Adrenal Insufficiency

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Adrenal Insufficiency

• 23/02/07
• Naree Panamonta, MD.

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Adrenal steroids and Pathways
Cholesterol
Dehydroepi androsterone
Pregnenolone
17-hydroxypregnenolone
Progesterone
17-hydroxyprogesterone
Androstenedione
21-hydroxylase
Aldosterone
Cortisol
21-hydroxylase
Mineralocorticoid
Glucocorticoid
Androgens
Glomerulosa
Fasciculata
Reticularis
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Physiologic actions of adrenal steroids

• Steroid
  Effect
• Cortisol - BP
  control
• -
  Glucose control
• -
  Stress response
• -
  Lymphocyte inhibition
• -
  Movement of neutrophils from
  
  vascular wall to bloodstream
• -
  Thymus regression
• -
  Osteoclast stimulation
• Aldosterone - Salt
  retention
• -
  K excretion
• -
  Acid secretion
• DHEA/ - Muscle
  maintenance
• Androstenedione - Bone
  anabolism
• -
  Mental drive
• -
  Sexual function

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Causes

• Primary adrenal insufficiency
• Secondary adrenal insufficiency

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Primary adrenal insufficiency

• Causes
• Anatomic destruction of gland
• Metabolic failure in hormone production
• ACTH-blocking antibodies
• Mutation in ACTH receptor gene
• Adrenal hypoplasia congenita

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Secondary adrenal insufficiency

• Hypopituitarism due to hypothalamic-pituitary
  disease
• Suppression of H-P axis
• - By exogenous steroid
• - By endogenous steroid from tumor

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Primary adrenal insufficiency

• (Addisons disease)
• - Involve gt 90 of the glands

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Pathophysiology

• 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

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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

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Idiopathic atrophy

• 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

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PGA syndrome

• PGA type1 (Autoimmune Polyendocrinopathy-
  Candidiasis-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

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PGA syndrome

• PGA type2
• - Polygenic, asso. with HLA DR3,DR4
• - Adult onset
• - Primary adrenal insufficiency, Graves
  disease, Autoimmune thyroiditis, DM type1,
  Primary hypogonadism, celiac disease

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• Infection
• - Granulomatous diseases eg.TB, MAC,
  Histoplasmosis, Cryptococcosis, blastomycosis,
  CMV necrotizing adrenalitis
• - AIDS
• AIDS associated adrenal insufficiency
• ( necrotizing adrenalitis)
• Opportunistic infection- CMV,TB, MAC
• Kaposis sarcoma

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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

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Metabolic failure in hormone production

• 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

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Secondary adrenal insufficiency

• 1.Suppression of H-P axis
• - By exogenous steroid
• - By endogenous steroid from tumor

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Steroid induced adrenal insufficiency

• 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.

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Secondary adrenal insufficiency

• 2. Hypopituitarism due to hypothalamic-pituitary
  disease
• - Sheehans syndrome- most common (not include
  exogenous steroid)
• - Pituitary tumor, metastasis
• - Craniopharyngioma
• - Infection TB
• - Pituitary surgery or radiation
• - Others lymphocytic hypophysitis,
  sarcoidosis, histiocytosisX

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Relative adrenal insufficiency

• Critical care and Resuscitation Journal of the
  Australasian Critical Care Medicine,2006
  Dec8(4)371-5
• - In septic shock
• - Increment of lt 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.

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• American Journal of Respiratory and Critical Care
  Medicine, 2006 Dec 15
• In sepsis, adrenal insufficiency is likely when
• - Baseline cortisol levels lt10 microg/dl
• or
• - Delta cortisol lt9 microg/dl
• Unlikely when
• - Cosyntropin-stimulated cortisol level gt 44
  microg/dl or
• - Delta cortisol gt 16.8 microg/dl

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Diagnosis
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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

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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

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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

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Clinical manifestations

• Persistent shock despite adequate volume
  repletion
• Abnormal Lab
• History of prolonged steroid useprecipitating
  factors/ Cushinoid appearance

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suspected adrenal insufficiency
Rapid ACTH stimulation test
Decreased ACTH reserve not excluded
Abnormal
Normal
Adrenocortical insufficiency
Exclude 1ry Adrenal insufficiency
Metyrapone or insulin hypoglycemia testing
Plasma ACTH
Elevated
Normal or low
Abnormal
Normal
1ry Adrenal insufficiency
2ry Adrenal insufficiency
Exclude 2ry Adrenal insufficiency
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• Morning plasma cortisol
• lt5 ug/dL--- Suspected adrenal insufficiency
• gt20 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 gt 20 ug/dL or gt7 ug/dL from
  baseline
• Adrenal insufficiency lt 20 ug/dL

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• Plasma ACTH level
• - Primary adrenal insufficiency gt52 pg/ml
• ( usuallygt200 pg/ml)
• - Secondary adrenal insufficiency normal orlt10
  pg/ml
• Aldosterone increment
• - Aldosterone response 60 min after cosyntropin
  250 mg IV or IM
• - Secondary adrenal insufficiency Normal
  increment gt 5 ng/dL
• - Primary adrenal insufficiency No increment

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Tests to confirm 2ry adrenal insufficiency

• 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 insufficiency- progressive
  increase in plasma cortisol, and level gt20 ug/dL

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Tests to confirm 2ry adrenal insufficiency

• 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 lt40 mg/dl---cortisolgt 20
  ug/dl
• ( Avoid when hypoglycemia is contraindicated,
  1ry adrenal insufficiency, stroke, epilepsy)

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Tests to confirm 2ry adrenal insufficiency

• Short metyrapone test
• - Metyrapone 30 mg/kg orally at 24.00 PM
• - Blood for cortisol and 11-deoxycortisol at
  8.00 AM
• Normal- cortisol lt 8 ug/dl
• deoxycortisol gt 7ug/dl
• (Metyrapone not available in Thailand)

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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

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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

• General clinical signs appetite, sense of
  well-being
• Cushings 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 lt5
  ng/mL/hr

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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
• Her only medication was nifedipine for her
  Raynaud syndrome.

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• Progress
• Admitted into hospital two weeks after initial
  presentation.
• 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.
• 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 (0.34.1 mU/l) serum FT3 18
  pmol/l (1123 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 (047 pg/l)
• Plasma renin activity 8.9 ng/ml/h (1.14.1
  ng/ml/h) and aldosterone lt50 pmol/l (220430
  pmol/l).

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Primary adrenal insufficiency Addisons disease
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• IV saline and dextrose.
• IV or IM hydrocortisone by multiple bolus
  injections or by continuous infusion 100-150 mg
  daily
• Patients condition improved Hydrocortisone
  given orally 40 mg in the morning and 20 mg in
  the evening
• 3-4 days hydrocortisone reduced to 20-30 mg daily
  in two or three divided doses,
• Mineralocorticoid is introduced at this stage
  (Fluodrocortisone 50-100 mg daily)

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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.

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• 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 lt10 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
• 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 (normallt46 pmol/L)
• Consistent with primary adrenal insufficiency.
• Adrenal CT - showed bilateral adrenal
  haemorrhages

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• Chest radiography confirmed right basal
  pneumonia.
• She received intravenous hydrocortisone and
  antibiotics, and made an uneventful recovery.

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Thank you For your attention