Adrenal insufficiency

Rungsima Tinmanee, MD.

 Case presentation
Case 60 Yr old man, previously healthy
Low grade fever, fatique, nausea and vomiting, poor apetite
and weight loss 10 Kg in last 6 months
Worsening symptoms, postural hypotension for 2 months
Unhealing tongue ulcer
Physical examination :
Supine BP 100/60mmHg, HR 100 bpm
Upright BP 80/50 mmHg, HR 130 bpm
Hyposthenic built, BMI 20Kg/m2, mildly pale
Hyperpigmentation at palmar creases, knuckles, oral mucosa
Ill defined border tongue ulcer 3x4 cm with tenderness
 Case presentation
Lab investigation
Normochromic normocytic anemia
BUN 30, Cr 1.8, Na 135, K 5.6, FBS 85 mg/dL
CXR : no infiltration
Basal cortisol level = 3.36 mcg/dL
250 mcg ACTH stimulation test
-> Cortisol 30 min = 6 mcg/dL, 60 min = 7 mcg/dL

Adrenal insufficiency
 Adrenal insufficiency

Manifestation of deficient production or action of

glucocorticoids

Classification
Primary
Secondary

Acute / Adrenal crisis

Chronic adrenal insufficiency
Hypothalamic-Pituitary-Adrenal Axis

Williams Textbook of
Endocrinology 12th edition
Circadian Regulation

Williams Textbook of
Endocrinology 12th edition
 Primary VS Secondary

Williams Textbook of Endocrinology 12th edition

Primary VS Secondary

Williams Textbook of Endocrinology 12th edition

 Causes of AI
Primary Secondary
- Autoimmune adrenalitis 1st - Exogenous glucocorticoid 1st

- Infection - Hypothalamic / Pituitary

Tuberculosis disease
Mycosis Pituitary macroadenoma
Bacterial Rathke cyst / Craniopharyngioma
HIV associated Cranial irradiation
Hypothalamic tumor
- Metastatic cancer sarcoidosis
Hypophysitis
- Medications : Traumatic brain injury
Etomidate Sheehan syndrome
Ketoconazole
Metopirone - Chronic administration of drug
with glucocorticoid activity
- Adrenal hemorrhage - Megestrol acetate
Adapted from Endocr Pract 2011;17(2):261-70
 Clinical presentation
Primary Secondary
Symptoms - Fatique, nausea, anorexia - Same
- Wt loss, abdominal pain
- arthralgia, low grade fever - Absent salt craving
- Salt craving, Postural dizziness
Postural dizziness
- decreased libido
decreased pubic hair or
axillary hair in women

Signs - Hyperpigmentation - Normal pigmentation

- Dehydration - Normovolemia
- Hypotension - minimal change in BP

- Decreased pubic hair or - Decreased pubic hair or

axillary hair axillary hair

- Sign of Cushings syndrome

Adapted from Endocr Pract 2011;17(2):261-70
Williams Textbook of Endocrinology 12th edition
 Clinical presentation
Primary Secondary
Major Lab - Low baseline serum cortisol - Low baseline serum cortisol
Findings
- High plasma ACTH level - Low or normal ACTH level
- Low serum aldosterone level - normal aldosterone level
- High plasma renin activity - normal plasma renin activity

- Low serum DHEA / DHEA-S - Low serum DHEA / DHEA-S

Other Lab - Hyponatremia - Same

Findings - Hyperkalemia - No hyperkalemia

- Azotemia
- Mild metabolic acidosis
- Hypercalcemia
- Hypoglycemia
- NCNC anemia
- Lymphocytosis, eosinophilia
Adapted from Endocr Pract 2011;17(2):261-70
 Adrenal crisis
Medical emergency condition
Hypotension or shock out of proportion to severity of
current illness
Acute circulatory failure
GI symptoms : nausea, vomiting, abdominal pain
Unexplained hypoglycemia
Unexplained fever
Hyperpigmentation / Vitiligo / Cushings syndrome
Other autoimmune endocrine deficiency : Hypothyroidism
Lab : hyponatremia, hyperkalemia, Azotemia,
Hypercalcemia, eosinophilia

Williams Textbook of Endocrinology 12th edition

 Diagnosis
History, PE, Lab investigation
Confirm Dx of AI : assess HPA axis function
Primary or Secondary AI
Identify cause of AI
Find intercurrent illness : Autoimmune disease
 Assessment of HPA axis Function

Serum cortisol level

ACTH stimulation test
Insulin tolerant test (ITT)
 Serum cortisol level
Serum cortisol = protein bound form + free form
Depend on CBG
CBG : pregnancy, estrogen therapy, HCV -> cortisol
CBG : hypoalbuminemia, illness -> cortisol

Basal serum cortisol : 8-9 AM

> 14.5 mcg/dL -> intact HPA axis
< 3-5 mcg/dL -> Adrenal insufficiency
Critically ill patient : random
< 15 mcg/dL -> suggest AI
> 33 mcg/dL -> appropriate response
Intermediate cortisol level -> perform ACTH stimulation
test Williams Textbook of Endocrinology 12th edition
JAMA, November 16, 2005-Vol 284, No. 19
 250 mcg ACTH stimulation test
Indicate in suspected AI except adrenal crisis -> Prompt Rx
Baseline cortisol at o minute
250 mcg synthetic ACTH IV or IM
Follow cortisol level at 30, 60 min
Normal response cortisol > 18 mcg/dL (>20 mcg/dL)
Limitation
Recent pituitary insult (< 4 wk) : Surgery, apoplexy
ACTH reaches plasma level 1000 times of normal
stress level
Falsely normal in partially impaired adrenal gland

Williams Textbook of Endocrinology 12th edition

JAMA, November 16, 2005-Vol 284, No. 19
 1 mcg ACTH stimulation test
More physiological ACTH dose
More sensitive for diagnosis secondary AI
250 mcg ACTH 1 vial -> diluted to concentration 1 mcg/ml
keep in 4 C for up to 4 months

Baseline cortisol at 0 min

1 mcg ACTH IV
Follow cortisol level at 20, 30, 40 min
Normal response cortisol > 18 mcg/dL

Need further validation

Williams Textbook of Endocrinology 12th edition
JAMA, November 16, 2005-Vol 284, No. 19
 Insulin tolerance test
Gold standard for evaluate HPA axis
Evaluate GH reserve in hypothalamic-pituitary disease
Baseline cortisol -> IV soluble insulin 0.1-0.15 U/Kg
Follow cortisol level + BS at 30, 45, 60, 90, 120 min
Induce hypoglycemia : BS < 40 or neuroglycopenic symptom
Normal Response : cortisol > 18 mcg/dL
ACTH Stimulation test : more cheaper, faster, safer
Indication : borderline ACTH stimulation test
but normal ITT : no hydrocortisone Rx
Contraindication : MI, Epilepsy, severe hypopituitarism
( basal cortisol < 6.5 mcg/dL ), critically ill
Williams Textbook of Endocrinology 12th edition
JAMA, November 16, 2005-Vol 284, No. 19
 Morning serum 250 mcg ACTH- Insulin tolerance
cortisol level stimulation test test (ITT)

Stimulus - 250 mcg ACTH IV RI 0.1 -0.15 U/kg IV

Blood drawing 8-9 AM 0, 30, 60 min 0, 30, 45, 60, 90,

time points 120 min

Measurements Serum cortisol Serum cortisol Serum cortisol, BS

Normal HPA >18 ug/dl > 18 ug/dl Serum cortisol

axis > 18 ug/dl
if PG <40 mg/dl

Limitation Cortisol binding Secondary AI Contraindication : MI,

globulin epiliepsy, severe
hypopituitarism
 Clinical suspicious of AI
Fatique, hypotension, nausea, anorexia, abdominal pain, Wt loss,
low grade fever, Postural dizziness, Adrenal crisis
Unexplained hypotension /
Confirm Diagnosis of AI hypoglycemia

Adrenal Crisis
Basal Cortisol Stress Cortisol Prompt Treatment
< 5 mcg/dL < 15 mcg/dL Stable - Blood : glucose, electrolyte,
> 14.5 mcg/dL > 33 : normal cortisol, ACTH
Intact HPA axis response - IV fluid resuscitation
- 100 mg hydrocortisone IV stat
Suggest AI
then 100-200mg IV in 24 hr
- Search + correct precipitating
250 mcg ACTH Insulin tolerance causes
stimulation test test : BS < 40
(1 mcg) Cortisol
Cortisol < 18 mcg/dL Confirm Dx of
< 18 mcg/dL Adrenal insufficiency
 Adrenal Insufficiency

Clues for Primary AI EndocrineNo Autoimmune

hyperkalemia
Disorder :
- PE : Postural hypotension - Hypo/Hyperthyroidism
Normal / Low ACTH Secondary AI
Hyperpigmentation - Vitiligo, Normal
Type 1 DM
renin
Volume depletion - Lab : thyroid function test
- Lab : Hyperkalemia Adrenal autoAb : 21-Hydroxylase Ab
Hypercalcemia
Primary AI
Cr rising Infection
High ACTH - Prolonged fever, Other organ affected
High renin - Immunocompromised host
low aldosterone - Lab : Anti HIV, CBC, LFT, CXR, Bacteria-fungus C/S

Metastatic cancer
- Lung, Breast
CT/ MRI adrenal gland - Stomach, colon, melanoma, lymphoma

Adrenal hemorrhage
- Bleeding tendency, Antiphospholipid syndrome
CT guided FNA adrenal gland - Meningococcemia
- Infection Lab : CBC, Coagulogram, APS panel, H/C
- mass
 Secondary AI

Exclude from Exogenous glucocorticoid

- Hx of exo. Steroid uses
- Cushing syndrome

- Hx of brain surgery, trauma, radiation

- Hx of antepartum / postpartum hemorrhage

Hypothalamus/pituitary abnormality
- mass effect
- visual field defect
- hormonal function abnormality
- Lab : Prolactin, TFT, Clue of DI

MRI pituitary gland

Williams Textbook of Endocrinology 12th edition
 Treatment
Adrenal Crisis Long term replacement therapy Patient Education

Intravenous access : uses large-gauge needle.

Draw blood stat for electrolytes, glucose, cortisol and ACTH
IV resuscitation
2-3 L of 0.9% saline solution or 5%D/NSS solution as quickly as possible
Volume status monitoring : central or peripheral venous pressure and
listening for pulmonary rales.
Reduce infusion rate if indicated.
Intravenous hydrocortisone
100 mg IV stat then
100-200 mg in 5% glucose IV drip in 24 h or q 6-8 hr
Other symptomatic and supportive Rx

Williams Textbook of Endocrinology 12th edition

J Clin Endocrinol Metab, April 2009, 94(4):1059-1067
 Treatment
Adrenal Crisis Long term replacement therapy Patient Education
After stabilization

IV fluid : continue NSS at a slower rate for next 24-48 hr.

Search and treat precipitating causes of the adrenal crisis.
Confirm diagnosis : Perform ACTH stimulation test
(if patient does not have known adrenal insufficiency).
Determine the type of adrenal insufficiency and its cause
Glucocorticoid replacement :
Taper to maintenance dosage over 1-3 days
(if precipitating or complicating illness permits)
Mineralocorticoid replacement : in primary AI
Fludrocortisones (0.1 mg by mouth daily) when saline infusion is stopped

Williams Textbook of Endocrinology 12th edition

 Treatment
Adrenal Crisis Long term replacement therapy Patient Education

Glucocorticoid Replacement
Low normal cortisol production rates : 8-15 mg/d
Patients usually cope with cortisol 15-25 mg/d
Smallest dose to relieve symptoms
Hydrocortisone 15-25 mg/d / Prednisolone 5-7.5 mg/d
Awakening : Hydrocortisone 15-20 mg/ Prednisolone 5 mg
6 PM : Hydrocortisone 5-10 mg/ Prednisolione 2.5 mg
Monitoring : well-being, BW, BMI, Blood pressure
morning plasma ACTH
Underreplacement : Wt. loss, fatique, nausea, myalgia
Overreplacement : Wt. gain, central obesity, stretch mark
Hypertension, osteoporosis, impaired glucose tolerance
Williams Textbook of Endocrinology 12th edition
J Clin Endocrinol Metab, April 2009, 94(4):1059-1067
 Treatment
Adrenal Crisis Long term replacement therapy Patient Education

Mineralocorticoid Replacement
In primary adrenal insufficiency
Fludrocortisone 0.1 (0.05 0.2) mg orally after awake OD
Liberal salt intake
Monitoring : BP (supine, upright), electrolyte, plasma renin activity

Approximate Relative Mineralocorticoid

equivalent dose, mg potency activity
Hydrocortisone 20 1 1
Prednisolone 5 4 0.75
Dexamethasone 0.75 26 0
Fludrocortisone - 12 125
Williams Textbook of Endocrinology 12th edition J Clin Endocrinol Metab, April 2009, 94(4):1059-1067
 Treatment
Adrenal Crisis Long term replacement therapy Patient Education

Adrenal Androgen Replacement

Both in primary or secondary adrenal insufficiency
Impaired well-being or mood despite optimized treatment of glucocorticoid
and mineralocorticoid
Woman with clinical of androgen deficiency
Dry iching skin, decrease libido
Dehydroepiandosterone
DHEA 25-50 mg orally once in the morning

Williams Textbook of Endocrinology 12th edition

J Clin Endocrinol Metab, April 2009, 94(4):1059-1067
 Treatment
Adrenal Crisis Long term replacement therapy Patient Education

Emergency bracelet or necklace

Steriod card
Education : stress-related glucocorticoid dose adjustment for patient and
their family
Vacation or living far from hospital : hydrocortisone emergency self-
injection kit (IM)

Williams Textbook of Endocrinology 12th edition

 Therapy during stress
Intercurrent illness Dose adjustment

- Minor febrile illness : Increase glucocorticoid dose 2x -3x

common cold, viral chest for few days
infection
- Persistent vomiting or Admission to hospital for IV
diarrhea (gastroenteririts) hydrocortisone

- Serious medical illness Hydrocortisone 100 mg IV every 8 hr

(severe sepsis, MI, continuous IV infusion 200 mg/24 hr
pancreatitis)
or major trauma

Williams Textbook of Endocrinology 12th edition

 Therapy during stress
Surgery
- Minor procedures under LA
and most radiologic studies
- Moderately stressful
procedure (Barium enema,
herniorrphaphy, EGD,
colonoscopy, CAG)
- Major surgery
(Intraabdominal,
Cardiothoracic surgery)
Dose adjustment
No extra supplementation
Single 100 mg IV hydrocortisone just
before procedure
Hydrocortisone 100 mg IV just before
induction of anesthesia
continue q8h for first 24 h
taper rapidly, decreasing by half per
day to maintenance level
Williams Textbook of Endocrinology 12th edition
 Therapy during stress
Intercurrent illness Increment in glucocorticoid dose

- Pregnancy - In third trimester : increase

hydrocortisone 5-10 mg/d

- Labour - Hydrocortisone 50 mg IM q 6 hr +
well hydrated

Williams Textbook of Endocrinology 12th edition

 Case presentation
ACTH = 1250 pg/ml
Tongue biopsy : Intracellular encapsulated yeast
CT adrenal protocol : Enlarged bilateral adrenal gland
with supcapsular calcium
Percutaneous aspiration :
Intracellular encapsulated yeast

Dx : Disseminated Histoplasmosis
with primary adrenal insufficiency
Thank You