sajeev menon md endocrinologist kcim
TRANSCRIPT
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!