Evaluacija serumskih biljega u dijagnozi hepatocelularnoga karcinom kod ciroze jetre alkoholne etiologije

doctoral thesis

• Title (english): Evaluation of serum markers in diagnosis of hepatocellular carcinoma in liver cirrhosis of alcohol etiology
• Author: Adriana Unić
• Mentor: Ivica Grgurević (mentor)
• Mentor: Marija Grdić Rajković (komentor)
• Committee member: Dunja Rogić (predsjednik povjerenstva)
• Committee member: Jozsef Petrik (član povjerenstva)
• Committee member: Mirjana Kalauz (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medical biochemistry and haematology); Zagreb
• Defense date and country: 2022-05-12, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Medical Biochemistry
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

Hepatocelularni karcinom (HCC) je epitelna zloćudna novotvorina s prisutnom hepatocelularnom diferencijacijom
i najčešća je primarna zloćudna novotvorina jetre. Ciroza jetre je najznačajni rizični čimbenik za razvoj HCC-a.
Dosadašnja istraživanja pokazuju da će 1/3 bolesnika s cirozom razviti i HCC, a oko 90% bolesnika s HCC-om
ima i cirozu jetre. S obzirom da je ciroza ključan rizični čimbenik u nastanku HCC-a, a etilogija ciroze ima ulogu
u mehanizmima kancerogeneze, temeljni cilj ovog istraživanja bio je ispitati individualnu i kombiniranu
dijagnostičku točnost alfa-fetoproteina (AFP), lens culinaris aglutinin A-reaktivne frakcije alfa-fetoproteina (AFPL3),
des-gama-karboksi protrombina (PIVKAII), glipikana 3 (GP3), antigena pločastih stanica karcinoma-1
(SCCA1), cistatina B (CSTB) i hepatocitnog faktora rasta (HGF) kao potencijalnih tumorskih biljega za dijagnozu
HCC-a kod bolesnika s alkoholnom cirozom jetre. Radiološke slikovne metode i/ili tkivno uzorkovanje (biopsija
tumora) korišteni su kao "zlatni dijagnostički standard" u dijagnozi HCC-a.
Ispitivanje je provedeno kod 31 bolesnika s alkoholnom cirozom bez HCC-a i 32 bolesnika s alkoholnom cirozom
sa HCC-om. U ispitivanje je uključeno i 20 zdravih ispitanika kako bi se verificirale granične vrijednosti za one
biljege za koje ne postoji specifikacija proizvođača. Prvo uzorkovanje periferne venske krvi provedeno je u stanju
gladovanja, a drugo nakon urađenih slikovnih pretraga i prije bilo kakvih terapijskih intervencija. Biopsija tumora
je rađena nakon uzorkovanja, ukoliko je bila indicirana.
Koncentracije PIVKAII i AFP-a, bile su značajno više u bolesnika s alkoholnom cirozom i HCC-om nego u
bolesnika s alkoholnom cirozom bez HCC-a, dok su pojedinačne dijagnostičke izvedbe ostalih ispitivanih biljega
bile nedostatne.
"Najbolja" kombinacija tumorskih biljega uključuje AFP i PIVKAII s dijagnostičkom točnosti od 97,4%. Također,
koncentracija AFP –a pokazala je diskriminativnu sposobnost za razlikovanje kurabilnog od inkurabilnog stadija
bolesti (s obzrom na veličinu i broj tumora), što je potrebno potvrditi daljnjim istraživanjima.
Među ostalim provedenim testovima, koncentracija hemoglobina, broj trombocita, aktivnosti alaninaminotransferaze
(ALT) i gama-glutamil-transferaze (GGT) te koncentracije amonijaka i feritina bile su značajno
više u bolesnika s HCC-om i alkohonom cirozom u odnosu na bolesnike s alkoholnom cirozom bez HCC-a.
Dodatno, serumske koncentracije CSTB i SCCA1 pokazale su dobru pozitivnu povezanost s funkcionalnim
stadijem ciroze.
Rezultati ovog istraživanja upućuju na zaključak da AFP i PIVKAII imaju najbolju diskriminativnu sposobnost za
dijagnozu HCC-a u bolesnika s alkoholnom cirozom jetre, uz dodatno poboljšanje dijagnostičke točnosti ukoliko
se koriste u kombinaciji. U usporedbi s ranijim istraživanjima, može se pretpostaviti da bi dijagnostička izvedba
tumorskih biljega mogla ovisiti o etiologiji bolesti jetre u podlozi HCC-a, za što su potrebna daljnja istraživanja.

Abstract (english)

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Approximately 90 % of HCC
cases are diagnosed in patients with pre-existing cirrhotic liver. Since cirrhosis is a key risk factor in the
development of HCC, and the etiology of cirrhosis plays a role in the mechanisms of carcinogenesis, the basic
goal of this study was to examine the individual and combined diagnostic accuracy of alpha-fetoprotein (AFP),
lens culinaris agglutinin (LCA) reactive fration of AFP (AFP-L3), protein induced by vitamin K absence or
antagonist-II (PIVKAII), glypican-3 (GP3), squamous cell carcinoma antigen 1 (SCCA1), cystatin B (CSTB) and
hepatocyte growth factor (HGF) as potential tumor markers for the diagnosis of HCC in patients with alcoholic
liver cirrhosis(ALC) using imaging techniques and/or tumor biopsy as reference standard in the diagosis of HCC.
The study was performed in 31 patients with ALC and 32 patients with ALC and HCC. 20 healthy subjects were
also included in order to verify cut-off values. The first sampling of peripheral venous blood was performed in the
fasting state, and the second after imaging tests and before any therapeutic interventions. Tumor biopsy was
performed after second sampling, if it was indicated.
Serum concentrations of AFP and PIVKAII were significantly higher in patients with ALC and HCC than in
patients with ALC, while individual diagnostic performance of the other markers was inadequate.
The “best” combination of tumor markers includes AFP and PIVKAII with diagnostic accuracy of 97,4%.
The concentration of AFP showed a discriminant ability to distinguish curable from incurable stage of the disease
(given the size and number of tumors), which needs to be confirmed by further research.
Among other performed tests, hemoglobin concentration, platelet count, alanine aminotransferase (ALT) and
gamma-glutamyl transferase (GGT) activities, and ammonia and ferritin concentrations were significantly higher
in patients with HCC and ALC than in patients with ALC.
Additionally, serum concentrations of CSTB and SCCA1 showed a good positive correlation with the functional
stage of cirrhosis.
The results of this study suggest that AFP and PIVKAII have the best discriminant ability to diagnose HCC in
patients with alcoholic liver cirrhosis, with a further improvement in diagnostic accuracy when used in
combination. Compared to previous studies, it can be assumed that the diagnostic performance of tumor markers
could depend on the etiology of HCC-based liver disease and further research is needed to confirm this.

• Keywords: hepatocelularni karcinom; alkohol; ciroza jetre; PIVKAII; cistatin B
• Keywords (english): hepatocellular carcinoma; alcohol; liver cirrhosis; PIVKAII; cystatin B
• Language: croatian
• URN:NBN: urn:nbn:hr:163:567242
• Promotion: 2022
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2022-11-10 15:59:46