MedKorat Endocrine Day 2018

Approach to common adrenal disorder

Rungnapa Laortanakul, MD Nov.2018 Outline

CAH Cushing’s syndrome Pheochromocytoma  Adrenal incidentaloma A 61-year-old man, Pulmonary TB, fatigue

Pulse 90/min, regular Thyroid not enlarged Hyperpigmented skin Other : normal Adrenal insufficiency

 The symptoms and signs of adrenal insufficiency depend upon the rate and extent of loss of adrenal function, whether mineralocorticoid production is preserved, and the degree of stress.

 The onset of adrenal insufficiency is often very gradual, and it may go undetected until an illness or other stress precipitates adrenal crisis. Causes of adrenal insufficiency

Primary adrenal insufficiency Secondary adrenal insufficiency Exogenous steroid prolong used Pituitary disease CIRCI (Critical illness related adrenal insufficiency) Chronic primary adrenal insufficiency Chronic primary adrenal insufficiency *Step 1 : Test for diagnosis (screening test Laboratory tests then confirmation test) *Step 2 : localization  Morning serum (hormonal test) *Step 3 : Imaging  1 mcg ACTH stimulation test  0 (before bolus), 20, 40 minutes for serum cortisol  Insulin-induced test  Most rational test of hypothalamic-pituitary-adrenal response to stress  Test is safe, if a clinician is present, in patients with no history of seizures or cardiovascular or cerebrovascular disease  Insulin (usually at a dose of 0.15 units/kg; in patients with low basal cortisol levels, the dose should be reduced to 0.1 units/kg) is given with the aim to achieve hypoglycemia < 35 mg/dL  Cortisol concentrations are measured at 0, 30, and 45 minutes, even if glucose has been given to reduce symptoms of hypoglycemia. Serum morning cortisol

< 3 mcg/dL 3 -18 mcg/dL > 18 mcg/dL

Dynamic test Exclude - 1 mcg ACTH stimulation test adrenal - Insulin induced hypoglycemia test insufficiency

Adrenal insufficiency < 18 mcg/dL > 18 mcg/dL

High CT Morning serum ACTH level Low or MRI pituitary gland within normal limit Causes of primary adrenal insufficiency Treatment of chronic primary adrenal insufficiency Treatment of chronic primary adrenal insufficiency A 61-year-old woman, no underlying disease, UTI sepsis

BP 80/40 mmHg, pulse 120/min Dry lips, dry tongue

Adequate hydration, empiric ATB, moderate dose of vasopressure >>> cannot maintain BP Cortisol at severe sepsis : 9 mcg/dL therapy in septic

 Laboratory assays of plasma cortisol concentration and response to adrenocorticotropic (ACTH) stimulation are likely unreliable in critically ill patients.  Guidelines support use of …  a change in baseline cortisol at 60 min of <9 mcg/dL after cosyntropin (250 mcg) administration  a random plasma cortisol of <10 mcg/dL  Severe septic shock :  SBP <90 mmHg for > 1 hour despite adequate fluid resuscitation and moderate to high dose of vasopressor administration

UptoDate2018 Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017 Glucocorticoid therapy in

 Most patients with septic shock, suggest not routinely using intravenous glucocorticoid therapy as initial treatment  When the decision is made to use glucocorticoid therapy, we suggest alone (<400 mg per day in divided doses)  Adverse effects : hypernatremia, hyperglycemia, and neuromuscular weakness.  The risk of superinfection does not appear to be consistently elevated among studies.  Typically administer hydrocortisone for at least 3 days (typically for 5-7 days) and taper the dose as guided by the clinical response.

UptoDate2018 Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017 A 61-year-old woman, no underlying disease, UTI sepsis

BP 80/40 mmHg, pulse 120/min Dry lips, dry tongue

Adequate hydration, empiric ATB, moderate dose of vasopressure >>> cannot maintain BP Cortisol at severe sepsis : 9 mcg/dL

Hydrocortisone 100 mg IV q 8 hours Virilization Ambiguous genitalia Congenital adrenal hyperplasia

 Inherited defects in the enzymatic steps of cortisol biosynthesis  Primary adrenal insufficiency, as they impair cortisol synthesis

 Clinical manifestations are related to ≥ 1 processes:  Impaired synthesis of cortisol  Impaired synthesis of  Excessive synthesis of precursor steroids because of the increase in ACTH secretion, which leads to oversecretion of steroids whose production does not require the deficient enzyme.  Excessive androgenic , which cause virilization  Excessive synthesis of mineralocorticoids such as deoxycorticosterone, which can cause hypertension. Cortisol biosynthesis (steroidogenesis) Copyrights apply 21-hydroxylase deficiency 17-hydroxylase deficiency 11-hydroxylase deficiency A 61-year-old woman, Underlying HT, proximal muscle weakness

• BP 160/100 mmHg, Pulse 80/min, regular • Proximal muscle weakness grade 3

Serum K = 2.3 mmol/L Secondary Hypertension

Endocrine hypertension  Mineralocorticoid hypertension  Pheochromocytoma  Cushing’s syndrome, Acromegaly, Thyroid diseases Renal disease  Renovascular hypertension  Renal parenchymal disease Other : NSAIDs, oral contraceptive drug, Sleep apnea History suggest Secondary HT

 Age < 30 years in nonobese, negative family history of hypertension and no other risk factors (eg, obesity) for hypertension.  Very strong family hx severe HT, renal disease

 Abrupt onset of HT Refractory  Sudden acceleration of previous existing HT HT = on anti HT  Rapid deterioration of renal function or after tx with ACEI moderate  Unresponse of standard anti HT dose ≥ 3 with diuretic drug  Rapid hypo K after tx with standard dose diuretic  Hx renal trauma, flank pain, hematuria…suggest renal infarct  Sudden onset HT with systemic emboli or emboli or infarction  Periodic paralysis or muscle weakness  Headache, palpitation, sweating Physical examination

 Malignant HT grade III or IV retinopathy  Occlusive vascular disease : pulseless, bruit  AAA  Radiofemoral pulse disparity  Sign of Cushing  Interscapular murmur  Muscle wasting  Postural with or without reflex tachycardia  Wide swing in BP  Abdominal or flank mass … Polycystic kidney  Tremor, wt loss… Hyperthyroidism  Sign of pheochromocytoma Lab evaluation

CBC UA Serum BUN, Cr, uric, Electrolyte FBS Lipid EKG Hypokalemia

Pseudohypo K

Transcellular K shift -Periodic hypo K paralysis -B12 Rx pernicious anemia

K loss ( True K deficiency ) 24 hr urine K

Extrarenal loss Renal loss Urine K < 20 mEq/L Urine K > 20 mEq/L Renal K loss

High BP Normal BP

High Low Low High plasma renin plasma renin - - HCO3 HCO3

Aldosterone Urine Cl Malignant HT RTA Renovascular dz. Renin tumor High < 10 mEq/L -Hyperaldosteronism Vomiting -Bilateral hyperplasia

>10 mEq/L Low Batter syndrome Mineralocorticoid ingestion Diuretic CAH Mg def. Cushing syndrome Primary aldosteronism

 Patient groups with high prevalence of primary aldosteronism  Moderate/ severe HT : SBP > 160, DBP > 100 (JNC7)  Resistant HT : SBP >140, DBP > 90 despite treatment with 3 hypertensive medication  HT with spontaneous or diuretic induced PA is hypo K  HT with adrenal incidentaloma

J Clin Endocrinol Metab 93: 3266-3281, 2008 Primary aldosteronism

Subtype prevalence (%)

 Aldosterone producing adenoma (APA) 65  Idiopathic (IHA) 34  Aldosterone producing carcinoma < 1  Primary adrenal hyperplasia (PAH) < 1  Glucocorticoid-remediable aldosteronism (GRA) < 1

J Clin Endocrinol Metab 93: 3266-3281, 2008 Primary Aldosteronism (PA)

 PRA (Plasma renin activity) ….. ng/ml/h Step 1  PAC (Plasma aldosterone conc.) > 15 ng/dL  ARR (Aldosterone-renin ratio) > 20-30

J Clin Endocrinol Metab 93: 3266-3281, 2008 Protocol

 The test is performed by measuring a morning (preferably 8 AM), ambulatory.  Random PAC and PRA  Correct hypo K  Normal sodium intake  Withdraw agents that markedly affect the ARR for at least 4 weeks: A. Spironolactone, epherenone, amiloride, and triamterene B. Potassium-washing diuretics C. Products derived from liquorice root

J Clin Endocrinol Metab 93: 3266-3281, 2008 Protocol

 If the results of ARR off above the agents are not diagnosis, withdraw other medications that may affect the ARR for at least 2 weeks : A. Beta blocker, clonidine, alpha-methyldopa, NSAIDs B. ACEI, ARB, renin inhibitors, dihydropyridine CCB  Medications that have minimal effects on ARR Verapamil SR, Hydralazine, Prazosin, Doxazosin

J Clin Endocrinol Metab 93: 3266-3281, 2008 HT with HypoK

TTKG Correct K Avoid antiHT : ACEI, ARB, ß blk, diuretic, CCB Normal Na intake

PAC ng/dl PRA ng/ml/hr

PAC PRA PAC PRA PAC PRA PAC/PRA ≥ 20-30 & PAC ≥ 15 -CAH 2°Hyperaldosteronism -11ßHSD def. -Exogenous mineralocorticoid -Cushing’s syndrome -Liddle syndrome -Essential HT Primary Aldosteronism (PA)

 PRA (Plasma renin activity) ….. ng/ml/h Step 1  PAC (Plasma aldosterone conc.) > 15 ng/dL  ARR (Aldosterone-renin ratio) > 20-30

 Confirmation test : Saline infusion of 2 liters over 4 hours Step 2  Post-infusion  Plasma aldosterone level < 5 ng/dL ...unlikely PA  Plasma aldosterone level > 10 ng/dL ...very probably sign of PA

Step 3  Adrenal CT J Clin Endocrinol Metab 93: 3266-3281, 2008 Adrenal venous sampling (AVS)

Lateralization of excessive aldosterone secretion Sensitivity 95% and specificity 100% Infusion cosyntropin (ACTH) 50 µg/hr before 30 min and continuous during AVS Correct blood : aldosterone, cortisol (both adrenal vein, IVC below renal vein) Cortisol gradient (Adrenal vein : IVC) > 5:1

No Yes

Not cannulate Cortisol-corrected aldosterone to adrenal vein = PAC (ng/dL)/ cortisol (mcg/dL) Higher side : Lower side ratio

> 4 3-4 < 3 APA Overlap IHA Medical treatment

Spironolactone : IHA Start: 12.5-25 mg/d max 400 mg/d serum K response promptly but … HT response ~ 4-8 weeks Side effect : painful gynecomastia, erectile dysfunction, decrease libido, menstrual irregularity Surgical treatment

APA, PAH Laparoscopic adrenalectomy F/U : PAC postop day 1-2 F/U : K q 1 week x 4 BP normalized in 1-3 month after Surgery Cushing’s syndrome (CS)

ACTH dependent Ectopic ACTH  • รถ = Carcinoid tumor >> Cushing’s disease • Pan = Pancreatic tumor Ectopic ACTH • คันเล็ก = Small cell lung CA ACTH independent • หมอเมด = Medullary CA thyroid Adrenal tumor • ให้ฟรี = Pheochromocytoma Who should be tested?

 Suggest testing for hypercortisolism in patients in whom a diagnosis is most likely, including the following : ●Osteoporosis or HT in young adults ●Multiple progressive features of Cushing's syndrome (CS), particularly those that are predictive of CS such as facial plethora, proximal myopathy, striae (>1 cm wide and red/purple), and easy bruising ●Unexplained severe features (resistant HT, osteoporosis) at any age ●Adrenal incidentalomas

 Exclude exogenous — Before evaluation for possible CS, it has excluded exogenous glucocorticoid intake of Cushing's syndrome

 More common  Less common Examples of conditions associated with physiologic hypercortisolism that may have some clinical features of CS :  Pregnancy  Patients with severe obesity, especially those with visceral obesity or PCOS  Patients with psychological stress, especially patients with a severe major depressive disorder and melancholic symptoms  Poorly controlled diabetes mellitus Pseudo  Rarely, chronic alcoholism Cushing’s

Examples of conditions associated with physiologic hypercortisolism that are unlikely to have clinical features of CS :  Physical stress (illness, hospitalization/surgery, pain)  Malnutrition, anorexia nervosa  Intense chronic exercise  Hypothalamic amenorrhea  High corticosteroid-binding globulin (CBG) (increased serum cortisol but not UFC)  Glucocorticoid resistance

Initial testing Subsequence testing Any one of Any other one or two of the rest •Urine free cortisol x 2d •Urine free cortisol x 2d

•Late night salivary cortisol x 2d •Late night salivary cortisol x 2d

•1 mg overnight DST •1 mg overnight DST

•Standard low dose DST •Standard low dose DST

•LDDST CRH test

•Midnight serum cortisol DDx of Cushing’s syndrome

ACTH < 5 pg/ml ACTH > 20 pg/ml

ACTH independent CS ACTH dependent CS

-equivocal or negative MRI CT adrenal gland -clinical suspicious of ectopic ACTH

Plasma ACTH 5 - 20 pg/mL : less definitive !! Pituitary -But usually indicate that cortisol secretion is BIPSS Adenoma ACTH-dependent. -For these patients, a CRH stimulation test may be helpful Ectopic ACTH syndrome Chest & Abdominal imaging Pheochromocytoma

 Catecholamine-producing neuroendocrine tumours from chromaffin cells of adrenal medulla or extra- adrenal paraganglia.

 Paraganglioma : extra-adrenal pheochromocytomas and tumors from parasympathetic tissue

Lancet 2005; 366: 665–675 Pheochromocytoma

 80-85% of pheochromocytomas arise from adrenal medulla  15-20% are from extra-adrenal chromaffin  Catecholamine-producing extra-adrenal paragangliomas usually found in abdomen  Tumors from parasympathetic tissue in H&N, most not produce catecholamines

Lancet 2005; 366: 665–675 Hereditary Pheochromocytoma

Multiple endocrine neoplasia type 2 Von Hippel-Lindau syndrome Neurofibromatosis type 1 Familial paragangliomas

Hereditary forms most often before age 40 years

Lancet 2005; 366: 665–675

Lancet 2005; 366: 665–675 Biochemistry testing

Urinary and plasma catecholamines, Urinary metanephrines (normetanephrine and metanephrine) Urinary vanillylmandelic acid (VMA) Plasma-free metanephrines (normetanephrine and metanephrine) Lancet 2005; 366: 665–675 Interference with measurements of cathecholamine

Lancet 2005; 366: 665–675

Imaging procedures

CT ± contrast or MRI abdomen include pelvis 123I-metaiodobenzylguanidine (MIBG) PET

Lancet 2005; 366: 665–675 Preoperative management

 α-adrenoceptors with phenoxybenzamine, prazosin, doxazosin, or urapidil eg. Doxazosin is given in increasing doses from 1 to 16 mg once a day  ß-adrenoceptor blocker **after α-blocker eg. propranolol 40 mg three times daily or atenolol 25-50 mg once daily  Calcium-channel blockers  Treatment usually lasts for 10-14 days

Lancet 2005; 366: 665–675 Adequate preoperative preparation

Several criteria have been proposed

BP below 160/90 mmHg for at least 24 h

should be present, but BP in the upright position should not fall below 80/45 mmHg

Lancet 2005; 366: 665–675 Postoperative hypotension Treatment consists of fluid replacement and occasionally intravenous ephedrine. If ephedrine infusion is ineffective, vasopressin might be used. Risk of hypoglycaemia is related to rebound hyperinsulinaemia due to recovery of insulin release after tumour removal

Lancet 2005; 366: 665–675 Surgical treatment

Laparoscopic removal of intra-adrenal and extra-adrenal phaeochromocytomas is now the preferred surgery

Lancet 2005; 366: 665–675 Adrenal incidentaloma

 Prevalence is higher in older, obese, DM, and hypertensive patients

 Functional ?  Malignancy ?

 Bilateral masses : -Metastatic disease -Infection (eg, tuberculosis, fungal) -Congenital adrenal hyperplasia -Cortical adenomas -Lymphoma -Hemorrhage -ACTH-dependent Cushing’s -Pheochromocytoma -Primary aldosteronism -Amyloidosis -Infiltrative disease of adrenal glands -Bilateral macronodular adrenal hyperplasia (BMAH) Adrenal incidentaloma

Functional testing • Pheochromocytoma • Cushing’s syndrome • Primary aldosteronism : only in HT EVALUATION FOR MALIGNANCY

Size Adrenocortical carcinomas were significantly associated with mass size 90 % being more than 4 cm in diameter when discovered Imaging phenotype : CT, MRI Imaging phenotype (CT, MRI)

Benign adenoma Pheochromocytomas

 Round and homogeneous  Increased attenuation on density, smooth contour and nonenhanced CT (>20 HU) sharp margination  Increased mass vascularity  Diameter < 4 cm, unilateral  Delay in contrast medium  Low unenhanced CT washout (10 minutes after attenuation values (<10 HU) contrast, an absolute contrast medium washout of < 50 %)  Rapid contrast medium washout (10 minutes after  High signal intensity on T2 contrast, an absolute contrast weighted MRI medium washout of > 50 %)  Cystic and hemorrhagic  Isointensity with liver on both T1 changes & T2 weighted MRI sequences  Variable size and may be  Chemical shift evidence of lipid bilateral on MRI FOLLOW-UP

For incidentalomas with a benign appearance on imaging, repeat imaging after 6 to 12 months should be performed to reevaluate for possible malignancy