{"id":1282,"date":"2017-09-28T09:25:54","date_gmt":"2017-09-28T07:25:54","guid":{"rendered":"http:\/\/www.newslab.sk\/2017\/09\/28\/neinvazivne-markery-pecenovej-fibrozy\/"},"modified":"2017-09-28T11:50:43","modified_gmt":"2017-09-28T09:50:43","slug":"non-invasive-markers-of-liver-fibrosis","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/non-invasive-markers-of-liver-fibrosis\/","title":{"rendered":"Non-invasive markers of liver fibrosis"},"content":{"rendered":"<pre><span style=\"color: #ff0000;\"><strong>*V\u0161etky tabu\u013eky, grafy a obr\u00e1zky, ktor\u00e9 s\u00fa s\u00fa\u010das\u0165ou \u010dl\u00e1nku, n\u00e1jdete v prilo\u017eenom PDF s\u00fabore na konci \u0161t\u00fadie.<\/strong><\/span><\/pre>\n<p>&nbsp;<\/p>\n<p><strong>\u00davod<\/strong><\/p>\n<p>V\u00fdskyt chronick\u00fdch ochoren\u00ed pe\u010dene (COP) v dne\u0161nej mo\u00addernej dobe narast\u00e1 a celosvetovo predstavuj\u00fa popredn\u00fa pr\u00ed\u00ad\u010dinu mortality. \u0160pecifick\u00e9 postavenie pe\u010dene v centre me\u00adtabolick\u00fdch funkci\u00ed organizmu a unik\u00e1tne krvn\u00e9 z\u00e1sobenie predisponuj\u00fa tento org\u00e1n na viacn\u00e1sobn\u00e9 potencion\u00e1lne rizi\u00adko po\u0161kodenia. Pe\u010de\u0148 je atakovan\u00e1 v\u00edrusmi, tox\u00ednmi (alkohol, lieky, drogy) a na\u0161\u00edm nezdrav\u00fdm a r\u00fdchlym \u017eivotn\u00fdm \u0161t\u00fdlom, ktor\u00fd zah\u0155\u0148a fyzick\u00fa inaktivitu, nadbyto\u010dn\u00fd pr\u00edjem kal\u00f3ri\u00ed, ne\u00adzdrav\u00fd fastfood alebo prechemizovan\u00e9 potraviny. Nie je pre\u00adkvapen\u00edm, \u017ee naj\u010dastej\u0161\u00edmi pr\u00ed\u010dinami COP s\u00fa v\u00edrusov\u00e9 hepa\u00adtit\u00eddy typu C a B (VHC, VHB), nealkoholov\u00e1 tukov\u00e1 choroba pe\u010dene (NAFLD) a alkoholov\u00e1 choroba pe\u010dene (ALD). K\u00fdm mortalita na kardiovaskul\u00e1rne, onkologick\u00e9 a respira\u010dn\u00e9 cho\u00adroby vykazuje stabilizovan\u00fd, a\u017e mierne klesaj\u00faci trend, morta\u00adlita na COP narast\u00e1.<\/p>\n<p>V s\u00fa\u010dasnosti je takmer 30 mili\u00f3nov obyvate\u013eov Eur\u00f3py postihnut\u00fdch r\u00f4znymi formami COP. V\u00edrusom hepatit\u00eddy C je v eur\u00f3pskych krajin\u00e1ch infikovan\u00fdch 19 mili\u00f3nov z celkov\u00e9ho po\u010dtu 750 mili\u00f3nov obyvate\u013eov, pri\u010dom prevalencia infekcie v jednotliv\u00fdch krajin\u00e1ch kol\u00ed\u0161e medzi 0,15 &#8211; 3,26 %<sup>(1)<\/sup>. Preva\u00adlencia NAFLD, naj\u010dastej\u0161ej hepatopatie v eur\u00f3pskej popul\u00e1\u00adcii, kol\u00ed\u0161e v dospelej popul\u00e1cii medzi 4 &#8211; 49,6 % a u pacien\u00adtov s diabetom 2. typu medzi 42,6 &#8211; 69,5 %<sup>(23)<\/sup>.<\/p>\n<p>S\u00fa\u010das\u0165ou \u0161truktur\u00e1lnych a funk\u010dn\u00fdch zmien pri chronic\u00adk\u00fdch ochoreniach pe\u010dene je fibr\u00f3za, ktor\u00e1 priamo koreluje s rizikom vzniku cirh\u00f3zy a jej komplik\u00e1ci\u00ed (port\u00e1lna hypertenzia, hepatocelul\u00e1rny karcin\u00f3m). Stupe\u0148 fibr\u00f3zy predsta\u00advuje najv\u00fdznamnej\u0161\u00ed prognostick\u00fd faktor COP Mana\u017ement pacientov s COP zah\u0155\u0148a potvrdenie a staging fibr\u00f3zy, ktor\u00fd identifikuje jedincov so zv\u00fd\u0161en\u00fdm rizikom progresie do cirh\u00f3\u00adzy, a tie\u017e grading fibr\u00f3zy, ktor\u00fd pos\u00fadi stupe\u0148 z\u00e1palovej alebo metabolickej odpovede a v pr\u00edpade VHC predikuje pravdepo\u00addobnos\u0165 dosiahnutia trvalej lie\u010debnej odpovede na antiviro\u00adtick\u00fa lie\u010dbu<sup>(4)<\/sup>.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Fibrogen\u00e9za<\/strong><\/p>\n<p>Pe\u010de\u0148ov\u00fa fibr\u00f3zu mo\u017eno definova\u0165 ako \u0161truktur\u00e1lnu pre\u00adstavbu tkaniva s nadmern\u00fdm ukladan\u00edm v\u00e4zivovej hmoty. Fy\u00adziologickou reakciou na nekr\u00f3zu \u010di apopt\u00f3zu hepatocytov je aktiv\u00e1cia z\u00e1palovej kask\u00e1dy a n\u00e1sledne fibrogen\u00e9zy. Tento proces zah\u0155\u0148a ukladanie extracelul\u00e1rnej hmoty (ECM), ktor\u00e1 vedie k oprave a regener\u00e1cii, ak je vyv\u00e1\u017een\u00e1 fibrol\u00fdzou. Fibro\u00adgen\u00e9za aj fibrol\u00fdza s\u00fa indukovan\u00e9 a udr\u017eiavan\u00e9 p\u00f4soben\u00edm viacer\u00fdch typov pe\u010de\u0148ov\u00fdch buniek, ktor\u00e9 sa aktivuj\u00fa r\u00f4zny\u00admi vyvol\u00e1vaj\u00facimi pr\u00ed\u010dinami (obr\u00e1zok 1).<\/p>\n<p>K\u013e\u00fa\u010dov\u00e9 postavenie medzi \u0161pecializovan\u00fdmi bunkami pe\u010de\u0148ovej fibrogen\u00e9zy maj\u00fa hviezdicovit\u00e9 bunky, naz\u00fdva\u00adn\u00e9 aj peris\u00ednusoid\u00e1lne lipocyty alebo Itove bunky, ktor\u00e9 s\u00fa schopn\u00e9 premeny na myofibroblasty. K aktiv\u00e1cii a prolifer\u00e1cii hviezdicovit\u00fdch buniek prispieva cel\u00e1 plej\u00e1da profibrog\u00e9nnych a promitog\u00e9nnych faktorov uvo\u013e\u0148ovan\u00fdch z in\u00fdch typov buniek, napr. hepatocytov (IL-33), Kupferov\u00fdch buniek (TGF-p, TGF-a &#8211; transforming growth factor-p, a), trombocytov (PDGF &#8211; platelet-derived growth factor, TGF-p), endotelov\u00fdch s\u00ednusoid\u00e1lnych buniek (endotel\u00edn), monocytov a \u010fal\u0161\u00edch preva\u017ene z\u00e1palov\u00fdch buniek (CTGF &#8211; connective tissue derived growth factor, INF-y, IL1-p, CD163).<\/p>\n<p>Extracelul\u00e1rna hmota pozost\u00e1va z 2 typov makromolek\u00fal: a. kolag\u00e9nov typu I, III, V a VI a b. nekolag\u00e9nov\u00fdch molek\u00fal: glykoprote\u00ednov (fibronekt\u00edn, laminin, tenasc\u00edn), proteoglyk\u00e1nov a glykozaminoglyk\u00e1nov (kyselina hyalur\u00f3nov\u00e1, chondroit\u00ednsulf\u00e1t, dermatansulf\u00e1t). Po\u010das fibrogen\u00e9zy prib\u00fada v pe\u00ad\u010deni kolag\u00e9n typu I, ktor\u00e9ho podiel sa zvy\u0161uje a\u017e na 60 &#8211; 70 % celkov\u00e9ho kolag\u00e9nu, k\u00fdm v zdravej pe\u010deni s\u00fa kolag\u00e9ny I a III zast\u00fapen\u00e9 v pomere 1 : 1.<\/p>\n<p>Rozvoj pe\u010de\u0148ovej fibr\u00f3zy je v\u00fdsledkom nerovnov\u00e1hy me\u00addzi zv\u00fd\u0161enou tvorbou ECM a jej zn\u00ed\u017een\u00fdm odb\u00faravan\u00edm. Na odb\u00faravan\u00ed ECM sa z\u00fa\u010dast\u0148uj\u00fa tkanivov\u00e9 enz\u00fdmy, metaloprotein\u00e1zy (MMP), ktor\u00fdch funkciu moduluj\u00fa viacer\u00e9 tka\u00adnivov\u00e9 inhibitory (TIMP-1, -3)<sup>(5)<\/sup>. V situ\u00e1cii, ke\u010f fibrogen\u00e9za preva\u017euje nad fibrol\u00fdzou, napr. pri pretrv\u00e1van\u00ed etiologick\u00e9ho faktora, prejav\u00ed sa patologick\u00fdm zmno\u017een\u00edm v\u00e4zivov\u00e9ho tka\u00adniva, vaskul\u00e1rnymi aj nodul\u00e1rnymi regenerat\u00edvnymi zmena\u00admi, ved\u00facimi k poruche \u0161trukt\u00fary a n\u00e1sledne funkcie pe\u010dene.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Diagnostika fibr\u00f3zy<\/strong><\/p>\n<p>Pe\u010de\u0148ov\u00e1 biopsia ost\u00e1va historicky zlat\u00fdm \u0161tandardom v ur\u010dovan\u00ed tzv. stagingu a gradingu pe\u010de\u0148ov\u00e9ho ochorenia v\u00edrusovej aj nev\u00edrusovej etiol\u00f3gie. V prvom pr\u00edpade sa hod\u00adnot\u00ed stupe\u0148 z\u00e1palu a nekr\u00f3zy hepatocytov, v druhom stupe\u0148 zjazvenia, t. j. rozsah periport\u00e1lnej fibr\u00f3zy a\u017e cirh\u00f3zy. Z mno\u00adh\u00fdch histologick\u00fdch stupn\u00edc na hodnotenie fibr\u00f3zy pe\u010dene sa naj\u010dastej\u0161ie pou\u017e\u00edva sk\u00f3rovac\u00ed syst\u00e9m Ishak a Metavir, oba vyvinut\u00e9 pre v\u00edrusov\u00e9 hepatit\u00eddy (tabu\u013eka 1).<\/p>\n<p>Nev\u00fdhodou biopsie je jej invazivita, subjektivita pri hodno\u00adten\u00ed n\u00e1lezu, bolestivos\u0165, emo\u010dn\u00e1 z\u00e1\u0165a\u017e u pacienta (strach), zriedkavo aj krv\u00e1cav\u00e9 komplik\u00e1cie. Pr\u00ed\u010dinou ve\u013ek\u00fdch intra- a interindividu\u00e1lnych rozdielov v hodnoten\u00ed (a\u017e do 38 %) je naj\u010dastej\u0161ie nedostato\u010dn\u00e1 ve\u013ekos\u0165 vzorky, jej nehomogenita a miesto odberu. V snahe optimalizova\u0165 v\u00fdznam pe\u010de\u0148o\u00advej biopsie pri hodnoten\u00ed fibr\u00f3zy s\u00fa navrhnut\u00e9 odpor\u00fa\u010dania t\u00fdkaj\u00face sa d\u013a\u017eky (&gt; 15 mm s minim\u00e1lne 5 portobili\u00e1rnymi priestormi), priemeru vy\u0161etrovanej vzorky (&gt; 16 nm), pou\u017ei\u00adtia vhodn\u00e9ho sk\u00f3rovacieho syst\u00e9mu a erudovanosti hodno\u00adtiaceho patol\u00f3ga<sup>(4)<\/sup>.<\/p>\n<p>U pacientov s NAFLD sa navy\u0161e vzh\u013eadom na vysok\u00fd v\u00fd\u00adskyt steat\u00f3zy s n\u00edzkym rizikom progresie do cirh\u00f3zy biopsia pe\u010dene nepova\u017euje za vhodn\u00fd test prvej vo\u013eby<sup>(6)<\/sup>.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>S\u00e9rov\u00e9 a zobrazovacie neinvaz\u00edvne markery<\/strong><\/p>\n<p>V posledn\u00fdch dvoch desa\u0165ro\u010diach sa intenz\u00edvne sk\u00fama\u00adli neinvaz\u00edvne met\u00f3dy hodnotenia pe\u010de\u0148ovej fibr\u00f3zy a cirh\u00f3\u00adzy najm\u00e4 s oh\u013eadom na rizik\u00e1, obmedzenia a kontraindik\u00e1cie pe\u010de\u0148ovej biopsie. Ich diagnostick\u00fa efektivitu vyjadruje vypo\u010d\u00edtan\u00e1 hodnota plochy pod opera\u010dnou krivkou AUROC (Area Under the Receiver Operating characteristic Curve), ktor\u00e1 sa vz\u0165ahuje k referen\u010dn\u00e9mu \u0161tandardu &#8211; biopsii pe\u010de\u00adne. Sk\u00faman\u00fd diagnostick\u00fd test \u010di met\u00f3da sa vo v\u0161eobecnos\u00adti hodnot\u00ed ako dobr\u00fd, ak hodnota AUROC dosahuje viac ako 80 % a ako excelentn\u00fd, ak AUROC je viac ako 90 %.<\/p>\n<p>Neinvaz\u00edvne met\u00f3dy hodnotenia pe\u010de\u0148ovej fibr\u00f3zy sa de\u00adlia na dve skupiny: 1. kvantitat\u00edvne stanovovan\u00e9 s\u00e9rov\u00e9 bio\u00admarkery, ktor\u00e9 viac alebo menej odr\u00e1\u017eaj\u00fa zmeny v pe\u010deni a 2. meranie tuhosti pe\u010dene (elastografia), ktor\u00e1 odr\u00e1\u017ea fyzik\u00e1lne vlastnosti pe\u010de\u0148ov\u00e9ho tkaniva zmenen\u00e9ho fibr\u00f3zou.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>S\u00e9rov\u00e9 biomarkery<\/strong><\/p>\n<p>Viacer\u00e9 biomarkery boli identifikovan\u00e9 ako vhodn\u00e9 indi\u00adk\u00e1tory pe\u010de\u0148ovej fibr\u00f3zy. \u017diaden z nich nesp\u013a\u0148a krit\u00e9ri\u00e1 na ide\u00e1lny biomarker, ale ich diagnostick\u00e1 hodnota sa v\u00fdrazne zvy\u0161uje, ak s\u00fa pou\u017eit\u00e9 v kombin\u00e1ci\u00e1ch. S\u00e9rov\u00e9 markery pe\u00ad\u010de\u0148ovej fibr\u00f3zy mo\u017eno rozdeli\u0165 do dvoch z\u00e1kladn\u00fdch skup\u00edn: Nepriame markery &#8211; preva\u017ene \u0161iroko dostupn\u00e9 tzv. hepat\u00e1lne testy, ktor\u00e9 len nepriamo odr\u00e1\u017eaj\u00fa produkciu a kvanti\u00adtu v\u00e4ziva v pe\u010deni a ich koncentr\u00e1cie v krvi sa menia sekun\u00add\u00e1rne v d\u00f4sledku zmien \u0161trukt\u00fary pe\u010dene \u010di sleziny a n\u00e1rastu port\u00e1lneho tlaku:<\/p>\n<ul>\n<li>tradi\u010dn\u00e9 \u201epe\u010de\u0148ov\u00e9&#8221; enz\u00fdmy odr\u00e1\u017eaj\u00face poruchu integri\u00adty a\u017e nekr\u00f3zu hepatocytov (AST, ALT) alebo cholest\u00e1zu (GMT, ALP);<\/li>\n<li>markery odr\u00e1\u017eaj\u00face sekund\u00e1rny hypersplenizmus ale\u00adbo zn\u00ed\u017een\u00fa synt\u00e9zu koagula\u010dn\u00fdch faktorov (trombocyty, protromb\u00ednov\u00fd \u010das, INR &#8211; International Normalized Ratio);<\/li>\n<li>prote\u00edny syntetizovan\u00e9 alebo degradovan\u00e9 pe\u010de\u0148ou (a2-makroglobul\u00edn, album\u00edn, ferit\u00edn, imunoglobul\u00edny);<\/li>\n<li>z\u00e1palov\u00e9 cytok\u00edny, o ktor\u00fdch je zn\u00e1me, \u017ee poch\u00e1dzaj\u00fa z he\u00adpatocytov alebo aktivovan\u00fdch z\u00e1palov\u00fdch buniek v pe\u010deni (IL-6, TNF-a a pod.)<\/li>\n<\/ul>\n<p>Priame markery &#8211; poch\u00e1dzaj\u00fa priamo z procesu fibrogen\u00e9zy a v krvi sa zvy\u0161uj\u00fa v d\u00f4sledku ich zv\u00fd\u0161en\u00e9ho vychyt\u00e1va\u00adnia v hepat\u00e1lnych s\u00ednusoidoch. V klinickej praxi sa doposia\u013e najviac \u0161tudovali nasleduj\u00face (preh\u013ead v 7):<\/p>\n<p>N-termin\u00e1lny peptid prokolag\u00e9nu typu III (PIIINP) &#8211; je markerom fibrogen\u00e9zy. Od\u0161tepuje sa enzymaticky z moleku\u00adly prokolag\u00e9nu III pred jeho integr\u00e1ciou do ECM. Nev\u00fdhodou markera je jeho n\u00edzka \u0161pecifickos\u0165 pre pe\u010de\u0148 a mo\u017en\u00e1 inter\u00adferencia fibr\u00f3zy in\u00e9ho p\u00f4vodu (p\u013e\u00faca, obli\u010dky, \u010drevo a pod.)<\/p>\n<p>Kyselina hyalur\u00f3nov\u00e1 (HA) &#8211; glykozaminoglyk\u00e1n pr\u00edtom\u00adn\u00fd v ECM, je rovnako priamym markerom fibrogen\u00e9zy. V \u0161t\u00fa\u00addi\u00e1ch s r\u00f4znymi typmi COP, av\u0161ak najm\u00e4 pri chronickej VHC a NAFLD, bola potvrden\u00e1 jej schopnos\u0165 detegova\u0165 pokro\u010dil\u00fa fibr\u00f3zu, cirh\u00f3zu a tie\u017e poklesom reagova\u0165 na \u00faspe\u0161n\u00fa lie\u010dbu pacientov s VHC.<\/p>\n<p>Metaloprotein\u00e1zy (MMP-1, -2, -9) &#8211; 3 enz\u00fdmy typu kolagen\u00e1z a gelatin\u00e1z, ktor\u00e9 sa priamo z\u00fa\u010dast\u0148uj\u00fa na degrad\u00e1\u00adcii ECM. Ich koncentr\u00e1cia v krvi nepriamo koreluje so z\u00e1va\u017e\u00adnos\u0165ou fibr\u00f3zy aj nekr\u00f3zy pe\u010dene. V klinickej praxi sa ve\u013emi neosved\u010dili.<\/p>\n<p>Tkanivov\u00fd inhib\u00edtor metaloprotein\u00e1zy-1 (TIMP-1) &#8211; je\u00adden z viacer\u00fdch tkanivov\u00fdch prote\u00ednov, ktor\u00fdch koncentr\u00e1cia v krvi odr\u00e1\u017ea intenzitu fibrogen\u00e9zy. Zv\u00fd\u0161en\u00e9 hodnoty TIMP-1 boli opakovane referovan\u00e9 v r\u00f4znych \u0161t\u00e1di\u00e1ch fibr\u00f3zy najm\u00e4 u pacientov s chronickou VHC.<\/p>\n<p>Cytok\u00edny a chemok\u00edny priamo viazan\u00e9 na proces fibr\u00f3zy pe\u010dene boli \u0161tudovan\u00e9 najm\u00e4 vo vz\u0165ahu k progresii ochore\u00adnia. TGF-p je najd\u00f4le\u017eitej\u0161\u00edm stimul\u00e1torom ukladania ECM. TGF-a podporuje prolifer\u00e1ciu pe\u010de\u0148ov\u00fdch hviezdicovit\u00fdch bu\u00adniek a PDGF sa zd\u00e1 naj\u00fa\u010dinnej\u0161\u00edm mitog\u00e9nom hviezdicovi\u00adt\u00fdch buniek in vitro. V\u0161etky p\u00f4sobky preuk\u00e1zali korel\u00e1ciu so stup\u0148om fibr\u00f3zy a\/alebo z\u00e1palu.<\/p>\n<p>Nev\u00fdhodou v\u0161etk\u00fdch spomenut\u00fdch priamych markerov je ich n\u00edzka org\u00e1nov\u00e1 \u0161pecifickos\u0165 pre pe\u010de\u0148 a mo\u017en\u00e1 interfe\u00adrencia fibr\u00f3zy in\u00e9ho p\u00f4vodu (p\u013e\u00faca, \u010drevo a pod.) Biochemic\u00adk\u00e9 markery pe\u010de\u0148ovej fibr\u00f3zy boli v po\u010detn\u00fdch \u0161t\u00fadi\u00e1ch validovan\u00e9 najm\u00e4 pre pacientov s chronickou VHC, VHB, NAFLD, v men\u0161ej miere pre in\u00e9 chronick\u00e9 ochorenia pe\u010dene, napr. al\u00adkoholov\u00fa chorobu pe\u010dene a len ojedinele pre zriedkav\u00e9 auto- imunitn\u00e9 alebo metabolick\u00e9 pe\u010de\u0148ov\u00e9 ochorenia.<\/p>\n<p>Boli vypracovan\u00e9 mnoh\u00e9 matematick\u00e9 modely zalo\u017een\u00e9 na kombin\u00e1ci\u00e1ch priamych a nepriamych s\u00e9rov\u00fdch marke\u00adrov, pr\u00edpadne na kombin\u00e1cii s\u00e9rov\u00fdch markerov a zobrazova\u00adc\u00edch elastografi\u00ed, ktor\u00e9 sa r\u00f4znou mierou stali s\u00fa\u010das\u0165ou rutin\u00adnej praxe v hepatol\u00f3gii (tabu\u013eka 2). Mnoh\u00e9 vzorce na v\u00fdpo\u010det sk\u00f3re s\u00fa patentovan\u00e9 (FibroTest, Hepascore, FibroMeter), in\u00e9 s\u00fa nepatentovan\u00e9 (napr. APRI, Fornosov index, FIB-4). Tieto rozhodovacie algoritmy umo\u017enili neinvaz\u00edvnym sp\u00f4so\u00adbom kategorizova\u0165 viac ako 90 % pacientov do kateg\u00f3ri\u00ed n\u00edz\u00adkej, stredne z\u00e1va\u017enej a z\u00e1va\u017enej fibr\u00f3zy. Treba zd\u00f4razni\u0165, \u017ee v\u00e4\u010d\u0161ina biomarkerov op\u00edsan\u00fdch v literat\u00fare m\u00e1 schopnos\u0165 predikova\u0165 pokro\u010dil\u00fa fibr\u00f3zu (&gt; 2 Ishak alebo &gt; 2 Metavir), ale v porovnan\u00ed s pe\u010de\u0148ovou biopsiou neodl\u00ed\u0161i dostato\u010dne presne po\u010diato\u010dn\u00e9 \u0161t\u00e1di\u00e1 fibr\u00f3zy a zdrav\u00fa pe\u010de\u0148.<\/p>\n<p>U pacientov s NAFLD malo najv\u00e4\u010d\u0161iu diagnostick\u00fa efekti\u00advitu pou\u017eitie modifikovan\u00e9ho FibroMeter testu alebo NAFLD sk\u00f3re po\u010d\u00edtan\u00e9ho pomocou online kalkul\u00e1tora, FIB-4 alebo APRI index mali ni\u017e\u0161iu senzit\u00edvnos\u0165a \u0161pecifickos\u0165<sup>89<\/sup>\/ Najviac \u00fadajov o valid\u00e1cii s\u00e9rov\u00fdch biomarkerov pe\u010de\u0148ovej fibr\u00f3zy je u pacientov s chronickou VHC. Slovensk\u00ed autori tie\u017e prispe\u00adli k vytvoreniu vlastn\u00e9ho sk\u00f3rovacieho syst\u00e9mu NSF (neinvaz\u00edvne sk\u00f3re fibr\u00f3zy), ktor\u00fd bol validovan\u00fd na 104 pacientoch s VHC pred pl\u00e1novanou lie\u010dbou<sup>(10)<\/sup>.<\/p>\n<p>&nbsp;<\/p>\n<p>Medzi sk\u00f3rovacie syst\u00e9my zalo\u017een\u00e9 na meran\u00ed priamych biomarkerov, presadzovan\u00e9 v s\u00fa\u010dasnosti, patr\u00ed tzv. ELF (En\u00adhanced Liver Fibrosis) test, ktor\u00fd je s\u00fa\u010das\u0165ou NICE odpo\u00adr\u00fa\u010dan\u00ed pre mana\u017ement COP vo Ve\u013ekej Brit\u00e1nii a v praxi po\u00adu\u017e\u00edvan\u00fd tie\u017e v Austr\u00e1lii<sup>(11)<\/sup>. Test je zalo\u017een\u00fd na v\u00fdpo\u010dte ELF sk\u00f3re z meran\u00fdch s\u00e9rov\u00fdch markerov synt\u00e9zy a odb\u00farava\u00adnia extracelul\u00e1rnej hmoty kyseliny hyalur\u00f3novej, PIIINP a TIMP-1. Podobne ako mnoh\u00e9 \u010fal\u0161ie modely v\u00fdpo\u010det ELF sk\u00f3re zoh\u013ead\u0148uje vek a pohlavie pacienta. Viacer\u00e9 \u0161t\u00fadie deklarovali schopnos\u0165 ELF sk\u00f3re rozl\u00ed\u0161i\u0165 z\u00e1va\u017en\u00fa, miernu a \u017eiadnu fibr\u00f3zu pe\u010dene (AUROC 0,90 &#8211; 0,82 &#8211; 0,76) a predikova\u0165 komplik\u00e1cie COP<sup>(1213)<\/sup>. Neinvaz\u00edvny ELF test bol po\u00adu\u017eit\u00fd aj v ned\u00e1vnej \u0161t\u00fadii Tanwara a kol. na monitorovanie 24-mesa\u010dnej antivirotickej lie\u010dby u pacientov s chronickou VHC (pred lie\u010dbou, po 12 a 24 mesiacoch), ktor\u00ed podst\u00fapi\u00adli aj biopsiu pe\u010dene na za\u010diatku a na konci sledovan\u00e9ho obdobia<sup>(14)<\/sup>. Absol\u00fatne zmeny hodn\u00f4t ELF sk\u00f3re po 12 mesia\u00adcoch signifikantne korelovali so zmenami ELF aj histol\u00f3gie po 24 mesiacoch. V\u00fdsledky tejto \u0161t\u00fadie nazna\u010duj\u00fa, \u017ee zme\u00adny s\u00e9rov\u00fdch biomarkerov predikuj\u00fa v\u00fdvoj pe\u010de\u0148ovej fibr\u00f3zy \u00fa\u010dinkom lie\u010dby v zmysle jej regresie (AUROC 0,81 &#8211; 0,84) aj progresie (AUROC 0,86 &#8211; 0,91). Porovnanie priamych a ne\u00adpriamych s\u00e9rov\u00fdch biomarkerov uk\u00e1zalo, \u017ee ich diagnostic\u00adk\u00e1 efektivita pri predikcii fibr\u00f3zy pe\u010dene je porovnate\u013en\u00e1, av\u00ad\u0161ak n\u00e1klady, a t\u00fdm aj dostupnos\u0165 priamych biomarkerov s\u00fa ove\u013ea vy\u0161\u0161ie<sup>(1516)<\/sup>. Vo v\u00e4\u010d\u0161ine eur\u00f3pskych kraj\u00edn nie s\u00fa priame markery fibr\u00f3zy hraden\u00e9 zo zdravotn\u00e9ho poistenia, preto s\u00fa sk\u00fasenosti s ich vyu\u017eit\u00edm v rutinnej klinickej praxi minim\u00e1lne.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Zobrazovacie met\u00f3dy na pos\u00fadenie fibr\u00f3zy<\/strong><\/p>\n<p>Tranzientn\u00e1 ultrazvukov\u00e1 elastografia (TE) je neinvaz\u00edvna met\u00f3da merania tuhosti pe\u010de\u0148ov\u00e9ho tkaniva, ktor\u00e1 sa zvy\u00ad\u0161uje so z\u00e1va\u017enos\u0165ou fibr\u00f3zy aj so st\u00fapaj\u00facou vaskul\u00e1rnou rezistenciou a port\u00e1lnym ven\u00f3znym tlakom. Met\u00f3da vy\u017e\u00edva vysokofrekven\u010dn\u00fd ultrazvuk (MHz) a sondu, ktor\u00e1 generuje a emituje do pe\u010dene n\u00edzkofrekven\u010dn\u00e9 vibr\u00e1cie (50 Hz). R\u00fdch\u00adlos\u0165 \u0161\u00edrenia t\u00fdchto vibr\u00e1ci\u00ed je priamo\u00famern\u00e1 tuhosti tkaniva, ktor\u00e1 je vyjadren\u00e1 v kilopascaloch (kPa). Senzit\u00edvnos\u0165 a \u0161pe\u00adcifickos\u0165 TE je vysok\u00e1 u pacientov s cirh\u00f3zou (a\u017e do 90 %), av\u00ad\u0161ak u pacientov so stredne z\u00e1va\u017enou a\u017e pokro\u010dilou fibr\u00f3zou (F2 &#8211; F4) TE dosahuje len 70 % senzitivitu a 80 % \u0161pecificitu. Cut-off hodnoty TE na potvrdenie cirh\u00f3zy u pacientov s chro\u00adnickou VHC kol\u00ed\u0161u v rozmedz\u00ed 11 &#8211; 17 kPa<sup>(1718)<\/sup>.<\/p>\n<p>Modernou met\u00f3dou na stanovenie elastick\u00fdch vlastnos\u00adt\u00ed pe\u010de\u0148ov\u00e9ho parench\u00fdmu je aj magnetick\u00e1 rezonancia vo forme tzv. MR elastografie. Podobne ako TE met\u00f3da vyu\u017e\u00ed\u00adva mechanick\u00e9 vibr\u00e1cie s frekvenciou 40 &#8211; 90 Hz, generova\u00adn\u00e9 pomocou zdroja n\u00edzkofrekven\u010dn\u00fdch v\u013an. Po prechode pe\u00ad\u010de\u0148ou tieto vlny sp\u00f4sobuj\u00fa pohyby \u010dast\u00edc a druhotn\u00e9 vlnenie, ktor\u00e9 je zachyt\u00e1van\u00e9 \u0161peci\u00e1lnymi MR technikami a softv\u00e9\u00adrom na generovanie MRE obrazov vznikaj\u00fa MRE elastogramy. Senzitivita MRE pre \u0161t\u00e1di\u00e1 fibr\u00f3zy F2 a\u017e F4 pod\u013ea Metaviru bola 98 %, 95 % a 100 %<sup>(19)<\/sup>.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Porovnanie neinvaz\u00edvnych markerov fibr\u00f3zy pe\u010dene<\/strong><\/p>\n<p>Priame a nepriame s\u00e9rov\u00e9 biomarkery boli porovn\u00e1van\u00e9 navz\u00e1jom aj vo vz\u0165ahu k TE v desiatkach \u0161t\u00fadi\u00ed. Metaanal\u00fdza Hounota a kol. (2016) 71 \u0161t\u00fadi\u00ed z obdobia 2001 &#8211; 2014 sys\u00adtematicky presk\u00famala pomocou matematicko-\u0161tatistick\u00fdch met\u00f3d priame porovnania \u0161tyroch naj\u010dastej\u0161ie pou\u017e\u00edvan\u00fdch a diskutovan\u00fdch neinvaz\u00edvnych met\u00f3d u pacientov s chronic\u00adkou VHC a VHB, a to FibroTest, APRI a FIB-4 sk\u00f3re a tranzientn\u00fa elastografiu<sup>(20)<\/sup>. Ich anal\u00fdza potvrdila lep\u0161iu diagnos\u00adtick\u00fa efektivitu FibroTestu v porovnan\u00ed s APRI, FIB-4 a TE pri diagn\u00f3ze z\u00e1va\u017enej fibr\u00f3zy, k\u00fdm pri diagn\u00f3ze cirh\u00f3zy sa testy nel\u00ed\u0161ili. Toto zistenie mo\u017eno zov\u0161eobecni\u0165 pre v\u00e4\u010d\u0161inu kom\u00adplexn\u00fdch sk\u00f3rovac\u00edch syst\u00e9mov zalo\u017een\u00fdch na priamych biomarkeroch alebo kombin\u00e1cii priamych a nepriamych s\u00e9rov\u00fdch biomarkerov. Obe skupiny neinvaz\u00edvnych met\u00f3d na diagn\u00f3zu pe\u010de\u0148ovej fibr\u00f3zy maj\u00fa svoje v\u00fdhody aj nev\u00fdhody (tabu\u013eka 3), ich klinick\u00e1 vyu\u017eite\u013enos\u0165 z\u00e1vis\u00ed vo v\u00e4\u010d\u0161ine kraj\u00edn od ich dostupnosti a ceny.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Z\u00e1ver<\/strong><\/p>\n<p>Klinici maj\u00fa k dispoz\u00edcii dve neinvaz\u00edvne alternat\u00edvy na identifik\u00e1ciu z\u00e1va\u017enej fibr\u00f3zy alebo cirh\u00f3zy pe\u010dene. Vy\u0161et\u00adrenie elasticity pe\u010dene naj\u010dastej\u0161ie pomocou ultrazvukovej TE je r\u00fdchle, bezpe\u010dn\u00e9 a relat\u00edvne dostupn\u00e9. S\u00e9rov\u00e9 biomar\u00adkery sa pou\u017e\u00edvaj\u00fa najm\u00e4 v r\u00f4znych kombin\u00e1ci\u00e1ch na v\u00fdpo\u00ad\u010det rozhodovacieho sk\u00f3re alebo cut-off hodnoty, ktor\u00e1 v da\u00adnom sk\u00f3rovacom syst\u00e9me sl\u00fa\u017ei na vyl\u00fa\u010denie alebo predikciu fibr\u00f3zy<sup>(4)<\/sup>. Dostupnos\u0165 dostato\u010dne citliv\u00fdch a \u0161pecifick\u00fdch s\u00e9\u00adrov\u00fdch biomarkerov umo\u017e\u0148uje skr\u00edning a monitorovanie z\u00e1\u00adva\u017en\u00e9ho ochorenia pe\u010dene vo ve\u013ek\u00fdch skupin\u00e1ch pacientov a pos\u00fadenie skuto\u010dn\u00e9ho rozsahu COP v be\u017enej popul\u00e1cii. Neinvaz\u00edvne markery pe\u010de\u0148ovej fibr\u00f3zy maj\u00fa svoje miesto pri ur\u010dovan\u00ed \u0161t\u00e1dia fibr\u00f3zy u pacientov bez jasnej indik\u00e1cie biopsie, u pacientov s chronick\u00fdmi hepatit\u00eddami vy\u017eaduj\u00fa\u00adcimi dlhodob\u00e9 monitorovanie progresie fibr\u00f3zy, u pacientov s autoimunitn\u00fdmi hepatit\u00eddami, ktor\u00ed vy\u017eaduj\u00fa monitorovanie dlhodobej imunosupres\u00edvnej lie\u010dby. V\u00fdvoj nov\u00fdch lie\u010div pre vybran\u00e9 typy pe\u010de\u0148ov\u00fdch ochoren\u00ed, napr. chronickej VHC, VHB a NAFLD rovnako zvy\u0161uje potrebu \u010dastej\u0161ieho pos\u00fade\u00adnia fibr\u00f3zy v r\u00e1mci monitorovania efektu lie\u010dby. Neinvaz\u00edvne markery m\u00f4\u017eu byt\u2019 pou\u017eit\u00e9 aj na monitorovanie antifibrotickej lie\u010dby, preto\u017ee koreluj\u00fa s histologick\u00fdm n\u00e1lezom pacientov a umo\u017e\u0148uj\u00fa v\u010dasn\u00fa identifik\u00e1ciu pacientov, ktor\u00ed m\u00f4\u017eu profi\u00adtova\u0165 z dlhodobej lie\u010dby. Aj ke\u010f v s\u00fa\u010dasnosti neinvaz\u00edvne markery nie s\u00fa schopn\u00e9 nahradit biopsiu pe\u010dene, v\u00fdznamnou mierou zni\u017euj\u00fa jej po\u00adtrebu. V\u00fdvoj nov\u00fdch \u0161pecifick\u00fdch biomarkerov a biomarkerov v kombin\u00e1cii s nov\u00fdmi zobrazovac\u00edmi a fyzik\u00e1lnymi met\u00f3da\u00admi m\u00f4\u017ee v bud\u00facnosti navodi\u0165 stav, ke\u010f pou\u017eite biopsie pri vy\u0161etreniach pe\u010dene bude v\u00fdnimo\u010dn\u00e9.<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>LITERAT\u00daRA<\/p>\n<ol>\n<li>Negro F. Epidemiology of hepatitis C in Europe. Dig Liv Dis 2014; 46: S158-S164.<\/li>\n<li>Blachier M, Leleu H, Peck-Radosavljevic M, et al. The burden of liver disease in Europe: A review of available epidemiological data. J Hepatol 2013; 58: 593-608.<\/li>\n<li>Younossi ZM, Koenig AB, Abdelatif B, et al. Global epidemiology of nonalcoholic fatty liver disease &#8211; Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64: 73-84.<\/li>\n<li>European association for the Study of the Liver. EASL-ALEH Clinical practice guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015; 63: 237-264.<\/li>\n<li>Liu T, Wang W, Karsdal MA, et al. Molecular serum markers of liver fibrosis. Biomarker Insights 2012; 7: 105-117.<\/li>\n<li>Buzzetti E, Lombari R, De Luca L, et al. Noninvasive assessment of fibrosis in patients with nonalcoholic fatty liver disease. Int J Endokrin 2015; 2015: Article ID 343828, 9 pages <a href=\"http:\/\/dx.doi.org\/10.1155\/2015\/343828\">http:\/\/dx.doi.org\/10.1155\/2015\/343828<\/a><\/li>\n<li>Fallatah HI. Noninvasive biomrkers of liver fibrosis: An overview. Advances in Hepatology 2014; 2014: Article ID 357287, 15 pages. http:\/\/ dx.doi.org\/10.1155\/2014\/357287.<\/li>\n<li>Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. J Hepatol 2013; 58: 1007-1019.<\/li>\n<li>Boursier J, Vergniol J, Guillet A, et al. Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurements by FibroScan in non-alcoholic fatty liver disease. J Hepatology 2016; 65: 570-578.<\/li>\n<li>Koller T, Kollerov\u00e1 J, Huorka M, et al. Noninvasive scoring algorithm to identify significant liver fibrosis among treatment-naive chronic hepatitis C patients. Eur J Gastroenterol Hepatol 2014; 10: 1108-1115.<\/li>\n<li>Non-alcoholic fatty liver disease (NAFLD): assessment and management. (j\u00fal 2016). Dostupn\u00e9 na Internete: NICE guideline [NG49]: <a href=\"http:\/\/www.nice.org.uk\">nice.org.uk<\/a><\/li>\n<li>Guha IN, Parkers J, Chattopadhyay D, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validation the European Liver Fibrosis Panel and exploring simple markers. Hepatology 2008; 47: 455-460.<\/li>\n<li>Kim BK, Kim H-S, Yoo EJ, et al. Risk assessment of clinical outcomes in Asian patients with chronic hepatitis B using enhanced liver fibrosis test. Hepatology 2014; 60: 1911-1919.<\/li>\n<li>Tanwar S, Trembling PM, Hogan BJ, et al. Noninvasive markers of liver fibrosis: on-treatment changes od serum markers predict the outcome of antifibrotic therapy. Eur J Gastroenterol Hepato 2017; 29: 289-298.<\/li>\n<li>Castera L. Noninvasive methods to assess liver disease in patients with hepatitis. Gastroenterology 2012; 142: 1293-1302.<\/li>\n<li>Chindamo MC, Boursier J, Luiz RR, et al. Fibrosis assessment using FibroMeter combined to first generation tests in hepatitis C. W J Hepatol 2017; 28: 310-317.<\/li>\n<li>Friedrich-Rust M, Ong M-F, Martens S, et al. Performance of transient elastography for staging of liver fibrosis: Meta-analysis. Gastroenterology 2008; 137: 960-974.<\/li>\n<li>Tsochatzis A, Gurusamy K, Burrough A, et al. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: A metaanalysis of diagnostic accuraccy. J Hepatol 2011; 54: 650-659.<\/li>\n<li>Huwart L, Salameh N, ter Beek L, et al. MR elastography of liver fibrosis: preliminary results comparing spi-echo and echo-planar imaging. Eur radiology 2008; 18: 2535-2541.<\/li>\n<li>Houot M, Ngo Y, Munteanu M, et al. Systemic review with meta\u00adanalysis: direct comparisons of biomarkers for diagnosis of fibrosis in chronic hepatitis C and B. Aliment Pharmacol Ther 2016; 43: 16-29.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"<p>*V\u0161etky tabu\u013eky, grafy a obr\u00e1zky, ktor\u00e9 s\u00fa s\u00fa\u010das\u0165ou \u010dl\u00e1nku, n\u00e1jdete v prilo\u017eenom PDF s\u00fabore na konci \u0161t\u00fadie. &nbsp; \u00davod V\u00fdskyt chronick\u00fdch ochoren\u00ed pe\u010dene (COP) v dne\u0161nej mo\u00addernej dobe narast\u00e1 a celosvetovo predstavuj\u00fa popredn\u00fa pr\u00ed\u00ad\u010dinu mortality. \u0160pecifick\u00e9 postavenie pe\u010dene v centre me\u00adtabolick\u00fdch funkci\u00ed organizmu a unik\u00e1tne krvn\u00e9 z\u00e1sobenie predisponuj\u00fa tento org\u00e1n na viacn\u00e1sobn\u00e9 potencion\u00e1lne rizi\u00adko po\u0161kodenia.<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[289],"tags":[545,546,547,548],"class_list":["post-1282","post","type-post","status-publish","format-standard","hentry","category-biochemistry","tag-chronic-liver-disease","tag-fibrogenesis","tag-non-invasive-biomarkers","tag-scoring-systems","typ_clanku-review-article"],"acf":{"abstrakt":"<p>Determining the presence and degree of fibrosis is an important step in the assessment of disease severity in patients with the chronic liver disease. Liver biopsy has been the gold standard for estimating the extent of fi\u00adbrosis and inflammation, although the procedure has some limitations such as sampling error and variability in interpretation. Non-invasive tests, e. g. serum biomarkers and imagine-based tests have been validated dur\u00ading the past decades and have been shown to be equally predictive in ruling out fibrosis or ruling in advanced fibrosis or cirrhosis, with more limited predictive ability when classifying intermediate stages. Using a combi\u00adnation of serum markers and imaging tests can help identify patients who require antiviral treatment sooner and also in the monitoring of antifibrotic therapy without the need for biopsy.<\/p>\n<p><strong>Keywords:<\/strong> chronic liver disease, fibrogenesis, non-invasive biomarkers, scoring systems<\/p>\n<p>&nbsp;<\/p>\n","casopis":[{"ID":1223,"post_author":"7","post_date":"2017-09-26 14:15:30","post_date_gmt":"2017-09-26 12:15:30","post_content":"<ul>\r\n \t<li>Fertility disorders: immunological causes and possible curative impact<\/li>\r\n \t<li>The first results of galactose-deficient IgA1 measurement in diagnosis and monitoring of patients with IgA nephropathy<\/li>\r\n \t<li>Application of autovaccines in the treatment of chronic and recurrent colpitises<\/li>\r\n \t<li>Infections of the hip endoprostheses<\/li>\r\n \t<li>Non-invasive markers of liver fibrosis<\/li>\r\n<\/ul>","post_title":"Newslab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-2017-2","to_ping":"","pinged":"","post_modified":"2017-09-26 14:19:35","post_modified_gmt":"2017-09-26 12:19:35","post_content_filtered":"","post_parent":0,"guid":"http:\/\/www.newslab.sk\/casopis\/newslab-2017-2\/","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"100","upload_clanok":{"ID":1279,"id":1279,"title":"NEWSLAB 2-2017_\u010eurovcov\u00e1","filename":"NEWSLAB-2-2017_\u010eurovcov\u00e1-1.pdf","filesize":596582,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2017\/09\/NEWSLAB-2-2017_\u010eurovcov\u00e1-1.pdf","link":"https:\/\/www.newslab.sk\/en\/non-invasive-markers-of-liver-fibrosis\/newslab-2-2017_durovcova-2-2\/","alt":"","author":"7","description":"","caption":"","name":"newslab-2-2017_durovcova-2-2","status":"inherit","uploaded_to":1282,"date":"2017-09-28 07:22:35","modified":"2017-09-28 07:22:35","menu_order":0,"mime_type":"application\/pdf","type":"application","subtype":"pdf","icon":"https:\/\/www.newslab.sk\/wp-includes\/images\/media\/document.png"}},"_links":{"self":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1282","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/comments?post=1282"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1282\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=1282"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=1282"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=1282"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}