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Resident Version
Adrenal Insufficiency Module
Created by Dr. Hemanth Pai
Objectives:
By the end of this module, you should be able to:
1. Differentiate between primary vs secondary adrenal insufficiency
2. Give a definition of relative adrenal insufficiency (RAI)
3. Recognize signs and symptoms of adrenal insufficiency
4. Understand the utility and limitations of diagnostic tests in adrenal
insufficiency
5. Understand reasons for different treatment regimen in primary vs secondary vs
RAI
References:
1. Krieger et al
2. Vermes et al. J Clin Endocrinol Metab 1995
3. Annane et al. JAMA 2000
ADRENAL INSUFFICIENCY
Definitions:

Primary adrenal insufficiency (AI): Failure of adrenal glands resulting in
insufficient production of BOTH glucocorticoids (GC)- cortisol and
mineralocorticoids (MC)-aldosterone.

Secondary AI: Due to insufficient pituitary ACTH production resulting in
decreased production of adrenal GC. MC production usually not affected.

Relative AI: Transient insufficiency of adrenal GC (ie cortisol) production
associated with critical illness/septic shock.
Etiologies:

Primary AI: autoimmune adrenalitis (70%), bilateral adrenal hemorrhage, TB,
Histoplasmosis, N. meningitides, medications (eg etomidate, ketoconazole),
metastatic disease, Addison’s disease

Secondary AI: pituitary disease (adenoma, empty sella, tumors), chronic steroid
use (i.e. prednisone), history of cranial irradiation

Relative AI: critical illness, septic shock
Symptoms:

Nausea, vomiting, abdominal pain, anorexia and weight loss, myalgias (flu-like
symptoms), arthralgias, dizziness, orthostasis. Salt-craving may also be present in
primary AI
Signs:
 Physical examination:
o
Primary AI: Hypotension, hyperpigmentation of skin folds and palmar
creases, generalized tanned skin
o
Secondary AI: Hypotension, decreased visual acuity or visual field cuts or
diplopia (seen with pituitary disease)
Laboratories:
o
Electrolytes: hyponatremia, hyperkalemia (only in primary AI), azotemia,
hypoglycemia
o
Hematologic: lymphocytosis, eosinophilia
Diagnosis of Primary & Secondary Adrenal Insufficiency:

Random Cortisol Level is seldom used to diagnose adrenal insufficiency because
normal cortisol level fluctuates significantly throughout the day, see Figure 1.
i.e. a serum cortisol level of 3 ug/dl may be normal in the afternoon, although
would be considered low at 8am. Therefore there is no way of setting up normal
parameters for random cortisol level since it depends on time of day it is drawn.
Figure 1. Variation in normal serum cortisol and ACTH levels (Krieger et
al)

8am cortisol Level is sometimes used because cortisol peaks in early morning so
level <3 ug/dl may be suggestive but not diagnostic of adrenal insufficiency

Cosyntropin (ACTH)-stimulation test is best for the diagnosis of adrenal
insufficiency
Can be done any time of day
Check baseline cortisol level
Give Cosyntropin 0.25 mg IV push
Check cortisol at 30 and 60 min post-Cosyntropin
60 min cortisol < 20 ug/dl diagnostic of adrenal insufficiency
Check baseline ACTH level only if trying to determine/distinguish primary vs
secondary adrenal insufficiency (ACTH high in primary AI and low in secondary
AI)
o
o
o
o
o
o
Pitfalls of Cosyntropin-stimulation test:

Sensitivity is decreased in diagnosing partial secondary AI as adrenal glands may
only be partially atrophied and respond normally to exogenous ACTH

Cannot be used immediately following pituitary injury as adrenal glands do not
atrophy for at least ~8 wks (for example, cosyntropin stimulation test may be
normal immediately following surgery as adrenal glands respond normally to
ACTH administration)

No reference ranges for baseline cortisol in critically ill (ie ICU) patients

Serum cortisol is dependent on albumin and cortisol-binding globulin (CBG);
conditions that decrease albumin and CBG will decrease serum cortisol
Diagnosis of Relative Adrenal Insufficiency (RAI):



o
o
Normal reference range for primary or secondary adrenal insufficiency (< 20
ug/dl) does not apply in the critically ill population (Figure 2) as baseline cortisol
levels are increased in critically ill subjects.
60 min cortisol < 20 ug/dl after a cosyntropin stimulation test is diagnostic of
adrenal insufficiency in most settings; although it does not apply in the critically
ill population, because baseline cortisol levels are already increased, see Figure 2.
Although, patients in this population may still have diminished response and
capacity to stress, referred to as relative adrenal insufficiency. Therefore a new
reference has to be applied to the critically ill patients.
RAI is defined by an increase in cortisol ≤ 9 ug/dl following a 250 ug
cosyntropin/ACTH stim test (Figure 3). A cortisol increment ≤ 9 ug/dl suggests
diminished adrenal reserve and diminished capacity to respond to stress, termed
relative adrenal insufficiency. Diagnosing relative adrenal insufficiency in
critically ill patients is important because probability of survival decreases in this
population as shown in Figure 3 below.
Treatment for RAI/AI
Hydrocortisone 50mg IV Q6h or 100mg IV Q8h for 7 days (remember that once
hydrocortisone is started, you cannot do cosyntropin stim test since
hydrocortisone cross reacts with assay for cortisol and so does prednisone;
Alternative to IV hydrocortisone is Dexamethasome 4mg IV qd).
Outpatient dose is usually Hydrocortisone 15mg qam and 5pm or 20mg qam and
10mg qpm.
o Fludrocortisone generally not necessary due to mineralcorticoid properties of
hydrocortisone
o Glucocorticoid treatment associated with improvement in 28-day mortality, ICU
mortality, hospital mortality, and time to vasopressor withdrawal.
Figure 2. Baseline Cortisol levels in normal subjects and the critically ill
(adapted from Vermes et al. J Clin Endocrinol Metab 1995)
Figure 3. Outcomes of septic shock associated with relative adrenal
insufficiency and baseline cortisol level
(adapted from Annane et al. JAMA 2000)
CASE
A 74 yo man veteran presents to the ER with fatigue, SOB, and productive cough.
A diagnosis of COPD is present in the chart. He is on chronic home oxygen. He
reports that he has lost ~15 lbs over the past 6 mos. Looking over his chart, his
medical history is significant for COPD, BPH. PFTs done by his PCP reveal a
FEV1 of 1.1 L. His outpatient medications are atrovent and albuterol MDIs and
nebulizers. He has had three hospitalizations in the past year for COPD
exacerbations. Each time, he was discharged home with antibiotics and a
prednisone taper.
On physical examination, temperature 99.0 F, BP 98/60, HR 114 (after Duoneb
was given), RR 20 with O2 sat 88% while on 4L of oxygen. Weight is 115 lbs,
BMI 21. Physical examination is significant for a thin man with globally
diminished breath sounds without any crackles or wheezing. He is breathing with
pursed lips with contraction of accessory respiratory muscles. Remainder of the
exam is normal.
Laboratories reveal the following:
Na 133, K 4.0, Cl 92, CO2 40, BUN/Cr 6/0.4, Glu 138
WBC 12.1 (42%N, 46%L, 4%M, 6%E), H/H 13/40, Plt 225,000
Coags, LFTs, and a cardiac panel are normal.
Imaging:
PA/LAT CXR reveals no evidence of infiltrate or nodules. There is flattening of
the diaphragms bilaterally.
Hospital Course:
A diagnosis of COPD exacerbation is made. The patient is admitted to the
hospital started on atrovent and albuterol nebs Q6H, doxycycline, and prednisone
40mg taper. He improves over the course of 3 days.
1. Is there anything else you would consider prior to discharge?
2. Does the patient have adrenal insufficiency?
3. Does the patient have adrenal insufficiency?
4. How would you treat this patient now?
5. Does this patient need fludrocortisone?
Follow-up
The patient is seen in the Pulmonary Clinic 3 months after hospital discharge and
is started on Prednisone 10mg daily for his COPD.
6. What would you do with the hydrocortisone?
7. Is there anything else you would do?
QUESTION
A woman was admitted this morning in the medical intensive care unit for
elective cholecystectomy. Before surgery, her physical exam, including vital
signs, was normal. The procedure went well, and there were no noticeable
complications. However, three hours after returning to her room, she was noted to
be unresponsive, and her blood pressure was barely palpable. She was intubated
for respiratory failure. Her blood pressure has been refractory to intravenous
fluids and pressors. You are consulted to help in the workup of suspected adrenal
insufficiency.
Which of the following statements regarding adrenal insufficiency is true?
A. The most common cause of adrenal insufficiency in the US is tuberculosis
B. The critical test for the diagnosis of chronic adrenal insufficiency is the
cosyntropin test
C. Chronic secondary adrenal insufficiency is treated with hydrocortisone and
fludrocortisone, whereas chronic primary adrenal insufficiency is treated with
hydrocortisone alone
D. In idiopathic or autoimmune adrenal insufficiency, CT of the abdomen shows
enlarged adrenal glands
Post Module Evaluation
Please place completed evaluation in an interdepartmental mail envelope and address to
Dr. Wendy Gerstein, Department of Medicine, VAMC (111).
1) Topic of module:__________________________
2) On a scale of 1-5, how effective was this module for learning this topic? _________
(1= not effective at all, 5 = extremely effective)
3) Were there any obvious errors, confusing data, or omissions? Please list/comment
below:
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
4) Was the attending involved in the teaching of this module? Yes/no (please circle).
5) Please provide any further comments/feedback about this module, or the inpatient
curriculum in general:
6) Please circle one:
Attending
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