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PHEOCROMOCYITOMA

PHEOCROMOCYITOMA. History – adrenal medulla. 1805 – Cuvier Makes the difference between adrenal cortex and medulla 1907 - Stoltz Purification & synthesis of epinephrine 1904 Synthesis of epinephrine 1946 - Holtz Norepineprine is recognized as:

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PHEOCROMOCYITOMA

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  1. PHEOCROMOCYITOMA

  2. History – adrenalmedulla • 1805 – Cuvier • Makes the difference between adrenal cortex and medulla • 1907 - Stoltz • Purification & synthesis of epinephrine • 1904 • Synthesis of epinephrine • 1946 - Holtz • Norepineprine is recognized as: • A product of secretion of edranal medulla • Neurotransmiter of sympathetic system

  3. history - pheocromocytoma • 1886 – Franklin • First description of pheocromocytoma • 1908 - AlezaissiPeyron • Definition of paragangloma • 1921 - Pick • Establishes the term of pheocromocytoma • 1961 - J.Sipple • descrieasociereafeocromocitomului cu carcinomtiroidianmedular • 1962 • recunoastereacaracterului familial al acesteiasocieri

  4. Adrenergic hormone secretorycells and tumorsderivedfromit Cells derived from neural creast NGF EGF

  5. anatomy • site • In the midle of the adrenal gland (without clear limits) • Weight • cca 1 g (10% of adrenal weight) • Nerves • paraganglionic fibres from CNS - mediatie colinergica • vascularity • arteries • Superior, median and inferior adrenal arteries • Intramedullary portal system • veins • MSR right – to vena cava • MSR left – to renal vein

  6. Microscopic anatomy pheocromocytes (chromaphine cells) • Large cells (ovalar) situated in clusters or alveolae • Well developed Golgi apparatus • Granules containing cathecolamines • Browns color with chromic acid due to oxidation of norepineprine (NE)and epinephrine (E)into melanine

  7. Thyrosine OH HO H C O Dopa OH thyrozine-OH HO NH2 C C H C O H H HO Dopamine HO NH2 C C Dopa-decarboxilasis H H HO NH2 C C H H H H Norepinephrine HO H OH Dopamine -OH HO NH2 C C H H HO OH H OH PNMT HO NH2 C C Epinephrine H H Cathecolaminessynthesis

  8. Cathecolamineinterractionwithreceptors E = epinefrina, NE = norepinefrina, I = isoproterenol

  9. Pheocromocytoma Definition • Chromaphin cells derived tumor wich is abe to produce: • Epinephrine, norepinephrine, dopamine • Peptides especially ACTH Ethyology and pathogenicity • < 0,1% of all hypertensive patients • prevalence: 1-2/106 • Of adrenal origin - 90% of all • extraadrenal(paraganglioamas) – 10% • unilateral - 90% of cases • benign - 90%

  10. Characteristics

  11. Clasification sporadic • 90% of cases • Sollitary tumor, usualy situated on the right adrenal gland Familial forms • Autosomal dominant forms • Associated with other tumors of APUD system

  12. Dominant autosomal syndromes associated with pheocromocytoma

  13. 68% Sporadic pheocromocytoma 6% SDHB 4% SDHD NF1 4% MEN 2 5% VHL 13% Familial and sporadic pheocromocytoma

  14. Informed consent for genetic testing Familial hystory or < 50 ani Multiple Malignant bilaterally VHL RET SDHD SDHB SDHD VHL SDHB VHL VHL RET SDHB SDHD Monitoring Genetic Counselling for the first degree relatives

  15. Nat Clin Pract Endocrinol Metab.  2007;3(2):92

  16. Type 2° Multipe Endocrine Neopasia(MEN 2A – Sipple syndrome) • associetes • Medullary thyroid cancercinoma • Pheocromocytoma • hyperparathyroidism • Pheocromocytoma • Hyperpasia of adrenal medulla, mucentricity, bilateral • Hypertension less frequently paroxistical • Produces especially epinephrine

  17. Type 2B MEN Gorlin syndrome • Ess frequent than MEN 2A • includes • pheocromocitoma • Medullry theroid carcinoma • Mucosal neurinomas al affected individuals • Localized on gthe lips, tongue, bucal mucosa giving an typical aspect of “bumpy lips” • mai rar pot exista • Intestinal ganglioneuromas • Corneal ganglioneurinomas • Marphanoid habitus • cca 1/2 of patients have complet picture of the disease

  18. MEN 2B • Marphanoidhabitus • Neurinomas

  19. MEN 2b Neurinomas eyelids tongue lips

  20. Retinal and cerebelous hemangioblastosis (von Hippel-Lindau syndrome) • 10-25% have pheocromocytoma • It presents • Neural hemangiomas • Visceral cysts • hypernephroma • A small retinal angioma may be associated with an undiagnozed pheocromocytoma

  21. Hemangioblastomatosis

  22. Hemangioblastomatosis

  23. Neurofibromatosis (Recklinghausen diseasze) • 1/3000 newborn, recognized during adolescence • Pheocromocytoma in families with Recklinghausen disease • Large series< 1% of cases • 5% of pheocromocytomas have neurophybromatosis • Incomplete forms • 5-6 café-au lait spots • cyphoscoliosis • Vertebral deformities

  24. Neuro-fibromatosis

  25. Neuro-fibromatosis

  26. Neuro-fibromatoza Original case presented by von Recklinghausen 1882

  27. Pheocromocytoma – clinicalcharacteristics Depends of • Tumor secretion • norepinephrine • Domoinant vasoconstricive effectsHTA paroxistical • epinephrine • Beta effects, vasodilatation, stable high blood pressure stable hypertension • dopamine • hypotension • Tumor size • Small tumors(<50g) – high turn-over • active, nonmetabolised cathecolamines, • Large tumors (>50g) – low turn over • catecolamines degradation products • Tissue response • Down regulation of receptors - tachiphylaxis

  28. Clinics: PAROXISTICAL HYPERTENSION THE CHRISIS: • Sudden begining • Produced by: • Phisical effort, even minimal, changes in body position, abdominal compression , large meal • drfugs (histamine, antidepressants, metoclopramide) • Generally not produced by psychological stress • Without apparent cause • Arterial hypertension • Very high values, sometimes cannot be measured • Sometimes cound not be measured because of short duration of the chrisis

  29. PAROXISTICAL HYPERTENSION

  30. CLINICAL SIGNSASSOCIATED SYMPTOMS HEADACHE • MOST COMMON(80%) • severe • pusatile • Occipital or frontal Tachicardia • 1 receptors stimulation • High frecquency, arhitmias • Rapid palpitations(64%) • Tachicardia + HTA = suggestive for diagnosis Transpitarations • 61% of cases • Severe, generalized •  receptors stimulation

  31. An association of • HYPERTENSION + Headache + TACHICARDIA + TRANSPIRATION 90% of cases = pheocromocytoma

  32. Other shymptom, Pale skin (42%), flush, cold extremities Chest pain, abdominal pain, nausea, vomiting Tremor, pardesthesias Anxiety, iminent death feelings hyperglicaemia, Hygh BUN End of the chrisis Exausting sensation bradicardia Congestive skin hypotension poliuria Duration of the chrisis variablea, min -hours(< 15’) Some chrisis/week With evolution of the disease the frequency of chrisis increases Clinics Crisis occurs in the same way in a certain patient)

  33. clinicsPERMANENT HYPERTESNION • Severe, mailignant hypertension • No response to medical treatment but responsive to alpha blokers agents (prazosin, labetalol) • dSevere abnormalities on gthefundus of the eye, std.III-IV, occurs rapidly • Useful for diagnosis • Paroxistic hyprertension on stable hypertension • anxiety • Weight loss • transpirations • Ortostatic hypotension

  34. Otherclinicalsigns and symptoms Ortostatic hypotension • Devcreased plasma volume • Rfeduction of postural reflexed due to catecolamine exposure) Hearth symptoms • angina, miocardial infarction • Without coronary artery \disease • arhitmias(TPSV, FbA, Es, synusal bradicardia), • ECG abnorfmalities in the absence of coronary artery disease • cardiomiopathy (hyperthopic or congestive) • Lung edema

  35. Otherclinicalsymptoms • Increasaed basal metabolic rate • + transpirations, termophobia, weight loss • Glucose intolerance • Moderate, during chrisis • hypercalcemia • In association with hyperparathyroidism (MEN tip 2A si 2B) • In absence of it (stimulation of the parathyroid glands by cathecoamines) • Waterry diarheea • + hypokaliemia and achlorhidria in Verner-Morrison syndrome • Due to VIP secretion • Cushing syndrome due to ectopic ACTH secretion Asymptomatic forms • Incidentalomas accidentaly descovered during a CT examination for other purposes

  36. Complications • Of hypertension • retinopatihy nephropaty • Stroke, encephalopthy, • Lung edema, congestive hearth failure • Cathecoamineds-associated cardiomiopathy • Cause of sudden death • Miocardial hypoxemia • Exccessive hearth effort • Direct toxic effect of cathecolamines • Arterial hypotension and shock • After a hypertensive chrisis • Tumor hemorrhage • Aortic anevrism

  37. Diagnosis steps • Suspicion of the disease due to symptoms • Confirm cathecolamine excess • Tumor localisation

  38. Hormonal assays -urinary Collection of urine • 24 hours • Acidified urine must be maitained at cold temperature • Possible errors: • Drugs (levodopa, methyldopa, MAOI) • food (bananas NE, vanilla containing food in case of the dosage for vanil mandelic acid)

  39. Urinaryassays • Free urinary cathecolamines • Specificity and sensitivity over 98% • normal values < 500 g/24 h • pheocromocytom a > 1500 g/24 h. • Urinary metabolites • 3 x normal values in pheocromicytoma • vanil-mandelic acid (VMA) • normal < 7 mg/d • Low sensitivity and specificity • homovanilic acid (dopamine metabolites) • Total urinary methanephrines (metaneprine and normetanephrine) • normal < 1,3 mg/day • Screening test

  40. Increase value Acetaminophen (Tylenol) Aminophillina Cafeina Chloralhidrat Clonidine Disulfiram Eritromicina Insulina Levodopa Lithium Methenamina Methyldopa Acidic nicotinic (doze mari) Nitroglicerina Quinidina Tetracicline Decrease value Clonidina Disulfiram Guanethidina Imipramina IMAO Fenotiazine Reserpina Salicilati Drugs that intefere with cathecolamines dosage

  41. HTA de 5 ani, greu controlata de triterapie atenolol, amlodipina, tiazidic Atcd nesemnificative BMI 29,7 kg/m2 TA 170/100 mmHg FC 56/min Absenta suflurilor abdominale Cord clinic normal Na 145 mmol/l K 3,6 mmol/l Creat 1 mg/dl Urina Metanefrine 0,3 mg/24 h (N<1,3) NA 108 mcg (N <80) A 10 mcg (N <20) DA 255 (N<400) Rx toracic normal Doppler artera renala normal Caz clinic - barbat de 56 ani

  42. Care este urmatorul pas? • CT abdominal • 123I-MIBG • Adaugarea unui al doilea vasodilatator (eg ACE inhibitor) • Determinarea raportului A/ARP • Masurarea reninei venoase renale

  43. Care este urmatorul pas? • CT abdominal • 123I-MIBG • Adaugarea unui al doilea vasodilatator (eg ACE inhibitor) • Determinarea raportului A/ARP • Masurarea reninei venoase renale

  44. Biochemical markes of pheocromocytoma

  45. Tests Suppressive tests Phentolamine test(Regitina) • alfa blokers with rapid action- 1-5 mg. i.v. • Rapid dxecrease kin bood pressure (TAsys minim 35 mmHg Tadyas withu 25 mmHg) • Response in 2-3 min and last for 10 min

  46. tests Suppressive Clonidine test • 2-agonist • 300 g p.o. • Bood after 2-3 hours • Normally blood pressure drops with 30 mmHg • Decreases cathecola mines • In pheocromocytoma there is no response

  47. Tests Glucagon test • Glucagon liberates cathecolamines from pheocromocytoma but n ot from normal adrenae medulla • 1 mg i.v. • Cathecolaminele increase 3 times • Blood pressure increases with40 mmHg Cold pressor test • Normally after hands are put in cold water with ice, bood pressure increases in normal persons. In pheocromocytoma there is not such an increase in blood pressure.

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