c2. curs hipotalamus si diabet insipid 2014
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medicinaTRANSCRIPT
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NeuroendocrinologieNeuroendocrinologie
HipotalamusulHipotalamusulPatologia vasopresineiPatologia vasopresinei
Diabetul insipidDiabetul insipid
Corin Badiu, 2013
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NeuroEndocrinologieSistem nervos
SSiiststeem m endocrendocriinn
SSiiststeem m imunimun
cito
kine
cito
kine
neurohormoni
neurohormoni
citokinecitokine
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ProprietatiProprietati
ComuneComune
• PotentiPotentiaallee d de e actiactiuunnee
• SSeecrcreetitiee
• MMeediadiatoritori (Peptide) (Peptide)
• RReeceptceptoorrii
SpSpecificeecifice
• AmplAmploaoarreaea raspunsuluiraspunsului
• LatenLatentata
• DuDuratarata
• RReglajeglaj
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Neuroseecreetie
Neurohormoni Neuromodulatori
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Sistemul port hipotalamo-hipofizarSistemul port hipotalamo-hipofizar
Gr. Popa and U. Fielding, Lancet, 238, 1930
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• ὑποθαλαμος = sub talamus
• Localizat inferior de talamus, portiunea majora a diencefalului ventral
• Regleaza procese metabolice si activitati ale SNV
• Leaga sistemul nervos de sistemul endocrin via glanda pituitara, prin sinteza si secretia neurohormonilor, (liberine si statine).
• Neuronii care secreta GnRH sunt conectati cu sistemul limbic, care este implicat primar in controlul emotiilor si activitatii sexuale.
• Hipotalamusul controleaza temperatura, foamea, setea si ritmul circadian.
• Hipotalamusul este conectat cu SNC, formatiunea reticulata, sistemul limbic (amigdala, septum, banda diagonala Broca, bulbul olfactiv) si cortexul cerebral).
HipotalamusHipotalamus
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Martin, Reichlin, 1987
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FunctiiFunctii• Responsiv la:• Lumina: lungimea zilei si fotoperioada pentru a genera ritmurile circadian
si sezonier• Olfactie: stimuli, inclusiv feromoni (parfumuri) • Steroizi: gonadali si corticosteroizi • Informatii vegetative periferice : cardiovascular, stomac, tract reproductiv
– SN Autonom– Stimuli hormonali: leptina, ghrelin, angiotensina, insulina, hormoni
adenohipofizari, citokine, glicemie, osmolaritate etc. • Stress • Microrganisme: prin cresterea temperaturii, resetand termostatul.
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Nuclei hipotalamiciNuclei hipotalamici
• Medial Area• Anterior• Medial preoptic nucleus
Supraoptic nucleusParaventricular nucleusAnterior nucleusSuprachiasmatic nucleus
• Tuberal• Dorsomedial nucleus
Ventromedial nucleusArcuate nucleus
• Posterior• Mammillary nuclei (part of
mammillary bodies)Posterior nucleus
Lateral AreaAnteriorLateral preoptic nucleusLateral nucleus Part of supraoptic nucleusTuberalLateral nucleusLateral tuberal nucleiPosteriorLateral nucleus
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Neurohormonii
• Corticotropin-releasing hormone (CRH) • Dopamina • Gonadotropin-releasing hormone (GnRH) • Growth hormone releasing hormone (GHRH) • Somatostatin • Thyrotropin-releasing hormone (TRH) • Oxytocin• Antidiuretic Hormone (Vasopresina, ADH)
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Median EminenceMedian Eminence
Organ circumventricularOrgan circumventricular
Ependimal: tight J.Tanicitele (T4T3)
Intermediar: VP&OT axons
Extern: capilare fenestrate
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• INTRACRINE
• AUTOCRINE
• PARACRINE
• ENDOCRINE
• NEUROENDOCRINE
Semnalizare chimica /
Hormonala
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Control genetic
Biosinteza
Transport axonal
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Slide Source:www.obesityonline.org
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Slide Source:www.obesityonline.org
Neuroendocrinologia aportului alimentar Neuroendocrinologia aportului alimentar Trunchiul cerebral - tinta pentru semnale de satietate perifericeTrunchiul cerebral - tinta pentru semnale de satietate periferice
Modified from Marx, Science 2003 February 7; 299: 846-849. (in News)
LeptinInsulin
PYYGhrelinGI tract
Spinalnerves
VagCCK
HypothalamusARC
NTS/AP
Area Postrema:
part of dorsal vagal complex
chemoreceptive (no BBB)
site of neural integration– bi-directional projections to the
GI tract (via vagal afferents and efferents)
– bi-directional projections to the hypothalamus, amygdala and other regions
Amylin+ peptide intestinale
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Slide Source:www.obesityonline.org
Obezitatea endocrinaObezitatea endocrina
Lenard and Berthoud, Obesity, 16, S3 (2008), S11-S22
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Slide Source:www.obesityonline.org
Reglarea aportului alimentarReglarea aportului alimentar
CreierCreier Factori externiEmotiiTipul de alimenteComportament alimentarFactori de mediu
NPYAGRPgalanin
Orexin-Adynorphin
StimuleazaStimuleazaα-MSHCRH/UCNGLP-I
CARTNE5-HT
InhibaInhiba
Semnale centraleSemnale centrale
Glucoza
CCK, GLP-1,Apo-A-IVAferente vagale
Insulina
Ghrelina
Leptina
Cortizol
Semnale perifericeSemnale periferice Organe perifericeOrgane periferice
+
+
Tract GI
Tesut adipos
Aport de alimente
Suprarenale
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Slide Source:www.obesityonline.org
Afectiuni pulmonareAfectiuni pulmonareApneea obstructiva Apneea obstructiva de somnde somnSindrom de hipoventilatieSindrom de hipoventilatie
Hepatopatia steatozica Hepatopatia steatozica non-alcoolicanon-alcoolicasteatozasteatozasteatohepatitasteatohepatitacirozaciroza
Boala coronarianaBoala coronariana
DiabetDiabet
DislipidemieDislipidemie
Hipertensiune arterialaHipertensiune arteriala
Anomalii ginecologiceAnomalii ginecologiceTulburari de CMTulburari de CMinfertilitateinfertilitateSindromul ovarelor polichisticeSindromul ovarelor polichistice
OsteoartritaOsteoartrita
Afectiuni cutanateAfectiuni cutanate
Litiaza biliaraLitiaza biliara
CancerCancersan, uter, col, colon, esofag, san, uter, col, colon, esofag, pancreas, rinichi, prostatapancreas, rinichi, prostata
FlebitaFlebitaStaza venoasaStaza venoasa
GutaGuta
Complicatiile medicale ale obezitatiiHipertensiune Hipertensiune intracraniana idiopaticaintracraniana idiopatica
AVCAVC
CataractaCataracta
Pancreatita Pancreatita
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Slide Source:www.obesityonline.org
Tulburarile alimentatieiTulburarile alimentatiei
Anorexia nervosa– Teama intensa de castig ponderal– Imagine corporeala distorsionata– Refuzul de a mentine greutatea corporala
minima recomandata– Amenoree secundara– 1% din femeile tinere sunt afectate– 95% - femei
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Slide Source:www.obesityonline.org
Tulburarile alimentatieiTulburarile alimentatiei
Bulimia nervosa– Episoade repetate de apetit exagerat urmate
de inducerea varsaturilor– Acest comportament apare de 2-3 ori / sapt,
3 luni– Simptomele pot apare independent de
anorexie– 1-2% din tinerele femei sunt afectate– 95% -femei
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Cai neurale implicate in homeostazia osmoticaCai neurale implicate in homeostazia osmotica
Antidiureza Osmoreceptori
Sete Sete
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Reeves et al, 1998
Volum circulant
Osmolaritate LEC
Setea si balanta apeiSetea si balanta apei
2%Crestere
Osmolaritatea LEC 10% Scadere
Volum circulant
Osmoreceptori CNS Baroreceptori
Descarca ADH Angiotensina II
AntidiurezaStimuli
Sete
Aport de apaConservarea apei
ANP&BNP ANP&BNP
Apetit de Na
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Neuroimagistica seteiNeuroimagistica seteiZece subiecti au efectuat PET-CT si o evaluare psihologica a setei (Denton, PNAS, 96, 5304-5309, 1999)
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Oxytocin-like peptidesOxytocin-like peptides
1 2 3 4 5 6 7 8 9
Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (NH2)
Oxytocine * * * * * * * Ile *
Mesotocine * * * Ser * * * Ile *
Isotocine * * * Ser * * * Glu *
Glumitocine * * * * * * * Val *
Valitocine * * * Asn * * * * *
Aspargtocine
Vasopressin-like peptidesVasopressin-like peptides
1 2 3 4 5 6 7 8 9
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly (NH2)
Vasopressine
* * * * * * * Lis *
Lisine-vasopressine
* Phe * * * * * * *
Phenipressine
* * Ile * * * * * *
Vasotocine
Structura hormonilor neurohipofizari
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TM I
TM IIITM II
TM IV
TM V
TM VI
TM VII
Receptor V1a
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Noyau paraventriculaire
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Noyau supraoptique
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Neurohypophyse de rat -ME
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Vasopresina Oxitocina
Uter
Sin
Gonade
? AH
?Adipocite
Creier
Suprarenale
Ficat
AH
Muschi neted
Rinichi
Hipotalamus
Creier
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SeteSete
AVPAVP
Sindroame poliuro-polidipsiceSindroame poliuro-polidipsice
•Hipotalamus Hipotalamus
Polidipsie psihogenaPolidipsie psihogena
Absenta AVPAbsenta AVP
Vasopresinaza Vasopresinaza
•Rinichi: Rinichi: rezistenta la AVPrezistenta la AVPinsuficienta renalainsuficienta renala
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IRM normalIRM normal
Lechan RM. Neuroendocrinology of Pituitary Hormone Regulation. Endocrinology and Metabolism Clinics 16:475-501, 1987
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Diabet insipid: Deficitul de AVPDiabet insipid: Deficitul de AVP• Deteriorarea hipotalamusului (site-ul de sinteza AVP), tijei pituitare
(transportul AVP) sau a retrohipofizei (site-ul de stocare AVP), va duce la o boala cunoscută sub numele de diabet insipid central.
• Mulți dintre acești pacienți nu au hipersemnal in T1 in lobul posterior al hipofizei pe imagistica RMN a creierului.
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Diabet Insipid
Caracteristici clinice sunt rezultatul deficientei de AVP
• Excreția unor volume mari de urină (poliurie)
• Excreția de urină diluată (OSM <200 mOsm/L)
• Cresterea osmolaritatii plasmei (și Na+ seric)
• Stimularea setei (polidipsie)
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Craniofaringiom
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Infiltrat hipotalamic• Sarcoidoza• Histiocitoza• Metastaza
• Tumora de tija• Germinom• Agenti patogeni
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Diabet Insipid• Cele mai multe cazuri de diabet insipid central sunt datorate
unor leziuni care implica zona hipotalamusului și în jurul bazei ventriculului trei.
Deoarece pacienții cu diabet insipid devin simptomatici numai la o reducere de 80-85% din celulele AVP, leziunea trebuie să fie suficient de mare.
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Nivelurile AVP la pacienții cu DI Central
Pe măsură ce crește osmolalitatea plasmatică, AVP se ridică la subiecții normali, dar rămâne scăzută la pacienții cu deficit de AVP complet sau parțial.
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Diagnosticul Diabetului Insipid
• Determinați dacă pacientul are un răspuns adecvat la deshidratare, care provoacă atât – Hiperosmolalitate– Hipovolemie
• Ambele ar trebui să stimuleze o creștere a AVP
• Testul de privare de apă permite diagnosticul• Când pacientul a pierdut 2-3% din greutatea totala a corpului și
două urini consecutive diferă în osmolalitate cu <10%, este obținută o proba de sange pentru sodiu si osmolalitate plasmatica (rar se dozeaza ADH).
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Raspunsul la Deshidratare
• Pacienții cu diabet insipid complet hipotalamic, in momentul de deshidratare maximă vor avea:
• o osmolalitatea urinară <200 mOsm
• o osmolalitatea serica crescuta (> 295)
• (au un nivel scăzut de AVP)
• creșterea osmolarității in urină cu mai mult de 50% dacă este administrată exogen AVP
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Tratament Diabet Insipid
• DDAVP (Desamino-D-Arginine Vasopressin)-
• 10-20 g 1-3 /zi instilatii nazale
• Per os , DDAVP cp 0,2 mg , 1 cp la 8-12 ore
• SLG: 120- 240 g 1-3/zi
• IM/SC la 1/10 din doza.
• Etiologie !!!
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Hipernatremia
• Na+> 145 mEq/L Hipodipsie primara, DI (central sau nefrogen)
Diureza osmotica (DZ dezechilibrat)
• Neurologic: astenie, stare confuzionala, convulsii, deficit focal.
• Trat: Desmopresina 10 g intranazal sau 0.12 mg x 3/zi slg (Minirin Melt) aport hidric po sau 5% glucoza: 1-2 L
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Hiponatremia
• Neurologic: greata, edem cerebral, cefalee, obnubilare, coma
• Semnele afectiunii de baza (Addison, hipopituitarism, SIADH)
• Scadere Na+ hTa• Rapiditatea instalarii hNa+
• Na+ < 120 mEq/L: risc vital
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Hiponatremia - tratament
• Etiologic• SIADH: Restrictie hidrica ± Antagonist Rec V2 AVP = Vaptan
• Substitutie corticoida (HHC ± Fludrocortizon, 2 x 0.1 mg/zi)
• Substitutie tiroidiana: LT4 in doze de la 25 la 100 g/zi, sub protectie antiagreganta
• Cresterea capitalului de Na: < 10-15 mEq / 24h
Solutii fiziologice sau saline hipertone 0.5 - 2 L/zi
Creste> 15mEq/zi Risc de mielinoza pontina (sdr de demielinizare osmotica), mai sever in hNa+ cronica
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Reglarea şi explorarea hipofizeiReglarea şi explorarea hipofizei
• Hipofiza: anatomie funcţionalăHipofiza: anatomie funcţională• Tipuri celulare şi implicaţii funcţionaleTipuri celulare şi implicaţii funcţionale• Comunicarea hipotalamo – hipofizarăComunicarea hipotalamo – hipofizară• Axa de creştere:Axa de creştere: reglare şi explorare funcţională reglare şi explorare funcţională• Axa tiroidiană:Axa tiroidiană: reglare şi explorare funcţională reglare şi explorare funcţională• Axa suprarenală:Axa suprarenală: reglare şi explorare funcţională reglare şi explorare funcţională• Axa gonadică:Axa gonadică: reglare şi explorare funcţională reglare şi explorare funcţională
Explorarea: farmacologică / fiziologică ?Explorarea: farmacologică / fiziologică ?
• Concluzii Concluzii
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Cell Type Secretory Products Cell Population %
Somatotroph Growth hormone 50
Lactotroph Prolactin 15
Corticotroph Adrenocorticotropic hormone 15
Thyrotroph Thyroid stimulating hormone 10
Gonadotroph Luteinizing hormone-Follicle-stimulating hormone
10
Cell types in pars distalis
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Substances Cell Types Peptides:
Activin B, inhibin, follistatin F, G Aldosterone-stimulating factor UN Angiotensin II (angiotensinogen, angiotensin I-converting enzyme, cathepsin B, renin) C,G,L, S Atrial naturetic peptide G Corticotropin-releasing hormone-binding protein C Dynorphin G Galanin L, S,T GAWK (chromogranin B) G Growth hormone-releasing hormone UN Histidyl proline diketopiperazine UN Motilin S Neuromedin B T Neuromedin U C Neuropeptide Y T Neurotensin UN Protein 7B2 G, T Somatostatin 28 UN Substance P (Substance K) G,L,T Thyrotropin-releasing hormone G, L,S,T Vasoactive intestinal poltpeptide G,L,T
Growth factors: Basic fibroblast growth factor C,F Chondrocyte growth factor UN Epidermal growth factor G,T Insulin-like growth factor I S,F Nerve growth factor UN Pituitary cytotropic factor UN Transforming growth factor alpha L,S,G Vascular endothelial growth factor F
Cytokines: Interleukin-I beta T Interleukin-6 F Leukemia inhibitory factor C,F
Neurotransmitters: Acetylcholine C,L Nitric oxide F
C-corticotroph: F -Folliculostellate cell; G-gonadotroph; L-Lactotroph; S-somatotroph, T -thyrotroph; UN-unknown.
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Disorders of the Endocrine System
• Excess or deficiency
• Impaired synthesis
• Transport and metabolism of hormones
• Resistance to hormone action
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Reglarea Axei GHReglarea Axei GH
• GHRH (44) SMS (14)
• GH
• IGF1
• GHRP
• Ghrelin
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Insulin Tolerance Test
0.1/0.15 UI/Kgc, i.v.
Obese: 0,3 UI/Kgc
Contraindicate Epileptic seizures
Severe heart ischemia
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Oral Glucose Tolerance Test
Oral glucose 75g
GH peak level > 1 g/L
Acromegaly:
positive & differential diagnosis
Diabetes Mellitus
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IGF-1 : variation with age & sex
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Reglarea Axei CSRReglarea Axei CSR
• CRH / VP
• ACTH
• Cortisol
• Leptina
• Citokine
• GR, CRHR, V1b, ACTH R,
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Short ACTH Stimulation Test
250 g ACTH i.v.
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Screening in Cushing Syndrome
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Diagnosis in Cushing Syndrome
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Inferior Petrosal Sinus Sampling
V. femurala ... IPS
CRH 100 ug i.v.
Control - VCI
IPS:IPS: -5, 0, 2, 5, 10 min
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Reglarea Axei TiroidieneReglarea Axei Tiroidiene
• TRH
• TSH
• T4 / T3
• Type II deiodinase
• Leptina
• TR, TRH R, TSH R
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TRH test
400 g i.v. TRH
TSH is measured each 30 mins, for 3 h
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Reglarea Axei GonadiceReglarea Axei Gonadice
• GnRH
• LH & FSH
• Prolactina
• Testosteron /E2, Pg
• Inhibina /activina
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HypothalamicHypophysealPortal System
Gonadotrophs
GnRH este eliberat in sistemulport hipotalamo- hipofizar, pornind din eminenţa mediană şi legând vascular adeno-hipofiza.
Eliberarea este pulsatilă tonică, iniţial nocturnă, apoi şi diurnă, ulterior apare o descărcare majoră, pre-ovulatorie. Eliberarea tonică provine din MBA, cea pre-ovulatorie din AHPO
Controlul sintezei LH şi FSH de către GnRh
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Stage 1: Prepubertal, no pubic hair growth
Stage 2: Testes grow; scrotal skin becomes redder and
coarser; sparse and fine hair develops at base of penis
Stage 3: Penis lengthens with small increase in diameter;
scrotal skin reddens, thickens and crinkles,
pubic hair thicker and coarser
Stage 4: Penis and testes continue to grow; pubic hair coarser,
darker and more curly
Stage 5: Penis at adult size; pubic hair covers symphysis pubis
and extends to inner thighs
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
StaStadiile dezvoltarii diile dezvoltarii pubertpubertareare (Tanner)(Tanner)
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Pulsatile LH Pattern in Human
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Pulsatility in gonadal axis
Pulsatile hormones: Mix & Measure
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CONCLUZII
• Evaluarea bazala pentru hormonii cu secreţie
cvasiconstanta.
• Evaluare dinamica pentru hormoni cu ritm, sau secretie
pulsatila.
• Teste de inhibiţie pentru sindroame de hipersecretie.
• Teste de stimulare pentru deficit hormonal.
• Integrarea rezultatelor clinice, biochimice, imagistice.
• Tineti cont de : hormoni, transport, metaboliozare,
receptori, interferente de reglare (feed-back nespecific).