Lecture 14: Adrenal Disorders Part 1 Flashcards
Where are adrenal glands located?
Atop the kidneys
What makes up the adrenal cortex layers?
Zona Glomerulosa
Zona Fasciculata
Zona Reticulairs
Superficial to deep: GFR
What are the 3 layers of the adrenal gland?
Capsule
Cortex
Medulla
Superficial to deep
What is made in the Zona Glomerulosa?
Mineralcorticoids (Aldosterone)
Go Find Rex, Make Good Sex
What are the 4 functions of aldosterone?
- Sodium Retention
- Water Retention
- Potassium Excretion
- Increases BP and blood volume
What happens to renin in aldosterone deficiency and excess?
Aldosterone def: Increased renin
Aldosterone excess: Decreased renin
What is secreted in the Zona Fasciculata?
Glucocorticoids (Cortisol)
Go Find Rex, Make Good Sex
What are the 3 functions of cortisol?
- Gluconeogenesis in the liver
- Immune system suppression
- Inflammation suppression
When is our serum cortisol highest and lowest?
Highest in the morning.
Lowest at night.
What overall mechanism controls cortisol release?
HPA Axis
Hypothalamus-Pituitary-Adrenal
What kind of feedback is cortisol controlled by?
Negative feedback
What does the Zona Reticularis secrete?
Gonadocorticoids (DHEA)
RGD
What does DHEA do?
Controls/stimulates the development of sexual characteristics.
What does the adrenal medulla secrete?
EPI
NE
MEN
Chromaffin cells make up the adrenal medulla
What would cause a chronic increase in ACTH and CRH levels?
Adrenal gland destruction.
Lack of cortisol = lack of negative feedback to the hypothalamus
What does ACTH stimulate adrenals to do? What does it need?
Stimulates steroid synthesis.
It requires cholesterol to synthesize steroid hormones.
What is the precursor to all steroid hormones besides cholesterol?
Pregnenolone.
What does a 21A-2 deficiency result in?
Cortisol deficiency
Aldosterone deficiency
Androgen excess
What is unique about primary adrenal insufficiency vs the other 2 types?
It includes aldosterone insufficiency as well.
What is the MCC of addison’s disease and what specific CYP deficiency is it?
Autoimmune (80%)
CYP21A2 (21-hydroxylase) MC autoantigen
What does a CYP11A1 deficiency result in? CYP17A1?
11A1: Excess Cholesterol, deficient in everything else.
17A1: Excess Aldosterone, deficient in everything else.
11A1 is #1, because cholesterol is the precusor steroid.
When does addison’s typically present? Why?
10-40 y/o, because adrenal function decreases over time into insufficiency.
What is adrenoleukodystrophy?
Genetic disorder, resulting in accumulation of very long FA chains in adrenal cortex, inhibiting ACTH effects.
What is congenital adrenal insufficiency/hyperplasia?
Genetic mutation or absence of adrenal cortex.
Although rare to cause addison’s, what is the MC infection that can cause it?
TB
What are the 4 etiologies that result in chronic addison’s?
- Autoimmune (80%)
- Adrenoleukodystrophy
- Congenital adrenal insufficiency/hyperplasia
- Infection
In what 4 ways can drugs induce chronic addison’s?
- Inhibiting cortisol synthesis
- Accelerate metabolism of cortisol
- Adrenocorticolytic drug that inhibit cortisol synthesis
- Suppressing CRH or ACTH release
What drug is used to treat adrenocortical carcinoma and can result in addison’s?
Mitotane
Why does using glucocorticoids suppress CRH and ACTH?
Our body thinks we are making cortisol, so it sends negative feedback to the hypothalamus and pituitary.
This is why we should taper steroid use down if > 10d.
What are the two etiologies of acute addison’s?
- Adrenal hemorrhage
- Adrenal addisonian crisis
What causes adrenal hemorrhage?
- Sepsis
- HIT
- Anticoag
- APS
- Trauma
- Surgery
What is the pathophysiology behind an addisonian crisis?
Insufficient cortisol.
How would an addisonian crisis present?
- Profound fatigue
- Dehydration
- Vascular collapse (decreased BP)
- Renal shut down
- Hyponatremia
- Hyperkalemia
Results of aldosterone and cortisol deficiency.
How does someone with addison’s generally present?
- Bronze pigmentation of skin
- Hypogylcemia
- Postural hypotension
- Weight loss
- Weakness
- GI disturbances
- Changes in distribution of body hair
Why is hyperpigmentation common in addison’s?
ACTH has affinity for melanin. If the adrenal gland is not functioning, the ACTH binds to melaninotic receptors instead.
It is often the first and only symptom!
Why does vitiligo/hypopigmentation occur in addison’s?
Autoimmune destruction of dermal melanocytes
Not related to ACTH affinity for melaninotic receptors.
10% of pts
What are the the typical first symptoms of chronic addison’s?
- Anorexia
- Weight loss
- Fatigue
- Decreased stamina
Why do people with addison’s present with lymph tissue hyperplasia?
Increased immune system responses since lack of modulation.
Deficiency in which CYP would cause excess pubic/axillary hair growth in women?
21A2, excess testosterone
Why do people in addison’s commonly complain of generalized pain?
Inflammation everywhere, since cortisol normally modulates it.
How would someone with addison’s present in terms of psychiatric symptoms?
- Anxious
- Irritable
- Depressed
Which CYP deficiency results in amenorrhea in addison’s?
21A2 (excess androgens)
What generally differentiates adrenal crisis from adrenal hemorrhage?
Crisis involves a severe febrile state of > 105F.
What is a common DDx for adrenal crisis?
Abdominal complaints like appendicitis.
Adrenal crisis presents with acute abdominal symptoms, like pain, N/V.
What are the two reasons people with adrenal crisis get hypotensive?
- Lack of aldosterone
- Vomiting
What would I expect in a CBC and CMP for addison’s?
CBC: eosinophilia, lymphocytosis
CMP: hypoN, hyperK, elevated BUN/Cr, low BG.
HyperK can be masked by vomiting.
What is the overall concern with treating an addisonian crisis?
Finding the underlying cause. Order cultures.
What lab values of plasma cortisol and ACTH would suggest addison’s?
Low cortisol + high ACTH.
8am Cortisol < 3mcg + elevated ACTH is usually diagnostic.
When does a random cortisol rule out addison’s?
> 25 mcg/dL
How do I perform a rapid ACTH stimulation test? What finding confirms addison’s?
Step 1: Measure serum cortisol
Step 2: Administer synthetic ACTH 0.25mg IM
Step 3: Measure serum cortisol 45 mins post IM.
Positive Finding: Rise in serum cortisol < 20 mcg.
Only used when serum cortisol and ACTH are non-diagnostic.
Use of what drug would give false readings on a rapid ACTH stimulation test?
Any exogenous steroid use.
If on dexamethsasone, must be switched to hydrocortisone prior to test.
When do we order a plasma renin test? What kind of findings do I expect in addison’s?
Monitor treatment.
Plasma renin is typically increased in addison’s, which indicates the need for mineralcorticoid replacement.
Non-diagnostic test.
What kind of CT abdomen finding suggests autoimmune addison’s?
Small without calcifications on adrenal gland.
When is a CXR ordered to evaluate addison’s?
Suspected TB etiology or pneumonia
What is the overall goal in treating addison’s?
Baseline therapy using oral glucocorticoids to replace the lack of endogenous cortisol production.
Lifelong treatment
How do we dose hydrocortisone for addison’s?
15-30mg daily.
2/3 morning, 1/3 night (mimicking natural cortisol levels)
Alternatives: prednisone or methylprednisolone
What is glucocorticoid stress therapy? Why do we do it?
Increasing steroid dose in anticipation of incoming stress.
Designed to prevent adrenal crisis.
When we give glucocorticoid stress therapy, what is the main secondary concern?
Infection. Increasing steroid intake means a weakened immune system.
In what situations do we add mineralcorticoid therapy to an addison’s patient? What is the DOC?
If they are on LOW doses of hydrocortisone, they probably need supplementation.
Fludrocortisone 0.05-0.3mg.
Monitor with PRA. High PRA = need more fludrocortisone.
If a patient presents with suspected adrenal crisis with no prior Hx of addison’s, what are the first steps for treating them?
Order Serum cortisol + ACTH.
Initiate treatment, do not wait for results.
What is the treatment protocol for adrenal crisis?
1: Loading dose of IV hydrocortisone
2: Continuousn IV hydrocortisone
3: Switch to oral hydrocortisone (if PO tolerable)
4: Broad spectrum ABX
5: Treat any electrolyte/glucose/volume abnormalities.
What electrolyte abnormalities are common in Addison’s?
HyperK is likely
HypoN is likely
What are we monitoring for in addison’s besides cortisol levels?
- No development of Cushing’s
- WBC diff and electrolytes returning to normal
- DEXA scan for osteoporosis
What are some patient education/recommendations for addison’s?
- Medical alert bracelet
- All infections must be treated immediately.
- Injectable hydrocortisone
What is the MCC of Cushing’s Syndrome?
Iatrogenic (99%)
Excessive corticosteroids.
What is the MCC of Cushing’s Disease?
Benign anterior pituitary adenoma
More common in females
What is Cushing syndrome also known as etiology-wise?
ACTH independent hypercortisolism
What is Cushing Disease also known as etiology-wise?
ACTH dependent hypercortisolism
Disease for dependent
What are the 4 etiologies of ACTH dependent hypercortisolism?
- Pituitary hypersecretion of ACTH
- Ectopic secretion of ACTH
- Ectopic secretion of CRH
- Iatrogenic/factitious Cushing’s syndrome
What is often the first & long lasting symptom of Cushing’s?
- Fatigue
- Reduced physical endurance
What are the 4 main locations for fat deposition in Cushing’s?
- Central obesity
- Moon face
- Supraclavicular fat pads
- Buffalo hump (back of the neck)
What is a key difference between an obese person and an obese person with Cushing’s?
Cushing’s typically have thin extremities.
What is the typical clinical presentation symptoms of someone with Cushing’s besides the weight gain?
- Skin atrophy with large, purple striae
- Easy bruisability
- Proximal muscle weakness
- Immune system suppression (frequent infections)
- Females only: menstrual irregularities
Proximal muscle weakness often presents as difficulty carrying things overhead.
Difficulty sitting up from seated position
What are some of the common symptoms associated with increased ACTH?
- Hyperpigmentation
- Elevated BP
- Hirsutism, male pattern hair loss
What would I expect to see on a CBC and CMP of a Cushing’s pt?
CBC: leukocytosis with neutrophilia but lymphocytopenia and decreased eosinophils
CMP: elevated BG, possible hyperN, hypoK
What are the 3 diagnostic goals for Cushing’s?
Determine if its exogenous/endogenous.
Establishing the presence of hypercortisolism.
Determine the underlying cause.
Which Cushing’s type requires a work-up?
Endogenous/disease only.
How do we establish the presence of hypercortisolism?
2 out 3 first line tests must be positive.
* Dexamethasone suppression test
* 24 Urine Free cortisol (2 separate measurements)
* Late night salivary cortisol (2 separate measurements)
How do I perform a dexamethasone suppression test? What is a positive finding?
- Take dexamethasone 1mg PO at 11pm.
- Serum cortisol at 8AM.
- <5mcg likely rules OUT Cushing’s syndrome
What can cause a false-negative or false-positive in a dexamethasone suppression test?
False-Neg: 8% of cushing’s disease have normal cortisol suppression, antiseizure drugs, rifampin, and estrogens.
False-Pos: 20-30%, psychiatric disorders, stress
How do I perform a 24 Urine Free Cortisol? What is a positive finding?
- After first morning void, begin collection.
- Document time of first morning void.
- Collect all urine, including next morning void.
Positive = 3x UNL on BOTH occasions.
How do I perform a late night salivary cortisol? What is considered positive?
- Saturate a swab in your mouth for 90 secs between 11pm and midnight.
- Both readings must be > 100ng to be positive.
What can interfere with a late night salivary cortisol test?
- Steroid use
- Brushing teeth
- Oral intake of anything
- Inadequate collection
- Night shift people
- Pregnancy
- anticonvulsants
- stress
What do I do if both of my Cushing’s tests are negative? What if only 1 is positive? What if both are positive?
2 Negatives = no further workup, but if you are very suspicious still, send to endo.
1 Negative (24UFC or saliva), 1 positive = repeat test at random intervals and consider a cyclic cushing disease. Refer to endo.
2 positive = refer to endo
Always refer to endo :)
How do we determine the cause of hypercortisolism?
Serum ACTH.
How do we order a serum ACTH and interpret it?
6-9AM collection in an EDTA tube stored at -20C until assay.
<20 pg = adrenal CT
> 20 pg = Pituitary MRI
Low ACTH + high cortisol suggests adrenal tumor
High ACTH + high cortisol suggests a source making ACTH.
What are the red flags for a malignant carcinoma of the adrenal gland?
- > 4cm
- Growth of nodule (if previous CT)
- Density > 10 Hounsfield Units
What MRI results indicate treatment for a pituitary adenoma? What indicates more testing?
Lesion > 5mm = treatment.
Lesion < 5mm = Inferior petrosal sinus sampling. (elevated ACTH = pituitary)
If sampling is negative, CT chest/abd.
If CT neg, order whole body PET.
How do we manage Exogenous Cushing’s syndrome?
Slowly titrate down exogenous glucocorticoid/ACTH therapy.
Rapid withdrawal can cause adrenal insufficiency
What are the two treatment options for adrenal or pituitary adenomas?
Surgical removal (requires lifelong glucocorticoid replacement therapy)
Pituitary radiation
If my patient is waiting for surgery/has a CI for an adrenal adenoma, what can we do for them?
11-beta-hydroxylase inhibitor: blocking cortisol steroidogenesis (metyrapone and osilodrostat)
Ketoconazole: inhibits early steps of steroidogenesis
If my patient is waiting for surgery for their pituitary tumor, what drug can they take?
Pasireotide: somatostatin analog that inhibits ACTH secretion.
PasieroTide = Pituitary Tumor
What are the DOCs for mineralcorticoid hypertension?
Spironolactone or eplerenone.
Second: ACEI
What is the DOC for hyperandrogenism in women?
Flutamide, which inhibits androgen uptake.
Female
What are some common cortisol-related complications to monitor?
- Osteoporosis
- CVD
- Psychiatric disorders
- DM
- HypoK
- Muscle weakness
- infections
- Sleep apnea
