Analyse secundaire hypertensie: het feochromocytoom Henri Timmers Internist-endocrinoloog Radboudumc Bijniercentrum Nijmegen
Disclosure belangen spreker Henri Timmers, Radboudumc Geen (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk Bedrijfsnamen relevante relaties: • Sponsoring of Nvt onderzoeksgeld • Honorarium of andere Nvt (financiële) vergoeding • Aandeelhouder Nvt • Andere relatie, namelijk … Nvt
Overview Case presentation ✓ screening ✓ localization ✓ peri-operative care ✓ malignancy ✓ genetics ✓ follow-up
Pheochromocytoma & paraganglioma extra-adrenal pheochromocytoma paraganglioma PPGL Fauci et al., Harrison ’ s Principle of Internal Medicine
Pheochromocytoma & paraganglioma extra-adrenal pheochromocytoma paraganglioma PPGL head & neck paraganglioma Fauci et al., Harrison ’ s Principle of Internal Medicine Lack et al. AFIP Atlas of Tumor Pathology: American Registry of Pathology
J Clin Endocrinol Metab, June 2014, 99(6):1915-1942
Case 25 yo male History • Fatigue >1 year. Difficulty sleeping. BP 150-160/85-90 mmHg. No paroxysms of headache, palpitations or sweating. No nausea, anxiety, weight loss or orthostatic dizziness. No medications, no drug abuse. • Family history: father with hypertension, coronary heart disease and surgical resection of neck tumor. Physical exam • Normal BMI • Supine BP 152/96 mmHg, pulse rate 52 bpm • Standing BP 148/90 mmHg, pulse rate 62 bpm • Otherwise normal
Symptoms and signs Lenders et al., Lancet 2005
Should this patient be screened for PPGL? A. Yes B. No
Clinical settings for PPGL screening • Signs and symptoms of PPGL, in particular if paroxysmal • Adrenal incidentaloma, with or without hypertension • Hereditary predisposition or syndromic features • Previous history of PPGL • PPGL symptoms provoked by use of medications associated adverse effects - Anesthetics (opioid analgesics, neuromuscular blocking agents) - Dopamine D2 antagonists - Tricyclic antidepressants - Adrenergic receptor blockers - Sympathomimetics - Monoamine oxidase inhibitors - Corticosteroids - ACTH, glucagon Endocrine Society clinical practice guideline, JCEM 2014
How to screen this patient for PPGL? A. 24h urinary VMA B. Plasma free metanephrines C. 24h urinary fractionated metanephrines 123 I-MIBG scan D.
Low pre-test probability Prevalence of PPGL • 0.2-0.6% of adults with hypertension in general outpatient clinics • 1.7% of children with hypertension • 0.05-0.1% in autopsy studies
Catecholamine metabolism Eisenhofer et al. Endocr Relat Cancer 2011
Catecholamine metabolism Eisenhofer et al. Endocr Relat Cancer 2011
Plasma free vs urinary fractionated metanephrines Sensitivity Specificity Study Plasma Urine Plasma Urine Lenders et al, 2002 98.6% 97.1% 89.3% 68.6% (211/214) (102/105) (575/644) (310/452) Unger et al., 2006 95.8% 93.3% 79.4% 75.0% (23/24) (14/15) (54/68) (39/52) Hickman et al., 2009 100.0% 85.7% 97.6% 95.1% (14/14) (12/14) (40/41) (39/41) Grouzmann et al., 2010 95.7% 95.0% 89.5% 86.4% (44/46) (38/40) (102/114) (121/140) Unger et al., 2012 89.5% 92.9% 90.0% 77.6% (17/19) (13/14) (54/60) (38/49) Endocrine Society clinical practice guideline, JCEM 2014
Sampling conditions for plasma metanephrines From IV catheter after 30 minutes of supine rest Normetanephrine: influence of posture Lenders et al. Clin Chemistry 2007
Drugs with potential pharmacodynamic interference Plasma Urine NMN MN NMN MN Tricyclic antidepressants ++ - ++ - Phenoxybenzamine ++ - ++ - MAO-inhibitors ++ ++ ++ ++ Sympathomimetics + + + + Cocaine ++ + ++ + Levodopa (3MT only) + + ++ + Endocrine Society clinical practice guideline, JCEM 2014
Drugs with potential pharmacodynamic interference Endocrine Society clinical practice guideline, JCEM 2014 Neary et al. N Engl J Med 2011
Case Biochemical evaluation Plasma Reference range Result Metanefrine 57-295 pmol/l 263 Normetanefrine 48-495 pmol/l 11989 (H) 3-Methoxytyramine <100 pmol/l 236 (H)
But what if MNS were only mildly elevated?
How to localize PPGL in this patient? A. MRI scan adrenals B. CT scan abdomen 123 I-MIBG scintigraphy C. 18 F-FDG PET scan D.
Endocrine Society clinical practice guideline, JCEM 2014
Endocrine Society clinical practice guideline, JCEM 2014
Endocrine Society clinical practice guideline, JCEM 2014
How to prepare this patient for surgery? A. Phenoxybenzamine B. Doxazosin C. Metyrosine D. Labetalol E. Other drug
Pre-surgical preparation Drug Starting before surgery Starting dose Final dose ** (adults) (adults) 1. Phenoxybenzamine 10-14 days before surgery 2 x 10 mg/day 1 mg/kg/day or: Doxazosin 10-14 days before surgery 2 mg/day 32 mg/day 2. Nifedipine * as add on to 1 when needed 30 mg/day 60 mg/day or: Amlodipine * as add on to 1 when needed 5 mg/day 10 mg/day 3. Propranolol after at least 3-4 days of 1 3 x 20 mg/day 3 x 40 mg/day or: Atenolol after at least 3-4 days of 1 25 mg/day 50 mg/day * to add when blood pressure can not be controlled by alpha-adrenoceptor blockade ** usually it is not necessary to use higher doses High-sodium diet and fluid intake Endocrine Society clinical practice guideline, JCEM 2014
Case Presurgical work-up and treatment • ECG and cardiac ultrasound: normal • Targets: supine BP <130/80 mmHg, pulse rate <80 mmHg, standing systolic BP 90-110 mmHg, pulsepulse <100 mmHg • Doxazosin increases upto 20 mg BID • Metoprolol upto 50 mg BID • NaCl ~15 gram/day followed by IV infusion
Surgical resection of PPGL • Usually laparoscopic surgery: transperitoneal or retroperitoneal approach • Open surgery: in case of large or invasive pheochromocytoma and, depending on the location, extra-adrenal paraganglioma Posterior retroperitoneoscopic adrenalectomy
Case Surgery and peri-operative monitoring • Laparotomy: tumor resection, including part of liver caudate lobe and cholecystectomy • VATS: tumor resection • Norepinephrine to overcome hypotension • Overnight monitoring at ICU: BP, HR, glucose
Case Pathology • Both tumors consistent with PPGL
Does this patient have malignant PPGL? A. Yes B. No C. Unclear
Malignant PPGL • No reliable histological criteria or molecular markers! • Defined by the presence of metastases in locations where chromaffin tissue is not normally present: lymph nodes, bone, liver, lung Markers of malignancy • Tumor size: 10 cm tumor 5-fold higher risk than 4 cm tumor • Tumor location: extra-adrenal tumour 3.6-fold higher risk than adrenal tumor • Genotype: SDHB mutation • Plasma free methoxytyramine
Does this patient have hereditary PPGL? A. No, sporadic B. Yes: RET C. Yes: VHL D. Yes: SDHB E. Yes: SDHD
Susceptibility genes MDH2 EGLN2/PHD1 ‘Classic’ syndromes Hereditary: 10%.........................>25%........................................................>30% Adapted from Gimenez-Roqueplo et al., Horm Met Res 2012
Susceptibility genes MDH2 EGLN2/PHD1 Succinate dehydrogenase Hereditary: 10%.........................>25%........................................................>30% Adapted from Gimenez-Roqueplo et al., Horm Met Res 2012
Hereditary PPGL • At least one third of PPGLs is caused by a germline mutation • Mutation rate is still 11-13% in apparently sporadic PPGL Buffet et al., Horm Metab Res 2012 Brito, et al., Clin Endocrinol (Oxf) 2015
Decisional algorithm for genetic testing Endocrine Society clinical practice guideline, JCEM 2014; Eisenhofer et al. Clinical Chemistry 2011
Next generation sequencing
Case Genetic counseling and testing • SDHB mutation • Family counseling Van Nederveen et al., Lancet Oncol 2009 Korpershoek et al., JCEM 2011
Case Follow-up • Normalization of plasma metanephrines (2-6w post surgery) • Life-long follow-up • Yearly visit, including plasma metanephrines, 3-methoxytyramine • Screening for head/neck PGL: MRI head/neck • Screening for (silent) PPGL: MRI chest/abdomen Plouin et al. European Journal of Endocrinology 2016
Endocrine Society clinical practice guideline, JCEM 2014
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