Adrenal disease Real and Unreal J R Minkoff MD, FACP Endocrinology 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 excess Aldosterone 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
Normal Function: Hypothalamic-Pituitary- Adrenal Axis is Centrally Determined Cortisol ( - ) ( - ) cortisol CRF PITUITARY ACTH Adrenal coretx HYPOTHALAMUS Classic negative feedback loop 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 Electrolytes Serum Cortisol Aldosterone Plasma ACTH Plasma renin activity Labs
Adrenal Insufficiency Addison's: primary adrenal failure History: Fatigue, weight loss, dizziness, polyuria - dipsia, salt-craving, abdominal pain, diarrhea. Indolent onset Associated autoimmune diseases Sudden onset infection, hemorrhage Signs: Hypotension. Dehydration. Hyperpigmentation with 1 o adrenal failure Labs: 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 Labs BUN 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
Normal Function : Hypothalamic-Pituitary- Adrenal Axis is Centrally Determined Cortisol ( - ) ( - ) cortisol CRF PITUITARY ACTH Adrenals HYPOTHALAMUS Classic negative feedback loop Intranuclear receptor stress Cortisol If not previously diagnosed obtain serum for 0' cortisol and ACTH level (special handling required and if you suspect addisonian crisis (hypotension, hyponatremia, etc.) - give fluids and Dexamethasone 4mg IV do 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 Insufficiency Primary adrenal failure BUN > Cr, Na +, K +, hypoglycemia, hypercalcemia, eosinophilia Cortisol is low and does not stimulate ACTH 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 for Look for precipitating causes Primary adrenal failure idiopathic, autoimmune, hemorrhagic, TB Metastatic Secondary pituitary/hypothalamic disease Steroid withdrawal Rx: Crystalloid - lots Hydrocortisone 100mg IV q8h Florinef 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 cortisol Further 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, Asthma Admitted with fatigue - Na + 121 Meds: 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 1 Cortisol Na + 7/11 9.4 121 7/12 24h UFC 10 (normal is 20-50) 7/13 0 ACTH 10 6 126 30 18.2 60 13.7 8/24 FSH 54 122 0 <1 30 4.9 60 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 and anesthesiologist 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 CFS Self-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 Remember the Pituitary! Cortisol ( - ) ( - ) cortisol CRF PITUITARY ACTH Adrenals HYPOTHALAMUS Classic negative feedback loop Intranuclear receptor stress Cortisol