Sajeev Menon MD

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ADRENAL INSUFFICIENCY?FATIGUE?

Sajeev Menon MD

Endocrinologist

KCIM

OBJECTIVES

• Review primary and adrenal insufficiency including clinical and laboratory findings

• To appropriately interpret the results of basal and dynamic tests of adrenal function.

• Discuss the treatment of adrenal insufficiency including new options

• List the drugs that interfere with the HPA axis and cortisol metabolism

• Discuss Relative Adrenal Insufficiency and dispel the myth of Adrenal Fatigue

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OUTLINE

• Four case studies – in the inpatient and outpatient settings - which address

the learning objectives.

PATIENT 1

• 17 yr old Caucasian male

• Collapses in London in 1947

Hypotension, Na 129 mEq/L, K 4.9 mEq/L

Hx of diarrhea and weight loss

• Evaluated at Mayo clinic, diagnosed to have Addison’s disease

“He has one year to live”

PATIENT 1 : CLINICAL COURSE

• Deoxycorticosterone acetate (DOCA) pellets under his skin every 3 months.

• 1949 : introduction of cortisone (Kendall/Hench at Mayo Clinic)

• 1954: Archives of Surgery report after back surgery

• 1955: BMR -15 , compatible with hypothyroidism.

• Younger sister develops Addison’s disease

• 1963: Dies of GSW.

• Post mortem: no adrenal tissue

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SYMPTOMS OF ADRENAL INSUFFICIENCY

• Weakness, fatigue 100%

• Anorexia 100%

• Nausea 86%

• Vomiting 75%

• Abdominal Pain 31%

• Salt Craving 16%

• Postural dizziness 12%

• Muscle or joint pain 6-12 %

HYPERPIGMENTATION

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HYPERPIGMENTATION

BIOCHEMICAL DIAGNOSIS OF PAI

Paired cortisol and ACTH

• Serum cortisol < 5 mcg/dl

• Plasma ACTH >2 x upper normal

• Elevated renin/PRA

• Low DHEA / DHEAS

PAI: OTHER TYPICAL FINDINGS

• Hyponatremia 88% (low cortisol)

• Hyperkalemia 64% (low aldosterone)

• Hypercalcemia 6%

• Azotemia 55%

• Mild anemia 40%

• Eosinophilia 17%

• Lymphocytosis Varies

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ADDITIONAL DIAGNOSTIC TESTS

• Cosyntropin Stimulation Test –

- 250 mcg ACTH IM or IV

- Cortisol @ 30-60 min: >18-20 mcg/dl Normal

Low dose Cosyntropin Test (1 mcg)

- Not recommended

ADDITIONAL DIAGNOSTIC TESTS

• Insulin Tolerance Test

- 0.1 – 0.2 mcg/Kg Regular insulin IV bolus

Glucose < 40 mg/dl and Cortisol > 18 mcg/dl

• Metyrapone test (11 beta hydroxylase inhibitor)

30 mg/kg p.o at 2300. Labs 0800.

11 Deoxycortisol > 7 mcg/dl - Normal

- Cortisol < 5 mcg / dl - Required to fail

ANTIBODIES

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DIAGNOSTIC ALGORITHM

TREATMENT OF ADRENAL INSUFFICIENCY

• Adrenal crisis is a life threatening emergency and requires immediate treatment.

• The goal of treatment is correction of hypotension and reversal of electrolyte abnormalities and cortisol deficiency.

• IVF (NS), IV HCN

• Mineralocorticoid administration is not necessary in the acute setting.

• HCN in 2-3 divided doses is the drug of choice for management of chronic primary adrenal insufficiency.

TREATMENT OF ADRENAL INSUFFICIENCY

• Chronic management invariably requires Fludrocortisone.

• Adjust the dose to lower PRA to the upper normal range.

• ACTH measurement is usually not helpful or necessary.

• UFC is not completely reliable to assist in HCN dose titration.

• DHEA maybe helpful is some women.

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TREATMENT OF ADRENAL INSUFFICIENCY

• The adrenal glands only produce 8-12 mg (6-7 mg/sq m/day) of cortisol

daily.

• Doses of HCN 10-20 mg daily in divided doses is adequate in most patients.

• There is no “physiologic” prednisone dose.

SERUM CORTISOL PROFILE : PLENADREN VS HC

SUBCUTANEOUS PUMP THERAPY

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PATIENT 2

• 20 yr old Caucasian male

• Seems quite nervous

• Has palpitations, anxiety with panic attacks, fatigue

• Normal exam and BP. Weight has been stable. BMI 22.

• Integrative Family Wellness Center :

Salivary cortisol profile showed ‘adrenal fatigue’ .

• Treated with “adrenal support” (no active steroids listed)

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SALIVARY CORTISOL GRAPH

PATIENT 2

• Labs : Normal CBC and CMP.

• Morning serum cortisol : 1.4 mcg/dl

• CST (250 mcg IV)

Cortisol increased from 1.8 to 11.6

ACTH at baseline was < 5 pg/ml

• FT4, IGF-1, TSH, PL and total testosterone - WNL

PATIENT 2 : NEXT BEST TEST ?

• Pituitary MRI was done and found to be normal.

• Subsequently other tests were considered:

-Long chain fatty acid profile

-21 hydroxylase antibodies

-Synthetic glucocorticoid screen

-17 hydroxyprogesterone

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PATIENT 2 : CLINICAL COURSE

• A few days later, his father calls to inform that patient was found

to be abusing Buprenorphine.

OPIOID INDUCED ADRENAL INSUFFICIENCY

• Heroin addicts (60-70%) have impaired cortisol response to stimulation.

• Methadone attenuates ACTH / Cortisol response to Naloxone.

• Clinically significant adrenal insufficiency / crisis seems rare.

OR is it ?

• There are 17,000 deaths annually from narcotic overdose.

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DRUG INDUCED ADRENAL INSUFFICIENCY

• Corticosteroids and progesterone (medroxy progesterone)

• Opioids

• Adrenostatic/lytic and GR antagonist

• Ipilimumab (CTLA-4 Mab, can cause hypophysitis)

• Psychotropic drugs: benzodiazepine, atypical antipsychotics etc

PATIENT 3

• 75 yr old, diabetic gentleman

• Admitted with lobar pneumonia a week ago

• Developed hypotension and oliguria 36 hours ago

• Transferred to ICU

• Intubated, broad spectrum ABX, IVF, Insulin gtt

PATIENT 3 : LAB TESTS

• Glucose 128 mg/dl

• Na 133 mEq/L

• K 3.7 mEq/L

• Cl 94 mEq/L

• HCO3 28 mEq/L

• Ca 7.9 mg/dl

• Albumin 1.9 mg/dl

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PATIENT 3 : LAB TESTS

• Serum cortisol 11 mcg/dl at baseline and 17.5 mcg/dL after stimulation.

• Aldosterone 3.5 ng/dl

• PRA 12 ng/ml/h

• ACTH 17 pg/ml

“RELATIVE ADRENAL INSUFFICIENCY”

• This concept was based on an initial report by Rothwell in 1991

Definition: Incremental cortisol response to Cosyntropin < 9 mcg/Dl

Important prognostic feature in septic shock

• Subsequent reports used the same definition

• Used to define need for HC therapy (Annane et al; JAMA 288:862;2002)

(Serious limitation – most patients responding to HCN had received Etomidate)

• Rapid increase in similar publications 2003-2006

• *Arafah B; JCEM : 91: 3725

PATIENT 3 : WHAT IS THE BEST NEXT STEP ?

• 1. Administer hydrocortisone and fludrocortisone

• 2. Initiate high dose dexamethasone

• 3. Measure ‘free’ cortisol

• 4. Obtain pituitary MRI

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MEASURE FREE CORTISOL

• Measuring free cortisol in critical illness may identify patients with true adrenal insufficiency and distinguish them from patients with low cortisol related to decreased binding proteins.

• However this test is not available in most labs and even if available might not be reported back for a few days.

Raff H, et al. Endocrine 34: 68-74, 2008

FREE CORTISOL LEVELS DURING CRITICAL ILLNESS PREDICT MORTALITY

FREE CORTISOL

Free cortisol levels during critical illness predict mortality

SM1

Slide 42

SM1 Sajeev, 10/15/2016

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PATIENT 3 :

• Although ACTH levels actually decline, decreased cortisol clearance and

slightly increased production rates sustain cortisol levels during critical

illness and may require a dose adaptation when HCN treatment is

considered.

• Despite elevated PRA, low aldosterone is seen in 20% of critically ill

patients.

• DHEA levels may also be subnormal.

CORTICUS TRIAL

• 499 ICU patients with septic shock were randomized.

• 233 (47%) had abnormal CST, defined as <9 mcg/dL increase in total cortisol.

• (30 increasing to 32 was considered abnormal and 28 increasing to 46 was considered normal)

• 125 received HCN for 11 days.

• 108 received placebo.

• There was no decrease in mortality with HCN.

• *Sprung CL et al NEJM 2008: 358: 111-124

CORTICUS TRIAL

• Hydrocortisone reversed shock more quickly BUT caused more superinfection and new sepsis / shock.

• It had no impact on mortality or length of stay

• Cosyntropin testing did not predict responsiveness to HC

• Despite that study, some intensivists continue to use the term : “relative adrenal insufficiency”.

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RELATIVE ADRENAL INSUFFICIENCY IN CRITICAL ILLNESS

• Weak scientific evidence

• Iatrogenic steroids, propofol, opioids, psychotropic meds

• Total cortisol is misleading due to low CBG

• Steroid therapy is unhelpful

• High steroid levels = worse prognosis

• The adrenal glands never fatigue!

RELATIVE ADRENAL INSUFFICIENCY IN CRITICAL ILLNESS

• HPA axis is generally highly activated; not as well apparent from

measurements of serum total cortisol levels.

• Secretion of other ACTH dependent steroids (DHEA) is also increased.

• When HCN is used, the therapeutic response is not typical of that in adrenal

insufficiency.

NEW ONSET ADRENAL INSUFFICIENCY IN THE ICU

• It does exist…BUT..

• NOT AS CURRENTLY DEFINED

• It is a rare event

• Can be iatrogenic (e.g. etomidate)

• Should be considered for patients at risk.

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DIAGNOSIS OF ADRENAL INSUFFICIENCY DURING CRITICAL ILLNESS

• Diagnosis is difficult

• Always suspect it in patients at risk

• Always look for a cause

• Consider limitations of tests (serum cortisol)

• Can rely on random serum cortisol as long as binding protein abnormalities

are taken into account

• Take advantage of ACTH dependent steroids (DHEAS).

DIAGNOSIS OF ADRENAL INSUFFICIENCY DURING CRITICAL ILLNESS

• Cosyntropin test is NOT necessary

• Serum free cortisol is desirable but not readily available

• Can rely on random serum total cortisol

• Recommendations are based on data in nearly 300 patients

DIAGNOSIS OF ADRENAL INSUFFICIENCY DURING CRITICAL ILLNESS

In the absence of binding protein abnormalities:

• Expected total cortisol is often >15 mcg/Dl

• If cortisol is 10-15, consider the diagnosis

• If cortisol is < 10, diagnosis is likely.

• If unclear, can treat and diagnose later

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DIAGNOSIS OF ADRENAL INSUFFICIENCY DURING CRITICAL ILLNESS

When binding proteins are low:

• Cortisol should be at least > 11

• If cortisol is 8-11, consider the diagnosis

• If level is <8, diagnosis is likely.

TREATMENT OF ADRENAL INSUFFICIENCY IN CRITICAL ILLNESS

Principles of therapy

• Provide appropriate doses of glucocorticoids for the critical illness.

• No definitive studies regarding dosage

• Lower doses maybe effective based on data in critically ill patients with AI

• Recent data do show decreased cortisol clearance during critical illness.

• At times high doses may be needed to treat associated inflammatory

processes.

TREATMENT OF ADRENAL INSUFFICIENCY IN CRITICALLY ILL PATIENTS WITH KNOWN OR

NEWLY DIAGNOSED ADRENAL INSUFFICIENCYCRITICAL ILLNESS WITHOUT SHOCK:

• Use HCN 25 mg Q 6 Hrs

• Taper as clinically indicated

• In patients with primary disease, add Fludrocortisone when total daily dose of HCN is < 50 mg/day

CRITICAL ILLNESS WITH SHOCK:

• Use HCN 50 mg Q 6 Hrs

• Taper as clinically indicated

• No need for Fludrocortisone

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HCN 25 mg IV every 6 hrs

USE OF GLUCOCORTICOIDS IN PATIENTS WITH SEPTIC SHOCK BUT WITHOUT ADRENAL

INSUFFICIENCY• Data is limited. It is possible that HCN might benefit a small number of

patients with septic shock and severe inflammatory response.

• GC therapy in this setting may represent pharmacologic therapy of an

inflammatory disease.

• There are no available tests that can identify patients who might benefit

from this therapy.

• Patients who received Etomidate should be treated with HCN for at least 24

hours.

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ADRENAL FUNCTION DURING CHRONIC STRESS

• AIDS patients

• PTSD

• Chronic Fatigue Syndrome

PATIENT 4

• Patient is a 46 year old Caucasian male

• He has a high stress job. Travels a lot. Doesn’t sleep well.

• Reports anxiety, palpitations, near syncope and dizziness.

• Medical history is negative for any significant illness. Does not take any meds.

• Vitals: P 80 BP 130/74 BMI 29.6

• Normal physical exam.

• Referred to Integrative Family Wellness Center

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“I HAVE ADRENAL INSUFFICIENCY”

• When someone tells you that…. he or she probably does not !

• 99.9% is iatrogenic

• 100% should have weight loss

• Should have a Lazarean response to treatment.

• There is no such thing as “Adrenal Fatigue”.

• Corticosteroids dull pain.

SUMMARY: LIST OF DO’S

• Do suspect exogenous GC

• Do suspect Narcotics

• Do determine etiology of primary adrenal insufficiency

• Do check Albumin in the ICU setting

• Do measure DHEAS for confirmation

• Do consider adrenal insufficiency for unexplained hyponatremia

SUMMARY:LIST OF DON’TS

• Don’t accept adrenal fatigue as a diagnosis

• Don’t diagnose ‘Relative Adrenal Insufficiency’

• Don’t recommend CST in ICU

• Don’t forget narcotics and GC

• Don’t overtreat chronically

• Don’t forget Fludrocortisone

• Don’t follow ACTH in primary adrenal insufficiency

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Thank you!