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
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 hypothalamic- pituitary 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 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 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
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 - 2 nd 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 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 - Delta cortisol <9 microg/dl Unlikely when - Cosyntropin-stimulated cortisol level > 44 microg/dl or - Delta cortisol > 16.8 microg/dl
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
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
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 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 >20 ug/dL
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 20 ug/dl ( Avoid when hypoglycemia is contraindicated, 1ry adrenal insufficiency, stroke, epilepsy)
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 < 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
Response to therapy General clinical signs: appetite, sense of well- being 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
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.
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
IV saline and dextrose. IV or IM hydrocortisone by multiple bolus injections or by continuous infusion 100-150 mg daily Patient’s 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)
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,
ECG showed sinus bradycardia and Osborn waves, which disappeared after rewarming.
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 (normal<46 pmol/L) Consistent with primary adrenal insufficiency. Adrenal CT - showed bilateral adrenal haemorrhages