vasopressin (V2) Receptor Antagonists (e.g., Conivaptan, Tonivaptan)
• Hypertonic saline (3%) infusion for severe, symptomatic hyponatremia
Important to limit rate of sodium correction to avoid central pontine myelinolysis
Etiology and Clinical Presentation of SIADH
a. Etiology of SIADH
i. CNS disturbances (e.g., mass lesion, inflammatory diseases, degenerative/ demyelinative diseases, head injury, subarachnoid hemorrhage, hydrocephalus).
ii. Drugs:
o Stimulate AVP release: morphine, nicotine, phenothiazine, tricyclic antidepressants
o Direct renal effects and/or potentiates AVP effects- prostaglandin synthesis inhibitor
o Mixed or uncertain actions: carbamazepine, clofibrate, vincristine, cyclophosphamide, haloperidol.
iii. Pulmonary disease (e.g., infections, mechanical ventilation)
iv. Tumors (e.g., bronchogenic carcinoma, thymoma, leukemia, sarcoma, mesothelioma).
v. Other: idiopathic, AIDS, prolonged physical exercise, nausea, pain
b. Clinical Presentation of SIADH
• Presentation depends on the severity and rate of hyponatremia development
• Manifests with neurological symptoms from osmotic fluid shifts and brain edema
• Symptoms range from mild → severe, and include: headaches, fatigue, anorexia, nausea, vomiting, altered sensorium, seizure, coma and death
Clinical Presentation and Diagnosis of SIADH
a. Clinical Presentation of SIADH
i. Presentation depends on the severity and rate of hyponatremia development
ii. Manifests with neurological symptoms from osmotic fluid shifts and brain edema
iii. Symptoms range from mild → severe, and include: headaches, fatigue, anorexia, nausea, vomiting, altered sensorium, seizure, coma and death
b. Criteria for Diagnosis
1) Hyponatremia (Na+ <135 mEq/L) and hypotonic plasma (osmolality <275 mOsm/kg)
2) Inappropriate urine concentration (Urine Osm >100 mOSm/kg) with normal renal function
3) Euvolemic Status
4) Elevated urinary sodium excretion (with normal salt and water intake)
5) Exclude other potential causes of euvolemic hypo-osmolality:
o Hypothyroidism
o Hypocortisolism
Diagnosis and Treatment of SIADH
a. Criteria for Diagnosis
1) Hyponatremia (Na+ <135 mEq/L) and hypotonic plasma (osmolality <275 mOsm/kg)
2) Inappropriate urine concentration (Urine Osm >100 mOSm/kg) with normal renal function
3) Euvolemic Status
4) Elevated urinary sodium excretion (with normal salt and water intake)
5) Exclude other potential causes of euvolemic hypo-osmolality:
o Hypothyroidism
o Hypocortisolism
b. Treatment of SIADH
i. Treat underlying etiology
ii. Water restriction to 500-1000 mL/24 h
iii. Vasopressin (V2) Receptor Antagonists (e.g., Conivaptan, Tonivaptan)
iv. Hypertonic saline (3%) infusion for severe, symptomatic hyponatremia
Important to limit rate of sodium correction to avoid central pontine myelinolysis
Diabetes insipidus
Introudction
a. Diabetes Insipidus (DI) is a syndrome of hypotonic polyuria from either inadequate AVP secretion (central or neurogenic DI) or inadequate renal response to AVP (nephrogenic DI).
b. The hallmark of DI is the excretion of voluminous amounts of dilute urine.
c. Presentation
i. Polyuria/Nocturia
ii. Polydipsia
iii. Hypernatremia quickly develops if the patient does not have an intact thirst mechanism (e.g., adipsia from hypothalamic injury), or has limited access to water (such as in the elderly).
Etiologies of Diabetes insipidus
- Neurogenic (Central) DI
• Neoplasms-Craniopharyngioma, metastatic pituitary disease (e.g., colon, breast and lung), Rathke’s cleft cysts.
• Idiopathic: +AVP antibodies
• Congenital-autosomal dominant AVP neurophysin gene mutation
• Inflammatory/Infectious/granulomatous pituitary diseases-lymphocytic hypophysitis, meningitis, encephalitis, histiocytosis, sarcoidosis
• Trauma/Vascular event-neurosurgery injury, deceleration injury/traumatic brain injury
• Trauma-neurosurgery injury, deceleration injury
o Classic ‘triphasic’ response: 1) Axonal shock/decreased AVP release (DI),
2) Degenerating neurons/excessive AVP release (SIADH), 3) Depleted AVP stores (permanent DI). Requires loss of >80 of SON/PVN nuclei
o Transient DI and isolated secondary SIADH are more common than permanent DI. - Nephrogenic DI
• Congenital-X-linked recessive AVP V2 receptor gene mutation; autosomal recessive
aquaporin-2 water channel gene mutation
• Drugs-demeclocycline, lithium, cisplatin, amphotericin B
• Electrolyte abnormalities-hypokalemia and hypercalcemia
• Infiltrative kidney diseases-sarcoidosis an
Diagnosis of Diabetes insipidus
a. Confirm polyuria with a 24 hr urine volume collection (normalize to a 24 hr creatinine)
b. Exclude hyperglycemia, renal insufficiency and electrolyte disturbances (K+, Ca2+).
c. Assess plasma osmolality and urine osmolality
d. Water Deprivation Test
e. Pituitary Imaging (for suspected neurogenic DI).
