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Adrenal Physiology and Hypofunctioning States Heidi Chamberlain Shea, MD Endocrine Associates of Dallas.

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Presentation on theme: "Adrenal Physiology and Hypofunctioning States Heidi Chamberlain Shea, MD Endocrine Associates of Dallas."— Presentation transcript:

1 Adrenal Physiology and Hypofunctioning States Heidi Chamberlain Shea, MD Endocrine Associates of Dallas

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

3 Adrenal Development Derived Derived –Neuroectodermal cells (medulla) –Mesenchymal cells (cortex) Fetal adrenal is present by 2 months gestation 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 Adult adrenal –2-3cm wide –1cm thick –4-6 grams Located Located –Upper pole of kidneys Vascular supply Vascular supply –12 small arteries from aorta

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

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7 Congenital Adrenal Hyperplasia Most adrenal biosynthetic defects result in Most adrenal biosynthetic defects result in –Virilized female –Normally virilized male –Deficiencies  Mineralocorticoid  Glucocorticoid –21-OH deficiency –11-OH deficiency

8 Congenital Adrenal Hyperplasia Deficiency of CYP 17 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

9 Congenital Adrenal Hyperplasia Deficiency of CYP 17 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 Cortisol sufficient Cortisol sufficient –Tolerates general anesthesia and surgery Treatment Treatment –Steroids to suppress excess –Gonadal replacement

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

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

13 Renin and Aldosterone Renin 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 Aldosterone Aldosterone –Sodium homeostasis –Regulates arterial pressure –Regulated  Angiotensin 2 –Increases  Renal sodium retention  Renal potassium excretion –Low Aldosterone  Adrenal insufficiency –High renin  Hyperkalemia

14 Renin and Aldosterone

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

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

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

18 Mineralocorticoid Deficiency Primary Hypoaldosteronism Pseudohypoaldosteronism 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 Features of hypoaldosteronism Features of hypoaldosteronism –Hyopnatremia –Hyperkalemia –Hyper-reninemia –Increased aldosterone levels Many kindreds Many kindreds –Homozygous mutation in amiloride-sensitive epithelial sodium channel Treatment Treatment –NaCl –K + binding resins

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

20 Adrenal Physiology ACTH and cortisol 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 Increase in response to stress Increase in response to stress –Hypoglycemia –Surgery –Illness –Hypotension –Smoking –Cold exposure Blunted response Blunted response –Chronic illness

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

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

23 Cortisol Effects Growth Growth –Accelerate development of fetal tissues  Lung maturity –Inhibit linear growth  Decreased growth hormone Erythrocytes Erythrocytes –Minimal effect Leukocytes Leukocytes –Increase PMN by increasing release from bone marrow –Decreases lymphocytes, monocytes and eosinophils Immunologic Immunologic –Inhibit prostaglandin synthesis  Phospholipase A 2 –Decreases IL-1  IL-1 stimulates CRH and ACTH –Impairs AB production and clearance

24 Cortisol Effects Cardiovascular Cardiovascular –Increase CO –Increase peripheral vascular tone –Hypertension Renal function Renal function –Mineralocorticoid receptors  Na retention  Hypokalemia  HTN –Glucocorticoid receptors  Increased GFR Nervous system 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

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

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

27 Adrenal Insufficiency Presentation Signs and symptoms Signs and symptoms –Rate and degree of loss of adrenal function –Degree of physiologic stress –Primary  Mineralocorticoid deficiency –Secondary/Tertiary  Mineralocorticoid sufficient

28 Adrenal Insufficiency Presentation Dehydration Dehydration Hypotension/shock Hypotension/shock –Syncope Abdominal pain Abdominal pain –Recurrent and unexplained Mental status changes Mental status changes Nausea and vomiting Nausea and vomiting Weight loss Weight loss Fatigue Fatigue Hyperpigmentation Hyperpigmentation Vitiligo Vitiligo

29 Adrenal Crisis Presentation Unexplained hypoglycemia Unexplained hypoglycemia Hyponatremia Hyponatremia Hyperkalemia Hyperkalemia Hypercalcemia Hypercalcemia Eosinophilia Eosinophilia Other autoimmune deficiencies Other autoimmune deficiencies –Hypothyroid –Hypogonadal

30 Adrenal Crisis Populations at Risk Secondary adrenal insufficiency Secondary adrenal insufficiency –Exogenous steroid use  Joint injections  Herbals from Mexico  High dose inhaled steroids Congenital Adrenal Hyperplasia Congenital Adrenal Hyperplasia

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

33 Primary Adrenal Insufficiency Etiology Bilateral adrenal hemorrhage Bilateral adrenal hemorrhage –Ill patients on anticoagulants –Coagulopathies –Heparin  Thrombosis and thrombocytopenia –Primary antiphospholipid antibody syndrome

34 Primary Adrenal Insufficiency Etiology Adrenoleukodystrophy and adrenomyeloneuropathy 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 Insufficiency Etiology Familial glucocorticoid Deficiency 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 Insufficiency Etiology HIV/AIDS HIV/AIDS –Adrenal necrosis  Infiltrative etiologies –CMV or TB Bilateral metastatic infiltration Bilateral metastatic infiltration –Breast cancer –Bronchogenic carcinoma –Renal malignancies

37 Primary Adrenal Insufficiency Etiology Drugs that inhibit cortisol synthesis Drugs that inhibit cortisol synthesis –Aminoglutethimide –Etomidate –Ketoconazole –Metyrapone –Suramin –Mitotane Accelerate cortisol metabolism Accelerate cortisol metabolism –Phenytoin –Barbituates –Rifampin

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

39 Adrenal Insufficiency Diagnosis Always test for thyroid sufficiency Always test for thyroid sufficiency Insulin Hypoglycemia test 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 Contraindicated –Elderly, CAD, seizures

40 Adrenal Insufficiency Diagnosis Overnight Metyrapone testing 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 Normal result –Increased ACTH –Increased 11β- deoxycortisol Metyrapone is difficult to obtain Metyrapone is difficult to obtain

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

42 Steroids Potency Steroid Anti- Inflammatory Action HPA Suppression Salt Retention Cortisol111 Prednisolone340.74 Methylprednisolone6.240.5 Dexamethasone26170 Fludrocortisone1212125

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

44 Outpatient Treatment Cortisol Cortisol –Hydrocortisone  10mg AM and 5 mg PM  6-8 mg/m 2 /day  Stress dosing –Fever, illness, surgery –20 mg/m 2 /day –Double or triple daily dose –100 mg x1 then 25-50 mg Q6-8hrs All adrenal insufficient patients need a medic alert bracelet All adrenal insufficient patients need a medic alert bracelet

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

46 Questions?


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