Prognostic Significance of Serum Albumin Level and Albumin-Based Mono- and Combination Biomarkers in Patients with Hepatocellular Carcinoma

Simple Summary This review provides a comprehensive summary of the literature published thus far to highlight the prognostic significance of serum albumin (ALB) level and various ALB-based mono- and combination biomarkers in predicting the prognosis of patients with hepatocellular carcinoma (HCC) treated with different therapies. Abstract Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Although many surgical and nonsurgical therapeutic options have been established for treating HCC, the overall prognosis for HCC patients receiving different treatment modalities remains inadequate, which causes HCC to remain among the most life-threatening human cancers worldwide. Therefore, it is vitally important and urgently needed to develop valuable and independent prognostic biomarkers for the early prediction of poor prognosis in HCC patients, allowing more time for more timely and appropriate treatment to improve the survival of patients. As the most abundant protein in plasma, human serum albumin (ALB) is predominantly expressed by the liver and exhibits a wide variety of essential biological functions. It has been well recognized that serum ALB level is a significant independent biomarker for a broad spectrum of human diseases including cancer. Moreover, ALB has been commonly used as a potent biomaterial and therapeutic agent in clinical settings for the treatment of various human diseases. This review provides a comprehensive summary of the evidence from the up-to-date published literature to underscore the prognostic significance of serum ALB level and various ALB-based mono- and combination biomarkers in the prediction of the prognosis of HCC patients after treatment with different surgical, locoregional, and systemic therapies.


Introduction
Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer and is responsible for up to 90% of primary liver malignancies [1,2]. Although remarkable progress has been made in the prevention and treatment of HCC, HCC remains the sixth most frequent human cancer and the third leading cause of cancer-related death worldwide, leading to nearly 900,000 new cases and 800,000 new deaths each year [3,4]. Although curative therapeutic options such as liver transplantation and hepatic resection surgery are available for the treatment of HCC patients, the survival benefits of the therapies

Prognostic Significance of Serum ALB Level in HCC Patients
Multiple lines of studies have validated the prognostic value of a pre-treatment serum ALB level in HCC patients (Table 1). Studies conducted by Chen et al. [20], Chen et al. [21], and Wang et al. [22] showed that a low pre-treatment serum ALB level independently predicted worse overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) in HCC patients undergoing curative surgical resection. Another study conducted by Zeng et al. [23] revealed that a low pre-treatment serum ALB level was independently correlated with worse OS in HCC patients treated with external beam radiation therapy (EBRT). In addition, studies conducted by Castellano et al. [24] and Kuriyama et al. [25] identified that a low pre-treatment serum ALB level is a factor that is independently associated with worse OS in HCC patients treated with percutaneous ethanol injection (PEI). Studies conducted by Xu et al. [26] and Toshikuni et al. [27] demonstrated that a low pre-treatment serum ALB level independently predicted worse OS in HCC patients treated with radiofrequency ablation (RFA) or percutaneous microwave ablation (PMWA). Studies conducted by Ikeda et al. [28] and O'Suilleabhain et al. [29] confirmed that a low pre-treatment serum ALB level is an independent factor which predicts worse OS in HCC patients treated with transarterial embolization (TAE) or transarterial chemoembolization (TACE). Furthermore, a study conducted by Lerose et al. [30] ascertained that a low pretreatment serum ALB level was independently associated with worse OS in HCC patients treated with curative surgical resection, PEI, TACE, or antihormonal therapy. Another study conducted by Baek et al. [31] verified that a low pre-treatment serum ALB level was an independent predictor for worse OS and failure-free survival (FFS) in HCC patients receiving molecular targeted therapy with sorafenib. Table 1. Prognostic significance of serum ALB level in HCC patients.

Biomarkers Patients and Treatment Modalities Prognostic Significance Year References
Pre-treatment ALB level 145 patients with small HCC (≤3 cm) treated with curative surgical resection.
Collectively, these studies support the use of a low pre-treatment serum ALB level as a valuable independent prognostic biomarker for poor outcomes in HCC patients after treatment with various therapies.

Prognostic Significance of Serum ALB/Alkaline Phosphatase (ALP) Ratio in HCC Patients
Other than serum ALB level alone, many serum ALB-based biomarkers, which are developed based on ALB and various other factors, have been verified as having prognostic value in HCC patients in multiple lines of studies. One such biomarker is the ratio of the pretreatment serum ALB level to the serum ALP level (Table 2). ALP is a kind of phosphatase that catalyzes the hydrolysis of various organic phosphate esters at alkaline pH values [32]. Studies conducted by Chan et al. [33], Li et al. [34], and Zhang et al. [35] showed that a low pre-treatment serum ALB/ALP ratio independently predicted worse OS, DFS, and RFS in HCC patients receiving curative surgical resection. Another study conducted by Li et al. [36] determined an independent association between a low pre-treatment serum ALB/ALP ratio and worse OS in HCC patients undergoing liver transplantation. Furthermore, a study conducted by Zhang et al. [37] confirmed that a low pre-treatment serum ALB/ALP ratio was independently correlated with worse OS and RFS in HCC patients treated with RFA. A study conducted by Chen et al. [38] identified a low pre-treatment serum ALB/ALP ratio as an independent factor which predicted worse OS in HCC patients treated with TACE. Another study conducted by Cai et al. [39] demonstrated that a low pre-treatment serum ALB/ALP ratio was a factor that was independently associated with worse OS in HCC patients treated without any standard anti-cancer therapies. Taken together, these studies suggest that a low pre-treatment serum ALB/ALP ratio has a significant independent prognostic value for poor outcomes in HCC patients after treatment with various therapies.

Prognostic Significance of Serum C-Reactive Protein (CRP)/ALB Ratio in HCC Patients
The prognostic value of another serum ALB-based biomarker, which is the ratio of the pre-treatment serum CRP level to serum ALB level, in HCC patients has been validated in multiple lines of studies (Table 3). CRP is a plasma protein that is produced by the liver and functions as a key component in acute-phase inflammatory response [40]. Studies conducted by Shimizu et al. [41] and Ren et al. [42] showed that a high pre-treatment serum CRP/ALB ratio independently predicted worse OS and tumor-free survival (TFS) in HCC patients undergoing curative surgical resection. Studies conducted by Kinoshita et al. [43], Chen et al. [44], and Li et al. [45] revealed that a high pre-treatment serum CRP/ALB ratio was independently correlated with worse OS and RFS in HCC patients treated with curative surgical resection, RFA, PEI, or TACE. A study conducted by Tada et al. [46] ascertained an independent association between a high pre-treatment serum CRP/ALB ratio and worse OS in HCC patients receiving molecular targeted therapy with lenvatinib. Consistent with the aforementioned findings, a study conducted by Wu et al. [47] identified a low pre-treatment serum ALB/CRP ratio as an independent predictor for worse OS and DFS in HCC patients treated with curative surgical resection, RFA, TACE, or systemic chemotherapy. In addition to the pre-treatment serum CRP/ALB or ALB/CRP ratio, a high post-treatment serum, high-sensitivity CRP (hsCRP)/ALB ratio was shown in a study conducted by Oh et al. [48] to independently predict worse OS and RFS in HCC patients receiving curative surgical resection. Table 3. Prognostic significance of serum CRP/ALB ratio in HCC patients.

Biomarkers Patients Prognostic Significance Year References
Pre-treatment CRP/ALB ratio a 239 patients with HCC treated with curative surgical resection.
High hsCRP/ALB ratios predicted worse OS and RFS (>0.625 and >0.500 vs. ≤0.625 and ≤0.500, respectively). 2018 Oh et al. [48] a CRP/ALB ratio was calculated by dividing serum CRP level (mg/L) by serum ALB level (g/L). b ALB/CRP ratio was calculated by dividing serum ALB level (g/L) by serum CRP level (mg/L). c Post-treatment hsCRP/ALB ratio was calculated by dividing hsCRP level (mg/L) by ALB level (g/L) using data on day 0 or day 1 after treatment.
Overall, these studies indicate that a high pre-treatment or post-treatment serum CRP/ALB ratio is a valuable independent biomarker for prediction of poor outcomes in HCC patients after treatment with various therapies.

Prognostic Significance of Serum ALB/Globulin (GLB) Ratio in HCC Patients
The ratio of the pre-treatment serum ALB level to serum GLB level is another serum ALB-based biomarker with prognostic value in HCC patients that has been validated in multiple lines of studies (Table 4). GLB is another abundant blood protein that consists of hundreds of serum globular proteins including enzymes, complement, carrier proteins, and immunoglobulins [49]. A study conducted by Deng et al. [50] showed that a low pre-treatment serum ALB/GLB ratio independently predicted worse OS and greater recurrence in HCC patients undergoing curative surgical resection. Studies conducted by Zhang et al. [51] and Utsumi et al. [52] revealed that a low pre-treatment serum ALB/GLB ratio was independently correlated with worse OS and RFS in HCC patients undergoing curative surgical resection. Another study conducted by Zhang et al. [53] verified an independent association between a low pre-treatment serum ALB/GLB ratio and worse OS in HCC patients receiving curative surgical resection or liver transplantation. Consistent with the aforementioned findings, a study conducted by Shimizu et al. [54] demonstrated that a high pre-treatment serum GLB/ALB ratio was an independent factor which predicted worse OS in HCC patients receiving curative surgical resection.
Altogether, these studies propose that a low pre-treatment serum ALB/GLB ratio holds a valuable independent prognostic value for poor outcomes in HCC patients after treatment with various therapies. Table 4. Prognostic significance of serum ALB/GLB ratio in HCC patients.

Biomarkers Patients Prognostic Significance Year References
Pre-treatment ALB/GLB ratio a 172 patients with HCC treated with curative surgical resection.

Prognostic Significance of Serum ALB-BILirubin (BIL) Grade in HCC Patients
The prognostic value of the pre-treatment serum ALB-BIL grade, which is another serum ALB-based biomarker, in HCC patients has been validated in multiple lines of studies (Table 5). BIL is a major end-product of heme catabolism in the systemic circulation and is an essential component of bile [55]. Studies conducted by Ma [64], and Tsai et al. [65] showed that a high pre-treatment serum ALB-BIL grade independently predicted worse OS and RFS in HCC patients undergoing curative surgical resection. Studies conducted by Lee et al. [66] and Fagenson et al. [67] revealed that a high pre-treatment serum ALB-BIL grade was independently correlated with greater early recurrence (≤1 year) and 30-day mortality in HCC patients undergoing curative surgical resection. Additionally, studies conducted by Bernardi et al. [68] and Liao et al. [69] identified a high pre-treatment serum ALB-BIL grade as an independent predictor for worse OS and RFS in HCC patients undergoing liver transplantation. Studies conducted by Lo et al. [70] and Murray et al. [71] ascertained an independent association between a high pre-treatment serum ALB-BIL grade and worse OS in HCC patients treated with stereotactic body radiation therapy (SBRT) and stereotactic ablative radiation therapy (SABR). Studies conducted by Kao et al. [72], An et al. [73], Chen et al. [74], and Long et al. [75] showed that a high pre-treatment serum ALB-BIL grade was a factor that was independently associated with worse OS and RFS in HCC patients treated with RFA or PMWA. Studies conducted by Hickey et al. [76], Gui et al. [77], Kim et al. [78], Antkowiak et al. [79], Khalid et al. [80], Lee et al. [81], Zhong et al. [82], Ho et al. [83], and Chen et al. [84] confirmed that a high pre-treatment serum ALB-BIL grade was an independent factor which predicted worse OS in HCC patients receiving TACE or transarterial radioembolization (TARE). Furthermore, studies conducted by Kuo et al. [85], Nguyen et al. [86], and Tada et al. [87] showed that a high pre-treatment serum ALB-BIL grade independently predicted worse OS in HCC patients receiving molecular targeted therapy with sorafenib. Studies conducted by Ho et al. [88], Ho et al. [89], Ho et al. [90], Chang et al. [91], Ho et al. [92], and Ko et al. [93] demonstrated that a high pre-treatment serum ALB-BIL grade was independently correlated with worse OS in HCC patients treated with curative surgical resection, liver transplantation, radiotherapy, RFA, PEI, TACE, molecular targeted therapy, or supportive care. Another study conducted by Kim et al. [94] revealed that a high pre-treatment serum ALB-BIL grade was a factor that was independently associated with worse OS and progression-free survival (PFS) in HCC patients treated with proton beam therapy (PBT). Table 5. Prognostic significance of serum ALB-BIL grade in HCC patients.

Biomarkers Patients Prognostic Significance Year References
Pre-treatment ALB-BIL grade a 318 patients with HCC treated with curative surgical resection (160 as training cohort and 158 as validation cohort).

Biomarkers Patients Prognostic Significance Year References
Pre-treatment ALB-BIL grade a 260 patients with HCC treated with molecular targeted therapy with sorafenib.
High ALB-BIL grade predicted worse OS (grade 2/3 vs. 1). 2019 Ho et al. [88] 1846 patients with HCC treated with curative surgical resection, liver transplantation, radiotherapy, local ablation therapy, TACE, molecular targeted therapy, or supportive care.   Moreover, a study conducted by Huang et al. [95] showed that a high pre-treatment serum ALB-BIL grade independently predicted worse OS in HCC patients treated with TACE combined with cryoablation (CRA). Studies conducted by Wang et al. [96] and Zhong et al. [97] found that a high pre-treatment serum ALB-BIL grade was independently associated with worse OS in HCC patients receiving TACE combined with molecular targeted therapy with sorafenib. A study conducted by Dong et al. [98] demonstrated that a high pre-treatment serum ALB-BIL grade was an independent predictor for worse OS and RFS in HCC patients receiving hypofractionated radiation therapy (HFRT) or SBRT combined with immunotherapy with camrelizumab or sintilimab.
In addition, a study conducted by Ho et al. [99] showed that a high pre-treatment serum easy ALB-BIL grade independently predicted worse OS in HCC patients treated with curative surgical resection, liver transplantation, local ablation therapy, TACE, systemic chemotherapy, molecular targeted therapy, or supportive care. Another study conducted by Tada et al. [100] revealed that a high pre-treatment serum modified ALB-BIL grade was a factor that was independently correlated with worse OS in HCC patients receiving molecular targeted therapy with lenvatinib.
Other than the pre-treatment serum ALB-BIL grade, a high on-treatment serum ALB-BIL grade was shown in a study conducted by Wang et al. [101] to independently predict worse OS in HCC patients receiving molecular targeted therapy with sorafenib followed by regorafenib. Furthermore, studies conducted by Amisaki et al. [102], Cho et al. [103], and Lin et al. [104] confirmed that a high post-treatment serum ALB-BIL grade was an independent factor which predicted worse OS and RFS in HCC patients undergoing curative surgical resection. Another study conducted by Lee et al. [105] verified an independent association between a high post-treatment serum ALB-BIL grade and worse post-progression survival (PPS) in HCC patients who received molecular targeted therapy with sorafenib and developed progressive disease (PD). Moreover, studies conducted by Li et al. [106] and Ye et al. [107] revealed that an increased or high post-treatment serum ALB-BIL grade change was independently correlated with worse OS and RFS in HCC patients undergoing curative surgical resection. A study conducted by Lin et al. [108] identified increased post-treatment serum ALB-BIL grade change as an independent predictor for worse OS and greater recurrence in HCC patients treated with TACE. Another study conducted by Unome et al. [109] showed that a high post-treatment serum ALB-BIL grade change was a factor that was independently associated with worse OS in HCC patients receiving molecular targeted therapy with atezolizumab and bevacizumab.
Collectively, these studies suggest that a high pre-treatment, on-treatment, or posttreatment serum ALB-BIL grade is a significant independent prognostic biomarker for poor outcomes in HCC patients after treatment with various therapies.

Prognostic Significance of Serum Platelet (PLT)-ALB-BIL Grade in HCC Patients
On the basis of serum ALB-BIL grade, the pre-treatment serum PLT-ALB-BIL grade has been developed as another serum ALB-based biomarker and has been validated with prognostic value in HCC patients in multiple lines of studies (Table 6). PLT plays a critical role in not only hemostasis, thrombosis, and wound healing, but also inflammatory response and immune regulation [110]. Studies conducted by Luo et al. [111], Lu et al. [112], Wu et al. [113], and Pang et al. [114] showed that a high pre-treatment serum PLT-ALB-BIL grade independently predicted worse OS and RFS in HCC patients undergoing curative surgical resection. A study conducted by Ho et al. [115] revealed that a high pre-treatment serum PLT-ALB-BIL grade was independently correlated with worse OS in HCC patients treated with hypofractionated radiation therapy (HFRT). A study conducted by Carling et al. [116] ascertained that a high pre-treatment serum PLT-ALB-BIL grade was independently associated with worse OS in HCC patients treated with drug-eluting embolic TACE (DEE-TACE). Another study conducted by Lee et al. [117] demonstrated an independent association between a high pre-treatment serum PLT-ALB-BIL grade and worse OS in HCC patients receiving curative surgical resection, RFA, TACE, or supportive care. Furthermore, studies conducted by Ni et al. [118] and Hu et al. [119] identified a high pre-treatment serum PLT-ALB-BIL grade as an independent predictor for worse OS in HCC patients receiving TACE combined with PMWA or molecular targeted therapy with sorafenib. In addition to the pre-treatment serum PLT-ALB-BIL grade, a non-increased post-treatment serum PLT-ALB-BIL grade change was shown in a study conducted by Wang et al. [120] to be an independent factor which predicted worse OS and RFS in HCC patients treated with curative surgical resection. Table 6. Prognostic significance of serum PLT-ALB-BIL grade in HCC patients.

Biomarkers Patients Prognostic Significance Year References
Pre-treatment PLT-ALB-BIL grade a 785 HBV-infected patients with HCC treated with curative surgical resection.
High PLT-ALB-BIL grade predicted worse OS (grade 3 vs. 1). 2021 Hu et al. [119]   Taken together, these studies suggest that a high pre-treatment or post-treatment serum PLT-ALB-BIL grade is a significant independent biomarker for prediction of poor outcomes in HCC patients after treatment with various therapies.

Prognostic Significance of Other Serum ALB-Based Mono-Biomarkers in HCC Patients
The prognostic value of various other pre-treatment serum ALB-based mono-biomarkers in HCC patients has been validated in multiple lines of studies (Table 7). Studies conducted by Xu et al. [121] and Mai et al. [122] showed that a high pre-treatment serum fibrinogen (FIB)/ALB ratio was an independent predictor for worse OS and DFS in HCC patients undergoing curative surgical resection. Studies conducted by Shen et al. [123] and Liu et al. [124] revealed that a low pre-treatment serum ALB/gamma-glutamyltransferase (GGT) ratio was independently correlated with worse OS and RFS in HCC patients receiving curative surgical resection or RFA. Consistent with the findings of the aforementioned studies, studies conducted by Liu et al. [125] and Zhang et al. [126] verified an independent association between a high pre-treatment serum GGT/ALB ratio and worse OS and DFS in HCC patients treated with curative surgical resection. Furthermore, studies conducted by Gan et al. [127], Haruki et al. [128], Li et al. [129], Meira Junior et al. [130], Shen et al. [131], and Iida et al. [132] demonstrated that a high pre-treatment serum lactic dehydrogenase (LDH)/ALB ratio, serum prothrombin time-international normalized ratio (PT-INR)/ALB ratio, serum PLT/ALB ratio, serum PLT-ALB grade, serum neutrophil to lymphocyte ratio (NLR)/ALB ratio, and a low pre-treatment serum CRP-ALB-lymphocyte (LYM) index independently predicted worse OS, DFS, and RFS in HCC patients treated with curative surgical resection. Another study conducted by Peng et al. [133] revealed that a high pre-treatment serum aspartate aminotransferase (AST)/ALB ratio was a factor that was independently correlated with worse OS and RFS in HCC patients undergoing curative surgical resection.  High LDH/ALB ratio predicted worse OS and RFS (≥5.5 vs. <5.5). 2018 Gan et al. [127] Pre-treatment PT-INR/ALB ratio e 199 patients with HCC treated with curative surgical resection.
High AST/ALB ratio predicted worse OS and RFS (>1.6 vs. <0.7). 2022 Peng et al. [133] a FIB/ALB ratio was calculated by dividing serum FIB level (mg/dL) by serum ALB level (mg/dL). b ALB/GGT ratio was calculated by dividing serum ALB level (g/L) by serum GGT level (U/L). c GGT/ALB ratio was calculated by dividing serum GGT level (U/L) by serum ALB level (g/L). d LDH/ALB ratio was calculated by dividing serum PLT count (U/L) by serum ALB level (g/L). e PT-INR/ALB ratio was calculated by dividing PT-INR by serum ALB level (g/dL). f PLT/ALB ratio was calculated by dividing serum PLT count (10 9 /L) by serum ALB level (g/L). g PLT-ALB score was calculated by the formula −0.777 × serum ALB level (g/dL) −0.575 × log 10 serum PLT count (10 10 /L) and stratified as grade 1 (≤−3.77), grade 2 (>−3.77 to ≤−3.04), or grade 3 (>−3.04). h NLR was calculated by dividing serum NEU count (10 9 /L) by serum LYM count (10 9 /L), and NLR/ALB ratio was calculated by dividing NLR by serum ALB level (g/L). i CRP-ALB-LYM index was calculated by the formula [serum ALB level (g/dL) × serum LYM count ( Overall, these studies support that serum ALB-based mono-biomarkers have a valuable and independent prognostic value for poor outcomes in HCC patients after treatment with various therapies.

Prognostic Significance of Serum ALB-Based Combination Biomarkers in HCC Patients
Multiple lines of studies have validated the prognostic value of combinations of various pre-treatment serum ALB-based biomarkers and other biomarkers in HCC patients (Table 8). A study conducted by Li et al. [134] showed that a high score of pre-treatment serum ALB-BIL grade combined with a pre-treatment serum PLT/LYM ratio independently predicted worse OS and RFS in HCC patients undergoing curative surgical resection. Studies conducted by Liao et al. [135] and Zhang et al. [136] revealed that a high score or grade of a pre-treatment serum ALB-BIL combined with pre-treatment fibrosis-4 (FIB-4) score was independently correlated with worse OS and RFS in HCC patients undergoing curative surgical resection. Another study conducted by Luo et al. [137] verified that a high score of pre-treatment serum ALB-BIL grade combined with pre-treatment serum AST/PLT ratio was independently associated with worse OS and RFS in HCC patients receiving curative surgical resection. Additionally, a study conducted by Zhang et al. [138] revealed that a high pre-treatment serum ALB-BIL grade combined with pre-treatment serum GGT level was an independent factor which predicted worse OS and DFS in HCC patients receiving curative surgical resection. Studies conducted by Pan et al. [139] and Liang et al. [140] showed that a high score or grade of the pre-treatment serum ALB-BIL combined with pre-treatment prognostic nutritional index (PNI) independently predicted worse OS and DFS in HCC patients treated with curative surgical resection or RFA. Studies conducted by Yang et al. [141] and Ha et al. [142] ascertained that a high grade or score of the pretreatment serum ALB-BIL combined withpre-treatment systemic immune-inflammation index (SII) was independently correlated with worse OS, RFS, and cancer-specific survival (CSS) in HCC patients treated with RFA, PMWA, or TACE. A study conducted by Qin et al. [143] identified a high pre-treatment serum ALB-BIL grade combined with pretreatment clinically significant portal hypertension (CSPH) as an independent predictor for worse OS and RFS in HCC patients undergoing curative surgical resection. Table 8. Prognostic significance of serum ALB-based combination biomarkers in HCC patients.

Biomarkers Patients Prognostic Significance Year References
Pre-treatment ALB-BIL grade combined with pre-treatment PLT/LYM ratio a 475 patients with HCC treated with curative surgical resection.
High score of ALB-BIL grade combined with PLT/LYM ratio (score 1 or 2) independently predicted worse OS and RFS than low score (score 0). 2018 Li et al. [134] Pre-treatment ALB-BIL grade combined with pre-treatment FIB-4 score 350 patients with HCC treated with curative surgical resection.
High score of ALB-BIL grade combined with FIB-4 score (score 2 or 3) independently predicted worse OS and RFS than low score (score 1) c . 2019 Zhang et al. [136] Pre-treatment ALB-BIL grade combined with pre-treatment AST/PLT ratio d 239 patients with HCC treated with curative surgical resection.
High score of ALB-BIL grade combined with AST/PLT ratio (score 2 or 3) independently predicted worse OS and RFS than low score (score 1). 2019 Luo et al. [137] Pre-treatment ALB-BIL grade combined with pre-treatment GGT level e 520 patients with HCC treated with curative surgical resection.
High grade of ALB-BIL grade combined with GGT level (grade 2 or 3) independently predicted worse OS and DFS than low grade (grade 1). 2019 Zhang et al. [138] Pre-treatment ALB-BIL grade combined with pre-treatment PNI 110 patients with HCC treated with RFA.
High score of ALB-BIL grade combined with PNI (score 1, 2, or 3) independently predicted worse OS than low grade (score 0) f .
High grade of ALB-BIL grade combined with PNI (grade 4) independently predicted worse OS and DFS than low grade (grade 1) g .

2021
Liang et al. [140] Pre-treatment ALB-BIL grade combined with pre-treatment SII 405 patients with HCC treated with RFA or PMWA.
High grade of ALB-BIL grade combined with SII (grade 2 or 3) independently predicted worse OS, RFS, and CSS than low grade (grade 1) h .
High score of ALB-BIL grade combined with SII (score 2) independently predicted worse OS than low score (score 0 or 1) i .

2023
Ha et al. [142] Pre-treatment ALB-BIL grade combined with pre-treatment CSPH j 1679 HBV-infected patients with HCC treated with curative surgical resection.
High grade of ALB-BIL grade combined with CSPH (grade 2 or 3) independently predicted worse OS and RFS than low grade (grade 1).

2021
Qin et al. [143] Pre-treatment modified ALB-BIL grade combined with pre-treatment AFP level k 480 patients with HCC treated with curative surgical resection.
High score of modified ALB-BIL grade combined with AFP level (score 1 or 2) independently predicted worse OS and RFS than low grade (score 0). 2022 Kaibori et al. [144] 426 patients with HCC treated with molecular targeted therapy with atezolizumab and bevacizumab (255 as training cohort and 171 as validation cohort).
High score of modified ALB-BIL grade combined with AFP level (score 1 or 2) independently predicted worse OS and PFS than low grade (score 0). 2022 Hatanaka et al. [145] Pre-treatment ALB-BIL grade combined with post-treatment AFP level change l 75 patients with HCC treated with molecular targeted therapy with atezolizumab and bevacizumab (38 as training cohort and 37 as validation cohort).
High score of ALB-BIL grade combined with AFP level change (score 2) independently predicted worse OS and PFS than low grade (score 0 or 1). 2022 Campani et al. [146]

Biomarkers Patients Prognostic Significance Year References
Pre-treatment CRP/ALB ratio combined with pre-treatment NLR m 172 patients with HCC treated with TACE followed by RFA.
High grade of CRP/ALB ratio combined with NLR (grade 3) independently predicted worse OS than low grade (grade 1 or 2). 2019 Shen et al. [147] Pre-treatment ALB/FIB ratio combined with pre-treatment GGT/PLT ratio n 616 patients with HCC treated with curative surgical resection.
High grade of ALB/FIB ratio combined with GGT/PLT ratio (grade 2 or 3) independently predicted worse OS and RFS than low grade (grade 1).

2020
Zhang et al. [148] Pre-treatment ALB level combined with pre-treatment HBV pre-S2 gene mutation o 75 HBV-infected patients with HCC treated with curative surgical resection.
Post-treatment AFP level change was calculated by subtracting pre-treatment AFP level from post-treatment 3rd-week AFP level and categorized as decreased (≥20%) or non-decreased (<20%). The combination of ALB-BIL grade and AFP level change was categorized as score 0 (ALB-BIL grade 1 and decreased AFP level change), score 1 (ALB-BIL grade 2 or non-decreased AFP level change), or score 2 (ALB-BIL grade 2 and non-decreased AFP level change). m CRP/ALB ratio was categorized as low (≤0.275) or high (>0.275) ratio. NLR was categorized as low (≤2.205) or high (>2.205) ratio. The combination of CRP/ALB ratio and NLR was categorized as grade 1 (low CRP/ALB ratio and low NLR ratio), grade 2 (high CRP/ALB ratio or high NLR ratio), or grade 3 (high CRP/ALB ratio and high NLR ratio). n ALB/FIB ratio was calculated by dividing serum ALB level (mg/dL) by serum FIB level (mg/dL) and stratified as low (<9.6) or high (≥9.6) ratio. GGT/PLT ratio was calculated by dividing serum GGT level (U/L) by serum PLT count (10 9 /L) and categorized as low (<0.24) or high (≥0. 24) ratio. The combination of ALB/FIB ratio and GGT/PLT ratio was categorized as grade 1 (high ALB/FIB ratio but low GGT/PLT ratio), grade 2 (high ALB/FIB ratio and high GGT/PLT ratio or low ALB/FIB ratio and low GGT/PLT ratio), or grade 3 (low ALB/FIB ratio but high GGT/PLT ratio). o Serum ALB level was categorized as low (≤3.8 g/dL) or high (>3.8 g/dL) level. HBV pre-S2 gene mutation was defined by the presence of deletion mutations spanning the pre-S2 gene segment of viral DNA in serum. The combination of ALB level combined with HBV pre-S2 gene mutation was categorized as grade 1 (high ALB level but absence of mutation), grade 2 (low ALB level and absence of mutation), grade 3 (high ALB level and presence of mutation), or grade 4 (low ALB level but presence of mutation  Moreover, a study conducted by Kaibori et al. [144] revealed that a high score of the pre-treatment serum modified ALB-BIL grade combined with pre-treatment serum AFP level was a factor that was independently correlated with worse OS and RFS in HCC patients treated with curative surgical resection. A study conducted by Hatanaka et al. [145] ascertained that a high score of the pre-treatment serum modified ALB-BIL grade combined with pre-treatment serum AFP level independently predicted worse OS and PFS in HCC patients receiving molecular targeted therapy with atezolizumab and bevacizumab. Another study conducted by Campani et al. [146] showed that a high score of the pretreatment serum ALB-BIL grade combined with post-treatment serum AFP level change was independently correlated with worse OS and PFS in HCC patients receiving molecular targeted therapy with atezolizumab and bevacizumab. Furthermore, a study conducted by Shen et al. [147] confirmed an independent association between a high grade of the pre-treatment serum CRP/ALB ratio combined with pre-treatment serum NLR and worse OS in HCC patients treated with TACE followed by RFA. A study conducted by Zhang et al. [148] demonstrated that a high grade of the pre-treatment serum ALB/FIB ratio combined with pre-treatment serum GGT/PLT ratio was independently associated with worse OS and RFS in HCC patients receiving curative surgical resection. Another study conducted by Jeng et al. [149] verified that a high grade of the pre-treatment serum ALB level combined with a pre-treatment hepatitis B virus (HBV) pre-S2 gene deletion mutation as an independent predictor for worse RFS in HCC patients undergoing curative surgical resection.
Altogether, these studies indicate that serum ALB-based combination biomarkers hold a significant and independent prognostic value for poor outcomes in HCC patients after treatment with various therapies.

Conclusions
This review provides a comprehensive summary of the up-to-date published literature that validates the independent prognostic significance of pre-treatment, on-treatment, or post-treatment serum ALB level and various ALB-based mono-and combination biomarkers in predicting the prognosis of HCC patients undergoing different surgical, locoregional, and systemic treatments. Considering that different HCC patient groups may have distinct clinicopathological backgrounds and treatment modalities, it is quite important to choose the type of ALB-based biomarker which exhibits the most optimal prognostic performance for individual HCC patients in order to achieve the best prediction of patient outcomes after therapy. Moreover, since ALB has been commonly applied in clinical settings as a powerful biomaterial and therapeutic agent for the treatment of a broad range of human diseases [16][17][18][19], identification of HCC patients with poor prognosis by ALBbased biomarkers may hold great promise in selecting the patients suitable for receiving ALB-based therapeutic strategies.
In addition, the molecular structure of ALB has been shown to undergo extensive damage under conditions of chronic-liver-disease-related liver failure such as decompensated cirrhosis due to systemic inflammation and oxidative stress, leading to a decline in the functional capacity of ALB [150,151]. Furthermore, many post-translational modifications of ALB, including phosphorylation, glycation, methylation, carbonylation, and acetylation, have been identified and display different potential impacts on ALB functions [152,153]. These structural and post-translational alterations of ALB may possibly explain the complexity of the use of serum ALB level in medical applications and may hold a great promise to discover novel prognostic value of serum ALB in HCC patients.