Transcript Adrenal Insufficiency - Khon Kaen University

Adrenal Insufficiency
23/02/07
Naree Panamonta, MD.
Adrenal steroids and Pathways
Cholesterol
Pregnenolone
17-hydroxypregnenolone
Dehydroepi
androsterone
Progesterone
17-hydroxyprogesterone
Androstenedione
21-hydroxylase
Aldosterone
Cortisol
21-hydroxylase
Mineralocorticoid
Glomerulosa
Glucocorticoid
Fasciculata
Androgens
Reticularis
Physiologic actions of adrenal steroids
Steroid
 Cortisol

Aldosterone
DHEA/
Androstenedione
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Effect
- BP control
- Glucose control
- Stress response
- Lymphocyte inhibition
- Movement of neutrophils from
vascular wall to bloodstream
- Thymus regression
- Osteoclast stimulation
- Salt retention
- K excretion
- Acid secretion
- Muscle maintenance
- Bone anabolism
- Mental drive
- Sexual function
Causes
Primary adrenal insufficiency
 Secondary adrenal insufficiency

Primary adrenal insufficiency
Causes
 Anatomic destruction of gland
 Metabolic failure in hormone production
 ACTH-blocking antibodies
 Mutation in ACTH receptor gene
 Adrenal hypoplasia congenita
Secondary adrenal insufficiency
Hypopituitarism due to hypothalamicpituitary disease
 Suppression of H-P axis
- By exogenous steroid
- By endogenous steroid from tumor

Primary adrenal
insufficiency
(Addison’s disease)
- Involve > 90% of the glands
Pathophysiology
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Gradual adrenocortical destruction
- Initial phase: Decreased adrenal reserve
Basal steroid secretion- Normal
Not increase in stress response
- Further loss of cortical tissue
Impair basal secretion of glucocorticoid and
mineralocorticoid
Plasma ACTH elevation- Earliest and most
sensitive indication
Anatomic destruction of gland
1. Idiopathic atrophy: Autoimmune,
adrenoleukodystrophy
2. Surgical removal
3. Infection: TB, Fungus, Virus esp. in AIDS
4. Hemorrhage
5. Invasion: Metastasis eg. CA thyroid, breast,
kidney, lymphoma
Idiopathic atrophy
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Most common cause 70-80%
Autoantibody: adrenal cortex Ab, 21-hydroxylase
Ab
Isolated or associated with polyglandular
autoimmune syndrome
PGA syndrome 2 types
1).PGA type1- more common
2).PGA type2
PGA syndrome

PGA type1 (Autoimmune PolyendocrinopathyCandidiasis-Ectodermal Dysplasia)
- Autosomal recessive (no HLA association)
- Childhood onset
- 2/3 of these clinicals
:Chronic mucocutaneous candidiasis
:Chronic hypoparathyroid
:Autoimmune adrenal insufficiency
- Other: Hypogonadotropic hypogonadism, DM type1,
Autoimmune thyroid disease, Lymphocytic
hypophysitis, Pernicious anemia, Chronic active
hepatitis, Vitiligo, Alopecia
PGA syndrome

PGA type2
- Polygenic, asso. with HLA DR3,DR4
- Adult onset
- Primary adrenal insufficiency, Grave’s
disease, Autoimmune thyroiditis, DM
type1, Primary hypogonadism, celiac
disease
Infection
- Granulomatous diseases eg.TB, MAC,
Histoplasmosis, Cryptococcosis,
blastomycosis, CMV necrotizing adrenalitis
- AIDS
: AIDS associated adrenal insufficiency
( necrotizing adrenalitis)
: Opportunistic infection- CMV,TB, MAC
: Kaposi’s sarcoma

Histoplasmosis:
Large bilateral
adrenal masses
(arrows) patchy&
peripheral
enhancement,
central
hypodensities,
septations.
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Hemorrhage and infarction
- Anticoagulant
- Hypercoagulable states eg. Antiphospholipid
syndrome
- Meningococcemia, pseudomonas infection
(Waterhouse-Friderichsen syndrome)
Infiltration:
- Metastasis: breast, lung, kidney, pancrease,
melanoma, stomach
- Lymphoma
- Other infiltrative diseases: amyloidosis,
sarcoidosis, scleroderma
Metabolic failure in hormone
production

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Congenital adrenal hyperplasia
: Inborn error of cortisol synthesis
: 5 types ( classified by type of enz. deficiency)
- Most common :21-hydroxylase deficiency
- 2nd most common: 11-hydroxylase deficiency
Drugs
- Enzyme inhibitors: Metyrapone, phenytoin ,
barbiturate, ketoconazole, aminoglutethimide
- Cytotoxic agent: Mitotane
Secondary adrenal insufficiency
1.Suppression of H-P axis
- By exogenous steroid
- By endogenous steroid from tumor
Steroid induced adrenal insufficiency
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Long-term glucocorticoid therapy (suppression of CRH
production).
15 mg qd prednisone (or equivalent) for 3+ weeks---- HPA
axis can be suppressed for ~ 8-12 months.
Divided daily dosing more suppressive than once daily
dosing.
Giving steroid every other day avoids axis suppression
QOD dosing helps with all side effects except the
cumulative ones: osteoporosis, cataract.
Clue to adrenal HPA axis suppression is small joint
aches (hands, feet) when glucocorticoid is withdrawn.
Large doses of progesterone or megace also suppress
adrenal axis.
Secondary adrenal insufficiency
2. Hypopituitarism due to hypothalamic-pituitary
disease
- Sheehan’s syndrome- most common (not
include exogenous steroid)
- Pituitary tumor, metastasis
- Craniopharyngioma
- Infection: TB
- Pituitary surgery or radiation
- Others: lymphocytic hypophysitis,
sarcoidosis, histiocytosisX
Relative adrenal insufficiency

Critical care and Resuscitation: Journal of the
Australasian Critical Care Medicine,2006
Dec;8(4):371-5
- In septic shock
- Increment of < 250 nmol/L in total serum
cortisol level after administration of 250 microg
corticotropin
- RAI associated with increased risk of death
- There is strong, but not overwhelming,
evidence that administration of low doses of
hydrocortisone to patients with septic shock,
especially those with RAI, improves survival.
American Journal of Respiratory and Critical Care
Medicine, 2006 Dec 15
 In sepsis, adrenal insufficiency is likely when
- Baseline cortisol levels <10 microg/dl
or
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- Delta cortisol <9 microg/dl
Unlikely when
- Cosyntropin-stimulated cortisol level > 44
microg/dl or
- Delta cortisol > 16.8 microg/dl
Diagnosis
Clinical manifestations

Chronic Primary adrenal insufficiency
- Weakness, fatigue, anorexia, Wt. loss: cardinal
symptom
- Hyperpigmentation: Sun-exposed area,
pressured area, skin creases, mucous
membrane
- Arterial hypotension, dehydration
- Abnormality of GI function: N/V, diarrhea
- Lab abnormalities: Anemia (NCNC/pernicious
anemia), Lymphocytosis, Eosinophilia,
hypoglycemia, hyponatremia, hyperkalemia,
hyperchloremic metabolic acidosis
Clinical manifestations

Acute adrenal crisis
- Hypovolemic shock (unexplained
vascular collaspe)
- Abdominal pain
- Weakness, apathy, and confusion
- Precipitated by stress
- Acute adrenal hemorrhage: abdominal,
flank, or back pain with rigidity/ rebound
tenderness
Clinical manifestations

Secondary adrenal insufficiency
- Clinically same as 1ry Adrenal insufficiency
- No hyperpigmentation, severe hyponatremia,
severe dehydration, or hyperkalemia
- Multiple hormone deficiency: total pituitary
insufficiency
- Cushinoid appearance: prolonged excess
glucocorticoid
Clinical manifestations
1.
2.
3.
Persistent shock despite adequate
volume repletion
Abnormal Lab
History of prolonged steroid
use+precipitating factors/ Cushinoid
appearance
1ry and 2ry adrenal
insuff.
1ry adrenal insuff. and
associated disorder
2ry adrenal insuff. and
associated disorders
-Tiredness, weakness,
mental depression,
headache
-Anorexia, wt. loss
-Hyperpigmentation
-Hyperkalemia
-Vitiligo
-Pale skin with out
marked anemia
-Dizziness, orthostatic
hypotension
-Abdominal cramps,
N/V, diarrhea
-Hyponatremia
-Hypoglycemia
-Mild normocytic
anemia,
lymphocytosis,
eosinophilia
-Hypercalcemia(rare)
-Loss of body hair in
women
-Autoimmune thyroid
disease
-CNS symptoms in
adrenomyeloneuro
pathy
-Salt craving
-Acidosis (type IV RTA)
-Increased taste
sensitivity (to salt)
-Hyperacusis
-Amenorrhea,
decraesed libido, and
potency
-Scanty axillary and
pubic hair
-Small testicles
-Secondary
hypothyroidism
-Prepubertal growth
deficit, delayed puberty
-Headache, visual
symptoms
-Thorn’s sign: auricular -Diabetes insipidus
calcification (male
only)
suspected adrenal insufficiency
Rapid ACTH stimulation test
Abnormal
Normal
Adrenocortical
insufficiency
Exclude 1ry Adrenal
insufficiency
Plasma ACTH
Elevated
1ry Adrenal
insufficiency
Normal or low
2ry Adrenal
insufficiency
Abnormal
Decreased ACTH
reserve not excluded
Metyrapone or insulin
hypoglycemia testing
Normal
Exclude 2ry Adrenal
insufficiency
Morning plasma cortisol:
<5 ug/dL--- Suspected adrenal insufficiency
>20 ug/dL--- Exclude adrenal insufficiency
 Rapid ACTH stimulation test
- Serum cortisol at 8.00 am
- Cosyntropin 250 ug iv. or IM
- Plasma cortisol at 30 and 60 min after
injection
: Normal cortisol > 20 ug/dL or >7 ug/dL from
baseline
Adrenal insufficiency < 20 ug/dL
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Plasma ACTH level
- Primary adrenal insufficiency >52 pg/ml
( usually>200 pg/ml)
- Secondary adrenal insufficiency –normal or<10
pg/ml
Aldosterone increment
- Aldosterone response 60 min after
cosyntropin 250 mg IV or IM
- Secondary adrenal insufficiency: Normal
increment > 5 ng/dL
- Primary adrenal insufficiency: No increment
Tests to confirm 2ry adrenal
insufficiency
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Prolong ACTH stimulation
- Baseline plasma cortisol
- Cosyntropin 250 ug iv q 8 hr for 48 hr.
: Primary adrenal insufficiency- plasma
cortisol no change
: Secondary adrenal insufficiencyprogressive increase in plasma cortisol,
and level >20 ug/dL
Tests to confirm 2ry adrenal
insufficiency
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Insulin induced hypoglycemia
- Suspected hypothalamic or pituitary disease
- NPO after midnight, 0.9% NSS iv
- Short acting insulin 0.05-0.1 u/kg at morning
- Blood for plasma glucose and cortisol at 30, 60,
90, and 120 min
Normal response- if BS <40 mg/dl---cortisol> 20
ug/dl
( Avoid when hypoglycemia is contraindicated, 1ry
adrenal insufficiency, stroke, epilepsy)
Tests to confirm 2ry adrenal
insufficiency
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Short metyrapone test
- Metyrapone 30 mg/kg orally at 24.00 PM
- Blood for cortisol and 11-deoxycortisol at
8.00 AM
Normal- cortisol < 8 ug/dl
deoxycortisol > 7ug/dl
(Metyrapone not available in Thailand)
Treatment :Acute Adrenal crisis
Glucocorticoid replacement
1.Hydrocortisone 100 mg iv every 6 hr. for 24 hr.
2. Hydrocortisone 50 mg every 6 hr. when stable
3. Maintenance therapy (10 mg 3 times/days) by day 4
or 5
4. Increase dose to 200-400 mg/day if complication
occurs
General and supportive measures
1. Correct volume depletion, dehydration,
hypoglycemia with iv saline and glucose
2. Correct infection and other precipitating causes
Treatment: Maintenance therapy
Hydrocortisone 15-20 mg in AM and 10
mg orally at 4-5 PM
 Fludrocortisone 0.05-0.1 mg orally in AM
 Clinical follow-up: Clinical feature, BW, BP,
Elyte
 Increased hydrocortisone during stress
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Response to therapy
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General clinical signs: appetite, sense of wellbeing
Cushing’s syndrome: overtreatment
ACTH and urine free cortisol not a reliable index
Mineralocorticoid replacement:
- BP without orthostatic change
- Elyte- Na and K
- Plasma renin activity (PRA)- upright <5
ng/mL/hr
Steroid coverage for surgery
Correct Elyte, BP, hydration
 Hydrocortisone 100 mg IM on call
 Hydrocortisone 50 mg IM or IV in recovery
room and q 6 hr. for 24 hr.
 Reduce dose to 25 mg q 6 hr. for 24 hr.
and taper to maintenance dose over 3-5
days
 Increase dose to 200-400 mg/day if
complications occur
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Case 1
69-year-old female presented with palpitations
and a history of tiredness and shortness of
breath for several weeks.
 She had a previous history of Raynaud
syndrome.
 Get a persistent tan since the previous summer
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Her only medication was nifedipine for her
Raynaud syndrome.
Progress
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Admitted into hospital two weeks after initial
presentation.
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Increasing lethargy and tiredness, reduced
appetite ,fainting, and weight loss.
On examination, she was pigmented and thin
Her pulse rate 76/min. BP 77/59 mm Hg.
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The rest of the examination was normal.
Serum sodium 132 mmol/l, potassium 5.1 mmol/l
BUN/Cr within normal limits
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SerumTSH 7.87 mU/l (0.3–4.1 mU/l); serum FT3 18
pmol/l (11–23 pmol/l)
Extractable-nuclear-antigen ribonucleic proteins positive
Thyroid microsomal antibodies- positive (titre greater
than 1/800)
ANA - negative.
Cortisol at baseline 135 mmol/l
Rapid ACTH test- cortisol at 30 minutes 144 mmol/l
Baseline ACTH 434 pg/l (0–47 pg/l)
Plasma renin activity 8.9 ng/ml/h (1.1–4.1 ng/ml/h);
and aldosterone <50 pmol/l (220–430 pmol/l).
Primary adrenal
insufficiency:
Addison’s disease
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IV saline and dextrose.
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IV or IM hydrocortisone by multiple bolus
injections or by continuous infusion 100-150 mg
daily
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Patient’s condition improved : Hydrocortisone
given orally 40 mg in the morning and 20 mg in
the evening
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3-4 days hydrocortisone reduced to 20-30 mg
daily in two or three divided doses,
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Mineralocorticoid is introduced at this stage
(Fluodrocortisone 50-100 mg daily)
Case 2
68-year-old woman found on the floor 28 hr
PTA
 Cough and diarrhea.
 No significant medical history ,not take any
regular medications.
 At presentation, her core temperature was
24.9 C, BP 80 mm Hg systolic, PR 40, and
GCS 11
 Physical examination
- Consistent with right basal pneumonia.
- No abdominal tenderness, or signs of
endocrine dysfunction or trauma.

Haemoglobin was 138 g/L, but fell to 97
g/L 24 h later.
 Electrolytes, clotting profile, DIC screen,
serum calcium, and TFT were normal.
 Toxicology screen- negative.
 CRP 170 mg/L (normal <10 mg/L).
 Antiphospholipid antibody screen negative.
 She was rewarmed, fluid-resuscitated,
given adrenaline and atropine,
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ECG showed sinus bradycardia and
Osborn waves, which disappeared after
rewarming.
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Persistent, inotrope-refractory hypotension
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Short Synacthen (ACTH) test : Basal
cortisol level 57 nmol/L
Failed to rise 30 and 60 min- 55 and 60
nmol/L, respectively.
 ACTH was 178 pmol/L (normal<46 pmol/L)
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Consistent with primary adrenal
insufficiency.
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Adrenal CT - showed bilateral adrenal
haemorrhages
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Chest radiography confirmed right basal
pneumonia.
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She received intravenous hydrocortisone
and antibiotics, and made an uneventful
recovery.
Thank you
For your attention