2Adrenal steroids and Pathways CholesterolDehydroepiandrosteronePregnenolone17-hydroxypregnenoloneProgesterone17-hydroxyprogesteroneAndrostenedione21-hydroxylaseAldosteroneCortisol21-hydroxylaseMineralocorticoidGlucocorticoidAndrogensGlomerulosaFasciculataReticularis
3Physiologic actions of adrenal steroids Steroid EffectCortisol BP control- Glucose control- Stress response- Lymphocyte inhibition- Movement of neutrophils from vascular wall to bloodstream- Thymus regression- Osteoclast stimulationAldosterone Salt retention- K excretion- Acid secretionDHEA/ Muscle maintenanceAndrostenedione Bone anabolism- Mental drive- Sexual function
5Primary adrenal insufficiency CausesAnatomic destruction of glandMetabolic failure in hormone productionACTH-blocking antibodiesMutation in ACTH receptor geneAdrenal hypoplasia congenita
6Secondary adrenal insufficiency Hypopituitarism due to hypothalamic-pituitary diseaseSuppression of H-P axis- By exogenous steroid- By endogenous steroid from tumor
7Primary adrenal insufficiency (Addison’s disease)- Involve > 90% of the glands
8Pathophysiology Gradual adrenocortical destruction - Initial phase: Decreased adrenal reserveBasal steroid secretion- NormalNot increase in stress response- Further loss of cortical tissueImpair basal secretion of glucocorticoid and mineralocorticoidPlasma ACTH elevation- Earliest and most sensitive indication
9Anatomic destruction of gland 1. Idiopathic atrophy: Autoimmune, adrenoleukodystrophy2. Surgical removal3. Infection: TB, Fungus, Virus esp. in AIDS4. Hemorrhage5. Invasion: Metastasis eg. CA thyroid, breast, kidney, lymphoma
10Idiopathic atrophy Most common cause 70-80% Autoantibody: adrenal cortex Ab, 21-hydroxylase AbIsolated or associated with polyglandular autoimmune syndromePGA syndrome 2 types1).PGA type1- more common2).PGA type2
11PGA syndromePGA 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
18Metabolic 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 deficiencyDrugs- Enzyme inhibitors: Metyrapone, phenytoin , barbiturate, ketoconazole, aminoglutethimide- Cytotoxic agent: Mitotane
19Secondary adrenal insufficiency 1.Suppression of H-P axis- By exogenous steroid- By endogenous steroid from tumor
20Steroid 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 suppressionQOD 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.
21Secondary 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
22Relative 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.
23American Journal of Respiratory and Critical Care Medicine, 2006 Dec 15 In sepsis, adrenal insufficiency is likely when- Baseline cortisol levels <10 microg/dlor- Delta cortisol <9 microg/dlUnlikely when- Cosyntropin-stimulated cortisol level > 44 microg/dl or- Delta cortisol > 16.8 microg/dl
27Clinical 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
28Clinical 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
301ry and 2ry adrenal insuff. 1ry adrenal insuff. and associated disorder2ry adrenal insuff. and associated disorders-Tiredness, weakness, mental depression, headache-Anorexia, wt. loss-Dizziness, orthostatic hypotension-Abdominal cramps, N/V, diarrhea-Hyponatremia-Hypoglycemia-Mild normocytic anemia, lymphocytosis, eosinophilia-Hypercalcemia(rare)-Loss of body hair in women-Hyperpigmentation-Hyperkalemia-Vitiligo-Autoimmune thyroid disease-CNS symptoms in adrenomyeloneuropathy-Salt craving-Acidosis (type IV RTA)-Increased taste sensitivity (to salt)-Hyperacusis-Thorn’s sign: auricular calcification (male only)-Pale skin with out marked anemia-Amenorrhea, decraesed libido, and potency-Scanty axillary and pubic hair-Small testicles-Secondary hypothyroidism-Prepubertal growth deficit, delayed puberty-Headache, visual symptoms-Diabetes insipidus
31suspected adrenal insufficiency Rapid ACTH stimulation testDecreased ACTH reserve not excludedAbnormalNormalAdrenocortical insufficiencyExclude 1ry Adrenal insufficiencyMetyrapone or insulin hypoglycemia testingPlasma ACTHElevatedNormal or lowAbnormalNormal1ry Adrenal insufficiency2ry Adrenal insufficiencyExclude 2ry Adrenal insufficiency
32Morning plasma cortisol: <5 ug/dL--- Suspected adrenal insufficiency>20 ug/dL--- Exclude adrenal insufficiencyRapid 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 baselineAdrenal insufficiency < 20 ug/dL
33Plasma ACTH level- Primary adrenal insufficiency >52 pg/ml( usually>200 pg/ml)- Secondary adrenal insufficiency –normal or<10 pg/mlAldosterone 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
34Tests 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
35Tests to confirm 2ry adrenal insufficiency Insulin induced hypoglycemia- Suspected hypothalamic or pituitary disease- NPO after midnight, 0.9% NSS iv- Short acting insulin u/kg at morning- Blood for plasma glucose and cortisol at 30, 60, 90, and 120 minNormal response- if BS <40 mg/dl---cortisol> 20 ug/dl( Avoid when hypoglycemia is contraindicated, 1ry adrenal insufficiency, stroke, epilepsy)
36Tests to confirm 2ry adrenal insufficiency Short metyrapone test- Metyrapone 30 mg/kg orally at PM- Blood for cortisol and 11-deoxycortisol at 8.00 AMNormal- cortisol < 8 ug/dldeoxycortisol > 7ug/dl(Metyrapone not available in Thailand)
37Treatment :Acute Adrenal crisis Glucocorticoid replacement1.Hydrocortisone 100 mg iv every 6 hr. for 24 hr.2. Hydrocortisone 50 mg every 6 hr. when stable3. Maintenance therapy (10 mg 3 times/days) by day 4 or 54. Increase dose to mg/day if complication occursGeneral and supportive measures1. Correct volume depletion, dehydration, hypoglycemia with iv saline and glucose2. Correct infection and other precipitating causes
38Treatment: Maintenance therapy Hydrocortisone mg in AM and 10 mg orally at 4-5 PMFludrocortisone mg orally in AMClinical follow-up: Clinical feature, BW, BP, ElyteIncreased hydrocortisone during stress
39Response to therapyGeneral clinical signs: appetite, sense of well-beingCushing’s syndrome: overtreatmentACTH and urine free cortisol not a reliable indexMineralocorticoid replacement:- BP without orthostatic change- Elyte- Na and K- Plasma renin activity (PRA)- upright <5 ng/mL/hr
40Steroid coverage for surgery Correct Elyte, BP, hydrationHydrocortisone 100 mg IM on callHydrocortisone 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 daysIncrease dose to mg/day if complications occur
41Case 169-year-old female presented with palpitations and a history of tiredness and shortness of breath for several weeks.She had a previous history of Raynaudsyndrome.Get a persistent tan since the previous summerHer only medication was nifedipine for her Raynaud syndrome.
42ProgressAdmitted into hospital two weeks after initial presentation.Increasing lethargy and tiredness, reduced appetite ,fainting, and weight loss.On examination, she was pigmented and thinHer 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/lBUN/Cr within normal limits
47IV saline and dextrose.IV or IM hydrocortisone by multiple bolus injections or by continuous infusion mg dailyPatient’s condition improved : Hydrocortisone given orally 40 mg in the morning and 20 mg in the evening3-4 days hydrocortisone reduced to mg daily in two or three divided doses,Mineralocorticoid is introduced at this stage (Fluodrocortisone mg daily)
48Case 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 11Physical examination- Consistent with right basal pneumonia.- No abdominal tenderness, or signs of endocrine dysfunction or trauma.
49Haemoglobin 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,
50ECG showed sinus bradycardia and Osborn waves, which disappeared after rewarming.
51Persistent, inotrope-refractory hypotension Short Synacthen (ACTH) test : Basal cortisol level 57 nmol/LFailed 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