Adrenal insufficiency-How to diagnose, treat and manage

Theodore C. Friedman, M.D., Ph.D.Professor of Medicine-UCLA

Chief, Division of Endocrinology, Molecular Medicine and Metabolism

Charles R. Drew Universitywww.goodhormonehealth.com

Magic ConventionChicago

June 13, 2010

Case (1961)

• 44 y.o male• PMH/PSH

-Age 23-Episode of hypotension -Age 28 -frail (150 lbs), looked tired, hollowed-eyed and anemic, then collapsed-Age 37- back surgery-Age 38-diagnosed with hypothyroidism-metabolic rate of -15 (low)- liiothyronine started

-lifelong history of GI symptoms (cramping, diarrhea, inability to gain weight)-age 38-43 intentional 35 lbs weight gain, including increased muscle mass

Family hx

• Sister-Addison’s disease• Son-Graves’ disease

Medications

• ascorbic acid, 500 mg twice daily• hydrocortisone, 10 mg daily• prednisone, 2.5 mg twice daily• methyltestosterone, 10 mg/d• liothyronine sodium, 25 mcg twice daily• fludrocortisone, 0.1 mg/d• diphenoxylate hydrochloride (opioid agonist)• atropine sulfate, 2 tablets as needed (Lomotil)

PE

• 6 feet, 175 lbs• Appeared pale and anemic• Appeared bronze (before treatment)• Impaired vibration sense

• Labs-Hgb 15.5 g/dL, hematocrit 41%• Otherwise none available

Case

• What is the diagnosis?• Who is it?• Why the medications?

President John F. Kennedy

• Dx: Polyglandular failure syndrome, Type 2

• (Mandel LR. Endocrine and autoimmune aspects of the health history of John F. Kennedy. Ann Intern Med. 2009, 151:350-4)

John F. Kennedy

1944- 27 year-old JFK at reunion with fellow navy mates

John F

Mandel L R Ann Intern Med 2009;151:350-354

©2009 by American College of Physicians

President Kennedy’s Medications

• ascorbic acid, 500 mg twice daily- Why?• hydrocortisone, 10 mg daily• prednisone, 2.5 mg twice daily Why both?• methyltestosterone, 10 mg/d Oral no longer given!, Suggests

hypogonadism secondary to steroid replacment vs primary hypogonadism vs hypophysitis. Helped with muscle mass and weight.

• liothyronine sodium, 25 mcg twice daily Why not desiccated thyroid? Levothyroxine first introduced in 1962

• fludrocortisone, 0.1 mg/d Good, check renin level• diphenoxylate hydrochloride/atropine sulfate-test for Celiac

disease instead

Polyglandular Failure Syndromes

• Type I autoimmune polyglandular syndrome (children)– mucocutaneous candidiasis – hypoparathyroidism– adrenal insufficiency

• Type II autoimmune polyglandular syndrome (Schmidt syndrome, adults)

– Addison’s disease– autoimmune thyroid disease (Graves disease or Hashimoto's thyroiditis)– insulin-dependent diabetes mellitus – Pernicious anemia– Gonadal failure– Hypophysitis– Celiac disease– Vitilgo

Adrenal Glands

• The adrenal glands lie at the superior pole of each kidney.

• They are composed of two distinct regions: the cortex and the medulla.

Adrenal Hormones

• Glucocorticoids-Cortisol

• Mineralocorticoids-Aldosterone

• Androgens-DHEA(S), testosterone, androstenedione

• Estrogens

• Catecholamines-Epinephrine, Dopamine

Cortisol

• Daily secretion 10-15 mg

• Circadian cycle

• Has three forms: – Free (5%), physiologically active– bound to CBG/albumin– Cortisol metabolites

Cortisol: Brain-Hypothalamic-Pituitary-Adrenal Axis

Renin-Angiotensin-Aldosterone Axis

Angiotensinogen (452 A.A.)Liver

Prorenin ReninKidney

Angiotensin I (10 A.A.)

Angiotensin II (8 A.A.)

Angiotensin II receptor

Aldosterone

Angiotensin-converting enzyme

Adrenal

Lung,Plasma

Adrenal,Vascular

Site

Actions of Glucocorticoids

• Maintains metabolic homeostasis– Regulates blood glucose levels– Raises insulin levels– Increases catabolism/decreases anabolism– Inhibits reproductive, thyroid and growth hormone axes– Mineralocorticoid activity of cortisol

• Affects connective tissue– Causes loss of collagen– Loss of connective tissue– Inhibits fibroblasts– Inhibits bone formation/incr. resorption

Actions of Glucocorticoids (2)

• Maintains cardiovascular function– Increases cardiac output– Increases vascular tone– Permissive effects on pressor hormones– Increases sodium retention

• Affects behavior and cognitive function• Affects immune system

– Decrease # of circulating lymphocytes, monocytes, and eosinophils

– decrease migration of PMNs to sites of injury• Regulates about 25% of human genome

Renin-Angiotensin-Aldosterone Actions

• Angiotensin II– vasopressor– stimulates aldosterone

• Aldosterone– Activates sodium/potassium pump– Increases plasma sodium– Decreases plasma potassium– Decreases plasma hydrogen

Daily ACTH/Cortisol Trends

• Primary Adrenal Insufficiency– Glucocorticoid and Mineralocorticoid Insufficiency

– Compensatory Increase in POMC (hyperpigmentation)

• Secondary (Central) Adrenal Insufficiency– Glucocorticoid Insufficiency Only

• Glucocorticoid Withdrawal– Glucocorticoid Insufficiency Only

Different Types of Glucocorticoid Insufficiency

Causes of Primary Adrenal Insufficiency

• Autoimmune (Addison’s Disease)

• Tuberculosis

• Fungal Disease

• AIDS (HIV, CMV, MAI)

• Metastatic Cancer

• Adrenal Hemorrhage

• Bilateral Adrenalectomy

• Agents which inhibit cortisol biosynthesis (ketoconazole)

• Sepsis

Causes of Secondary Adrenal Insufficiency(corticotropes are the most preserved cells in the pituitary)

• Pituitary Tumors

• Radiation

• Surgery

• Pituitary Apoplexy/Sheehan’s Syndrome

• Infiltrative Diseases

• After Cure of Cushing’s Syndrome

• Glucocorticoid Withdrawal

Symptoms of Glucocorticoid Insufficiency

• Fatigue

• Vomiting

• Diarrhea

• Anorexia

• Malaise

• Muscle and joint pain

• Abdominal pain

• Weight loss

• Hypoglycemia

• Hyponatremia (SIADH)

Symptoms of Mineralocorticoid Insufficiency

• Decreased intracellular volume

• Hypotension

• Dehydration

• Shock

• Hyponatremia

• Hyperkalemia

– Arrhythmias

• Acidosis

• Salt-craving

Laboratory Findings of Primary Adrenal Insufficiency

• Hyponatremia

• Hyperkalemia

• Hypoglycemia

• Lymphocytosis

• Eosinophilia

• Mild normochromic Anemia

Symptoms of Primary Adrenal Insufficiency

• Hypotension• Dehydration• Hyponatremia• Hyperkalemia• Salt-craving• Amenorrhea• Decreased libido• Hyperpigmentation

• Fatigue

• GI- vomiting, diarrhea, abdominal pain

• Anorexia/weight loss

• Malaise

• Muscle and joint pain

• Hypoglycemia

• Hyponatremia

• Depression

Hyperpigmentation

Symptoms of Secondary Adrenal Insufficiency

• Amenorrhea• Decreased libido

• Fatigue

• GI- vomiting, diarrhea, abdominal pain

• Anorexia/weight loss

• Malaise

• Muscle and joint pain

• Hypoglycemia

• Hyponatremia

• Depression

Stages in Development of Primary Adrenal Insufficiency

• Stage1- renin rises, aldosterone normal• Stage 2- ACTH rises, cortisol normal • Stage 3- impaired cortisol response to ACTH• Stage 4- aldosterone levels drop• Stage 5- cortisol levels drop

Copyright ©2001 The Endocrine Society

Ten, S. et al. J Clin Endocrinol Metab 2001;86:2909-2922

Stages in Development of Primary Adrenal Insufficiency

Diagnosis of Adrenal Insufficiency

• Goals:– Demonstrate inappropriately low cortisol and

aldosterone (if primary)– Determine whether the cortisol deficiency is

dependent or independent of ACTH deficiency

Is the Cortisol Level Low?

A Quick Approach• Checking an 8AM fasting cortisol level can usually make or

exclude the diagnosis in a patient levels of cortisol < 5 ug/dl or > 12 ug/dl respectively.

• Should only be done in subjects with signs/symptoms of adrenal insufficiency or history consistent with it.

• Can be used in those patients with a moderate index of suspicion.• Measurement of ACTH levels can differentiate between primary

and secondary insufficiency• Consistently high ACTH can be a sign of early adrenal

insufficiency [Roy, R., and Friedman, T.C. (2004) Subclinical Adrenal Insufficiency-A Disease, Like Subclinical Hypothyroidism, Whose Time Has Come. EndoTrends 11 (3):14-15.]

Problems with Just Checking Morning Cortisol Levels

Erturk et al. Evaluation of hypothalamic-pituitary adrenal axis by insulin hypoglycemia test J.Clin. J.Clin Endocrinol Met. 1998;83:2350

– Found that some patients with an AM cortisol between 12-18 mg/dL had a ITT-induced cortisol < 17 and would be classified as being adrenally-insufficient.

– I doubt these have clinically significant cortisol defiency and need replacement

– May need coverage during surgery or major illness.

Cosyntropin Stimulation Test

• 250 ug IV bolus of cosyntropin (synth. ACTH) in morning or afternoon

• Plasma cortisol at time 0, 30, 60 minutes• Cortisol >18 ug/dl from baseline rules out primary adrenal

insufficiency and 90% secondary insufficiency• if peak response is less than 10 g/dl, glucocorticoid replacement is

required• if peak response is between 10 and 20 g/dl, glucocorticoid

replacement is recommended during stresses and maybe during everyday

– Incremental increase in cortisol not recommended– Need to have central hypocortisolism for about 1 month (some articles

say 12 days) prior to enough adrenal atrophy and failed cosyntropin test.

1 mcg Cosyntropin Stimulation Test

• Proposed to be more physiological• By definition will pick up more cases of adrenal

insufficiency.• Loraiux and Fleseiru* point our several problems with this

test– A lower dose is on the steeper part of the dose-response curve resulting in

more variation.– “normals” will have a lower response to 1 mcg cosyntropin, but we don’t

know the cutoff for this test. – Calling someone abnormal based on a blunted response to 1 mcg

cosyntropin and putting them on lifelong glucocorticoids may be the worse thing we can do to a patient

• * Loraiux and Fleseiru Cur. Opin. Endocrinol. Diabetes Obe 16:392-400, 2009.

Salivary cortisol testingAdvantages

• Avoid anticipatory stress of blood draws• Measures free cortisol• Not affected by CBG variations• Easy to collect• More pleasant• Two studies suggest it was similar to serum cortisol to

diagnose adrenal insufficiency. One looked at baseline cortisol levels and one looked at during cosyntropin testing.

Salivary cortisol testingDisadvantages

• Cut-offs are not known.• Low levels of cortisol, accuracy might be a problem• Most cortisol in the morning is bound: Articles showed not as much

differences in salivary vs serum cortisol between adrenal insufficient patients and normals

• Reliable at standard labs: Esoterix, Labcorp, Quest, ACL• Less reliable at labs dealing directly to the consumer: Diagnos-tech,

Geneva, Great Smokie, Hormone Saliva Tests• Almost always low: I have had Cushing’s patients with low levels who

received steroids.• Big divide on this between Endos and Alternative Docs/Naturopaths

Insulin-Induced Hypoglycemia

• 0.1 units/kg insulin in morning (more if insulin-resistant)• Check glucose at time 0,15,30,45,60,90• Cortisol should rise above 18 ug/dL and glucose should fall below

40 mg/dL• Patients and docs do not like it.• If hypopit, missing counter-regulatory hormones (cortisol and

GH)-hard to get out of hypoglycemia.• Many hypopit patients are insulin resistant-have to give more

insulin.• Literature suggests giving a second dose of insulin if 1st one doesn

’t achieve hypoglycemia-but that already stimulates cortisol, so on the 2nd insulin dose, cortisol doesn’t respond-false positives.

Urine cortisol

• Urinary free cortisol and 17-OH corticosteroids• Not great at separating low normal from low.• Might give you a hint.

Reminder

• ACTH is the last hormone to be affected in pituitary insufficiency (GH, TSH, gonadotropins have to be invariably lost)

• Symptoms of glucocorticoid insufficiency are unique (weight loss, nausea, abdominal pain)

• Primary adrenal insufficiency is relatively rare and also has a unique symptom and lab complex.

• Once started, glucocorticoids may be hard to stop and are often very detrimental.

• Its probably a false-positive test, unless its in the right context.• Think twice before going on glucocorticoids.• Glucocorticoids stimulate mood, so the fact that you feel better on

glucocorticoids does not mean you have adrenal insufficiency

Adrenal Fatigue-Fiction• Wildly proposed by alternative and anti-aging doctors• Lots of internet discussion on it• Often based on salivary cortisol assays (sometimes marketed directly to

patients, which lack both precision and accuracy.• Theory is that “stress” leads the adrenals to work harder and make more

cortisol, then it burns out (peters out) and makes less cortisol• “It’s like a hormone factory and it wanes in its production, one of the

way it wanes is just by stress.”-Dr. Tori Hudson-Naturopathic Physician.• Alternative doctors may give herbs and supplements to stimulate the

adrenal gland but also give Isocort (ground up sheep adrenals) or hydrocortisone.

• “Eat lean, green and clean”-one alternative doctor said is the treatment for adrenal fatigue

Adrenal Fatigue-Fact• The adrenals are up-regulated during stress and make cortisol, not

less cortisol.• Mommersteeg et al. [Psychoneuroendocrinology (2006) 31, 216–

225] studied 74 clinically diagnosed burnout individuals mostly on sick-leave and compared with 35 healthy controls.

• They found similar salivary cortisol after awakening and at different times of the day and after an overnight dexamethasone suppression test in the 2 groups.

• Patients should not be put on cortisol unless they are shown to be adrenally insufficient.

• Isocort contains 2.5 mg of hydrocortisone (often 6 or more pills a day are given), plus aldosterone and DHEA/DHEAS and is dangerous.

Adrenal Insufficiency and Hypothyroidism

• Addison’s Disease and Hashimoto’s (autoimmune) hypothyroidism co-exist as part of Type II autoimmune polyglandular syndrome (Schmidt syndrome).

• In hypopituitarism, adrenal insufficiency and central hypothyroidism often co-exist

• Patients with full-blown adrenal insufficiency and hypothyroidism do need to have glucocorticoid replacement prior to thyroid replacement.

• That is because in hypothyroidism, cortisol metabolism is decreased (11b-HSD1 favoring cortisone to cortisol conversion). Treatment of hypothyroidism causes the low levels of cortisol to be broken down and will lead to an adrenal crisis.

• Probably not true in borderline adrenal insufficiency or “adrenal fatigue”• Statements of needing cortisol to support thyroid replacement are myths.

Adrenal Crisis

• Usually in Patients with Primary Adrenal Insufficiency

• Precipitated by Stress

• Newly diagnosed vs. established patient– stopped medicines– illness– vomiting

Presentation of Adrenal Crisis(usually primary adrenal insufficiency)

• Hypotension/shock (90%)

• Abdominal pain (80%)

• Fever (65%)

• Anorexia/nausea/vomiting (60%)

• Confusion (40%)

• Hyponatremia/hyperkalemia/acidosis (80%)

• Hypoglycemia (20%)

Workup/Treatment for Suspected Adrenal Crisis

• Establish IV access• Draw blood for electrolytes, glucose,

cortisol, ACTH, aldosterone and plasma renin activity

• Infuse up to 3 liters of normal saline• Follow fluid status• Give 100 mg of IV hydrocortisone• Supportive Measures

Subacute Measures for Suspected Adrenal Crisis

• Continue IV fluids

• Search for an infectious source

• Determine if primary or central adrenal insufficiency

• Give fludrocortisone if primary insufficiency (not required initially if hydrocortisone dose is more than 50 mg/day)

• Continue IV hydrocortisone

Maintenance Therapy for Adrenal

Insufficiency

Daily cortisol production rate in man

• Esteban et al. (JCEM, 72: 39, 1991) measured daily cortisol production rates in normal volunteers with a stable cortisol isotope method.

• 9.9 +/- 2.7 mg/day, 5.7 mg/m2 day.

• Not all of oral cortisol is absorbed, need to take 12-15 mg/day

• Most glucocorticoid replacement is supraphysiological.

• Leads to osteoporosis, glucose intolerance and increased infections.

• True physiological replacement is likely to be benign

Glucocorticoid Replacement• Most patients are over-treated• Earliest manifestation of excess treatment is easy bruisability• Weight gain, central obesity, etc.• Earliest manifestation of inadequate treatment is joint pain.• Reasonable to mimic circadian rhythm with most or all

cortisol given first thing in the morning• Want to avoid nighttime administration as it could lead to

sleep disturbances,• But, some patients need a bit of cortisol to go into deep sleep• No studies comparing different treatment regimens

Glucocorticoid Replacement (2)

• My approach is to use hydrocortisone mainly in AM-aim for dose between 15 and 20 mg/day in a women and slightly higher in a man.– Hydrocortisone 10-20 mg on awakening– Hydrocortisone 2.5-5 mg in mid-afternoon– Occasionally a 3rd dose is needed– More physiological than prednisone or dexamethasone

• Decrease dose slowly until some symptoms develop, then go back a dose.• Small changes make a big difference• Increase dose with illness, short term its better to err on giving more,

long term its better to give less• Cortef is brand name, hydrocortisone is generic (most of my patients

prefer generic)

Modified-Release Hydrocortisone

• Investigational- DuoCort hydrocortisone dual-release tablet combines both a rapid release dose and an extended release dose.

• Designed to better mimic circadian rhythm of cortisol• Website states: Existing administration forms cannot adequately mimic

the 24 hour circadian pattern of cortisol.• Probably best use will be in congenital adrenal hyperplasia.• Not sure replacement is a big problem in adrenal insufficient patients due

to cortisol-cortisone shuttle• Many patients do fine on a single dose of hydrocortisone in AM even

though blood cortisol levels are almost 0. This is due to the conversion of cortisol to cortisone, which goes back to cortisol in the tissues.

• 30 mg of modified hydrocortisone may over-replace individuals

Modified-Release Hydrocortisone-circadian rhythm

Debono, M. et al. J Clin Endocrinol Metab 2009;94:1548-1554

Modified-Release Hydrocortisone-only long-lasting

Debono, M. et al. J Clin Endocrinol Metab 2009;94:1548-1554

Maintenance Therapy for Primary

Adrenal Insufficiency • Primary adrenal insufficiency may need a bit more

glucocorticoids than secondary • Mineralocorticoid Replacement

– Fludrocortisone 0.05 mg to 0.5 mg daily (0.05 mg twice a day)– Should be given twice a day-half-life is 3.5 hrs– Fludrocortisone is generic; brand (Florinef) is not available)– Probably will need more fludrocortisone in the summer

• Med-Alert Bracelet (can also be given in secondary, but less crucial)

• Solucortef -100 mg in Act-O-vial

Monitoring glucocorticoid replacement

• Signs and symptoms• 24 hr UFC over-estimate cortisol as it reflects

amount in the urine right after dosing that exceeds 11b-HSD2 capacity.

• 17-OHS (can be corrected for creatinine excretion in g/day) reflects cortisol metabolism and is more integrated throughout the day.

• Day curves under-estimate cortisol as the ignore cortisone-cortisol shuttle

• ACTH is high unless over-replaced

Monitoring glucocorticoid replacement

• LW: Sheehan’s syndrome-very athletic and health conscious

• HC tapered from 20 mg/day to 17.5 mg/day (12.5 mg in AM, 5 mg in PM)-less bruising, slight weight loss

• On 17.5 mg a day-UFC 191 g/day (10-34)

• 17-OHS 4.7 mg/day (2-6)

• 17-OHS/gm Cr 3.5 mg/day (1.6-3.6)

• Went down to 15 mg/day of HC, had an adrenal crisis when had the flu

Monitoring mineralocorticoid replacement in primary adrenal

insufficiency• Plasma renin activity is very accurate and probably should

be measured every 2-3 months

• If its high, more fludrocortisone is given, if its low, less fludrocortisone is given

• Electrolytes are relatively insensitive and are not a substitute for frequent renin monitoring

Hormonal Interactions• Treating adrenal insufficiency may unmask

diabetes insipidus

Hormonal Interactions• Increased GH/ IGF-I leads to lower levels of cortisol (11-

HSD1).• Thus, treating a patient with hypopituitarism with GH will

decrease cortisol levels.• Similarly, treating a patient with hypopituitarism with

thyroid hormone will decrease cortisol levels.• We had one patient that was over-replaced on

glucocorticoids, under-replaced on thyroid hormone and not treated with GH.– We started GH, decreased her glucocorticoids and

increased her L-thyroxine-she went into adrenal crisis.• Make changes slowly. • Monitor frequently

Glucocorticoids are Needed for Sleep

• García-Borreguero D. et al. (J Clin Endocrinol Metab. 2000 85:4201-6).

• In Addison's patients, cortisol plays a positive, permissive role in REM sleep regulation and may help to consolidate sleep.

• Suggests a need for a low dose of hydrocortisone (2.5 mg) at night.

Physiological Equivalents of Glucocorticoids

• 20 mg of hydrocortisone

• 5 mg of prednisone

• 4 mg of methylprednisolone

• 0.75 mg of dexamethasone

Treatment of Minor Illnesses

– Fever– Vomiting

• Double glucocorticoid dose

Emergency Treatment of Severe Illnesses

• 100 mg of IM hydrocortisone

• Go to physician immediately

Peri-operative Glucocorticoid Replacement

•Normal adults: 50 mg/24hr of cortisol during minor surgery•75-100 mg/24 hr during major surgery

•The increase is mainly due to anesthesia

•“Common practice” to give “stress doses” of glucocorticoids peri-operatively

•Scant evidence to support this practice

•1950’s 2 young patients on glucocorticoids died unexpectedly during orthopedic surgery

•reduced tissue repair rates•increased susceptibility to infection•glucose intolerance

Risks of acute excessive glucocorticoids

Steroid coverage for illnesses or surgery

• Moderate illness– 50 mg of hydrocortisone twice a day

• Severe illnesses– 100 mg of IV hydrocortisone Q 8 hours

• Minor procedures without anesthesia– No extra coverage

• Moderately stressful procedures (endoscopy or arteriography– Single 100 mg IV dose of hydrocortisone prior to procedure

• Major surgery– 100 mg of IV hydrocortisone before anesthesia and Q 8 hours

References• Mandel LR. Endocrine and autoimmune aspects of the health history of John F.

Kennedy. Ann Intern Med. 2009 Sep 1;151(5):350-4.

• Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endocrinol Metab. 2009 Apr;94(4):1059-67.

• Loriaux DL, Fleseriu M. Relative adrenal insufficiency. Curr Opin Endocrinol Diabetes Obes. 2009 Oct;16(5):392-400.

• Mommersteeg PM, Heijnen CJ, Verbraak MJ, van Doornen LJ. Clinical burnout is not reflected in the cortisol awakening response, the day-curve or the response to a low-dose dexamethasone suppression test. Psychoneuroendocrinology. 2006 Feb;31(2):216-25. Epub 2005 Sep 16.

• Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003 Feb 20;348(8):727-34.

• García-Borreguero D, Wehr TA, Larrosa O, Granizo JJ, Hardwick D, Chrousos GP, Friedman TC. Glucocorticoid replacement is permissive for rapid eye movement sleep and sleep consolidation in patients with adrenal insufficiency. J Clin Endocrinol Metab. 2000 Nov;85(11):4201-6.

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