Anu Ambos SA PER Mustame korpus
Endokriinssteem Anu Ambos SA PER Mustame korpus Kilpnre Koosneb kahest sagarast ja neid hendavast koesillakesest istmusest Asub kaela eespinnal fossa jugularise kohal kri ees Kaalub tiskasvanud 15-25g Jaotub hukeste fibroossete septide abil lobulusteks, mis koosnevad omakorda folliklist Follikulaarse epiteeli rakud sisaldavad spetsiifilist valku treoglobuliini Parafollikulaarsed rakud (C-rakud) toodavad kaltsitoniini Kilpnrme hormoonid ja talitlus
Hpofsi rakkudest vabanev TSH seondub retseptoriga follikulaarse epiteeli rakkude pinnal TSH retseptor kuulub G-proteiiniga seonduvate retseptorite perekonda G-proteiini aktiveerumine rakusisese cAMP kilpnrme kasvu, hormoonide snteesi ja vabanemise stimuleerimine cAMP sltuvate proteiinkinaaside kaudu Kilpnrmehormoonide sisalduse tus veres prsib negatiivse tagasiside mehhanismiga TSH snteesi ja vabanemist hpofsi eessagaras (ka TRH snteesi ja vabanemist hpotaalamuses) Kilpnrmehormoonide sntees
Jodiid transporditakse aktiivselt follikulaarsetesse rakkudesse naatrium-jodiid smporteri (NIS) poolt Jodiid oksdeeritakse kilpnrme peroksdaasi (TPO) poolt Toimub trosljkide iodinatsioon monojoodtrosiin (MIT) ja dijoodtrosiin (DIT) Jodotroslid hinevad moodustades troksiini (T4) ja trijoodtroniini (T3) Kilpnrmehormoonid ja talitlus
Follikulaarse epiteeli rakkudest vabaneb troksiin (T4) ja trijoodtroniin (T3), mis veres seonduvad plasmavalkudega (TBG) Toimiv on hormoonide nn. vaba fraktsioon (FT4 ja FT3) Kudedes dejodineeritakse enamus FT4-st FT3-ks, viimase afiinsus on TR suhtes 10 korda suurem Seondumisel TR-ga (tuumaretseptor) tekib hormoon-retseptor kompleks, mis omakorda seondub kilpnrmeretseptori vastuselementidega (TRE) mrklaudgeenides mjutades nende transkriptsiooni Figure 2. Sites of Action of Triiodothyronine on Cardiac Myocytes
Figure 2. Sites of Action of Triiodothyronine on Cardiac Myocytes. Triiodothyronine enters the cell, possibly by a specific transport mechanism, and binds to nuclear triiodothyronine receptors. The complex then binds to thyroid hormone response elements of the genes for several cell constituents and regulates transcription of these genes, including those for Ca2+-ATPase and phospholamban in the sarcoplasmic reticulum, myosin, {beta}-adrenergic receptors, adenylyl cyclase, guanine-nucleotide-binding proteins, Na+/Ca2+ exchanger, Na+/K+-ATPase, and voltage-gated potassium channels. Nonnuclear triiodothyronine actions on ion channels for sodium (Na+), potassium (K+), and calcium (Ca2+) ions are indicated at the cell membrane. Dashed arrows indicate pathways with multiple steps, and mRNA denotes messenger RNA. Klein I and Ojamaa K. N Engl J Med 2001;344: Kilpnrmehormoonid ja talitlus
Kilpnrmehormoonid suurendavad ssivesikute ja rasvade katabolismi ja soodustavad valkude snteesi ainevahetus kiireneb Kilpnrmehormoonid on olulised aju arengus, normaalses kasvamises Kilpnrmehormoonid suurendavad sdame-veresoonkonna tundlikkust endogeensetele katehhoolamiinidele Kilpnrme patoloogia
Mahulised muutused Autoimmuunne patoloogia Talitlushired Mahulised muutused Palpatsioon suurus vastab pidla lppfalangi suurusele Ultraheliuuring Maht N: 18ml (N) 25ml (M) Kompuutertomograafia Pahaloomuline kasvaja Retrosternaalne struuma Struktuursed muutused
Ebahtlane kogu ulatuses viitab autoimmuunsele haigusele Slmelised struktuurid tsstid adenoomid kartsinoomid PNB nidustatud, kui slme lbimt > 10mm Hpoehhogeenne slm kilpnrme paremas sagaras
Figure 3. Cross-Sectional Ultrasonogram Showing a Solid, Hypoechoic Nodule (Dark Gray) in the Right Thyroid Lobe. Hegedus L. N Engl J Med 2004;351: Difuusne struuma Endeemiline struuma joodivaeguse piirkondades vi piirkondades, kus sakse goitrogeene sisaldavat toitu, kus >10% elanikkonnast kilpnre suurenenud Sporaadiline struuma phjuseks goitrogeenid, prilikud ensmdefektid vi tundmatud phjused (enamasti noortel naistel) Slmeline (multinodulaarne) struuma
Esinevad nii endeemilistes piirkondades kui sporaadiliselt Kujunevad difuussetest struumadest pikema aja jooksul follikullrsete rakkude omaduse tttu erinevalt vastata mitmetele mjuritele (TSH) Koos eksisteerivad nii pol- kui monoklonaalsed slmed Iseloomulik kolloidi ebahtlane kogunemine, hemorraagiad, kaltsifikatsioonid Multinodulaarne struuma
Sage patoloogia: USA 49-58a naised teadaoleva patoloogiata ultraheliuuringul slmed kilpnrmes 36% (Brander et al, Radiology 1989) Aja jooksul vib ks vi mitu slme muutuda autonoomseteks ja phjustada kilpnrme letalitlust Multinodulaarne struuma
Jlgimine TSH, sono 1 kord aastas Radiojoodravi multinodulaarsete toksiliste ja suurte eutreoidsete struumade korral (maht vheneb aasta jooksul 40%, pikema aja jooksul 50-60%) Operatiivne ravi likuse nidustuseks maht >50ml, trahhea dislokatsioon ja/vi kompressioon Kilpnrme healoomulised kasvajad
Follikulaarsed adenoomid hormonaalselt inaktiivsed toksilised sageli phjuseks aktiveerivad somaatilised mutatsioonid TSH-retseptori signaali lekande ssteemis monoklonaalne kasv ja hormooni liigproduktsioon Kolloidtsstid Stsintigramm parema sagara kuumast slmest
Figure 2. Scintigram of a Solitary Functioning Nodule in the Right Thyroid Lobe. Scintigraphy that was performed with the use of technetium-99m-labeled pertechnetate shows suppression of extranodular uptake in thyroid tissue. Hegedus L. N Engl J Med 2004;351: Kilpnrme kartsinoomid
Papillarne kartsinoom 75-85% juhtudest Follikulaarne kartsinoom 10-20% juhtudest Medulaarne kartsinoom 5% juhtudest (lhtub parafollikulaarsetest rakkudest) Anaplastiline kartsinoom 11,1mmol/l Thjakhu glkoosisisaldus venoosses plasmas >7mmol/l vhemalt kahel erineval peval 2 tundi peale OGTT-d plasma vi kapillaarse tisvere glkoosisisaldus >11,1mmol/l 1. tpi suhkurtbi Autoimmuunse geneesiga (T-lmfotsdid, autoantikehad, lokaalsed tstokiinid) Mratavad ICA, GAD65, IA-2A jt. tpi AK-d Seos HLA ssteemiga Esineb ka nn. LADA-vorm Manifesteerub, kui >90% -rakkudest hvinud Insuliin on eluthtis asendusravi MODY 2-5% diabeetikutest Primaarne -raku talitlushire
Autosoom-dominantne prilikkus Haigestumine alla 25-aastaselt -raku vastaste AK-de ja insuliinresistentsuse puudumine MODY 1-6 (MODY 2 glkokinaasi defekt jne) 2. tpi suhkurtbi Phjuseks geneetiliselt determineeritud insuliini sekretsiooni defekt ja hiritud insuliintundlikkus Keskkonnategurite oluline roll Seos metaboolse sndroomiga Insuliin vajalik haiguse progresseerudes normoglkeemia silitamiseks DM 2 patogenees Insuliin- resitsentsus Insuliin- defitsiitsus DM2 Metaboolsed defektid DM2 puhul
Progresseeruv insuliin sekretsiooni defekt PANKREAS Hper- glkeemia Glkoosi tootmine maksas Glkoosiutiliseerimi Teadmised DM2 patogeneesist on tienenud V/s tus on tingitud progresseeruvast insuliini sekretsiooni defektist. Tsedatel on oluline insuliini toime defekt kudedes (insulin resistance), tuues kaasa hired sv., v., rasvade a/v-s. 1 nendest, aga enamasti mlemad komponendid on DM2 puhul olemas. 3.komponent on glkoosi sisemine produktsioon. Normaalselt prast glkoosi (toitu), insuliin vabaneb portaalveeni kust suundub maksa, seal seotakse spetsiifiliste retseptoritega maksarakkudel ning seal suppresseerib insuliin Maksa glkoosi tootmise. Insulinresistentsus maksas resulteerub aga maksa glkoositoodangu vaba kulgemisena ja tulemuseks on (hommikune) hperglkeemia. Patog.mehhansmi mratlemine on oluline ravitaktika otsustamisel. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1998;21(suppl 1):S5-S19. DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM: a balanced overview. Diabetes Care. 1992;15: LIHAS MAKS Vimalikud defektid Preretseptortasandil kudede verevarustuse hired, kapillaarse perfusiooni hred, insuliini molekuli defekt jt. Retseptortasandil retseptorite arvu ja/vi afiinsuse langus Postretseptortasandil tenoliselt kige sagedasem 2. pi suhkurtve geneetika
Hpotees-phised kandidaatgeenid PPAR Kir 6.2 Genoomilesel skenneerimisel leitud TCF7L2 CDKAL1 FTO -raku funktsiooni langus 2.tpi suhkruhaigel
100 Diagnoosimine ? 80 60 -raku funktsioon (% normist HOMA jrgi) -raku funktsioon = 50% normaalsest 40 20 Six-year follow-up data from the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the decline in -cell function with T2DM over time. At the time of diagnosis, -cell function is already reduced by about 50% and continues to decline regardless of therapy. Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S215. UKPDS Group. Diabetes 1995;44:124958. 10 8 6 4 2 2 4 6 Aeg (aastates) HOMA=homeostasis model assessment. UKPDS Group. Diabetes 1995;44:124958. Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S215. Insuliini sekretsiooni faasid Suhkurtvega seotud erakorralised seisundid
Diabeetiline ketoatsidoos Hperosmolaarne mitteketootiline seisund Raske hpoglkeemia DKA ja HMS patogenees HMS DKA Ketoatsidoos Hperglkeemia glkosuuria
Stress,infektsioon ja/vi insuliinipuudus Tielik insuliinipuudus glkagoon,katehoolamiinid, Osaline insuliinipuudus kortisool,kasvuhormoon lipols proteols valgu snteesketogenees VRH maksa glkoneogeneesi substraat puudub/minimaalne ketogenees glkoosi utiliseerimine glkoneogenees glkogenols alkaalne reserv Ketoatsidoos Hperglkeemia glkosuuria vee,elektroltide kadu dehdratatsioonHperosmolaarsus hirunud neerufunktsioon trigltserool Hperlipideemia HMS DKA Suhkurtve kaugtsistused
Diabeetiline retinopaatia Diabeetiline nefropaatia Diabeetiline polneuropaatia Diabeetiline makroangiopaatia (sdameisheemiatbi, aju veresoonte ateroskleroos, alajsemete arterite ateroskleroos) Suhkurtve kaugtsistuste tekkemehhanismid
AGE-de moodustumine intra- ja ekstratsellulaarsete proteiinide mitteensmaatiline glkosleerumine Proteiinkinaas C aktiveerimine rakusisesest hperglkeemiast tingitud diatslgltserooli (DAG) snteesi stimulatsiooni kaudu Polooltee aktiveerumine ja rakusisese NADPH rakasutamine Diabeetiline retinopaatia
Taustaretinopaatia esineb peaaegu kigil 1. tpi diabeetikutel ja 80%-l 2-tpi diabeetikutel, kes on pdenud 20 aastat Proliferatiivne retinopaatia esineb kuni 50% 1. tpi diabeetikutest ja kuni 10% 2. tpi diabeetikutest , kes on pdenud 15 aastat Klein et al., 1984, 1995, 1998 Diabeetilise retinopaatia patogenees
Figure 2. Retinal Anatomy and Mechanisms of Diabetic Retinopathy. A normal retina is shown in Panel A, and a retina from a patient with proliferative diabetic retinopathy is shown in Panel B. Several polypeptide growth factors and their cell-membrane receptors have possible relevance to the pathogenesis of diabetic retinopathy, but vascular endothelial growth factor (VEGF) and its receptors, VEGFR-1 and VEGFR-2, and pigment-epithelium-derived factor (PEDF), for which no receptor has yet been identified, are currently undergoing the most intensive investigation. These two growth factors are both produced in the retinal pigment epithelium, where their constitutive secretion appears to be highly polarized.51,73 Retinal neovascularization in diabetic retinopathy and other proliferative retinal vascular diseases nearly always occurs away from the retinal pigment epithelium and toward the vitreous space. There is evidence that both VEGF and PEDF are produced in retinal neurons and in glial cells,52,53,69 such as the cells of Muller. In the normal retina, VEGFR-1 is the predominant VEGF receptor on the surface of retinal vascular endothelial cells, but in diabetes, VEGFR-2 appears on the endothelial-cell plasma membrane.54 Frank R. N Engl J Med 2004;350:48-58 Fluorstsiinangiograafia proliferatiivse retinopaatiaga patsiendi vasakust silmast
Figure 1. A Fluorescein Angiogram of the Left Eye in a Patient with Proliferative Diabetic Retinopathy. The angiogram, which was obtained during the late arteriovenous phase (when both arteries and veins are filled), after injection of the dye into an antecubital vein, shows retinal neovascularization adjacent to areas of vascular nonperfusion, which results in retinal hypoxia. The multiple, tiny fluorescent dots (small arrows) are microaneurysms. The black asterisk indicates retinal neovascularization just nasal to (to the left of) the optic-nerve head (large arrow). The blood-retinal barrier breaks down in neovascular lesions, which therefore fluoresce brightly and appear blurred as the dye leaks from the vascular lumina. Another, smaller neovascular lesion is present along the superotemporal vascular arcade at the upper right of the image. The white asterisk indicates a preretinal hemorrhage, notable for its boat-shaped appearance, with a flat top and curved bottom. Its location in front of the retina is evident in that it partially blocks the retinal vessels. Another preretinal hemorrhage is located above the optic-nerve head. Extensive areas of capillary dropout appear as black zones at the left, inferior, and superior margins of the picture. The border of this region is indicated by the arrowhead. The dark, vertical bar at the upper right of the picture is a fixation target, used to keep the patient focused steadily in one direction during the photographic session. Frank R. N Engl J Med 2004;350:48-58 Diabeetiline nefropaatia
Markeriks albumiini sisaldus uriinis >300mg/l Kumulatiivne intsidents 20 pdemisaasta jrel nii 1. kui 2. tpi diabeetikutel sarnane 26-27% ESRD patsientidest diabeetikuid: Soome 31% Saksamaa 36% USA 43,5% US Renal Data System 2003 Mikroalbuminuuria 30-300mg/l 20-200g/min
Albumiin/kreatiniin M>2,3; N>2,8 mg/mol NB! Mikroalbuminuuria on piisavaks nidustuseks AKEI vi ARB lisamiseks raviskreemi NB! Mikroalbuminuuria staadium on prduv! Perifeerne diabeetiline polneuropaatia
Esineb (7-80) % suhkruhaigetest Krooniline valu esineb 11-26% suhkruhaigetest Polneuropaatia risk suureneb 4-10% iga 5 aastaga ENMG-s tekivad muutused 5-10 aastaga olenemata polneuropaatia kliinikust Meestel suurem risk Perifeerne diabeetiline neuropaatia
The tissues of patients with diabetes undergo a range of enzymatic changes that affect their function and structure. Many of these changes are the result of overactivation of PKC , which is also involved in the expression and signaling of potentially pathogenic growth factors. This signaling can result in the alterations in endothelial cells that lead to the tissue damage that affect patients suffering from DPN. Lets look at a healthy foot and review the damage to nerves, blood vessels, and other tissues that can result from diabetic peripheral neuropathy. Healthy nerves receive a rich supply of blood from the neural microvasculature, otherwise known as the vasa nervorum. Here we see the interrelationship between the neural tissues of the nerve fibers and the surrounding microvasculature. Vascular changes in DPN may include vasodilatation and occlusion that result in decreased blood flow and lead to hypoxia. The changes are associated with sensory and motor nerve fiber degeneration. The clinical manifestations of these effects include symptoms, such as numbness, prickling, tingling, and pain. They may also include signs such as diminished vibratory sensation, pressure sensation, and ankle reflexes. In as many as 15% of individuals with DPN, vascular and neural deficits may eventually lead to foot ulcer formation. References: 1. Cameron NE, et al. Diabetologia. 2001;44: 2. Dyck PJ, Giannini C. J Neuropathol Exp Neurol. 1996;55: 3. Sheetz MJ, King GL. JAMA. 2002;288: 4. Thrainsdottir S, et al. Diabetes. 2003;52: 5. Vileikyte L, et al. Diabetes Care. 2003;26: Distaalne smmeetriline polneuropaatia
Sagedasem! Domineerivad sensoorsed kaebused, motoorne dsfunktsioon tagasihoidlik suured kiud valutud paresteesiad, svatudlikkuse hired vikesed kiud tugev neuropaatiline valu, valu- ja temperatuuritundlikkuse hire, sageli autonoomsed hired Trauma Trauma infekt Jalahaavandite kujunemise biomehhanismid
Figure 1. Biomechanics of Foot Ulcers. Panel A shows the biomechanics of gait. The normal mechanics of the foot and ankle result from the combined effects of muscle, tendon, ligament, and bone function. Gait is classically broken into four segments. The first segment is heel strike, when the lateral calcaneus makes contact with the ground and the muscles, tendons, and ligaments relax, providing for optimal energy absorption. The second is midstance, when the foot is flat and is able to adapt to uneven terrain, maintain equilibrium, and absorb the shock of touchdown. The calcaneus is just below the ankle, keeping the front and back of the foot aligned for optimal weight bearing. The third is heel rise, when the calcaneus lifts off the ground, the foot pronates, the muscles, tendons, and ligaments tighten, and the foot regains its arch. This segment is followed by the fourth, toe push-off. Panel B shows the forces on the foot. Friction and compressive forces are produced by the pushing down of the body weight and the pushing up of the ground reactive forces. Friction and pressure combine as a shear force during dynamic walking as the bones of the foot slide past each other in a direction parallel to their plane of contact during pronation and supination. Wasting of the intrinsic muscles of the foot results in an imbalance of the forces acting on the bony structures. This can lead to toe deformities, prominent metatarsal heads, equinus deformity, varus position of the hind foot, and proximal malalignment. Panel C shows the consequences of callus formation. Inadequate distribution of the forces of weight bearing or the presence of foot deformities can lead to abnormal movement, which produces excessive stress and results in the breakdown of connective tissue and muscle. Adapted from Habershaw and Chzran1 with the permission of the publisher. Sumpio B. N Engl J Med 2000;343: Nited diabeetilisest jalakahjustusest
Figure 2. Examples of Foot Lesions. Panel A shows digital ulceration with underlying osteomyelitis in a diabetic patient with neuropathy but with normal vascular perfusion. Digital contractures with underlying hypertrophic bone (hammer toes) and onychomycoses are visible. Panel B shows a neuropathic toe ulcer caused by rigid contracture of the interphalangeal joint. Panel C shows a combined ischemic and neuropathic ulcer. The exposed first metatarsal head with necrotic flexure tendon results in an extended toe. Panel D shows Charcot's foot with resulting ulcer. Panel E shows the "rocker-bottom" bony deformity of Charcot's foot on a plain film. Sumpio B. N Engl J Med 2000;343: Perifeerse diabeetilise neuropaata areng
smptomid tunnused refleksid puutetundlikkus vibratsioonitundlikkus nrvijuhtivuse hired kliiniline subkliiniline kliiniline diabeet 2.Tpi suhkurtve raviastmestik
7 9 HbA1c (%) 8 Eesmrgistatud ravi* STEP 4 Basaal+prandiaalne STEP 3 Basaalinsuliin STEP 2 OHA kombinatsioon Treatment for T2DM needs to be target driven and intensified as the disease progresses. The stepwise strategy, which begins with lifestyle modification followed by oral agents and then insulin therapy, is frequently applied at a slow pace with long delays between steps. Insulin treatment strategies should be used earlier to achieve and sustain HbA1c