Analyse secundaire hypertensie: het feochromocytoom Henri Timmers - - PowerPoint PPT Presentation

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Analyse secundaire hypertensie: het feochromocytoom Henri Timmers - - PowerPoint PPT Presentation

Jun 18, 2023 240 likes •678 views

Analyse secundaire hypertensie: het feochromocytoom Henri Timmers Internist-endocrinoloog Radboudumc Bijniercentrum Nijmegen Disclosure belangen spreker Henri Timmers, Radboudumc Geen (potentile) belangenverstrengeling Voor bijeenkomst

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Analyse secundaire hypertensie: het feochromocytoom

Henri Timmers Internist-endocrinoloog Radboudumc Bijniercentrum Nijmegen

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Disclosure belangen spreker

Henri Timmers, Radboudumc

Geen (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties: Bedrijfsnamen

  • Sponsoring of
  • nderzoeksgeld

Nvt

  • Honorarium of andere

(financiële) vergoeding Nvt

  • Aandeelhouder

Nvt

  • Andere relatie, namelijk …

Nvt

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Overview

Case presentation ✓ screening ✓ localization ✓ peri-operative care ✓ malignancy ✓ genetics ✓ follow-up

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Pheochromocytoma & paraganglioma

pheochromocytoma extra-adrenal paraganglioma

PPGL

Fauci et al., Harrison’s Principle of Internal Medicine

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Pheochromocytoma & paraganglioma

Fauci et al., Harrison’s Principle of Internal Medicine Lack et al. AFIP Atlas of Tumor Pathology: American Registry of Pathology

pheochromocytoma extra-adrenal paraganglioma

PPGL

head & neck paraganglioma

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J Clin Endocrinol Metab, June 2014, 99(6):1915-1942

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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
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Symptoms and signs

Lenders et al., Lancet 2005

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Should this patient be screened for PPGL?

A. Yes B. No

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Clinical settings for PPGL screening

Endocrine Society clinical practice guideline, JCEM 2014

  • 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
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How to screen this patient for PPGL?

A. 24h urinary VMA B. Plasma free metanephrines C. 24h urinary fractionated metanephrines D.

123I-MIBG scan

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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
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Catecholamine metabolism

Eisenhofer et al. Endocr Relat Cancer 2011

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Catecholamine metabolism

Eisenhofer et al. Endocr Relat Cancer 2011

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Endocrine Society clinical practice guideline, JCEM 2014

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)

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Sampling conditions for plasma metanephrines

Lenders et al. Clin Chemistry 2007

From IV catheter after 30 minutes of supine rest

Normetanephrine: influence of posture

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Drugs with potential pharmacodynamic interference

Endocrine Society clinical practice guideline, JCEM 2014

Plasma Urine NMN MN NMN MN Tricyclic antidepressants ++

  • ++
  • Phenoxybenzamine

++

  • ++
  • MAO-inhibitors

++ ++ ++ ++ Sympathomimetics + + + + Cocaine ++ + ++ + Levodopa (3MT only) + + ++ +

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Endocrine Society clinical practice guideline, JCEM 2014 Neary et al. N Engl J Med 2011

Drugs with potential pharmacodynamic interference

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Case

Plasma Reference range Result Metanefrine 57-295 pmol/l 263 Normetanefrine 48-495 pmol/l 11989 (H) 3-Methoxytyramine <100 pmol/l 236 (H)

Biochemical evaluation

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But what if MNS were only mildly elevated?

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How to localize PPGL in this patient?

A. MRI scan adrenals B. CT scan abdomen C.

123I-MIBG scintigraphy

D.

18F-FDG PET scan

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Endocrine Society clinical practice guideline, JCEM 2014

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Endocrine Society clinical practice guideline, JCEM 2014

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Endocrine Society clinical practice guideline, JCEM 2014

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How to prepare this patient for surgery?

A. Phenoxybenzamine B. Doxazosin C. Metyrosine D. Labetalol E. Other drug

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Pre-surgical preparation

Endocrine Society clinical practice guideline, JCEM 2014

Drug Starting before surgery Starting dose (adults) Final dose** (adults)

  • 1. Phenoxybenzamine

10-14 days before surgery 2 x 10 mg/day 1 mg/kg/day

  • r: 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

  • r: 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

  • r: 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

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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
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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

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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
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Case

Pathology

  • Both tumors consistent with PPGL
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Does this patient have malignant PPGL?

A. Yes B. No C. Unclear

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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
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Does this patient have hereditary PPGL?

A. No, sporadic B. Yes: RET C. Yes: VHL D. Yes: SDHB E. Yes: SDHD

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Susceptibility genes

Adapted from Gimenez-Roqueplo et al., Horm Met Res 2012

Hereditary: 10%.........................>25%........................................................>30%

‘Classic’ syndromes

MDH2 EGLN2/PHD1

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Adapted from Gimenez-Roqueplo et al., Horm Met Res 2012

Hereditary: 10%.........................>25%........................................................>30%

Succinate dehydrogenase

MDH2 EGLN2/PHD1

Susceptibility genes

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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

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Endocrine Society clinical practice guideline, JCEM 2014; Eisenhofer et al. Clinical Chemistry 2011

Decisional algorithm for genetic testing

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Next generation sequencing

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Case

Genetic counseling and testing

  • SDHB mutation
  • Family counseling

Van Nederveen et al., Lancet Oncol 2009 Korpershoek et al., JCEM 2011

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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

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Endocrine Society clinical practice guideline, JCEM 2014