D-Adrenal Physiology and Hypofunctioning States

1. D-Adrenal Physiology and Hypofunctioning States

2. Goals of Discussion • Review Adrenal Physiology • Identify the clinical features of Adrenal Insufficiency • Etiologies of Adrenal Insufficiency • Understand testing of adrenal function • Treatment of Adrenal Insufficiency

3. Adrenal Development • Derived • Neuroectodermal cells (medulla) • Mesenchymal cells (cortex) • Fetal adrenal is present by 2 months gestation • Mostly cortex • Glomerulosa and fasiculata are present at birth • Reticularis develops during first year of life

4. Adrenal Anatomy • Adult adrenal • 2-3cm wide • 1cm thick • 4-6 grams • Located • Upper pole of kidneys • Vascular supply • 12 small arteries from aorta

5. Adrenal Physiology • Glomerulosa • 15% of cortex • Aldosterone • Renin-Angiotensin • Fasciulata • 75% of cortex • Cortisol • DHEA • ACTH • Reticularis • Androgens and estrogens • ACTH • Medulla • Catecholamines

6. Congenital Adrenal Hyperplasia • Deficiency of CYP 17 • 17α- hydroxylase and 17-20 lyase deficiency • Rare cause • Diagnosed due to delayed pubertal development • 46xx • Hypertensive • +/- Hypokalemic • Primary amenorrhea • Absent secondary sex characteristics

8. Congenital Adrenal Hyperplasia • Most adrenal biosynthetic defects result in • Virilized female • Normally virilized male • Deficiencies • Mineralocorticoid • Glucocorticoid • 21-OH deficiency • 11-OH deficiency

9. Congenital Adrenal Hyperplasia • Cortisol sufficient • Tolerates general anesthesia and surgery • Treatment • Steroids to suppress excess • Gonadal replacement • Deficiency of CYP 17 • 46XY • Complete male pseudohermaphroditism • Female external genitalia • Blind-ended vagina • No mullerian structures • Testes intra-abdominal • Leydig cell hyperplasia • Hypertensive • +/- Hypokalemic

11. Congenital Adrenal Hyperplasia • Can present in puberty • Hyperandrogenemia • Hirsuitism • Oligomenorrhea • Treatment • Cortisol replacement • 3 β-Hydroxysteroid Dehydrogenase • Presents early infancy • Adrenal insufficiency • Females can be virilized due to DHEA • Males • Normal genital development • Hypospadias • Pseudohermaphroditism

12. Congenital Adrenal Hyperplasia • Congenital Lipoid Adrenal Hyperplasia • StAR Deficiency • Transports cholesterol to inner mitochondrial membrane • Rarest form • Autosomal recessive • All adrenal steroids are deficient • Present with adrenal insufficiency • Typically fatal infancy • Males • Female external genitalia

13. Renin and Aldosterone • Aldosterone • Sodium homeostasis • Regulates arterial pressure • Regulated • Angiotensin 2 • Increases • Renal sodium retention • Renal potassium excretion • Low Aldosterone • Adrenal insufficiency • High renin • Hyperkalemia • Renin • Enzyme released from the kidneys (macula densa) • Activates Angiotensinogen Angiotensin 1 Angiotensin 2 • Increased secretion • Low blood pressure • Low sodium • High potassium • Upright posture

14. Renin and Aldosterone

15. Mineralocorticoid Deficiency • Hyporeninemic Hypoaldosteronism • Impaired renin release • 50-70 years • Chronic assymptomatic hyperkalemia • Mild-moderate renal insufficiency • Muscle weakness • Cardiac arrhythmias

16. Mineralocorticoid Deficiency • Other diseases • SLE • Multiple myeloma • Renal amyloidosis • Cirrhosis • Sickle Cell • AIDS • POEMS • Transient with drugs • NSAID • Cyclosporin A • Mitomycin C • Cosyntropin • 50% of patients with Diabetes • Type IV RTA • Metabolic acidosis • Decreased renal ammoniagenesis • Decreased H ion secretion • Decreased bicarbonate resorbtion

17. Mineralocorticoid DeficiencyPrimary Hypoaldosteronism • Acquired • Heparin • Suppresses aldosterone • Increase in renin • Healthy person, asymptomatic • Critically ill, can be symptomatic • Aldosterone synthase deficiency (CYP11B2) • Autosomal recessive • Diagnosed in infancy • Recurrent dehydration • Failure to thrive • Salt wasting • Treatment • Florinef

18. Mineralocorticoid DeficiencyPrimary Hypoaldosteronism • Features of hypoaldosteronism • Hyopnatremia • Hyperkalemia • Hyper-reninemia • Increased aldosterone levels • Many kindreds • Homozygous mutation in amiloride-sensitive epithelial sodium channel • Treatment • NaCl • K+ binding resins • Pseudohypoaldosteronism • Salt wasting syndrome • Infancy • Renal tubular insensitivity to mineralocorticoids • Autosomal Dominant • Resistance to aldosterone at the renal tubule • Autosomal Recessive • Severe • Also affects sweat and salivary glands • Colon

19. POSTERIOR Adrenal Fasiculata HYPOTHALAMUS (-) PITUITARY CORTISOL ACTH HYPOTHALAMIC- PITUITARY (-) PORTAL SYSTEM CRH (+) ANTERIOR PITUITARY

20. Adrenal Physiology • Increase in response to stress • Hypoglycemia • Surgery • Illness • Hypotension • Smoking • Cold exposure • Blunted response • Chronic illness • ACTH and cortisol • Pulsatile secretion • Highest in AM at wakening • Lowest late afternoon and evening • Nadir is 1-2 hrs after the start of sleep • Circadian • Blind patient • Reverts to a 24.5-25hr • DHEA and Androstenedione regulated by ACTH

21. Circulation of Cortisol and Adrenal Androgens • Androgens • Albumin • Testosterone • Sex Hormone binding (SHBG) • Secreted unbound • In circulation bind to plasma proteins • Unbound is active • Cortisol • Free (10%) • Corticosteroid-binding globulin (CBG) (75%) • Albumin

22. Cortisol Effects • Calcium metabolism • Decrease intestinal calcium absorption • Stimulates renal 1α-hydroxylase • Increases 1,25 OH vitamin D synthesis • Increased calciuria • Increased phosphaturia • Connective Tissue • Inhibit fibroblasts • Loss of collagen • Thinning of skin • Bone • Inhibit bone formation • Stimulate bone resorption • Potentiate actions of PTH • Increased resorption

23. Cortisol Effects • Immunologic • Inhibit prostaglandin synthesis • Phospholipase A2 • Decreases IL-1 • IL-1 stimulates CRH and ACTH • Impairs AB production and clearance • Growth • Accelerate development of fetal tissues • Lung maturity • Inhibit linear growth • Decreased growth hormone • Erythrocytes • Minimal effect • Leukocytes • Increase PMN by increasing release from bone marrow • Decreases lymphocytes, monocytes and eosinophils

24. Cortisol Effects • Nervous system • Enters the brain • Euphoria • Irritability, depression and emotional lability • Hyperkinetic or manic behavior • Overt psychosis • Increased appetite • Impaired memory or concentration • Decreased libido • Insomnia • Decreased REM and increased Stage II sleep • Cardiovascular • Increase CO • Increase peripheral vascular tone • Hypertension • Renal function • Mineralocorticoid receptors • Na retention • Hypokalemia • HTN • Glucocorticoid receptors • Increased GFR

25. Cortisol EffectsMetabolism • Lipids • Activate lipolysis in adipose tissue • Redistributes body fat • Sparing of the extremities • Glycogen • Activates glycogen production\ • Deactivates glycogen breakdown • Glucose • Increase hepatic glucose production • Inhibits peripheral tissue utilization of glucose

26. Adrenal Insufficiency • Incidence • 6 cases per 1 million adults/year • Prevalence • 40-110 cases per 1 million adults • More common in females • 2.6:1 • Diagnosed in the 3-5th decades

27. Adrenal InsufficiencyPresentation • Signs and symptoms • Rate and degree of loss of adrenal function • Degree of physiologic stress • Primary • Mineralocorticoid deficiency • Secondary/Tertiary • Mineralocorticoid sufficient

28. Adrenal InsufficiencyPresentation • Dehydration • Hypotension/shock • Syncope • Abdominal pain • Recurrent and unexplained • Mental status changes • Nausea and vomiting • Weight loss • Fatigue • Hyperpigmentation • Vitiligo

29. Adrenal CrisisPresentation • Unexplained hypoglycemia • Hyponatremia • Hyperkalemia • Hypercalcemia • Eosinophilia • Other autoimmune deficiencies • Hypothyroid • Hypogonadal

30. Adrenal CrisisPopulations at Risk • Secondary adrenal insufficiency • Exogenous steroid use • Joint injections • Herbals from Mexico • High dose inhaled steroids • Congenital Adrenal Hyperplasia

31. Primary Adrenal InsufficiencyEtiology • Autoimmune adrenalitis • 70% of cases • Polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)- PGA I • Autosomal recessive disorder • Mutation in zinc finger protein • Adrenal failure, hypoparathyroidism, mucocutaneous candidiasis, dental enamel hypoplasia, dystrophy of the nails

32. Primary Adrenal InsufficiencyEtiology • Autoimmune adrenalitis • Polyglandular autoimmune II • Primary adrenal insufficiency, Autoimmune thyroid disease (hypo and hyper), Type I Diabetes, hypogonadism • Infectious • Tuberculosis • 5% of cases • Rifampin will increase cortisol metabolism-higher dose needed • Histoplasmosis • Ketoconazole inhibits steroid synthesis

33. Primary Adrenal InsufficiencyEtiology • Bilateral adrenal hemorrhage • Ill patients on anticoagulants • Coagulopathies • Heparin • Thrombosis and thrombocytopenia • Primary antiphospholipid antibody syndrome

34. Primary Adrenal InsufficiencyEtiology • Adrenoleukodystrophy and adrenomyeloneuropathy • X-linked • Defect in β-oxidation • Mutations in gene encoding a peroxisomal membrane protein of the ABC superfamily of membrane transporters • Demyelination of central and peripheral nervous system • High levels of very long chain fatty acids (VLCFA)

35. Primary Adrenal InsufficiencyEtiology • Familial glucocorticoid Deficiency • Autosomal recessive • ACTH resistance • High plasma ACTH concentrations • Cortisol and androgen deficiency • Aldosterone is normal • Presents in childhood • Hyperpigmentation • Muscle weakness • Hypoglycemia and seizures • Low epinephrine

36. Primary Adrenal InsufficiencyEtiology • HIV/AIDS • Adrenal necrosis • Infiltrative etiologies • CMV or TB • Bilateral metastatic infiltration • Breast cancer • Bronchogenic carcinoma • Renal malignancies

37. Primary Adrenal InsufficiencyEtiology • Drugs that inhibit cortisol synthesis • Aminoglutethimide • Etomidate • Ketoconazole • Metyrapone • Suramin • Mitotane • Accelerate cortisol metabolism • Phenytoin • Barbituates • Rifampin

38. Secondary Adrenal InsufficiencyEtiology • Developmental abnormalities • Pit-1 • Prop-1 • Septo-optic dysplasia • Glucocorticoid use • Pituitary • Tumors • Hemorrhage • Pituitary necrosis (Sheehan Syndrome) • Metastatic malignancies • Lymphocytic hypophysitis • Sarcoidosis • Histiocytosis X

39. Adrenal InsufficiencyDiagnosis • Always test for thyroid sufficiency • Insulin Hypoglycemia test • Tests anterior pituitary function • Insulin 0.15U/kg/body • Cortisol and growth hormone drawn at baseline • Repeat when glucose <35 mg/dl • Contraindicated • Elderly, CAD, seizures

40. Adrenal InsufficiencyDiagnosis • Overnight Metyrapone testing • Tests for secondary or tertiary abnormalities • Blocks 11β-deoxycortisol to cortisol • Can initiate adrenal crisis • Useful in determining return of function from steroid suppression • Normal result • Increased ACTH • Increased 11β-deoxycortisol • Metyrapone is difficult to obtain

41. Adrenal InsufficiencyDiagnosis • High dose- • 250 mcg ACTH • Evaluates primary disease • Critically ill • Inpatient setting • Low dose • 1 mcg ACTH • Evaluates primary • Secondary if long standing • Outpatient setting • Evaluating for return of adrenal function • Secondary cause • Normal renin-angiotensin system • Normal kalemia • No hyperpigmentation • Baseline critical samples • Hypoglycemia or hypotension • Metabolic panel, CBC, Cortisol, ACTH • Thyroid function studies

42. SteroidsPotency

43. Adrenal CrisisInpatient Treatment • Once stable • Wean hydrocortisone • 50 mg IV Q6-8hrs • Taper and transition to oral therapy • If primary • Once saline heplocked • Start Florinef (fludrocortisone 0.1 mg PO QD) • Fluid resuscitation • Saline and dextrose • Hydrocortisone (Solucortef) • 100 mg IV bolus then 100mg IV Q6hrs

44. Outpatient Treatment • Cortisol • Hydrocortisone • 10mg AM and 5 mg PM • 6-8 mg/m2/day • Stress dosing • Fever, illness, surgery • 20 mg/m2/day • Double or triple daily dose • 100 mg x1 then 25-50 mg Q6-8hrs • All adrenal insufficient patients need a medic alert bracelet

45. Outpatient Treatment • Alternative glucocorticoid replacement • Dexamethasone 0.5 mg (0.25-0.75) per day • Prednisone 5 mg (2.5-7.5) per day • Florinef dosing • Usual production 100mcg per day • 0.05-0.2 mg (50-200mcg) per day