Hepatocellular carcinoma (HCC) is the most serious common complication of hepatitis B (HBV). International data suggests a lifetime risk of about 15 percent, and this increases with age. While many cases occur in people with cirrhosis, some arise in non-fibrotic livers as a result of HBV integration into the host cell genome.
Diagnosis of HCC following clinical presentation has a poor prognosis: less than five percent of people in these cases survive past five years (El-Sarag & Davila, 2011).
Regular monitoring of HBV cases should include screening tests for HCC to try and detect cancers early enough for people to be cured, but diagnosis by current screening methods is often too insensitive to detect early tumours less than 3cm (Barcelona stage 0 or A). In these cases, patients’ outlook following treatment has been reported as 40-70 percent five-year survival (El-Sarag & Davila, 2011; Kao et.al, 2015).
Alpha-fetoprotein (AFP) is included in routine monitoring, but only detects about 36 percent of tumours at this stage³. Six-monthly ultrasounds are better, but sensitivity for early HCC is only about 45 percent - 63 percent in combination with AFP (Tzartzeva et. al, 2015) - and can only be offered to a minority of people who are defined as high risk, e.g. with a family history of HCC, known cirrhosis or a REACH-B risk score of HCC of more than five percent in 10 years.
There is, therefore, a pressing need to improve blood screening sensitivity for all chronic HBV cases.
PIVKA-ll
PIVKA-ll is a precursor of prothrombin, which is detectable in blood when vitamin K-dependent carboxylase is inhibited by an absence of the vitamin or presence of an antagonist. It is raised in a high proportion of HCC cases. At 61.5 percent, it is more sensitive than AFP in detection of early stage HCC (Huang & Yu, 2022). It can also be raised in biliary obstruction or cholestasis, and by vitamin K antagonists such as warfarin. Alpha-fetoprotein is still important, as a significant proportion of cases have one or the other biomarker raised, but not both (Roche studies). The Asian Pacific Association for the Study of the Liver (APASL) recommends PIVKA-ll for monitoring, and it is also included in national guidelines in Japan and China.
GAAD and GALAD
GAAD is a Roche commercial bioassay of AFP + PIVKA-ll adjusted for gender and age to give a GAAD score in addition to individual serum levels. It further increases specificity of the assay for HCC Chan et. al, 2022). GALAD is the same, except for the inclusion of a specific fraction of AFP (AFP-L3). However comparative studies have not suggested this has any advantage over GAAD (Chan et. al, 2022).
GAAD has shown a sensitivity of 73.1 percent in detection of early HCC and adds to that of ultrasound where this is performed (Huang & Yu, 2022).
Conclusion
The addition of PIVKA-ll and the GAAD score improves the sensitivity of screening for detection of early HCC, even when ultrasound is also used. Extensive experience overseas in many centres suggests this should be part of the standard of care of patients with chronic HBV.
Current situation
In co-operation with Roche NZ and the Hepatitis Foundation of New Zealand, Labtests in Auckland, in partnership with us and Roche NZ, will be trialing several hundred assays on chronic HBV carriers of different ethnic backgrounds to assess the GAAD process’ ease and economy. Following this trial, we hope to work towards acceptance of GAAD as a normal standard-of-care test in HBV monitoring.
Written by Dr Chris Moyes
Hepatitis Foundation of New Zealand clinician
November 2022
References
El-Serag, H.B. & Davila, J.A. (2011). Surveillance for hepatocellular carcinoma: in whom and how? Therap Adv Gastroenterol, 4(1), 5-10.
Kao, W.Y., Chao, Y., Chang, C.C., Li, C.P., Su, C.W., Huo, T.I., Huang, Y.H., Change, Y.J., Lin, H.C. & Wuet, J.C. (2015). Prognosis of early-stage hepatocellular carcinoma: The clinical implications of substages of Barcelona clinic liver cancer system based on a cohort of 1265 patients. Medicine, 94(43), 1929.
Tzartzeva, K., Obi, J., Rich, N.E., Parikh, N.D., Marrero, J.A., Yopp, A., Waljee, A.K. & Singal, A.G. (2018). Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: A meta-analysis. Gastroenterology, 154(6), 1706-1718.
Huang, C.F.S & Yu, M.L. (2022). The clinical utility of Elecsys GAAD score in the diagnosis of hepatocellular carcinoma. APASL single-topic conference on Hepatocellular Carcinoma.
Chan, H.L.Y., Vogel, A., Betg, T., De Toni, E.N., Kudo, M., Trojan, J., Malinowsky, K., Findeisen, P., Klein, H.G., Hegel, J.K., Schöning, W., Kröniger, K., Madin, K., Sharma, A. & Piratvisuth, T. (2022). A comparative analysis of Elecsys GALAD and Elecsys GAAD score to detect early-stage hepatocellular carcinoma in an international cochort. EASL International Liver Congress.
