MedKorat Endocrine Day 2018 Approach to common adrenal disorder

Transcription

1 MedKorat Endocrine Day 2018 Approach to common adrenal disorder Rungnapa Laortanakul, MD Nov.2018

2 Outline Adrenal insufficiency Cushing s syndrome Pheochromocytoma Primary Aldosteronism Adrenal incidentaloma CAH

3 A 61-year-old man, Pulmonary TB, fatigue Pulse 90/min, regular Thyroid not enlarged Hyperpigmented skin Other : normal

4 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.

5 Causes of adrenal insufficiency Primary adrenal insufficiency Secondary adrenal insufficiency Exogenous steroid prolong used Pituitary disease CIRCI (Critical illness related adrenal insufficiency)

6 Chronic primary adrenal insufficiency

7 Chronic primary adrenal insufficiency

8 Laboratory tests Morning serum cortisol 1 mcg ACTH stimulation test 0 (before bolus), 20, 40 minutes for serum cortisol Insulin-induced hypoglycemia test *Step 1 : Test for diagnosis (screening test then confirmation test) *Step 2 : localization (hormonal test) *Step 3 : Imaging 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.

9 Serum morning cortisol < 3 mcg/dl 3-18 mcg/dl > 18 mcg/dl Dynamic test - 1 mcg ACTH stimulation test - Insulin induced hypoglycemia test Exclude adrenal insufficiency Adrenal insufficiency < 18 mcg/dl > 18 mcg/dl Morning serum ACTH level High Low or within normal limit CT adrenal gland MRI pituitary gland

10 Causes of primary adrenal insufficiency

11 Treatment of chronic primary adrenal insufficiency

12 Treatment of chronic primary adrenal insufficiency

13 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

14 Glucocorticoid therapy in septic shock Laboratory assays of plasma cortisol concentration and response to adrenocorticotropic hormone (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

15 Glucocorticoid therapy in septic shock 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 hydrocortisone 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

16 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

17 Virilization Ambiguous genitalia

18 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 aldosterone 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 hormones, which cause virilization Excessive synthesis of mineralocorticoids such as deoxycorticosterone, which can cause hypertension.

19 Cortisol biosynthesis (steroidogenesis)

20 Copyrights apply

21 21-hydroxylase deficiency

22 17-hydroxylase deficiency

23 11-hydroxylase deficiency

24 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

25 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

26 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 Sudden acceleration of previous existing HT Rapid deterioration of renal function or after tx with ACEI Unresponse of standard anti HT 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 Refractory HT = on anti HT moderate dose 3 with diuretic drug

27 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 hypotension with or without reflex tachycardia Wide swing in BP Abdominal or flank mass Polycystic kidney Tremor, wt loss Hyperthyroidism Sign of pheochromocytoma

28 Lab evaluation CBC UA Serum BUN, Cr, uric, Electrolyte FBS Lipid EKG

29 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 Urine K < 20 meq/l Renal loss Urine K > 20 meq/l

30 Renal K loss High BP Normal BP High plasma renin Low plasma renin Low HCO 3 - High HCO 3 - Malignant HT Renovascular dz. Renin tumor Aldosterone High -Hyperaldosteronism -Bilateral hyperplasia RTA < 10 meq/l Vomiting Urine Cl Low Mineralocorticoid ingestion CAH Cushing syndrome >10 meq/l Batter syndrome Diuretic Mg def.

31 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: , 2008

32 Primary aldosteronism Subtype prevalence (%) Aldosterone producing adenoma (APA) 65 Idiopathic hyperaldosteronism (IHA) 34 Aldosterone producing carcinoma < 1 Primary adrenal hyperplasia (PAH) < 1 Glucocorticoid-remediable aldosteronism (GRA) < 1 J Clin Endocrinol Metab 93: , 2008

33 Primary Aldosteronism (PA) Step 1 PRA (Plasma renin activity).. ng/ml/h PAC (Plasma aldosterone conc.) > 15 ng/dl ARR (Aldosterone-renin ratio) > J Clin Endocrinol Metab 93: , 2008

34 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: , 2008

35 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: , 2008

36 HT with HypoK Correct K TTKG 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 15 -CAH -11ßHSD def. -Exogenous mineralocorticoid -Cushing s syndrome -Liddle syndrome -Essential HT PAC PRA 2 Hyperaldosteronism

37 Primary Aldosteronism (PA) Step 1 PRA (Plasma renin activity).. ng/ml/h PAC (Plasma aldosterone conc.) > 15 ng/dl ARR (Aldosterone-renin ratio) > Step 2 Confirmation test : Saline infusion of 2 liters over 4 hours 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: , 2008

38 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)

39 Cortisol gradient (Adrenal vein : IVC) > 5:1 No Not cannulate to adrenal vein Yes Cortisol-corrected aldosterone = PAC (ng/dl)/ cortisol (mcg/dl) Higher side : Lower side ratio > 4 APA 3-4 Overlap < 3 IHA

40 Medical treatment Spironolactone : IHA Start: 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

41 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

42 Cushing s syndrome (CS) ACTH dependent Pituitary adenoma >> Cushing s disease Ectopic ACTH ACTH independent Adrenal tumor Ectopic ACTH รถ = Carcinoid tumor Pan = Pancreatic tumor ค นเล ก = Small cell lung CA หมอเมด = Medullary CA thyroid ให ฟร = Pheochromocytoma

43 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 glucocorticoids Before evaluation for possible CS, it has excluded exogenous glucocorticoid intake

44 Signs and symptoms of Cushing's syndrome More common Less common

45 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 Rarely, chronic alcoholism 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 Pseudo Cushing s

46

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

48 DDx of Cushing s syndrome ACTH < 5 pg/ml ACTH > 20 pg/ml ACTH independent CS ACTH dependent CS CT adrenal gland -equivocal or negative MRI -clinical suspicious of ectopic ACTH Plasma ACTH 5-20 pg/ml : less definitive!! -But usually indicate that cortisol secretion is ACTH-dependent. -For these patients, a CRH stimulation test may be helpful BIPSS Ectopic ACTH syndrome Chest & Abdominal imaging Pituitary Adenoma

49 Pheochromocytoma Catecholamine-producing neuroendocrine tumours from chromaffin cells of adrenal medulla or extraadrenal paraganglia. Paraganglioma : extra-adrenal pheochromocytomas and tumors from parasympathetic tissue Lancet 2005; 366:

50 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:

51 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:

52

53 Lancet 2005; 366:

54 Biochemistry testing Urinary and plasma catecholamines, Urinary metanephrines (normetanephrine and metanephrine) Urinary vanillylmandelic acid (VMA) Plasma-free metanephrines (normetanephrine and metanephrine)

55 Lancet 2005; 366:

56 Interference with measurements of cathecholamine Lancet 2005; 366:

57

58 Imaging procedures CT ± contrast or MRI abdomen include pelvis 123 I-metaiodobenzylguanidine (MIBG) PET Lancet 2005; 366:

59 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 mg once daily Calcium-channel blockers Treatment usually lasts for days Lancet 2005; 366:

60 Adequate preoperative preparation Several criteria have been proposed BP below 160/90 mmhg for at least 24 h Orthostatic hypotension should be present, but BP in the upright position should not fall below 80/45 mmhg Lancet 2005; 366:

61 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:

62 Surgical treatment Laparoscopic removal of intra-adrenal and extra-adrenal phaeochromocytomas is now the preferred surgery Lancet 2005; 366:

63 Adrenal incidentaloma Prevalence is higher in older, obese, DM, and hypertensive patients Functional? Malignancy? Bilateral masses : -Metastatic disease -Congenital adrenal hyperplasia -Lymphoma -ACTH-dependent Cushing s -Primary aldosteronism -Infiltrative disease of adrenal glands -Infection (eg, tuberculosis, fungal) -Cortical adenomas -Hemorrhage -Pheochromocytoma -Amyloidosis -Bilateral macronodular adrenal hyperplasia (BMAH)

64 Adrenal incidentaloma Functional testing Pheochromocytoma Cushing s syndrome Primary aldosteronism : only in HT

65 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

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

67 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