Des-γ carboxyprothrombin may not be a good biomarker for hepatocellular carcinoma in those chronically infected with hepatitis B virus with basal core promoter double mutations (T^{1762},A^{1764}),a prospective study
Free accessResearch articleFirst published online August, 2017
Des-γ carboxyprothrombin may not be a good biomarker for hepatocellular carcinoma in those chronically infected with hepatitis B virus with basal core promoter double mutations (T^{1762},A^{1764}),a prospective study
The accuracy of des-γ -carboxyprothrombin (DCP) in the detection of hepatocellular carcinoma (HCC) in those infected hepatitis B virus (HBV) from cross-sectional or case-control studies is contradictory.
OBJECTIVE:
To resolve this contradiction using a prospective study.
METHODS:
Three hundred male individuals persistently infected with HBV were recruited from the Chinese cohort and followed up once per year from 2012 to 2015. Each subject was screened for HCC by measurements of serum alpha-fetoprotein (AFP), lectin-bound α -fetoprotein (AFP-L3), DCP concentrations and ultrasonographic examinations.
RESULTS:
Nineteen HCC cases were identified. The area under receiver operating characteristic (AUROC) at first, second and third visit for AFP, AFP-L3 and DCP ranges from 0.710-0.897, 0.566-0.637 and 0.520-0.595, respectively. The rate of elevated DCP is not significantly different between the HCC cases and controls (52.6% vs. 47.4%)(P > 0.05). The incidence of HCC in subjects with elevated DCP is not significantly higher than that of those with normal DCP (9.5% vs. 4.6%) (P > 0.05). The AUROC of combinations of these biomarkers was higher than that of AFP alone at the first visit. However, it was reduced at the second visit. At the third visit, the AUROCs of AFP + DCP and AFP + AFP-L3 + DCP, but not that of AFP + AFP-L3, were higher than that of AFP alone.
CONCLUSIONS:
AFP but DCP or AFP-L3 remains a valuable biomarker for HCC in those chronically infected with HBV. The combination with AFP-L3 and DCP may not increase the accuracy of AFP in differentiating HCC cases from controls, among those infected with HBV.
McGlynnKA, LondonWT. Epidemiology and natural history of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol. 2005; 19: 3-23. [PubMed: 15757802]
2.
El-SeragHB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology2012; 142: 1264-1273. [PubMed: 22537432]
3.
ZhangS, LiL, LuF. [Mortality of primary liver cancer in China from 1990 through 1992]. Zhonghua Zhong Liu Za Zhi. 1999; 21: 245-9. [PubMed: 11776805]
4.
YeFS. The progress in prevention and control of liver cancer in Guangxi. Guangxi Medical Journal. 1984; 6: 226-238.
5.
CabibboG, EneaM, AttanasioM, BruixJ, CraxìA, CammàC. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma. Hepatology. 2010; 51: 1274-1283. [PubMed: 20112254]
6.
HuangTS, ShyuYC, TurnerR, ChenHY, ChenPJ. Diagnostic performance of alpha-fetoprotein, lens culinaris agglutinin-reactive alpha-fetoprotein, des-gamma carboxy- prothrombin, and glypican-3 for the detection of hepatocellular carcinoma: a systematic review and meta-analysis protocol. Systematic reviews 2013; 2: 37. [PubMed: 23738605]
7.
MlynarskyL, MenachemY, ShiboletO. Treatment of hepatocellular carcinoma: Steps forward but still a long way to go. World Journal of Hepatology2015; 7: 566-74. [PubMed: 25848480]
8.
DurazoFA, BlattLM, CoreyWG, LinJH, HanS, SaabS, BusuttilRW, TongMJ. Des-gamma-carboxyprothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma. Journal of Gastroenterology and Hepatology2008; 23: 1541-8. [PubMed: 18422961]
9.
ToyodaH, KumadaT, TadaT, SoneY, KaneokaY, MaedaA. Tumor Markers for Hepatocellular Carcinoma: Simple and Significant Predictors of Outcome in Patients with HCC. Liver Cancer. 2015; 4: 126-36. [PubMed: 26020034]
10.
StefaniukP, CianciaraJ, Wiercinska-DrapaloA. Present and future possibilities for early diagnosis of hepatocellular carcinoma. World J Gastroenterol. 2010; 16: 418-24. [PubMed: 20101765]
11.
SongP, GaoJ, InagakiY, KokudoN, HasegawaK, SugawaraY, TangW. Biomarkers: evaluation of screening for and early diagnosis of hepatocellular carcinoma in Japan and china. Liver Cancer. 2013; 2: 31-9. [PubMed: 24159594]
12.
ShimizuA, ShirakiK, ItoT, SugimotoK, SakaiT, OhmoriS, MurataK, TakaseK, TamedaY, NakanoT.. Sequential fluctuation pattern of serum des-gamma-carboxy prothrombin levels detected by high-sensitive electrochemiluminescence system as an early predictive marker for hepatocellular carcinoma in patients with cirrhosis. International Journal of Molecular Medicine2002; 9: 245-50. [PubMed: 11836630]
13.
SterlingRK, JeffersL, GordonF, VenookAP, ReddyKR, SatomuraS, KankeF, SchwartzME, ShermanM. Utility of Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxy prothrombin, alone or in combination, as biomarkers for hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2009; 7: 104-13. [PubMed: 18849011]
14.
CarrBI, KankeF, WiseM, SatomuraS. Clinical evaluation of lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States. Dig Dis Sci. 2007; 52: 776-82. [PubMed: 17253135]
15.
HuoTI, HsiaCY, ChuCJ, HuangYH, LuiWY, WuJC, LeePC, ChiCW, LeeSD. The predictive ability of serum alpha-fetoprotein for hepatocellular carcinoma is linked with the characteristics of the target population at surveillance. J Surg Oncol. 2007; 95: 645-651. [PubMed: 17530668]
16.
VolkML, HernandezJC, SuGL, LokAS, MarreroJA. Risk factors for hepatocellular carcinoma may impair the performance of biomarkers: a comparison of AFP, DCP, and AFP-L3. Cancer Biomark. 2007; 3: 79-87. [PubMed: 17522429]
17.
ChanCY, LeeSD, WuJC, LinHC, HuangYS, LoGH, LeeFY, TsaiYT, LoKJ. The diagnostic value of the assay of des-gamma-carboxy prothrombin in the detection of small hepatocellular carcinoma. Journal of Hepatology1991; 13: 21-4. [PubMed: 1717542]
18.
YoonYJ, HanKH, KimDY. Role of serum prothrombin induced by vitamin K absence or antagonist-II in the early detection of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. Scandinavian journal of gastroenterology2009; 44: 861-6. [PubMed: 19391065]
19.
SongP, FengX, InagakiY, SongT, ZhangK, WangZ, ZhengS, MaK, LiQ, KongD, WuQ, ZhangT, ZhaoX, HasegawaK, SugawaraY, KokudoN, TangW. Japan-China Joint Team for Medical Research and Cooperation on HCC. Clinical utility of simultaneous measurement of alpha-fetoprotein and des-γ -carboxy prothrombin for diagnosis of patients with hepatocellular carcinoma in China: A multi-center case-controlled study of 1,153 subjects. Biosci Trends. 2014; 8: 266-73. [PubMed: 25382443]
20.
EtteAI, NdububaDA, AdekanleO, EkrikpoU. Utility of serum des-gamma-carboxyprothrombin in the diagnosis of hepatocellular carcinoma among Nigerians, a case-control study. BMC Gastroenterol. 2015; 15: 113. [PubMed: 26341083]
21.
FangZL, SabinCA, DongBQ, GeLY, WeiSC, ChenQY, FangKX, YangJY, WangXY, HarrisonTJ. HBV A1762T, G1764A mutations are a valuable biomarker for identifying a subset of male HBsAg carriers at extremely high risk of hepatocellular carcinoma: a prospective study. Am J Gastroenterol. 2008; 103: 2254-62. [PubMed: 18844615]
22.
LiebmanHA, FurieBC, TongMJ, BlanchardRA, LoKJ, LeeSD, ColemanMS, FurieB. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med. 1984; 310: 1427-1431. [PubMed: 6201741]
23.
YuenMF, LaiCL. Serological markers of liver cancer. Best Pract Res Clin Gastroenterol. 2005; 19: 91-9. [PubMed: 15757806]
24.
TateishiR, YoshidaH, MatsuyamaY, MineN, KondoY, OmataM. Diagnostic accuracy of tumor markers for hepatocellular carcinoma: a systematic review. Hepatol Int. 2008; 2: 17-30. [PubMed: 19669276]
25.
Di BisceglieAM, SterlingRK, ChungRT, EverhartJE, DienstagJL, BonkovskyHL, WrightEC, EversonGT, LindsayKL, LokAS, LeeWM, MorganTR, GhanyMG, GretchDR. HALT-C Trial Group. Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C Trial. J Hepatol. 2005; 43: 434-441. [PubMed: 16136646]
26.
GraziGL, MazziottiA, LegnaniC, JovineE, MinieroR, GallucciA, PalaretiG, GozzettiG. The role of tumor markers in the diagnosis of hepatocellular carcinoma, with special reference to the des-gamma-carboxy prothrombin. Liver Transpl Surg. 1995; 1: 249-255. [PubMed: 9346575]
27.
ChaiteerakijR, AddissieBD, RobertsLR. Update on biomarkers of hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2015; 13: 237-45. [PubMed: 24275343]
28.
CavigliaGP, AbateML, PetriniE, GaiaS, RizzettoM, SmedileA. Highly sensitive alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxyprothrombin for hepatocellular carcinoma detection. Hepatol Res. 2016; Mar; 46(3): E130-5. [PubMed: 26082262]
29.
HuB, TianX, SunJ, MengX. Evaluation of individual and combined applications of serum biomarkers for diagnosis of hepatocellular carcinoma: a meta-analysis. Int J Mol Sci. 2013; 14: 23559-80. [PubMed: 24317431]
Abu El MakaremM. An overview of biomarkers for the diagnosis of hepatocellular carcinoma. Hepat Mon. 2012; 12: e6122. [PubMed: 23162601]
32.
ArrigoniA, AndriulliA, GindroT, PiantinoP, CapussottiL, RizzettoM. Pattern analysis of serum alpha-fetoprotein in the early diagnosis of hepatocellular carcinoma in liver cirrhosis. Int J Biol Markers. 1988; 3: 172-6. [PubMed: 2466093]
33.
GianniniEG, SammitoG, FarinatiF, CiccareseF, PecorelliA, RapacciniGL, Di MarcoM, CaturelliE, ZoliM, BorzioF, CabibboG, FelderM, GasbarriniA, SaccoR, FoschiFG, MissaleG, MoriscoF, SvegliatiBG, VirdoneR, TrevisaniF. Italian Liver Cancer (Itali.CA). Group. Determinants of alpha-fetoprotein levels in patients with hepatocellular carcinoma: Implications for its clinical use. Cancer. 2014; 120: 2150-7. [PubMed: 24723129]
