Slayt 1 - Ankara Üniversitesi

Slayt 1 - Ankara Üniversitesi

Lipid Metabolizmas Bozukluklar Prof. Dr. Nilgn BAKAL Dislipidemili hastaya yaklam Anamnez-yk-aile sorgusu Risk faktrlerinin yorumu Tam sistematik fizik muayene Lipidler (Kolesterol-Trigliserid) Lipoprotein analizi-fenotipleme Primer sekonder ? Yorumlama ve tedavi karar Tedavi - izlem Kolesterol Drt halkal steroid nukleusu ve hidroksil grubu olan sterol Trigliserid Gliseroln ya asidi esteri Plazma lipidleri uzun zincirli ya asitlerinin esterleri Major - klinik nemde 1.Tracylglycerol Trigliseridler gliseroln ya asiti esterleri 2. Kolesterol

steroid nukleusu ve hidroksil grubu olan sterol - serbest - esterlemi Minor - fizyolojik nemde 1.Fosfolipidler Fosfatidilkolin LESTN Sfingomyelin 2. Glikolipidler 3. Sfingolipidler nsan plazmasnda bulunan ya asitleri Miristik asit Palmitik asit* Palmitoleik asit Stearik asit Oleik asit* Linoleik asit* Eiokosapentanoik asit Dokosaheksanoik asit * Adipz dokuda trigliserid olarak depolanr. Major ya asitleri

Kimyasal ad Genel ad Besin kaynaklar Doymu YA Laurik Miristik Palmitik Stearik Hindistan cevizi ya Hindistan cevizi tereya Ya, peynir, et Bonfile ukulata Tekli doymam YA Oleik Zeytinya-kanola ya Linoleik Araidonik Ayiei msr soya

Ayiei msr soya oklu goymam YA Omega 6 Omega 3 Eikosapentoneik Som marina uskumru ton Dokosaheksanoik balklar Lipoproteinlerin yaps Nonpolar lipidler ekirdek lipidler Trigliserid ve kolesterol ester amphipathic lipidler yzey lipdleri fosfolipid ve esterlememi kolesterol Spesifik apo lipoproteinler Apolipoproteinler (alfabetik terminoloji Aloupovic 1971) Apo Lp. Lp A (1,2,4) M-HDL

B (100) B (48) C (1,2) E (2,3,4) D VLDL-LDL-IDL M M,VLDL,HDL M,VLDL,IDL,HDL HDL Fonksiyonu Kolesteroln dokulardan uzaklatrlmas LCAT aktivatr LDL nin reseptrlere balan iin Ligand Yapsal protein LPL aktivatr LCAT aktivatr Reseptr (LDL ve M-artk) iin Ligand LCAT ile tersine kolesterol nakli Lipoproteinler Lp Elektroforetik mobilite (g/cm3)

Dansite Hakim ekirdek lipidi ap (nm) Apo Yapm yeri HDL HDL2 HDL3 ALFA ALFA ALFA 1.210-1.063 1.063-1.125 1.125-1.210 Kolesterol

7,510,5 A1,2-C-E-D Karacier nce barsak Plazma LDL BETA 1.063-1.019 Kolesterol 21,5 B 100,74-26 IDL den retilir IDL BETA 1.019-1.006

Kolesterol Trigiliserid 25-30 B100-C-E VDLD den tretilir. VLDL PREBETA < 1.006 Trigliserid (Endojen) 30-100 B100-C-E Karacier Chylomicron Orijin

< 1.006 Trigliserid (ekzojen) 80-500 B48-C-E-A 1,2,4 Prolinden zengi Apo nce barsak Lp(a) 1.040-1.080 Kolesterol 21-30 B100-Lp(a) PREBETA Lipoprotein (a)-Lp(a) Tanm: apo B 100 apo (a) kompleks proteinine sahip geni bir Lp fraksiyonu, 1990

Yaps: proteini farkl, boyut dansite heterojenitesine sahip LDL partikl. Kolesterol-Lp(a), TG Lp(a)-prebetaDansite: 1040-1080 apo(a)-plasminogen benzerlii Dzeyi: plazma < 7 mg/dl total < 30 mg/dl nemi: Proatherojenik faktr kpk hcre-yzey modifikasyonu Lipid Transportundaki enzimler Enzim Aktivite yeri Fonksiyonu LPL Vaskler yataktaki Endotel hcreleri Hepatik ve adrenal vaskler yatak Endotel hcreleri ntravaskler plazma

ilomikron ve trigliseridlerin hidrolizi Fosfolipidlerin hidrolizi Beta VLDL-TG ve IDL-TG ile HDL fosfolipidlerin hidrolizi Kolesteroln esterifikasyonu (fosfolipidlerden serbest ya asitlerinin transferi ile) HTL LCAT Lipoprotein reseptrleri Organ Lp Apo Lp Fonksiyonu Karacier M artk VLDL-artk LDL HDL M-artk

LDL HDL B-VLDL Modifiye LDL LDL LDL VLDL-artk HDL E B100,E B100,E A1,A2,A4 E B100,E A1 E, B100 B B100,E B100,E B100,E A1,2,4 Ekzojen kol. Temizlenii Ekzojen kol. temizlenii Ekzojen kol. temizlenii Ekzojen kol. temizlenii Steroid hormon sentezi

in kolesterol temini Adrenal Gonad Makrofaj Dier Dokular Fazla kolesterol iin scavanger -? Hcre bymesi iin Kolesterol temini Tersine kolesterol nakli Lipoprotein metabolizmas Lipoprotein metabolizmas VLDL LDL reseptr VLDL artk

KC Dier yerler LDL Lipoprotein trafii Londra metrosu.................... Lp.Transport sistemi Yolcular kolesterol, Trigliserid Skk-youn zaman..yemek sonras proje hatas genetik ar yklenme diyet ve endokrin denge bozukluu Multifaktriyel blokaj Lp. trafii; labirentte yelken amak iin gerekli gvenin kazanlmas ile anlalabilir. Micheal S: BROWN Joseph L.GOLDSTEIN 1985-nobel dl sahipleri Lipid-lipoprotein dzeylerine etki eden faktrler

Ya-seks Irk japonlarda HDL Vcut arl obezlerde TG ,HDL Fizik aktivite HDL2-LPL Diyet Hastalklar MI sonras 6-12 hf kol , TG Mevsimler yaz: majrler,HDL Hastann hazrlan Alk 12 saat TG Alkol 72 saat Postr oturur % 6 - yatar % 15 Turnike skma sresi 5 dak. aarsa % 10-15 Serumun bekletilmesi + 4 0C de birka gn -15 0c de 18 hafta Kapiller rnekleme % 3,6

HDLkolesterol dzeyini etkileyen faktrler Arttranlar strojen Egzersiz Kilo kayb (zayflama) Hipotrigliseridemik ilalar Alkol (HDL3) Feniton Ailevi hiperalfalipooroteinemi sendromlar Azaltanlar Puberte Androjenler, progestagenler Obezite Hipertrigliseridemi Tip 2 DM Sigara Ailevi HDL eksiklii sendromlar Dislipidemilerde klinik tablo Asemptomatik Semptomatik ASKH Pankreatit Safra ta Ksantoma

Dierleri Laboratuvar analizi Alkta plazma lipid, kolesterol ve trigliserid dzeylerine baklmas Laktesans baklmas Lipoprotein elektroforezi Ultrasantrifgasyon Apoprotein anlizi Dier biyokimyasal kan tetkikleri Total kolesterol mg/dl Normal 200 Snrda yksek 200-239 Orta yksek 240-300 Ciddi yksek 300 LDL kolesterol mg/dl 130 130-159 160-200 200

Trigliserid < 150 mg/dl National Cholesterol Education Programme (NCEP) Adult Treatment Guidelines (2001) (mg/dl/mmol/l) T. Kolesterol LDL HDL erkek kadn Trigliserid Normal Snrda Yksek < 200(5,2) 200-239 Yksek < 130 (3,4) 130-159 >160(4,1) > 40 (1,04) > 50 (1,30) < 150 (1,7) 150-199

> 60 (1,59) >240(6,2) > 200 (2,3) Friedwald Forml (mg/dl) LDL= Total Kolestrol- (HDL+TG/5) Primer hiperlipidemiler Tip I Tip II Tip III Tip IV Tip V Familyal lipoprotein lipaz eksiklii Ekzojen hipertrigliseridemi APO Cll eksiklii M-TG Familyal hiperkolesterolemi Hiperbetalipoproteinemi

F. Kombine hiperlipidemi a) heterozigot b) homozigot Familyal disbetalipoproteinemi Broad beta hastal VLDL artk -M-artk Familyal hipertrigliseridemi Hiperbetalipoproteinemi Endojen lip F. Kombine hiperlipidemi VLDL TG LDL Kol LDL kol - VLDL - TG Familyal hipertrigliseridemi (apo cll eksiklii) Mikst endojen ve ekzojen hiperlipidemi Tip I ve IV kombine VLDL-TG -M TG Primer hiperlipidemiler 1 2a

2b Sklk Seyrek Sk(polijenik-sporadik) En sk (OD) Lipid TG( 4000) Kolesterol (400) Kolesterol (300-500) TG.N. Kolesterol TG Lipoprotein M HDL (sekonder) LDL VLDL LDL

Patogenez Apo C2 LPL LDL-R(heterozigot) LDL-R Yok (homozigot) VLDL ve ApoB Sentezi Klinik Pankreatit Ksantoma (Erptif) Hepatomegali Splenomegali Lipemia retinalis KKH KKH Ksantoma Primer hiperlipidemiler 3

4 5 Sklk Seyrek Sk Seyrek Lipid Kolesterol ( 300) TG (400) TG (400) Kolesterol (250) TG (2000-3000) Kolesterol (400) Lipoprotein Beta VLDL VLDL M + VLDL

Patogenez ApoE yokluu ApoE reseptr hatas LDL reseptr VLDL retimi APOE4 anomalisi APOC 3 2 Klinik Pankreatit Palmar Ksantoma TuberozTuberoerptif Tendinoz Ksantoma Obezite DM Hepato-Splenomegali Obezite Hiperinslinemi DM Artralji artrit Az kuruluu

Hiperlipidemilerin fenotipik klasifikasyonu Fenotip I . IIa . IIb . III . IV . V . Lipoprotein M LDL LDL + VLDL Beta VLDL + IDL VLDL M+VLDL Sekonder hiperlipidemiler (1) Fenotip I LP M IIa IIb

LDL LDL + VLDL III IDL Sekonder neden Diabetes Mellitus Hipotiroidizm SLE Porfiria Hipotiroidizm Biliyer obstrksiyon Myelom Gebelik Hipotiroidizm Alkolizm Diabetes Mellitus Sekonder hiperlipidemiler (2) Fenotip IV LP VLDL V

VLDL +M Sekonder neden Lipodistrofiler Diabetes Mellitus Alkol Glukokortikoidler Kronik renal yetmezlik Estrojenler Gebelik Glikojen depo hastalklar Alkolizm Pankreatit Disglobulinemi Diabetes Mellitus Sekonder Hiperkolesterolemiler

Hipotiroidizm Cushing sendromu Anoreksiya nervoza Disglobulinemiler Akut intermmittan porfiria Nefrotik sendrom Hepatoma Kolestaz Hepatik yetmezlik Sekonder Hipertirigliseridemiler Hastalklar Obezite Diabetes Mellitus Hipotiroidizm Hipopituitarizm Akromegali Lipodistrofiler Glikojen depo hast. Akut stres (MI) remi Nefrotik sendrom SLE Waldenstrom makroglobulinemisi lalar Tiazidler Betablokerler

Estrojen Oral kontraseptifler Glukokortikoidler Dislipidemilerde Klinik Tablo Asemptomatik Semptomatik -Aterosklerotik Kalp Hastal -Pankreatit -Safra Ta -Ksantoma -Dierleri Hiperlipidemilerde klinik Organ-sistem Deri KBB Kalp GIS Renal Nromskler Belirti-semptom Erptif Ksanttoma Palmar ksantoma Ksantelazma Tuberoz- tendinoz-ksant.

Bukkal mukozada sar plaklar Koroner arter hastal Aort kapak hastal -Abdominal ar Hepatosplenomegali Renovaskler hastalk Periferik nropati Tip I-V III II-III II-III II II-V II I-V I-V II-III IV-V Dislipidemili hastaya yaklam Anamnez-yk-aile sorgusu Risk faktrlerinin yorumu Tam sistematik fizik muayene Lipidler (Kolesterol-Trigliserid) Lipoprotein analizi-fenotipleme Primer sekonder ?

Yorumlama ve tedavi karar Tedavi - izlem Hiperkolesterolemi nedenleri Hiperkolesterolemiler Primer Familyal hiperkolesterolemi Familyal kombine hiperlipidemi (multipl Tip) (Tip IIa, Tip IIb, Tip IV) HDL Kolesterol art Poligenik Hiperkolesterolemi Sekonder Hipotiroidizm Nefrotik Sendrom Disglobulinemiler Hepatoma Akut ntermittant portiria Cushing Sendromu Kolestaz Hepatik yetersizlik Anoreksiya Nervoza Hipertrigliseridemi nedenleri Hipertrigliseridemiler Primer Familyal hipertrigliseridemi (Tip IV-V) Familyal kombine hiperlipidemi (Multipl Tip) (Tip IIa, Tip IIb, Tip IV) Familyal LPL eksiklii (tip 1) Herediter Apo C2 eksiklii

Familyal Diabetalipoproteinemi (Tip III) Sekonder Obezite Diabetes Mellitus Akut Stress remi Nefrotik Sendrom Hipotiroidizm Kronik alkol alm Cushing Sendromu Hipopittarizm _ Akromegali Lipodistrofiler Glikojen depo hastalklar Disglobulinemiler Sistemik lupus eritematozus Waldenstrom makroglobulinemisi lalar (Tiazidler, Beta blokrler, estrojenler, oral kontraseptifler, glukokortikoidler) Primer hiperlipidemilerin snflandrmas Tip Plazma kolesterol LDL kolesterol Plazma trigliserid

Lipoprotein laktesans I IIa IIb Yksek Yksek-normal Yksek Dk-normal Yksek Yksek Yksek Normal Yksek Ar M Ar LDL Ar LDL-VLDL M-artk VLDL M VLDL

Krema tabakas Berrak III IV V Yksek Yksek-normal yksek Dk-normal Normal normal Yksek Yksek Yksek Genellikle berrak Bulank Bulank Krema+bulank Dislipidemik hastaya yaklam Anamnez-risk faktrleri Fizik Muayene Laboratuar

Hiperlipidemide diyet nerileri (American Heart Association and National Cholesterol Education Program) Komponent 1. Basamak 2. Basamak Total ya % 30 % 30 Sature % 10 %7 Monounsature % 5-15 % 5-15 Poliunsature % 10 % 10 Karbonhidrat Protein Kolesterol % 50-70 % 50-70 % 10-20 % 10-20 300 mg/gn 200 mg/gn Hiperlipidemide beslenme tedavisi

2.Kademe 2. Kademe Akdeniz diyeti < % 30 < % 30 < % 40 Doymu ya asiti < % 10 <%7 < % 10 Tekli doymam ya asiti %10-15 10-15 < % 20

oklu doymam ya asiti < % 10 <%7 < % 10 Karbonhidrat % 50-60 % 50-60 % 40-50 Protein % 10-20 % 10-20 % 10-20 Kolesterol < 300 mg

< 200 mg < 300 mg Total kalori deal vcut arlna ulalacak kalori Total ya deal kilo Kardiyovaskler risk drc yaam tarz deiiklik nerileri Yaam tarz deiiklikleri Diyet neriler Fiziksel aktivite Her hafta 3-4 gn ortalama 40 dk orta-ar younlukta egzersiz Kilo kontrol Obez (BKI>30) ve ar kilolu (BKI 25-30) hastalarda %3-5 lik srekli kilo kayplar

ASKVH riskini azaltmaktadr. Uzman bir diyetisyenle konsulte edilerek planl bir ekilde uygulanmaldr. Sebze ve meyveden zengin diyet, tahllar rnleri bakliyatlar, beyaz et, balk, dk yal st rnleri Kstlanmas gerekenler; krmz et, tatllar, tatlandrlm hazr meyve sular Diyette doymu ya oran gnlk toplam kalorinin %5-6sn gemeyecek ekilde olmal ve trans yalar kstlanmaldr. Hiperlipidemi Tedavisinde Kullanlan lalar 1 la Snf Doz Etkiledii Balca Lipoprotein Mekanizma *Kolestiramin *Kolestipol *Kolesevelam 4-12 g ( 2x1)

5-15 g ( 2x1) 3.75-4.375 (1x1) LDL Sterol atlm ve LDL klerensi Nikotinik asit *Niasin *Niaspan Fibrik asit deriveleri 1-3 g (1x1) 500-2000 mg (1x1) VLDL VLDL retimini azaltr *Gemfibrozil *Fenofibrat 600 mg (2x1) 30-200 mg (1x1) VLDL

VLDL retimini azaltr LPL aktivitesini artrr 10-80 mg (1x1) 5-40 mg (1x1) 5-80 mg (1x1) 10-40 mg (1x1) 10-80 mg (1x1) 20-80 mg (1x1) LDL Kolesterol sentezini azaltr, hepatositlerde LDL reseptr aktivitesini artrr Safra asit balayclar HMG-CoA redktaz nhibitrleri *Atorvastatin *Rosuvastatin *Simvastatin *Pravastatin *Lovastatin *Fluvastatin Hiperlipidemi Tedavisinde kullanlan ilalar 2

Kolesterol absorbsiyon inhibitrleri *Ezetimib 10 mg (1x1) LDL Kolesterol absorbsiyonunu inhibe eder VLDL VLDL retimini inhibe eder 200 mg/ haftalk subkutan enjeksiyon VLDL, LDL, Lp (a) Apolipoprotein B sentezini inhibe eder 5-60 mg (1x1) VLDL, LDL, Lp (a) Mikrozomal TG transfer proteini inhibe

eder Omega -3 ya asitleri Lovaza 4 g (1x1) Vascepa 4 g (1x1) Epanova 2-4 g (1x1) ApAntisense Oligonkleotidler Mipomersen Mikrozomal trigliserid transfer protein inhibitr Lomitapid Statin Tedavisi Yksek Younluklu Orta Younluklu Dk Younluklu LDL dzeylerinde

ortalama %50< d LDL dzeylerinde %3050 aras d LDL dzeylerinde <%30 d Atorvastatin 40-80 mg Rosuvastatin 20-40 mg Atorvastatin 10-20 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin 40 mg Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg J Am Coll Cardiol. 2014; 63: 2889-2934 Diyabetiklerde ya gruplarna gre statin tedavisi nerileri Standards of medical care in diabetes--2015: summary of revisions. Diabetes Care, 2015. 38 Suppl: p. S4.

Ya Risk F. Statin Dozu < 40 ya Yok KVH risk faktr Aikar KVH Yok Orta-yksek Yksek 40-75 ya Yok KVH risk faktr Aikar KVH Orta Yksek Yksek >75 ya

Yok KVH risk faktr Aikar KVH Orta Orta-yksek Yksek Statin Toksisitesi Asndan Riskli Durumlar Endojen Riskler leri ya (65 ya st) Dk vcut kitle indeksi Multisistem hastalklar Renal fonksiyon bozukluklar Karacier bozukluklar Tiroid fonksiyon bozukluklar, zellikle hipotiroidi Metabolik kas hastalklar Karnitin palmitil transferaz II eksiklii McArdle hastal Myoadenilat deaminaz eksiklii Kas semptomlar ve kreatin kinaz ykseklii Ekzojen riskler Alkol tketimi Ar egzersiz LDL kolesterol seviyesine gre tedavi yaklam LDL kolesterol (mg/dl) Tedavi plan

Tedavinin balamas iin Tedavinin minimal hedefi DYET KKH veya dier 2 risk faktr yok mg/dl nmol/L mg/dl mmol/L 160 (4.1) < 160 (4.1) 130 (3.4)

< 130 (3.4) 190 (4.9) < 160 (4.1) 130 (3.4) < 100 (2.6) KKH veya dier 2 risk faktr var LA KKH veya dier 2 risk faktr yok KKH veya dier 2 risk faktr var

LDL-Kolesterol gre ila tedavisi klavuzu Sekonder nleme Primer nleme -Risk faktr var (2) -Risk faktr yok LDL kolesterol mg/ dl (mmol/L) laca balama Tedavinin hedefi 130 (3.3) 100 (2.6) 160 (4.1) 190 (4.9) < 130 (3.3) < 160 (4.1) Hipolipidemik ilalarn lipoproteinlere % etkisi la Resin Nikotinik asit Fibrik asit Statin Probukol

Total LDL 10-25 15-30 10-25 20-30 10-25 **5-25 25-30 30-40 10-30 10-20 Kolesterol HDL Trigliserid (TG) 0-5 -0-15 10-35 30-50 10-25 20-50 5-15 20-25 15-30 * nceden hipertrigliseridemi varsa TG % 100 ykselebilir. ** Hipertrigliseridemililerde LDL nemli derecede ykselebilir. Mikst hiperlipidemilerde ila seimi Tek ila Kombinasyon

LDL - TG < 200 ise Resin resin + statin Statin resin + nikotinik asit Nikotinik asit statin + nikotinik asit LDL - TG =200-400 Nikotinik asit Statin Gemfibrozil Nikotinik A + Statin Statin + gemfibrozil Nikotinik A+ resin Nikotinik A + hgemfibrozil Diyabetik Dislipideminin farmakolojik tedavisi Bozukluk Primer Alternatif veya ek Dier LDL yksek Statin Ezetimib Niacin HDL dk Fibrat Niacin Statin TZD

TG yksek Fibrat Statin (yksek doz) Niacin Pioglitazon nslin Aterojenik Statin Statin + fibrat Metformin Lipid Triad veya statin+ niacin TZD fibrat Diyabetik dislipidemi tedavisi Hedef LDL < 100 (< 70) mg/dl TG < 150 mg/dl HDL > 40-50 mg/ dl Yaam tarz deiiklikleri Tbbi beslenme-egzersiz- kilo kontrol HDL < 40 Fibrat TZD LDL > Statin 100 Statin+ezetimib veya

niacin HDL < 40 mg/dl TG > 150 Statin+fibrat+ mg/dl niacin TG > 400 mg/dl Fibrat Hipolipidemi Kolesterol < 110 mg/dl (2.9 mmol/L) Trigliserid < 25 mg/dl (0.29 mmol/L) Primer hipolipidemiler HDL eksiklikleri: Tangier hastal Familial hipoalfalipoproteinemi LCAT eksiklii APO B ieren lipoproteinlerin eksiklii Resesif abetalipoproteinemi familial hipobetalipoproteinemi Normotrigliseridemik abetalipoproteinemi ilomikron retansiyon hastal

Tangier hastal Kolesterol < 120 mg/dl, TG hafif Genetik defekt HDL katabolizma deiiklii Heterozigot: HDL , Apo A1 Homozigot: HDL , Apo A1, A2 Otozomal resesif Tonsiller byk, oranj lipid dolu RES de kolesterol ester birikimi Tekrarlayan periferik nropati, motor gszlk Splenomegali, korneal infiltrasyon Sekonder hipolipidemiler Kronik kaeksi Kanser (ilerlemi) Myeloproliferatif hastalk Malabsorbsiyon Karacier yetersizlii mmnglobulin bozukluklar lenfoma-lenfositik lsemiler

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