Endocrine Hypertension: A Logical Approach. NORLELA SUKOR MD, MMED, PhD Consultant Endocrinologist University Kebangsaan Malaysia Medical Center

Transcription

1 Endocrine Hypertension: A Logical Approach NORLELA SUKOR MD, MMED, PhD Consultant Endocrinologist University Kebangsaan Malaysia Medical Center

2 Outline of PresentaEon Causes of Hypertension Endocrine Hypertension Causes Inves5ga5on Management Logical Approach

3 Causes of Hypertension 85% - Essen5al/primary 15% - Secondary causes - endocrine- related diseases - renal (renovascular hypertension) - cardiovascular (coarcta5on of aorta) - respiratory (sleep apnea) - drugs (OCP, etc)

4 Hyperparathyroidism Endocrine Hypertension Causes: Primary aldosteronism Pheochromocytoma Cushing s syndrome Acromegaly Hyperthyroidism/ Hypothyroidism

5 Who to screen The Endocrine Society Clinical Prac5ce Guideline Stage 2 hypertension (BP > / mmhg) Stage 3 hypertension (BP > 180/110 mmhg) Drug- resistant hypertension Hypertension and spontaneous or diure5c- induced hypokalaemia

6 Who to screen The Endocrine Society Clinical Prac5ce Guideline Hypertension with adrenal incidentaloma Hypertension and a family history of early- onset hypertension or cerebrovascular accident at young age (< 40 years) All hypertensive first- degree rela5ves of pa5ents with PA

7 Importance to detect the cause of endocrine hypertension 1) The cause is clear and can be traced to the ac5on of a hormone 2) Can implement a disease- specific targeted an5hypertensive therapy complete cure obviate the need for lifelong an5hypertensive therapy

8 Clinical Diagnosis of Endocrine Hypertension The first step is to exclude other causes of secondary hypertension par5cularly renal disorders detailed medical history and review of systems onset of hypertension response to previous an5hypertensive treatment compliance history of target organ damage re5nopathy, nephropathy, claudica5on, heart disease, abdominal or caro5d artery disease

9 Primary Aldosteronism

10 Primary Aldosteronism EXCESSIVE, AUTONOMOUS production of ALDOSTERONE Salt retention Potassium excretion HYPERTENSION SUPPRESSION OF RENIN LOW PLASMA K + (Hypokalemia)

11 Primary Aldosteronism Conn's first paeent with primary aldosteronism (PA), year old lady with: Severe hypertension Severe hypokalemia Cured by removal of a 4cm aldosterone-producing adenoma (APA) situated in the right adrenal

12 Primary Aldosteronism PA was thought to be a rare (<1%) cause of hypertension Recent evidence suggested that PA is much more common than was previously thought PA is the commonest poten5ally curable and specifically treatable form of hypertension accoun5ng for 5-10 % of cases

13 Primary Aldosteronism Subtypes: Bilateral adrenal hyperplasia (BAH) Aldosterone producing adenoma (APA) Unilateral adrenal hyperplasia (PAH) Glucocor5coid remediable aldosteronism Adrenocor5cal carcinoma

14 InvesEgaEons for PA Suspicious of PA Screening ARR Confirma5on FST/SST Subtype differen5a5on CT Adrenals AVS Unilateral PA (APA) Bilateral PA (BAH) Surgery Medical therapy

15 Inves5ga5ons for PA Screening tests Aldosterone renin ra5o (ARR) many factors can affect ARR: drugs, 5me of the day blood sample is taken, posture, potassium levels different centres use different cut- off values ARR > 30 (plasma aldosterone in ng/dl, direct renin in ng/ml/h)

16 Captopril suppression test Inves5ga5ons for PA Confirma5on of Diagnosis FludrocorEsone suppression test (FST) Fludrocor5sone acetate 0.1 mg every 6h, with a high sodium diet and slow release sodium chloride (Slow Na) 30 mmol thrice daily, as well as Slow K 6 hourly. Blood sample taken at baseline and at day 4 Failure to suppress upright PAC at 1000 h to < 6 ng/dl (166 pmol/l) at day 4 is diagnos5c of PA Saline suppression test

17 CT or MRI of adrenals high resolu5on adrenal CT with fine (2-3 mm) cuts with IV contrast lacks reliability Inves5ga5ons for PA Subtype differen5a5on CT mistakenly suggested APA in 24%, iden5fied correctly a unilateral or bilateral PA in 53% & falsely suggested a BAH in 21%, indicated wrong adrenal in 21%

18 Subtype differen5a5on Adrenal venous sampling (AVS) gold standard to differen5ate between unilateral and bilateral PAL an invasive procedure technically challenging Inves5ga5ons for PA no consensus in determining success of cannula5on and lateraliza5on

19 Treatment for PA The detec5on of PA is of par5cular importance provides an opportunity for a targeted treatment pa5ents affected by PA are more prone to CV events and target organ damage than age- matched and sex- matched pa5ents with essen5al HPT with similar BP levels unilateral adrenalectomy has posi5ve impact not only on BP & biochemical parameters but also QOL

20 Treatment for PA Unilateral PA : unilateral adrenalectomy Outcome of adrenalectomy Cure rate (normaliza5on of BP) 50-60% Improvement in the remainder Normaliza5on of K + level in almost all pa5ents QOL improved following unilateral adrenalectomy

21 Treatment for PA Bilateral PA: targeted medical therapy with Spironolactone/amiloride Eplerenone - a selec5ve mineralocor5coid receptor antagonist. - has similar a/hpt efficacy with spironolactone in BAH pa5ents. Role of unilateral adrenalectomy?

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23 Pheochromocytoma

24 PHEO: Background No longer rule of 10 20% extra- adrenal chromaffin 5ssue 24% familial (MEN, VHL, SDHx) Up to 36% metasta5c Malignant: up to 36% of pa5ents, no reliable markers, no effec5ve treatments Not diagnosed in at least 50% of pa5ents VHL: von Hippel- Lindau syndrome SDHx: succinate dehydrogenase subunit B, D, or C Lancet 2005; 366:665 DeGroot & Jamneson, Textbook of Endocrinology 2005

25 PHEO: Sites of origin C adrenal pheochromocytoma extra- adrenal pheochromocytoma head and neck paraganglioma

26 SDHx muta5ons and PHEO Succinate KREBS CYCLE Fumarate Hypoxia/apoptosis signaling Fp (SDHA) SDHB Hypoxia/ apoptosis promotes GROWTH cybs (SDHD) Q -. cybl (SDHC) PHEO

27 Succinate dehydrogenase (SDHx)- related PHEOs Younger age Ooen extra- adrenal, mul5ple, and metasta5c If metasta5c than more aggressive May secrete only dopamine

28 Gene5c tes5ng: Recommenda5ons from ISP 2005

29 Biochemical diagnosis: Caveats using catecholamines PHEO diagnosis is based on excessive produc5on of catecholamines (NE, EPI), which is usually assessed by measurements of urinary excre5on of catecholamines and metanephrines. Produced by the sympathoadrenal system and therefore not specific for PHEO. false- posi5ve test results Episodic catecholamine secre5on Small tumor may be silent false- nega5ve test results

30 Metanephrines are produced con5nuously and independently of catecholamine secre5on. What is specific about metanephrines? Bloodstream PHEO/chromaffin cell NE NE NMN MN NMN MN NE C O M T EPI EPI EPI

31 Sensi5vity and specificity " " " " " Sensitivity %" Specificity %" " " " " " "" Plasma Free Metanephrines " 98 " 90 " Plasma Catecholamines " " 81 " 81 " " " " "" "" Ur. Total Metanephrines " " 72 " 93" Ur. Fract. Metanephrines " 97 " 64 " Ur. Catecholamines " " 85 " 86 " Ur. VMA " " 62 " 93 " " Total = conjugated and free NMN and MN; Frac5onated = separate measurement of NMN and MN "" JAMA 2002; 287:1427

32 Biochemical tes5ng: Recommenda5ons from ISP 2005 Ini5al tes5ng for PHEO should include measurements of frac5onated metanephrines in plasma, urine, or both, as available. There was no consensus about plasma versus urine measurements as preferred test. Nature Clin. Pract. Endocrinol. Metab. 2007; 3:92

33 Drug- induced changes in NE and NMN CATECHOLAMINES METANEPHRINES NE E NMN MN Tricyclics α Blockers β Blockers Ca channel blocker Acetaminophen: stop: 3-5 days; interferes with HPLC method Harrison s Textbook online, 2004

34 Plasma free metanephrines + PHEO possible > 4 x URL PHEO: Biochemical algorithm < 4 x URL Clonidine test coupled with free normetanephrine (exclude drug effect) PHEO excluded PHEO confirmed IMAGING STUDIES Harrison s Textbook online, 2004

35 A tumor imaging approach: 2 op5ons 1. ANATOMICAL (CT/MRI) Defines the size, shape, and structure of the mass Adrenal pheochromocytoma Adrenal hemorrhage CT Addi5onal clinical informa5on is needed 2. FUNCTIONAL/MOLECULAR Explores unique characteris5cs of the mass CT

36 Func5onal imaging modali5es Specific 123 I/ 131 I- MIBG 18 F- fluorodopamine ( 18 F- DA) 11 C- epinephrine 11 C- hydroxyephedrine ( 11 C- HED) Non- specific 18 F- fluorodeoxyglucose (FDG) 18 F- fluorodopa 111 In- pentetreo5de (Octreoscan) Endocr. Rev. 2004; 25:568

37 Func5onal imaging of primary PHEO/PGL: NIH study SensiSviSes (per lesion) 123 I- MIBG scan: 67-86% 18 F- FDA PET: 75-92% 18 F- FDOPA PET: 67-93% 18 F- FDG PET: 83-93% (adrenal: 67%) Octreoscan: Adrenal: < 50% of pa5ents posi5ve J. Nucl. Med., in press

38 PHEO: pharmacological treatment Medical Prepara5on for Surgery The preopera5ve medical therapy is aimed at controlling hypertension (prevent a hypertensive crisis during surgery) and volume expansion. There is no universally accepted method of prepara5on for surgery

39 PHEO: pharmacological treatment Medical Prepara5on for Surgery Alpha- adrenergic blockade Star5ng 7 to 10 days preopera5vely to normalize BP and expand the contracted blood volume Beta- adrenergic blockade Started aoer adequate alpha- adrenergic blockade has been achieved Should never be started first because blockade of vasodilatory peripheral beta- adrenergic receptors with unopposed alpha- adrenergic receptor s5mula5on can lead to a further eleva5on in BP

40 PHEO: pharmacological treatment Medical Prepara5on for Surgery Target blood pressure is less than 120/80 mm Hg (seated), with systolic blood pressure greater than 90 mm Hg (standing)

41 PHEO: pharmacological treatment Pharmacological blockade Alpha: Phenoxybenzamine Beta: Atenolol (β1) propranolol (β1 & 2) Alpha and beta: Labetalol Ca channel blockers: Norvasc mg TID mg BID mg Blockade of catecholamine synthesis: Metyrosine (Demser 250 mg TID). Hypertensive crisis Phentolamine (Regi5ne): 5 mg i.v. bolus

42 PHEO: pharmacological treatment Metyrosine Inhibits catecholamine synthesis Pa5ents given metyrosine had a smoother periopera5ve course than those given phenoxybenzamine alone Should be used with cau5on and only when other agents have been ineffec5ve or in pa5ents where tumor manipula5on or destruc5on (eg, radiofrequency abla5on of metasta5c sites) will be marked Dose: 250 mg every six hours on day one, 500 mg every six hours on day two, 750 mg every six hours on day three, and 1,000 mg every six hours on the day before the procedure, with the last dose (1,000 mg) the morning of the procedure S/E: seda5on, depression, diarrhea, anxiety, nightmares, crystalluria and urolithiasis, galactorrhea, and extrapyramidal signs

43 PHEO: Preopera5ve blockade Option 1: Preferred by most medical centers α-adrenoceptor blocker (preferrably phenoxybenzamine) adjust every other day according to BP reading if tachycardia found add β-adrenoceptor blocker (preferrably cardioselective) not earlier than 2-3 days after α blockade add Demser (if available and preferred by a center) add calcium channel blocker (if BP still not well controlled) monitor BP and HR Fluid replacement add At midnight before operation (NIH): phenoxybenzamine & Demser Fluid replacement only* Option 2: Mainly for low risk patients calcium channel blocker (treatment period can be less than days) adjust according to BP reading add Demser (if available and preferred by a center) monitor BP and HR Fluid replacement add At midnight before operation (NIH): Demser Fluid replacement only outpatient preferrably 7-14 days intpatient 1-2 days operation

44 Main drugs contraindicated in PHEO Anesthe5cs: ooen hypertensive crisis aoer induc5on of anesthesia

45 PHEO: surgical treatment Benign lesion Unilateral laparoscopic adrenalectomy Morbidity & Mortality Overall periopera5ve mortality and morbidity rates were 2.4 and 24 %, respec5vely

46 TREATMENT OPTIONS FOR MALIGNANT PHEO No cura5ve treatment available. Surgical debulking may increase survival & decrease catecholamine burden; but data are not available. If a pt is: + MIBG > 131 I- MIBG therapy - MIBG > chemotherapy Chemotherapy: 1st choice in a rapidly progressive tumor!! Remember: 131 I- MIBG or chemotherapy: only about 1/3 of pa5ents respond (no cure, only a par5al response).

47 PROGNOSIS OF PHEO Surgical removal of a pheochromocytoma does not always lead to long- term cure of pheochromocytoma or hypertension, even in pa5ents with a benign tumor In one series of 176 pa5ents, pheochromocytoma recurred in 29 (16 %) and the recurrence was malignant in 15 of the 29 Recurrence was more likely in pa5ents with familial pheochromocytoma or paraganglioma right adrenal tumors extraadrenal tumors.

48 Asian Alliance for Pheochromocytoma /PGL and Neuroendocrine Tumors

49 Cushing s Syndrome

50 Inves5ga5on for Cushing s Syndrome Tes5ng is recommended in pa5ents with 1) mul5ple and progressive features of CS, especially those with a high discriminatory value such as easy bruising, facial plethora, proximal muscle weakness and reddish- purple striae 2) pa5ents with unusual features for their age (eg. osteoporosis or hypertension) 3) children with increasing weight with low height for age percen5le 4) pa5ents with an adrenal incidentaloma

51 Ini5al Tes5ng 1) 24 h UFC (at least 2 measurement) 2) late- night salivary cor5sol (2 measurement) 3) 1 mg overnight DST or 4) longer low dose DST (2 mg/day for 48 h) Individual pa5ent characteris5cs may help to determine test choice (eg. DST is not recommended for pa5ents on oestrogen therapy or on OCP as oestrogens increase CBG, giving rise to a false posi5ve result)

52 Ini5al Tes5ng If the ini5al tes5ng is abnormal, proceed with either: 1) Midnight serum cor5sol OR 2) CRH- Dexamethasone suppression test Other tests ACTH level MRI pituitary CT adrenals

53 Treatment for Cushing s Syndrome IdenEfy the cause of Cushing s syndrome: ACTH dependent Non- ACTH dependent

54 Treatment for Cushing s Syndrome Cushing s Disease Pituitary surgery Remission following surgery: 70-90% microadenomas 50-65% macroadenomas Recurrent hypercor5solism affects 10% pt with micro- 30% with macroadenomas Serum cor5sol should be assessed 6-12 weeks aoer surgery

55 Neurosurgery 2008 Treatment for Cushing s Syndrome Recurrent Cushing s Disease Repeat pituitary surgery - the odds of failure for pa5ents with repeat TSS were 3.7 5mes that of pa5ents undergoing first 5me TSS - remission achieved in 61% (22 of 36 pa5ents) and 83% aoer addi5onal treatment

56 Treatment for Cushing s Syndrome Recurrent Cushing s Disease Radiotherapy conven5onal - remission in 50% but response is delayed - only 50% enter remission aoer 18 mths - normaliza5on of cor5sol 6-60 mths stereotac5c - successful normaliza5on of cor5sol similar - mean 5me to normaliza5on is shorter 6-8 mths

57 Other agents: metyrapone, aminoglutethemide, mitotane Treatment for Cushing s Syndrome Recurrent Cushing s Disease Medical therapy Ketoconazole - block the first & last steps of cor5sol synt - extra effect on 17- αoh - effect is seen aoer 2-3 weeks - SE: hepatotoxicity Etomidate - inhibit both 11- βoh & 17- αoh - correct severe hypercor5solism - normalize cor5sol within 12 hr

58 Pasireo5de, Cabergoline & Ketoconazole - majority of ACTH- secre5ng adenomas express somatosta5n- receptor subtype 5 & dopamine- receptor subtype 2 Pasireo5de monotherapy 29% (5 of 17 pts) Pasireo5de + cabergoline add 24% Pasireo5de + cabergoline + ketoconazole 88% Bilateral adrenalectomy Nejm 2010

59 Endocrine Hypertension: A Logical Approach Suspicion of a secondary (endocrine) cause of hypertension Young hypertensives Presence of target organ damage that is dispropor5onate to the level of BP or dura5on of hypertension Presence of signs or symptoms of endocrine diseases Resistant hypertension Hypertension with hypokalaemia Hypertension with adrenal incidentaloma

60 Endocrine Hypertension: A Logical Approach Exclude renal causes Obtain thorough medical history and perform complete physical examina5on

61 Endocrine Hypertension: A Logical Approach Disease Important History Clinical Findings Primary Aldosteronism Difficult to control blood pressure, hypertension with hypokalaemia, family history of intracerebral haemorrhage Muscle or body weakness Pheochromo cytoma Cushing s syndrome Headaches, palpita5on and/or swea5ng Easy bruising, unable to stand up from a squa{ng posi5on, weight gain, fracture due to osteoporosis Significant postural drop or fluctua5ng blood pressure Cushingoid appearance, facial plethora, thin skin, reddish purple striae, proximal myopathy

62 Conclusion Endocrine hypertension is not as uncommon as previously thought The importance of diagnosing endocrine hypertension lies in the fact that it may convert an incurable disease into a poten5ally curable disease. Suspicion of an endocrine cause of hypertension is important in order to inves5gate it s cause in a logical approach.

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