Limdawati, dr.

FK UKM 2012

oUTLINE
Biochemistry and physiology Laboratory evaluation of adrenocortical function Hyperfunction of the adrenal cortex
Cushings syndrome Aldosteronism Virilization

Hypofunction of the adrenal cortex

Addisons disease Hypoaldosteronism

Pharmacologic clinical uses of adrenal steroids

BIOCHEMISTRY AND PHYSIOLOGY

PHYSIOLOGY
Adrenal cortex 1. Glucocorticoids (cortisol, corticosterone) Modulating intermediary metabolism and immune responses 2. Mineralocorticoids (aldosterone, deoxycorticosterone) Regulating blood pressure, vascular volume, and electrolytes 3. Adrenal androgens (DHEA, DHEAS) Secondary sexual characteristics

Steroid structure

Biosynthesis of adrenal steroids

Cholesterol LDL receptor Adrenal cortex Glomerulosa zone ( outer layer) Aldosterone Fasciculata reticularis zone ( inner layer) Cortisol & androgen

Steroid transport
Plasma cortisol 1. Protein bound cortisol Cortisol binding globulin (CBG) or transcortin High affinity, low capacity in inflammation in high estrogen state 70% exogenous cortisol binds to CBG Cortisol binding albumin

Steroid transport
2. Free cortisol ( < 5 %) Filterable at the glomerulus 3. Cortisol metabolites Filterable at the glomerulus Inactive biologically Bind weakly to circulating plasma protein Plasma aldosterone
Circulating aldosterone ( 50%) Protein bound aldosterone (<< than cortisol)

STERoid metabolism & excretion

Glucocorticoids Daily secretion between 15 30 mg Pronounced cicardian cycle Inactivated by the liver Regulated by two major enzyms 11-HSD 1 activate cortisone to cortisol 11-HSD 2 convert cortisol to cortisone

STERoid metabolism & excretion

Mineralocorticoids
Daily secretion between 50 250 g Influenced by salt intake 75 % was inactivated in the liver by conjugation with glucuronic acid

Adrenal androgens
Daily secretion between 15 30 mg In male, 2/3 of androgen derived from the adrenal, 1/3 from the testicular In female, all androgen derived from the adrenal

STERoid metabolism & excretion

Steroid regulated genes

Gluco corticoid

GR

MR

Mineralocorticoid Glucocorticoid

Acth physiology

Renin angiotensin physiology

Glucocorticoid physiology
Regulation of carboydrate metabolism Promotes hepatic glucose synthesis (gluconeogenesis) and hepatic glycogen content Antagonizing the secretion & action of insulin Inhibiting peripheral glucose uptake

Glucocorticoid physiology
Regulation of protein metabolism in protein breakdown & nitrogen excretion (catabolic) Inhibition of protein synthesis & amino acid uptake Mobilization of glycogenic amino acid precursors from peripheral supporting structures Stimulate the synthesis of certain enzymes (tyrosine aminotransferase, tryptophan pyrrolase)

Glucocorticoid physiology
Regulation of lipid metabolism
Enhancing the activation of cellular lipase by lipidmobilizing hormones (cathecholamines, pituitary peptides) Decreasing the peripheral adipose tissue mass & expanding the abdominal & interscapular fat

Glucocorticoid physiology
Anti-inflammatory Modulate the immune response via immune - adrenal axis Release of leukocytes from BM Depletion of circulating eosinophils & lymphoid tissue (T cells) via redistribution impairs CMI Inhibit the production & action of inflammatory mediators (lymphokine, phospholipase A2, IFN, IL-1, IL-6, IL-2, bradykinin, PAF, serotonin)

Glucocorticoid physiology
Regulate the extracellular fluid volume Retarding the migrating of water into cells Promoting renal water excretion via vasopressin suppression, in GFR, direct action on the renal tubule Weak mineralocorticoid like properties High doses renal Na reabsorption and K excretion

Glucocorticoid physiology
Influence behaviour & emotional Suppresses the secretion of pituitary POMC & its derivative peptides (ACTH, endorphin) Suppresses the secretion of hypothalamic CRH & vasopressin

Glucocorticoid physiology
Trigger of cortisol secretion Physical stress (trauma, surgery, exercise) Psychological stress (anxiety, depression) Physiologic states (hypoglycemia, fever) Mechanism are not understood

Mineralocorticoid physiology
Effects on epithelia cells (renal CCD, salivary ducts, sweat glands, GIT) Major regulators of ECFV & K+ metabolism gene expression for Na pump & K channel directly the number & activity of Na channels via a complex process

Expanding intra & extravascular volume

Mineralocorticoid physiology
Effects on nonepithelial cells (neurons, myocytes, endothelial cells, vascular smoothmuscle cells)
No modification of Na-K homeostasis Modify the expression of collagen genes controlling TGF No MR protection by 11-HSD 2 enzyme in myocardium & brain cortisol >> activates MR

Mineralocorticoid physiology

Androgen physiology
DHEA, androstenedione, 11hydrosyandrostenedione Regulate male secondary sexual characteristic Cause virilizing symptoms in women Regulated by ACTH not by gonadotropins

LABORATORY EVALUATION OF ADRENOCORTICAL FUNCTION

BLOOD LEVELS
Peptide ACTH plasma Cicardian rythm Pulsatile secretion rapid fluctuations Angiotensin II Vary diunarlly Influenced by dietary Na & K intakes Influenced by posture

BLOOD LEVELS
Peripheral Plasma Renin Activity (PRA) Measurement of generated angiotensin I Depends on the presence of sufficient angiotensinogen in the plasma as substrate Depends on the Na intake & ambulation Diurnal rythm (peak in a.m, nadir in p.m) Plasma active renin Easier Not dependent on endogenous substrate concentration Depends on the Na intake

BLOOD LEVELS
Steroids Plasma cortisol Secreted episodically (peak in a.m, nadir in p.m) Plasma aldosterone Secreted episodically (peak in a.m, nadir in p.m) Increased by dietary K loading, Na restriction, upright posture

BLOOD LEVELS
DHEA sulfate Formed in the gonads very little Half life of 7 9 hours Reflects both DHEA production and sulfatase activity

Urine levels
Assessment of glucocorticoid secretion Urinary free cortisol Rate of excretion >> in the daytime than at night Reflecting changes in the levels of unbound cortisol Urinary 17 ketosteroid Originate in either the adrenal gland (women 90%) or the gonad (men 60 %) Highest value in young adults Urinary creatinine should simultaneously measured

Stimulation test
Tests of glucocorticoid reserve (Rapid ACTH stimulation test)
Cortisol Level

30

60 Time

Cosyntropin 25U (0.25mg) IV or IM

Normal response : cortisol level > 18 g/dL or increment of > 7 g/dL above baseline

Stimulation test
Test of Mineralocorticoid reserve & stimulation of RAS
Sodium

restriction (10 mmol/d) for 3 5 days Normal response : aldosterone 2 3x of baseline

Upright posture for 2 3 hours Normal response : aldosterone 2 4x of baseline

Diuretic administration (40 80 mg furosemide followed by 2 3 hours of upright posture) Normal response : aldosterone 2 4 x of baseline

Suppression test
Tests of pituitary adrenal suppressibility (overnight Dexamethasone suppression test)
Dexamethasone 1 mg p.o @ midnight
Dexamethasone 0.5 mg q6h p.o + Urine specimen 24 hours 2 consecutive days Normal response : Urine free cortisol : < 10 g/day Plasma cortisol : < 5 g/dL

Plasma cortisol @ 8 a.m Normal response : < 5 g/dL

Suppression test
Tests of Mineralocorticoid suppressibility
IV infusion of 500 ml/h of NaCl for 4 hours High Na diet for 3 days + Fludrocortisone 0.2 mg bid

Plasma aldosterone : < 8 ng/dL, in Na-restricted diet < 5 ng/dL, in normal Na diet

Aldosterone excretion : < 10 g / day

Test of pituitary adrenal responsiveness

Insulin induced hypoglycemia
Stimulation of ACTH and growth hormone Reguler insulin (0.05 0.1 U/kg) iv Normal response : plasma cortisol > 18 g/dL

Metyrapone test
Inhibition 11-HDS in adrenal impair conversion of 11 deoxycortisol to cortisol Metyrapone 750 mg po q4h over 24 hrs Normal response : plasma 11-deoxycortisol > 7g/dL; plasma ACTH > 75 pg/mL

 Pituitary corticotroph test Bolus injection of ovine CRH 1 g/kg IV Normal response : plasma ACTH increment 40 pg/mL after 1 hour. Rapid ACTH test Distinguish the primary & secondary AI 25 U Cosyntropine IV or IM measurement of plasma cortisol & aldosterone before, 30, 60 after. Normal response : Plasma cortisol abnormal in both AI Plasma aldosterone 5 ng/dL in secondary AI

Hyperfunction of the adrenal cortex

 Excess cortisol Cushings syndrome Excess aldosterone aldosteronism Excess adrenal androgens adrenal virilism

cushings syndrome : definition

A syndrome characterized by truncal obesity, hypertension, fatigability and weakness, amenorrhea, hirsutism, purplish abdominal striae, edema, glucosuria, osteoporosis, and a basophilic tumor of the pituitary

cushings syndrome : etiology

cushings syndrome : etiology

Cushings disease Pituitary (ACTH) dependent adrenal hyperplasia Women 3x > men Age : 30 40 years old Primary defect (pituitary adenoma / hypothalamus adenoma) hyperstimulation of circulating cortisol Microadenoma (< 1 cm) >>>

cushings syndrome : etiology

The ectopic ACTH syndrome Nonpituitary tumors that secrete either ACTH and/or CRH bilateral adrenal hyperplasia Typical signs & symptoms of Cushings syndrome may be absent or minimal Hypokalemic alkalosis, hyperpigmentation Associated with
Primitive small cell type of bronchogenic Ca Carcinoid tumors of the thymus, pancreas, ovary Medullary carcinoma of the thyroid Bronchial adenoma

cushings syndrome : etiology

Adrenal neoplasia Incidence of 20 25% Usually unilateral, half are malignant Biochemical features both of pituitary ACTH excess and of adrenal adenoma

cushings syndrome : etiology

Iatrogenic causes The most common cause of Cushings syndrome Clinical features almost similar with adrenal tumors History and laboratory studies are the key for diagnosis

cushings syndrome : clinical manifestations

cushings syndrome : pathophysiology

Catabolic response in peripheral supportive tissue
Muscle weakness, fatigability, osteoporosis, broad violaceous cutaneous striae

Weakening & rupture of collagen fibers in the dermis

Broad violaceous cutaneous striae, easy bruisability

cushings syndrome : pathophysiology

Hypercortisolism
The deposition of adipose tissue in characteristic site (moon facies, buffalo hump, supraclavicular fat pads, mesenteric bed (truncal obesity) Plethoric face without in RBC Hypertension Emotional changes

cushings syndrome : pathophysiology

Increased hepatic gluconeogenesis & insulin resistance
Impaired glucose tolerance, overt DM (< 20%) Distribution of the adipose tissue (?) is associated with insulin resistance and/or elevated insulin level

Adrenal virilism
Acne, hirsutism, oligo/amenorrhea Less frequent

cushings syndrome : laboratory findings

Leukocytosis Hypokalemia, hypochloremia Metabolic alkalosis Elevated plasma & urine cortisol level (except in iatrogenic cause)

cushings syndrome : radiologic findings

CT scan of the abdomen Preferrable, in ectopic ACTH production should use HRCT For visualizing the adrenals, localizing adrenal tumor and diagnosing bilateral hyperplasia Hypersecretion of pituitary ACTH (+) pituitary MRI scan with gadolinium contrast

cushings syndrome : radiologic findings

Benign adrenal tumor Malignant adrenal tumor
Size < 4 cm Sharp margins Tumor homogeneity Low unenhanced CT values ( < 10 HU) May in size over several years of ff up Large size ( > 4 6 cm) Irregular margins Tumor inhomogeneity Soft tissue calcification High unenhanced CT attenuation values (> 10 HU)

FNA is not useful to distinguish between benign & malignant primary adrenal tumors

cushings syndrome : Differential diagnosis

Pseudo Cushings syndrome Obesity Generalized, not truncal Modest adrenocortical test Chronic alcoholism Modestly elevated urine cortisol Blunted circadian rythm of cortisol level Resistance to DST Depression Similar features with chronic alcoholism Acute illness Abnormal adrenocortical test Resistance to DST

cushings syndrome : Differential diagnosis

Iatrogenic Cushings syndrome
Induced by administration of glucocorticoids or other steroids that bind to the GR Similar clinical findings with noniatrogenic Low blood or urine cortisol in a basal state due to suppression of the pituitary adrenal axis Severity related to
Total steroid dose Biologic half life of the steroid Duration of therapy

cushings syndrome : treatment

Adrenal Neoplasm Laparoscopic resection with pre & post-op prevention of AI Mitotane (isomer of the insecticide DDT)
Suppresses corticol production plasma & urine steroid level Dose : < 6 g daily Side effects : anorexia, diarrhea, vomiting, lethargy, somnolence, dizziness Long term glucocorticoid maintanance therapy Regression of tumor and metastase( 1/3 px), inhibit steroidogenesis (2/3)

Chemotherapy platinum based (?)

cushings syndrome : treatment

Bilateral Hyperplasia

ASYMPTOMATIC ADRENAL MASS

Incidental adenoma (incidentaloma) Benign adenoma >>> adrenocortical Ca Steps of evaluation
History of prior malignancy ?? Is the tumor functioning ?
Screened for pheochromocytoma (plasma free metanephrines) Screened for subclinical Cushings syndrome and aldosteronism

Aldosteronism : definition
A syndrome associated with hypersecretion of the mineralocorticoid aldosterone Classification
Primary aldosteronism With an adrenal tumor Without an adrenal tumor Secondary aldosteronism

Primary aldosteronism
With an adrenal tumor (Conns syndrome) Usually unilateral adenoma Small in size Benign character Women > 2x men Age : 30 50 years old Present in 1 % of unselected hypertensive px

Primary aldosteronism
Without an adrenal tumor 80 % of px with primary aldosteronism Bilateral cortical nodular hyperplasia Idiopathic hyperaldosteronism DD/ : low renin essential hypertension Hypokalemia is unlikely, lower level of aldosterone, less radiologic evidence for adrenal pathology

Primary Aldosteronism : CLINICAL MANIFESTATIONS

Na reabsorption & extracellular volume expansion
Diastolic hypertension, may be severe Headache Edema infrequent in primary aldosteronism (escape phenomenon)

Potassium depletion
Muscle weakness, fatigue

Impairment of urinary concentrating ability Polyuria Polydypsia

Primary Aldosteronism : laboratory findings

Hypokalemia
Aldosteronism renal distal tubular exchange of intratubular Na for secreted K & H ions

Urine pH is neutral or alkaline

Excessive secretion of bicarbonate & NH4 as a compensation for metabolic alkalosis

Impaired overnight urine concentration test

Hypokalemia

Primary Aldosteronism : laboratory findings

Hypernatremia (infrequent)
Sodium retention Concomitant water loss from polyuria Resetting of the osmostat

Metabolic alkalosis
H+ ion loss into the urine Migration into K+ depleted cells capacity of the proximal convoluted tubule to reabsorb filtered bicarbonate

Hypomagnesemia
Severe hypokalemia (< 3 meq/L)

Primary Aldosteronism : diagnosis

Diagnostic criteria of primary aldosteronism
1. Diastolic hypertension without edema 2. Hyposecretion of renin (low PRA) that fails to increase appropriately during volume depletion 3. Hypersecretion of aldosterone that does not suppress appropriately in response to volume expansion

Primary Aldosteronism : differential diagnosis

PRIMARY Aldosteronism : differential diagnosis

Hyperaldosteronism ec adenoma DD/ idiopathic bilateral nodular hyperplasia
Limited diagnostic value of clinical and biochemical grounds Definitive diagnosis is by radiographic studies e.g., bilateral adrenal vein catheterization

Primary aldosteronism : treatment

Conns syndrome Surgical excision (laparoscopic approach) Dietary sodium restriction + aldosterone antagonist (spironolactone 25 100 mg q8h) MR antagonist (Eplerenone) Less potent, more specific Minimal antiandrogen effect Doses : 50 150 mg q8h

Primary aldosteronism : treatment

Idiopathic bilateral hyperplasia Medical therapy (aldosterone antagonist, MR antagonist) Surgery if medical therapy cant control the hypokalemia

Secondary aldosteronism : definition

An appropriately increased production of aldosterone in response to activation of the RAS

Production rate of aldosterone >>> primary aldosteronism

Secondary aldosteronism : etiology

1. Primary overproduction of renin (primary reninism)
Rare condition Renin secretion by juxtaglomerular cell tumor Radiographic : normal renal vasculature and/or a SOL in the kidney Unilateral increase in renal vein renin activity

Secondary aldosteronism : etiology

2. Overproduction of renin secondary to a decrease in renal blood flow and / or perfusion pressure
Atherosclerosis or fibromuscular hyperplasia of one or both of the major renal arteries Severe arteriolar nephrosclerosis (malignant hypertension) Profound renal vasoconstriction (the accelerated phase of hypertension) Hypokalemic alkalosis, high PRA and PA

Secondary aldosteronism : clinical manifestation

Hyperaldosteronism (accelerated phase of hypertension) Associated with an underlying edema disorder (cirrhosis, nephrotic syndrome, CHF) Without edema or hypertension (Bartter syndrome, Gitelman syndrome)

Syndromes of adrenal androgen excess

Excess production of DHEA & androstenedione

Elevated testosterone

Pure syndromes of virilization

Mixed syndromes

Virilization : definition
A condition in which androgen levels are sufficiently high to cause additional signs and symptoms such as deepening of the voice, breast atrophy, increased muscle bulk, clitoromegaly, and increased libido

Hirsutism : definition
Excessive male-pattern hair growth, affects approximately 10% of women, represents a variation of normal hair growth, but rarely it is a harbinger of a serious underlying condition.

Virilization : ETIOLOGY
Gonadal hyperandrogenism
Ovarian hyperandrogenism Polycystic ovary syndrome/functional ovarian hyperandrogenism Ovarian steroidogenic blocks Syndromes of extreme insulin resistance Ovarian neoplasms

Virilization : ETIOLOGY
Adrenal hyperandrogenism
Premature adrenarche Functional adrenal hyperandrogenism Congenital adrenal hyperplasia (nonclassic and classic) Abnormal cortisol action/metabolism Adrenal neoplasms

Virilization : ETIOLOGY
Other endocrine disorders
Cushing's syndrome Hyperprolactinemia Acromegaly

Peripheral androgen overproduction

Obesity Idiopathic

Virilization : ETIOLOGY
Pregnancy-related hyperandrogenism
Hyperreactio luteinalis Thecoma of pregnancy

Drugs
Androgens Oral contraceptives containing androgenic progestins Minoxidil Phenytoin Diazoxide Cyclosporine

True hermaphroditism

Virilization : clinical manifestations

History Age of onset & rate of progression of hair growth Age of onset of menarche The pattern of menstrual cycle (irregular : ovarian >> adrenal) Cushings syndrome Use of medications Family history of infertility and/or hirsutism (CAH)

Virilization : clinical manifestations

Physical examination
Body mass index Blood pressure Cutaneous signs (pustular acne, thinning hair, acantosis nigricans) Hair distribution & quantity assessment (Ferriman & Gallwey scale)

Virilization : treatment
Nonpharmacologic
1. Bleaching 2. Depilatory (shaving, chemical treatment) 3. Epilatory (plucking, waxing, electrolysis, laser)

Virilization : treatment
Pharmacologic
1. Suppression of adrenal and/or ovarian androgen production 2. Enhancement of androgen binding to plasma binding proteins 3. Impairment of the peripheral conversion of androgen precursors to active androgen 4. Inhibition of androgen action at the target tissue

Late response (4 6 mos after initiation of treatment)

Virilization : treatment
Combination estrogen progestin
production of ovarian androgens by LH suppression DHEAS by reducing ACTH level Direct, dose dependent suppressive effect on sebaceous cell function Progestin component (norgestrel, levonorgestrel) attenuate the estrogen induced increase in SBHG Contraindicated in thromboembolic disease history, risk of breast Ca Improve the extent of acne up to 70% Effect on hair growth after 9 12 months Improve the hirsutism (20%)

Virilization : treatment
Glucocorticoids
Mainstay of treatment in px with CAH Adrenal androgens are more sensitive than cortisol to the suppressive effects of glucocorticoid Dexamethasone 0.2 0.5 mg or Prednisone 5 10 mg at bedtime

Virilization : treatment
Cyproterone acetate
Prototypic of antiandrogen Competitive inhibition of the binding of testosterone & DHT to the androgen receptor Enhance the metabolic clearance of testosterone by inducin hepatic enzymes Dose : 50 100 mg daily on days 1 15 and ethinyl estradiol 50 mcg on days 5 26 of the menstrual cycle Side effects : irregular uterine bleeding, nausea, headache, fatigue, weight gain, decreased libido

Virilization : treatment
Spironolactone
A weak antiandrogen, mineralocorticoid antagonist Dose : 100 200 mg daily Side effects : hyperkalemia, hypotension, pregnancy, irregular menstruation May be combined with estrogen

Virilization : treatment
Flutamide A potent nonsteroidal antiandrogen in treating hirsutism Side effect : hepatocellular dysfunction

Finasteride A competitive inhibitor of 5-reductase type 2 Effective in hirsutism

Eflornithine cream (Vaniqa) ???

Hypofunction of the adrenal cortex

( Addisons disease)

addisons disease : definition

A syndrome characterized with general languor and debility, feebleness of the hearts action, irritability of the stomach, and a peculiar change of the color of the skin Rare, may occur at any age and sex

addisons disease : etiology

Gradual progressive destruction of the adrenals which must involve > 90 % of the glands before AI appears Etiology
Idiopathic atrophy (autoimmune) Granulomatous disease (tuberculosis) Bilateral hemorrhage Tumor metastases Viral infection (HIV, CMV) Amyloidosis Adrenomyeloneuropathy Familial adrenal insufficiency

addisons disease : clinical manifestations

addisons disease : laboratory findings

Subnormal or no increase at all of cortisol Na, Cl, bicarbonate Aldosterone deficiency (urinary losses of Na) Movement into the intracellular compartment Hyperkalemia Aldosterone deficiency Impaired glomerular filtration Acidosis Normocytic anemia, relative lymphocytosis, moderate eosinophilia (uncommon)

addisons disease : treatment

Glucocorticoid replacement therapy
Hydrocortisone (cortisol) Dose : 20 30 mg/day with meal (2/3 am; 1/3 pm) Side effects : insomnia, irritability, mental excitement, hypertension, hyperglycemia Monitor clinically, measurement of plasma ACTH, cortisol are not useful During severe illness, the dose to 75 100 mg/day by oral or iv

addisons disease : treatment

addisons disease : treatment

Mineralocorticoid replacement therapy
Fludrocortisone Dose : 0.05 0.1 mg / day p.o Maintain Na intake of 3 4 g daily Monitor blood pressure, serum electrolytes, plasma renin During strenuous exercise with sweating, extremely hot weather, GI upset : the dose and dietary salt intake

addisons disease : treatment

Adrenal androgen replacement therapy
DHEA Dose : 25 50 mg daily p.o. Improve quality of life and BMD

addisons disease : treatment

All px with AI should carry medical identification & should be instructed in the parenteral selfadministration of steroids

Mineralocorticoid administration is unnecessary at hydrocortisone doses > 100 mg/d

Secondary adrenocortical insufficiency : etiology

ACTH deficiency
Prolonged administration of excess glucocorticoids Panhypopituitarism

More common than primary adrenocortical insufficiency

Secondary adrenocortical insufficiency : clinical manifestation

Similar with Addisons disease EXCEPT hyperpigmentation Symptoms of multiple hormone deficiency (in panhypopituitarism) Exogenous steroid
Feature of Cushings syndrome Feature of adrenal insufficiency due to prolonged suppression of HPA axis & adrenal atrophy

Secondary adrenocortical insufficiency : laboratory findings

Low ACTH, low adrenal hormones Hyponatremia
Dilutional Subnormal increase in aldosterone secretion in response to severe Na restriction

Exogenous steroid
Low ACTH, low cortisol, abnormal ACTH & metyrapone responses

Secondary adrenocortical insufficiency : treatment

Glucocorticoid replacement therapy
Similar with primary adrenocortical insufficiency

Mineralocorticoid replacement therapy is unnecessary as aldosterone secretion is preserved

Acute adrenocortical insufficiency = adrenal crisis

Precipitating factors
1. Sepsis or surgical stress 2. Acute hemorrhagic destruction of both adrenal glands (Pseudomonas infection, anticoagulant therapy, coagulation disorder) 3. Rapid withdrawal of steroids from px with adrenal atrophy owing to chronic steroid administration 4. Drugs capable of inhibiting steroid synthesis or increasing steroid metabolism in underlying adrenal problem

Adrenal crisis : clinical manifestations

Intractable GI upset (nausea, vomiting, abdominal pain) Hypothermia or hyperthermia Lethargy deepens to somnolence Hypovolemic vascular collapse / shock

Adrenal crisis : treatment

Principles of therapy
Repletion of circulating glucocorticoid Replacement of Na & water deficit

IV infusion of D5NaCl rapidly Bolus IV infusion of 100 mg hydrocortisone followed by a continuous infusion at a rate of 10 mg / hour Alternative approach : Bolus hydrocortisone 100 mg IV q6h Vasoconstrictor (Dopamine) in extreme conditions

Hypoaldosteronism : etiology
Isolated aldosterone deficiency accompanied by normal cortisol production in association with :
Hyporeninism Inherited biosynthetic defect Postoperative aldosterone secreting adenomectomy During protracted heparin administration Pretectal disease of the CNS Severe postural hypotension

Hypoaldosteronism : clinical manifestations

Unexplained hyperkalemia exacerbated by restriction of dietary Na intake Most common in adults with DM & mild renal failure

Hypoaldosteronism : pathogenesis
1. Hyporeninemic hypoaldosteronism
Renal disease Autonomic neuropathy ECFV expansion Defective conversion of renin precursors to active renin

Hypoaldosteronism : pathogenesis
2. Hypereninemic hypoaldosternoism
Severely ill patient High mortality (80 %) Hyperkalemia (-) Adrenal necrosis (uncommon) Shift in steroidogenesis from mineralocorticoids to glucocorticoids due to prolonged ACTH stimulation

Hypoaldosteronism : diagnosis
Serum Potassium Pseudohyperkalemia -Hemolysis -Thrombocytosis ACTH stimulation test Abnormal Normal Renin & aldosterone stimulation test Hyperreninemic hypoaldosteronism

Addisons disease

Hyporeninemic hypoaldosteronism

Hypoaldosteronism : treatment
Fludrocortisone 0.05 0.15 mg PO daily Adequate salt intake (150 200 meq) daily Alternative approach : reduce salt intake + administration of furosemide

Pharmacologic clinical uses of adrenal steroids

How serious is the disorder ?

How long will therapy be required ? Does the individual have preexisting conditions that glucocorticoids may exacerbate ?

Which preparation is best ?

Checklist prior to pharmacologic uses of glucocorticoid

Presence of tuberculosis or other chronic infection Evidence of impaired glucose intolerance History of gestational DM or strong family history of T2DM in 1st degree relative Evidence of preexisting (or high risk for) osteoporosis

Checklist prior to pharmacologic uses of glucocorticoid

History of peptic ulcer, gastritis, or esophagitis Evidence of hypertension, CVD, hyperlipidemia History of psychological disorders

Supplementary measures to minimize undesirable metabolic effects of glucocorticoid

Diet
Monitor caloric intake to prevent weight gain Diabetic diet if glucose intolerant Restrict Na intake to prevent edema & minimize hypertension Provide supplementary potassium if necessary

Supplementary measures to minimize undesirable metabolic effects of glucocorticoid

Gastrointestinal upset prevention
Consider antacid, H2 receptor antagonist, and/or H+,K+,ATP-ase inhibitor therapy

Institute all-day steroid schedule if possible

Appropriate increase in hormone level during periods of acute stress A rule of thumb is to double the maintanance dose

Supplementary measures to minimize undesirable metabolic effects of glucocorticoid

Minimize loss of bone mineral density
Administer gonadal HRT in postmenopause women (0.625 1.25 mg conjugated estrogens given cyclically with progesterone, unless the uterus (-) Administer testosterone replacement in hypogonadal men Adequate Ca intake (1200 mg/d elemental Ca) Administer 800 1000 IU/d supplemental vit D Measure blood calciferol and 1,25(OH)2vitamin D Biphosphonate prophylaxis PO or parenteral in high-risk patient

Which preparation is best ?

Consider the biologic half life Rationale : the metabolic effects of steroids for a significant period while still producing a pharmacologic effect durable enough to be effective

Which preparation is best ?

Consider the mineralocorticoid effects of the steroid Most synthetic steroids have less mineralocorticoid effect than hydrocortisone

Which preparation is best ?

Consider the biologically active form of the steroid Cortisone & prednisone have to be converted to biologically active metabolites (hydrocortisone & prednisolone) before anti-inflammatory effects can occur

Which preparation is best ?

Consider the cost of medication Especially in chronic administration planning, this is a serious consideration Prednisone is the least expensive of available steroid preparation

Which preparation is best ?

Consider the type of formulation
Topical steroids Reducing the likelihood of systemic side effects compare with oral steroids All topical steroids can be absorbed into the systemic circulation
Inhaled steroids Increase hepatic inactivation if they are swallowed minimize side effects