503 Clin Med - Hypothalamus/Pituitary/Adrenal Disorders

Causes of hypopituitarism? What is most common?

most common = pituitary infarction

tumor or surgical removal

damaged pituitary stalk

decreased hypothalamic releasing hormones

inability to produce hormones (synthesis)

Most common hormonally active pituitary tumor?

prolactinoma

Dwarfism: Etiology (2)

1) Congenital: GH deficiency (Autosomal Recessive)

2) Acquired: GH deficiency due to radiation, compression, or trauma

Dwarfism: Pathophysiology

Congenital

Acquired

Congenital: Mutation in gene that codes for GH receptor -> No GH release to tissues

Acquired: Injury caused by radiation, compression, trauma to pituitary cells --> low GH release

Dwarfism: Epidemiology (2)

Congenital: Newborns

Acquired: 40s-50s (pituitary tumor)

Dwarfism: Clinical Presentation (Congenital)

Metabolic

Skin

Appendages

Body Structure/Bones

Developmental

Newborn:

- Hypoglycemia

- Jaundice

- Small penis

- Reduced birth length

Childhood:

- Short stature

- Delayed bone age

- Delayed puberty

Dwarfism: Clinical Presentation (Acquired)

Body Habitus

Neurological

Systemic

NO HEIGHT INVOLVEMENT

- Central obesity

- Impaired concentration, memory, and depression

- Reduced bone/muscle mass

What would be indicative of a mass or lesion causing dwarfism?

Headache or visual field defects (bitemporal hemaniopia)

Before specific diagnostics tests are performed, how should children with suspected dwarfism be worked up?

growth charts, bone age, CBC (looking for anemia), malnutrition or malabsorption causes

Dwarfism: Dx

IGF-1

GH

MRI

IGF-1: Low

GH: Low

MRI: if suspected hypothalamic or pituitary mass

What is the disadvantage of IGF-1 for diagnosing dwarfism? What test can you do instead?

only kids >5 who are adequately nourish

IGFBP-3 is not affected by nutritional status

Dwarfism: Tx (3)

- SQ recombinant GH immediately post-diagnosis 3x/wk

- Stop all estrogen

- Refer to cardiology (increased cardiovascular morbidity)

Laron Syndrome (Congenital Dwarfism): Etiology/Pathophysiology

Etiology:

Autosomal recessive

Pathophysiology:

Mutation in GH receptor -> GH resistance + IGF deficiency

Laron Syndrome (Dwarfism): Clinical Presentation

Body Structure

Body Habitus

Head

Neurological

- Short stature

- Central obesity

- Large forehead, depressed nasal bridge, small jaw

- Hypoglycemic seizures

Laron Syndrome (Dwarfism): Dx

IGF-1

GH

IGF-1: Low

GH: High

Laron Syndrome (Dwarfism): Tx

Mecasermin (resistant to normal recombinant GH).

Diabetes Insipidus: Etiology

Insufficient ADH release from posterior pituitary -> no water retention -> polyuria

Diabetes Insipidus: Pathophysiology (3)

1) Central/Neurogenic: decreased ADH release

- Primary central: genetic, autoimmunity, induced by meds

- Secondary central: lesion of hypothalamus or pituitary

2) Nephrogenic:

Renal collecting tubules insensitive to ADH due to abnormal V2 receptors (lithium)

3) Dipsogenic:

Excessive fluid intake lowers plasma osmolality below threshold of ADH secretion

Diabetes Insipidus: Clinical Presentation

- Polyuria

- Polydipsia

- Nocturia

- Ice water craving

Diabetes Insipidus: Dx

24hr Urine

Urine Osmolality

Urine Specific Gravity

Serum Sodium

24hr Urine: >2L in 24 hours (should be a lot)

Osmolality: Low (<300)

Specific Gravity: Low (<1.006)

Sodium: Hypernatremia (high plasma osmolality)

Can you rule out diabetes insipidus if there is less than 2L of urine in 24 hours?

Yes.

How do you differentiate central/neurogenic diabetes insipidus from nephrogenic?

Plasma Vasopressin

Neurogenic: Low (<1)

Nephrogenic: Normal/high (>2.5)

How is a water deprivation test done?

- Measure AM weight, serum electrolyte, and urine osmolality

- Collect urine hourly

- Allow dehydration (no PO intake)

- Recheck serum and urine osmolality

- Administer vasopressin

- Re-check serum and urine osmolality after 1 hour

What are the expected results for normal, central/neurogenic DI, and nephrogenic DI in the water deprivation test?

Normal:

- urine osmolality after dehydration > plasma osmolality

- after DDAVP, osmolality does not increase >5%

Neurogenic:

- unable to concentrate urine when dehydrated, remains dilute

- after DDAVP --> urine osmolarity increases

Nephrogenic:

- no response to DDAVP --> urine remains dilute

Diabetes Insipidus: Dx (MRI)

Neurogenic (primary central, not secondary)

Nephrogenic

Dipsogenic

What is normal?

Neurogenic: Absent posterior bright spot

Nephrogenic: Decreased posterior bright spot

Dipsogenic: Posterior pituitary bright spot present (normal)

Diabetes Insipidus: Tx

Mild Cases

Severe Cases (first and second line)

Mild: No treatment, maintain adequate fluid intake

Severe: Desmopressin (HCTZ if adverse rxn)

SIADH: Etiology

Ectopic Secretion of ADH:

Surgery, cancer (SCLC), or medications (desmopressin, anti-depressants)

SIADH: Pathophysiology (3-steps)

High ADH -> collecting ducts more permeable -> high water retention

SIADH is ____volemic, _____tonic, _______natremic condition.

euvolemic, hypotonic, hyponatremic

SIADH: Clinical Presentation

Mild

Moderate

Severe

Based on degree of hyponatremia:

Mild: Asymptomatic

Moderate: Neurological Issues (personality change, weak tendon reflexes, muscle weakness)

Severe: Coma, seizures, hypothermia, cranial nerve palsies

SIADH: Dx

Serum Sodium (mild, moderate, severe)

Mild: >120

Moderate: 105-120

Severe: <105

SIADH: Dx

Plasma Osmolality

Urine Osmolality

Plasma Sodium

Urine Sodium

Plasma Osmolality: Low

Urine Osmolality: High

Urine Sodium: >20

Plasma Sodium: Low

What do furosemide and urea do?

Diuresis.

SIADH: Tx

Mild (1)

Moderate (1)

Severe (2)

Mild: Restrict fluids (800-1000mL/day)

Moderate: Further restrict fluids (500mL/day)

Severe: Hypertonic saline and furosemide/urea (ICU admit)

At what point do know you have corrected severe SIADH and can slow down or stop treatment?

Sodium (125) and CNS involvement ceases.

Why is serum sodium normally corrected no more than 10-12 in 24 hours?

Central pontine demyelination:

- Neurologic injury/paralysis

Acromegaly: Etiology

Pituitary adenoma --> high GH secretion

(rarely ectopic GH or GnRH secretion)

Acromegaly: Pathophysiology

High GH secretion -> high IGF-1 -> hyperglycemia, connective tissue proliferation, bony proliferation, and hyperphosphatemia

Acromegaly: Epidemiology

Adults (sporadic, not familial) - growth plates have closed

Acromegaly: Clinical Presentation

Extremities

Head

Jaw

Voice

Extremities: Enlarged with carpal tunnel and large feet

Head: Enlarged skull/facial features, macroglossia

Jaw: Prominent jaw with enlarged tongue

Voice: Coarse

Acromegaly/Gigantism: Dx

IGF-1

MRI

X-Ray

IGF-1: VERY HIGH (if normal, rule out)

MRI: Likely will show pituitary tumor

X-Ray: Tufting of phalanges, thick heel pad

How would you use a glucose suppression test to rule out acromegaly?

- Give oral glucose syrup and measure GH after 60 minutes

- If GH is suppressed (< 0.4), then acromegaly is excluded

- Diagnose acromegaly if glucose fails to suppress GH

Acromegaly/Gigantism: Tx

Surgical

Transphenoidal Pituitary Surgery:

- Remove adenoma, preserve function

- Give corticosteroids over 1 week

What follows pituitary surgery if complete remission is not achieved? What must be done for life following this surgery?

Stereotactic Radiosurgery:

- Lifelong ASA because of small vessel strokes

Acromegaly/Gigantism: Tx

Pharmacological (3)

For incomplete biochemical remission post-operatively:

- Cabergoline (dopamine agonist)

- Octreotide/lanreotide (somatostatin analog)

- Pegvisomant (GH receptor antagonist)

Gigantism: Etiology

Pituitary macroadenoma -> high GH secretion

Gigantism: Pathophysiology

High GH -> INCREASED LONG BONE LENGTH

Gigantism: Epidemiology

CHILDREN:

- Epiphyseal plates have NOT closed

Gigantism: Clinical Presentation

Body Structure

Extremities

Development

- Very tall stature

- Large hands and feet

- Hypogonadism, delayed puberty

Medical complications of acromegaly?

HTN, cardiomegaly (increased mortality from CVD), glucose intolerance/DM, hypopituitarism (after surgery), obstructive sleep apnea

Pituitary Adenoma: Etiology/Pathophysiology

Etiology:

Benign neoplasm on gland

Pathophysiology:

Autonomous and excess hormone secretion without signaling from the hypothalamus -> no negative feedback

Pituitary Adenoma: Clinical Presentation (Mass Effects)

- Headache

- Vision loss (bitemporal hemianopia d/t compression)

- Diplopia

- Ptosis

- Ophthalmoplegia

- Decreased facial sensation (d/t CN compression)

Pituitary Adenoma: Clinical Presentation (Prolactinoma)

- Amenorrhea

- Galactorrhea

- Infertility

- Decreased libido

Pituitary Adenoma: Dx (by tumor type)

Prolactinoma

TSH

ACTH

Prolactinoma: High prolactin (check in morning)

TSH: elevated T4 and TSH

ACTH: 24 hour urine free cortisol, dexamethasone suppression test, plasma ACTH levels

Pituitary Adenoma: Dx

Imaging

MRI: With gadolinium before/after and specific cuts

CT: No contrast, coronal plane

Pituitary Adenoma: Tx

Surgical

Transsphenoidal resection (w/ radiation as an adjunct)

- Follow with medical hormone replacements if needed

Pituitary Adenoma: Tx (prolactinoma)

Dopamine Agonist:

- Cabergoline

- Bromocriptine

Addison's Disease: Etiology (MCC)

Autoimmune destruction of adrenal cortex.

Addison's Disease: Etiology (5 Less Common)

1) Infection (TB)

2) Adrenal hemorrhage (surgery or trauma)

3) Drug-Induced (mitotane/abiraterone)

4) Adrenoleukodystrophy (X-linked, males mainly)

5) Congenital (autosomal recessive, 21-hydroxylase deficiency)

Addison's Disease: Pathophysiology

Low corticosteroid and mineralocorticoid synthesis -> low cortisol

Will ACTH be elevated or decreased in Addison's disease? Why?

Is Addison's primary or secondary adrenal insufficiency?

ELEVATED

- Hypothalamus and pituitary work, but adrenal gland does not

- Primary insufficiency

Secondary Adrenal Insufficiency:

Etiology

MCC

What hormones are effected?

Etiology: anterior pituitary gland not making ACTH

MCC: exogenous steroid use (negative feedback on ACTH)

Hormone: only cortisol, adrenal still functioning and making mineralocorticoids

Addison's Disease: Clinical Presentation (4 main, 2 general)

Gradual onset over years:

- (Orthostatic) Hypotension

- Anorexia

- Skin hyperpigmentation

- Salt craving

- N/V/D, abd pain

- Cerebral edema --> gait disturbances

Addison's Disease: Dx

ACTH

Plasma Cortisol

Cosyntropin Stimulation

Imaging

BMP

ACTH: High

Plasma Cortisol: Low (especially morning)

Cosyntropin Stimulation: No rise in cortisol - diagnostic

Imaging: CT scan (if not autoimmune)

BMP: hyponatremia, hyperkalemia

How would the CT scan be different if Addison's disease was caused by TB instead of autoimmune? When is imaging more useful?

Autoimmune = small, non-calcified glands --> appear normal on CT (not useful)

TB or granulomatous = enlarged and calcified --> more useful diagnostic

Addison's Disease: Tx (2)

Corticosteroid Replacement:

- Hydrocortisone or prednisone

Mineralcorticoid Replacement:

- Fludrocortisone acetate

When should steroid replacement doses be increased in patient with Addison's?

sick, surgery, infection, trauma

summer time or extreme exercise (lose salt in sweat)

Congenital Adrenal Hyperplasia: Etiology/Pathophysiology

Etiology:

Autosomal recessive disorder -> no enzyme for cortisol synthesis (21-hydroxylase)

Pathophysiology:

Low cortisol + high ACTH = adrenal hyperplasia --> overproduction of other adrenal cortex products: androgens

Adrenal hyperplasia results in the overproduction of what?

Mineralcorticoids or androgens.

Congenital Adrenal Hyperplasia: Clinical Presentation

Female

Male/Female

Female: Virilization (due to high androgens)

Male/Female: Salt wasting

Congenital Adrenal Hyperplasia: Dx

ACTH

Serum Cortisol

ACTH Stimulation

17-Ketosteroid

ACTH: High

Serum Cortisol: Low

ACTH Stimulation: Unresponsive (cannot make cortisol)

17-Ketosteroid: High

Congenital Adrenal Hyperplasia: Tx

None.

Adrenal Crisis: Etiology (3)

Medical Emergency:

- Stressors (infection, surgery, stress)

- Medications that impair adrenal hormone synthesis (ketoconazole, mitotane)

- Steroid withdrawal

Adrenal Crisis: Pathophysiology

High corticosteroid demand with no increased production.

What specific history will you look for if an adrenal crisis is occurring in patient?

1) Addison's Disease

2) Adrenal Hyperplasia

Adrenal Crisis: Clinical Presentation

- Refractory hypotension (still hypotensive after fluids and pressors)

- Severe abdominal pain

- Shock

- Disorientation

- Dehydration

Adrenal Crisis: Dx

IDENTIFY STRESSOR/INFECTION/CAUSE:

- Blood

- Sputum

- Urine/blood cultures

Adrenal Crisis: Tx (2 main, 1 other)

- Hypotension: IV fluids (electrolytes and dextrose)

- Steroid Replacement: IV hydrocortisone

- Antibiotics

Cushing's Syndrome: Etiology

ACTH-Independent (2)

ACTH-Dependent (2)

Excess cortisol production:

- Adrenal Cortex Tumor: (primary, ACTH-independent)

- Iatrogenic, ectopic use of corticosteroids (ACTH-independent)

- Pituitary Adenoma: Cushing Disease (secondary, ACTH-dependent)

- Ectopic Tumor (secondary, ACTH-dependent)

Cushing's Syndrome: Pathophysiology (4-steps)

Catabolic Effects of Excess Cortisol:

- Muscle wasting

- Increased serum calcium (bone resorption)

- Loss of collagen/thinning of skin

- Melanocyte stimulation

Cushing's Syndrome: Clinical Presentation

- Purple Striae: Abdomen, thighs, breasts

- Buffalo hump

- Central obesity

- Moon face (with redness)

- HTN

- Osteoporosis

- ED, ameorrhea

How do you differentiate an ACTH-independant and ACTH-dependent cause of Cushing's disease in terms of ACTH and cortisol? Which is primary/secondary?

ACTH-Independant: ACTH low, Cortisol high (primary)

ACTH-Dependant: ACTH high, Cortisol high (secondary)

Cushing's Syndrome: Dx

Serum cortisol

Dexamethasone Suppression

24 Urine Free Cortisol

Cortisol: High (elevated @ midnight = diagnostic, loss of diurnal variation)

Dexamethosone Suppression: abnormal, cortisol >1.8

Urinary Free Cortisol: >100

Cushing's Disease: Dx (Imaging)

ACTH-Independant (primary)

ACTH-Dependant (secondary)

ACTH-Independant: CT of adrenals --> identify masses/lesion

ACTH-Dependant: MRI of pituitary

What should you do if MRI of pituitary shows normal or tiny irregularity in ACTH-dependent Cushing's?

First: selective catheterization of interior petrosal sinus veins draining pituitary --> measure ACTH levels compared to peripheral vasculature

Then: if sinus ACTH levels > 2x peripheral levels, indicative of pituitary Cushing's

If not: search for ectopic source of ACTH with CT scan of chest, abdomen, thymus, pancreas, adrenals

Cushing's Disease: Tx (3 surgical)

ACTH-Dependant (Pituitary):

- Transphenoidal resection of adenoma

ACTH-Dependant (Ectopic):

- Resect tumor or do laparoscopic bilateral adrenalectomy if it cannot be located

ACTH-Independant:

- Laparoscopic bilateral adrenalectomy

Cushing's syndrome: Tx

Pharmacologic (post-adrenal resection)

Pharmacologic (post-pituitary resection)

Adrenal resection: mitotane if suspected mets, hydrocortisone replacement if cortisol withdrawal

Pituitary: replace glucocorticoids

Cushing's Syndrome: Tx (no surgery)

Pasireotide, ketoconazole

Cushing's Syndrome: prognosis and complications

cognitive or psychiatric impairment

compression fractures from osteoporosis

HTN

**serious morbidity if untreated

Adrenal Cortex Neoplasm: Etiology

Somatic mutation in TP53 gene (tumor supressor).

Adrenal Cortex Neoplasm: Clinical Presentation

- Likely will not have S/S of excess corticosteroids

- Liver/lung metasteses common

Adrenal Cortex Neoplasm: Dx

Biopsies

Imaging (3)

Core Biopsy: Staging (fine needle = not good)

CT: C/A/P for metasteses

MRI: Offers better look

PET: Identify malignancy using FDG

Adrenal Cortex Neoplasm: Tx and prognosis

Surgery with chemotherapy

Highly malignant, median 15 month survival with treatment

Pheochromocytoma: Etiology

MEN2 mutation (autosomal dominant) -> tumor of adrenal medulla (Chromaffin cells)

Pheochromocytoma: Pathophysiology

Adrenal medulla hyperfunction -> excess catecolamine secretion

Pheochromocytoma: Clinical Presentation

- Episodic hypertension

- Palpitations, headache, perfuse sweating (triad)

If there is an episodic release of catecholamines in a patient with a pheochromocytoma, what will you likely see in the clinical presentation? What 4 things would cause these episodes?

Surgery/Position Change/Pregnancy/Medication:

- Anxiousness

- Pallor

- Palpitations

- Tachycardia

Pheochromocytoma: Dx (blood/urine)

Plasma/Urine Catecholamines/Metanephrines

Plasma fractioned free metanephrines

24hr urine fractioned free metanephrines

All high (plasma free, fractioned metanephrines are most sensitive).

Pheochromocytoma: Dx

Imaging (3)

CT: Non-contrast of abdomen to localize tumor --> add contrast if mass found

MRI: No gadolinium (preferred for pregnancy/childhood)

PET: Complements CT or MRI

Pheochromocytoma: Tx

Pharmacologic

- Alpha Blockers: 1st line

- Ca Channel Blocker: Added to alpha blockers

- Beta Blockers: Manage HTN before surgery (required after using alpha and calcium blockers)