Adrenal disease –Real and Unreal

J R Minkoff MD, FACPEndocrinology

Clinical Professor of Family and Community Medicine

UCSF

Objectives

Participants will:

1) understand the signs, symptoms, diagnosis and treatment of disorders of the adrenal glands and hormones

2) know how to evaluate and follow-up adrenal incidentalomas

3) feel comfortable discussing adrenal insufficiency and "adrenal fatigue"

Real

• Primary and Secondary:Cortisol deficiency or excessAldosterone deficiency or excess

• Masses• Carcinoma• Adenomas

• Inert• Biochemically active

• Enzyme defects

Adrenal glands – stress hormones and weak androgens

Just superior to the kidneys– Retroperitoneal; quite vascular

• Cortex – steroid hormones– Zona fasiculata: cortisol enhances hepatic

glucose release, promotes protein breakdown and modulates immunity

– Zona Glomerulosa: aldosterone increases sodium retention and potassium excretion

• Both essential for life and must be replaced if insufficiency is diagnosed

CORTISOL AND ALDOSTERONE

• No other essential hormones secreted by adrenals (not DHEA, weak androgens or anything else)

• Medulla: epinephrine and norepinephrine – also secreted by sympathetic ganglia

– No need (or way) to replace these hormones

CRF

ACTH

PITUITARY

Adrenal coretx

Normal Function: Hypothalamic-Pituitary-Adrenal Axis is Centrally Determined

HYPOTHALAMUS

Cortisol

( - )Classic negative feedback loop

cortisol

Cortisol ( - )

Intranuclear receptor

stress

DHEA-s

Endocrine 101- Work Up

• Too High – can you suppress it? – Lower it

• Too Low – can you stimulate it?– Raise it

• Bumps – secreting something?– Benign?– Malignant?

• Enzyme defects – multiple characteristics.

Adrenal function - control

• Cortex

- cortisol – stimulated by ACTH

- mineralocorticoids – stimulated by ACTH and renin/angiotensin axis.

• Medulla - sympathetic nervous system

- epinephrine

- norepinephrine

Labs

Electrolytes

Serum CortisolAldosterone

Plasma ACTHPlasma renin activity

Adrenal InsufficiencyAddison's: primary adrenal failureHistory: Fatigue, weight loss, dizziness, polyuria -

dipsia, salt-craving, abdominal pain, diarrhea.

Indolent onsetAssociated autoimmune diseases

Sudden onset – infection, hemorrhageSigns: Hypotension. Dehydration.

Hyperpigmentation with 1o adrenal failureLabs: BUN > Cr, ↓ Na+, ↑ K+, hypoglycemia,

hypercalcemia, eosinophilia

KR

• 20 y/o male type 1 DM for years – poor control– Several months hypoglycemic episodes– Weight loss, Nausea, vomiting, diarrhea– Salt craving

• Hypotension• Darkening skin• TSH and T4 OK on T4 replacement

LabsBUN H 56 mg/dL Chloride L 93 mEq/L CO2 L 20 mEq/L Creatinine H 1.86 mg/dL Glucose Random H 264 mg/dL Potassium C 7.9 mEq/L Sodium L 121 mEq/L Anion Gap 8 mEq/L

What else should you draw?How would you treat?What else could he have?

Gingival hyperpigmentation

Hyperpigmentation nails and knuckles

Differential diagnosis

Primary adrenal failure

• Autoimmune

• Infectious– TB

– Fungal

– Meningococcal

• Metastatic disease

• Hemorrhagic

• Retroperitoneal

• Medications

Secondary hypoadrenalism

• Pituitary– Tumor

– Hemochromatosis

– Sarcoidosis

– Metastatic disease

• Suppressive doses of corticosteroids

CRF

ACTH

PITUITARY

Adrenals

Normal Function : Hypothalamic-Pituitary-Adrenal Axis is Centrally Determined

HYPOTHALAMUS

Cortisol

( - )Classic negative feedback loop

cortisol

Cortisol ( - )

Intranuclear receptor

stress

If not previously diagnosed

obtain serum for 0' cortisol and ACTH level (special handling requiredand if you suspect addisonian crisis (hypotension, hyponatremia, etc.) - give fluids and Dexamethasone 4mg IVdo an ACTH (Cortrosyn) stimulation test:

– After 0' cortisol give 1 amp (.25mg) Cortrosyn IV and obtain a 30' and 60' cortisol. The Dex will save the patient's life if they were truly addisonian and will not cross-react with the cortisol assay.

– Once the 60' level is drawn may give hydrocortisone 100mg IV q 8 h. Continue until oral meds can be used or labs prove this is not adrenal crisis

Labs in Adrenal InsufficiencyPrimary adrenal failure

BUN > Cr, ↓ Na+, ↑ K+,hypoglycemia, hypercalcemia, eosinophilia

Cortisol is low and does not stimulateACTH is high

Secondary adrenal failure labs may be normal or may see low Na+, because mineralocorticoids may still respond to the Renin Angiotensin System.

Cortisol is low and ACTH is low due to pituitary damage or suppression from prior steroids

What to look forLook for precipitating causes• Primary adrenal failure

– idiopathic, autoimmune, hemorrhagic, TB– Metastatic

• Secondary – pituitary/hypothalamic disease– Steroid withdrawal

Rx: Crystalloid - lots Hydrocortisone 100mg IV q8hFlorinef 0.1mg p.o. daily

Rx for adrenal insufficiency

Emergency

Hydrocortisone 100 mg q 8 h IV, fluids

Long-term

• HC 10/5 up to 20/10 mg per day

• Monitor for cushingoid features

• Assess fluid status

• Medi-alert and instructions for emergencies.

• IM HC ?

Questions?

Cortisol excess (Cushing’s syndrome)May present with any of these signs or symptoms•Symptoms: fatigue, depression, weakness (proximal), easy bruisability

• Signs: HTN– Facies: ‘moon’, plethora. – striae (pigmented if due to ACTH excess) – supraclavicular and nuchal fat pads.– Central obesity

•Complications: HTN, DM, glaucoma, cataracts, osteoporotic fractures, decreased immune function with infection. These may be presenting symptoms

Testing to rule out Cushing’s

For suspected pituitary adenoma, ectopic or adrenal cause:• AM cortisol elevated (> 1.8) after 1 mg dexamethasone @hs

or• Elevated urine cortisol on 24 h collection for cortisol and

creatinine or• or Midnight salivary cortisolFurther work-up under endocrinology guidance – you will likely do

several different tests before definitive treatment

Cushingoid facies

Treatment

• Pituitary: – petrosal sinus sampling and

– neurosurgeon with extensive experience with cushing’s

• Adrenal: if adenoma or ACC, surgery in experienced hands

• BEWARE of post surgical hypoadrenalism as prior excess steroid must be slowly tapered

For secondary cushing’s: exogenous steroids suppress hypothalamic-pituitary-adrenal axis

Despite signs and stigmata of cushing’s, patient may have adrenal insufficiency symptoms.

This and a hx of steroid intake orally, parenterally or even high dose inhaled steroids suggest the diagnosis.•Low urine cortisol on 24 h collection for cortisol and creatinine•Low cortisol and ACTH•Low Midnight salivary cortisol

Replace and taper

• you must slowly taper –severe stress or illness can prompt adrenal crisis

• decrease dose about 5-10% per week

• Ask about steroid withdrawal symptoms– Weakness, dizziness, achiness

• Look for adrenal insufficiency– Weakness, dizziness

– Orthostatic hypotension

– Rare hyponatremia or hyperkalemia

• May go back up on dose and taper again

Case 1- BJK 66 y/o woman with DM, HTN, AsthmaAdmitted with fatigue - Na+ 121Meds: Lovastatin 20 mg daily.

Asmanex inhaler 220 mcg, two puffs b.i.d. Serevent, one puff b.i.d. Singulair 10 mg p.o. q.h.s. Diltia XT 180 mg b.i.d. Warfarin per protocol. Lisinopril 20 mg b.i.d. Clonidine 0.1 mg b.i.d. Omeprazole 20 mg daily. Triamterene/hydrochlorothiazide 37.5/25, 1/2 tab daily. Pro-Air HFA 90 mcg inhaler, two puffs q 6 hours

Case 1Cortisol Na+

7/11 9.4 1217/12 24h UFC 10 (normal is 20-50)7/13 0’ ACTH 10 6 126

30’ 18.260’ 13.7

8/24 FSH 54 122

0’ <130’ 4.960’ 5.8

• Had 2 other 5 day courses of prednisone over the year (Spring). None for several weeks prior to 8/24 stim test.

What’s happening?

• ACTH is low and cortisol is low

• urinary cortisol is low

• She has signs and symptoms of BOTH adrenal insufficiency and cortisol excess

Oral, injectable, topical, inhaled steroids:

25% of patients getting short term high dose or medium term steroids have HPA suppression.

5-10% become suppressed long term

Treat the underlying disorder

• SLOWLY taper steroid dose– 5-10% per week

– If symptoms recur, steroid withdrawal sxs, go back up and go more slowly

– Can try alternate day tapering

– May take months to YEARS to get off steroids

• At risk for adrenal crisis during taper and for about 1 year after discontinuing steroids

Congenital adrenal hyperplasia

• Neonates – hypotension, salt losing

Ambiguous genitalia

• Adult women – hirsutism, virilization, acne, oligomenorrhea. – Work up women with PCOS

DHEA-s

Pheochromocytoma

• 90% due to solitary medullary mass

• Symptoms and signs of adrenergic excess

• Pallor, dizziness, sense of impending doom, orthostatic hypotension/tachycardia

• Palpitations, weight loss

• An uncommon cause of secondary hypertension

• 24 h urine for catecholamines and metanephrines, cr

Pheochromocytoma

Do NOT biopsy adrenal mass prior to ruling out pheo.

Rarely bilateral, metastatic or paraganglioma

Pheochromocytoma

Once confirmed treat with alpha blockade, eventually beta blockade and adrenalectomy with

experienced surgeon andanesthesiologist

Nodules

• 10% prevalence in autopsy studies

• Most are incidentally noted on CT of chest or abdomen

• So what?

r/o hypersecretion:

cortisol

aldosterone

catecholamines - DO NOT BIOPSY without ruling out pheo

r/o cancer

1.5 cm

Nodules

• IF low attenuation, with washout, likely benign

• IF less than 4 cm do biochemistry and watch

• IF > 4 cm do biochemistry and remove.

Incidental Nodules – workup• r/o Pheochromocytoma – 24 h urine for

catecholes and metanephrines

– If elevated repeat with plasma metanephrines/normetanephrines

• Cortisol – 1 mg dex suppression or 24 h urine for cortisol and cr.

• DHEA-s (may be high in ACC, low if nodule is causing subclincial cushing’s)

• ↓ K+

• work-up spontaneous low K w or w/o hypertension.• replace and check Plasma Renin Activity,

Aldosterone, urinary Na+, K+

Benign nodules

• CT findings on dedicated adrenal scan– Smooth, less than 4 cm

– Lipid rich

– Rapid washout

– No growth on CT 6-12 months (< 1 cm)

• Follow benign adrenal nodules for 3 years with 1 mg overnight dex suppression

The other adrenal hormones

• Weak androgens– DHEAs 90% of adrenal DHEA is sulfated

• Measure in hirsute women

• may be elevated with PCOS

• 3-β-ol deficiency

– DHEA - Darling of alternative medicine – of no significant benefit*

– 17OH progesterone – 21 hydroxylase deficiency

* Although may also replace in adrenal insufficiency

DHEA-s

The other adrenal hormones

• Mineralocorticoids– Maintain BP and sodium/potassium balance

– aldosterone-secreting tumor may cause resistant hypertension and spontaneously low K+

– DOC (deoxycorticosterone) may cause hypertension – rare tumor

DHEA-s

Hyperaldosteronism

Small benign adenoma

Multinodular hyperplasia

1° hyperaldosteronism – may treat with aldactone

Signs:

Spontaneous hypokalemia, hypertension.

Labs:

High aldosterone – low Plasma Renin Activity

Consider bilateral adrenal vein sampling

Laproscopic adrenalectomy

Unreal

• Chronic Fatigue Syndrome is real– Altough cortisol dynamics may

be abnormal

– No benefit in RCT’s

• Adrenal fatigue is not a recognized diagnosis, yet patients are treated!

•

• Treatment with adrenal steroids is fraught – steroid dependence

– Side effects of excess glucocorticoids

– Unawareness of supplements can lead to adrenal crisis

• Ask about supplements

Adrenal fatigue and CFSSelf-critical perfectionism predicts lower cortisol response to experimental stress in patients with chronic fatigue syndrome. Kempke, S et al 2016 Health Psych 35(3), 298.

Effects of early childhood trauma on hypothalamic–pituitary–adrenal (HPA) axis function in patients with Chronic Fatigue Syndrome. Kempke, S et al 2015 Psychoneuroendo 52, 14

Adrenal fatigue does not exist: a systematic review

Flavio A Cadegiani and Claudio E Kater. 2016. BMC Endocrine Disorders 16:48 DOI: 10.1186/s12902-016-0128-4

Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study BMJ 2017;357:j1415. Akbar K Waljee

• Within 30 days of drug:

• Increase in rates sepsis (rate ratio 5.30, 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99),and fracture (1.87, 1.69 to 2.07)

• Increased risk diminished over 31-90 days.

• Risk persisted at prednisone equivalent doses of less than 20 mg/day (ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P<0.001).

• One in five American adults in a commercially insured plan were given prescriptions for short term use of oral corticosteroids during a three year period, with an associated increased risk of adverse events.

Summary

• Corticosteroids essential for survival• Deficiency may be life-threatening. If you

think of it grab a cortisol and ACTH level, give dexamethasone and do Cortrosyn stimulation with 30 and 60’ cortisol.

• Excess difficult to diagnose, but screening is easy – 24 h UFC or overnight 1 mg dex suppression

• r/o pheochromocytoma before procedures.• Follow benign adrenal nodules for 3 years

CRF

ACTH

PITUITARY

Adrenals

Remember the Pituitary!

HYPOTHALAMUS

Cortisol

( - )Classic negative feedback loop

cortisol

Cortisol ( - )

Intranuclear receptor

stress