FULL PAPER

British Journal of Cancer (2016) 114, 744–750 | doi: 10.1038/bjc.2016.33

Keywords: hepatocellular carcinoma; curative therapy; ALBI; indocyanine green (ICG)

Long-term impact of liver function on curative
therapy for hepatocellular carcinoma:
application of the ALBI grade
Hidenori Toyoda1, Paul BS Lai2, James O’Beirne3, Charing C Chong2, Sarah Berhane4, Helen Reeves5,6,
Derek Manas6, Richard P Fox7, Winnie Yeo8, Frankie Mo8, Anthony WH Chan9, Toshifumi Tada1,
Mercedes Iñarrairaegui10, Arndt Vogel11, Nora Schweitzer11, Stephen L Chan8, Bruno Sangro10,
Takashi Kumada1 and Philip J Johnson*,4,12
1

Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8052, Japan; 2Departmentof Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China; 3The Sheila Sherlock Liver Centre, Royal Free Hospital,
London NW3 2QG, UK; 4Department of Molecular and Clinical Cancer Medicine, The Duncan Building, Daulby Street, University of Liverpool,
Liverpool L69 3GA, UK; 5Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Framlington Place, Newcastle upon
Tyne NE2 4HH, UK; 6The Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne NHS Foundation Trust, The Freeman Hospital,
Freeman Road, Newcastle upon Tyne, Tyne and Wear NE7 7DN, UK; 7Cancer Research UK Clinical Trials Unit, School of Cancer Sciences,
University of Birmingham, Birmingham B15 2TT, UK; 8State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer,
Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong Cancer Institute, Hong Kong, China; 9Department of Anatomicaland Cellular Pathology, Chinese University of Hong Kong, Hong Kong Cancer Institute, Hong Kong, China; 10Liver Unit and HPB Oncology Area,
Clinica Universidad de Navarra, and Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Pamplona,
Spain; 11Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl Neuberg Strabe 1, 30625 Hannover,Germany and 12The Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Road, Bebington, Wirral CH63 4JY, UK

Background: Application of curative therapy for hepatocellular carcinoma is crucially dependent on underlying liver function.
Using the recently described ALBI grade we examined the long-term impact of liver dysfunction on survival of early-stage
hepatocellular carcinoma (HCC) patients.
Methods: This cohort study comprised 2559 HCC patients from different geographic regions, all treated with curative intent. We
also examined the relation between indocyanine green (ICG) clearance and ALBI score. Survival was measured from the date oftreatment to the date of death or last follow-up.
Results: The ALBI score correlated well with ICG clearance. Among those undergoing surgical resection, patients with ALBI grade1 (good liver function) survived approximately twice as long as those with ALBI grade-2 (less good liver function), although morethan 90% of these patients were classified as Child–Pugh (C-P) grade A. In the cohort receiving ablative therapies, there was asimilar difference in survival between ALBI grade-1 and grade-2. Cox regression analysis confirmed that the ALBI score along withage, gender, aetiology and tumour factors (AFP, tumour size/number and vascular invasion) independently influenced survival in
HCC patients receiving curative treatments.
Conclusions: The ALBI score represents a simple approach to the assessment of liver function in patients with HCC. Afterpotentially curative therapy, those with ALBI grade-1 survived approximately twice as long as those with ALBI grade-2. These datasuggest that ALBI grade-1 patients are appropriately treated with surgical resection whereas ALBI grade-2 patients may, where theoption exists, be more suitable for liver transplantation or the less invasive curative ablative therapies.
*Correspondence: Professor PJ Johnson; E-mail: Philip.Johnson@liverpool.ac.uk
Revised 17 December 2015; accepted 18 January 2016
& 2016 Cancer Research UK. All rights reserved 0007 – 0920/16

744

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Liver function in early hepatocellular carcinoma

The prognosis of patients with hepatocellular carcinoma (HCC) is
influenced by several factors, the primary ones being related to thetumour itself and the underlying liver function, the latter usually
being characterised by the Child–Pugh (C-P) score (Bruix andSherman, 2005; European Association For The Study Of The LiverEuropean Organisation For Research And Treatment Of Cancer,2012). Although potentially curative therapies for HCC are usuallyreserved for patients with C-P grade ‘A’ chronic liver disease(Bruix and Sherman, 2005; European Association For The Study Of
The Liver-European Organisation For Research And Treatment Of
Cancer, 2012), it is recognised that, within this single grade, there is awide variation in the degree of hepatic reserve (Schneider, 2004;
Seyama and Kokudo, 2009; Fan, 2010; Vauthey et al, 2010). For thisreason, additional more sophisticated quantitative measures of liverfunction such as indocyanine green (ICG) clearance (Hemming et al,1992) and hepatic venous pressure gradient (HVPG) measurements(Bruix et al, 1996; Thalheimer et al, 2004; Berzigotti et al, 2015) havebeen advocated. Such tests have been used predominantly to identify
those patients in whom liver resection can be safely undertaken (i.e.,
to avoid periprocedural, ‘short-term’ mortality because of posthepatectomy liver failure).
We have recently suggested that a new model, known as ‘ALBI’,
can accurately assess liver (dys)function in patients with HCC andidentify two distinct prognostic categories among C-P ‘A’ patients(Johnson et al, 2014). A simple formula, involving only albumin andbilirubin, generates an ‘ALBI score’ (ranging from  5 to 0.5, withhigher scores representing worse liver function) and defined ranges
are then applied to calculate a grade, from 1 to 3, with ‘one’representing the best liver function and ‘three’ the worst (Johnson
et al, 2014). In the first part, we provide evidence that the
ALBI score can identify two distinct prognostic groups among C-P‘A’ patients undergoing surgical resection or ablative therapies withcurative intent and that can significantly affect long-term survival. In
the second part of the present study, we examine how ICG clearanceand HVPG correlate with the ALBI score. Such observations may
have significant implications for surgical practice, specifically the
choice between transplantation and surgical resection in circumstances under which both such options are available.
MATERIALS AND METHODS

The study is based on large individual patient cohorts recruitedfrom major HCC centres as part of an international collaboration.
Centres were chosen so as to generate a data set that reflected
typical patients who undergo treatment with curative intent both interms of the therapeutic options applied and the aetiology of theassociated liver diseases.
Treatments were considered potentially curative if patients
underwent surgical resection, radiofrequency ablation (RFA),
microwave ablation (MWA) or, as in Western cohorts, livertransplantation. The latter was not offered at the Japanese andHong Kong centres. The cohorts comprised 1072 patients fromJapan where the aetiology was mainly chronic HCV infection, 738
from Hong Kong, where the aetiology was mainly chronic HBV
infection, and 749 from the United Kingdom, Spain and Germany,
merged under ‘Europe’, where the aetiology was mainly chronic
HCV or alcohol abuse. Aetiology, treatment and other clinicalcharacteristics of the cohorts are shown in Table 1. Aetiology isclassified as HCV, HBV, HCV/HBV co-infection and ‘other’. The
latter comprises alcoholic and fatty-liver disease, primary biliary
cirrhosis, haemochromatosis and cryptogenic cirrhosis.
Of those undergoing surgical resection, 94.3% were graded as
C-P ‘A’ by local investigators. The criteria for surgical resection in
Eastern patients (Hong Kong and Japan) were: a 15-min ICG
retention rate of o30%; single HCC, or not more than 3 HCCs,
located in the same segment; o85 years of age; and absence ofwww.bjcancer.com | DOI:10.1038/bjc.2016.33

BRITISH JOURNAL OF CANCER

extrahepatic metastasis. The European centres in Spain, Germany,
Birmingham and Newcastle followed BCLC guidelines forresection. The extent of surgical resection (major or minor) was
available for the Hong Kong cohort only (Strasberg, 2005).
Transplantation was undertaken according to the modified Milan
Criteria. Within the guidelines listed above, the final treatment
decision was based on a multidisciplinary team consensus in all
regions. In the Japanese and Hong Kong cohorts, data werecollected to permit assessment of changes in the ALBI score at 1, 3
and 6 months following resection and the degree of fibrosis(graded F0–F4) (Knodell et al, 1981) was available in all.
For patients undergoing surgical resection or liver transplantation, all patients had histological confirmation of the diagnosis; forthose undergoing ablative therapies the diagnosis was based oninternationally recommended criteria (Bruix and Sherman, 2005;
European Association For The Study Of The Liver-European
Organisation For Research And Treatment Of Cancer, 2012).
Recurrence was assessed by serial imaging and AFP assessment,
confirmed by biopsy in cases of doubt.
Correlation of the ALBI score with ICG clearance and HVPG
was studied. Indocyanine green was presented as percentage
retention at 15 min. Hepatic venous pressure gradient wasmeasured in the 53 UK patients using a balloon occlusion catheter
positioned in the right hepatic vein according to the techniquedescribed by Bosch et al (2009).
Post treatment antiviral therapies. After curative therapy, thoseJapanese HCV patients without specific contraindications (35% of
the total HCV cohort) received conventional interferon-based
antiviral therapy. Among those with HBV-related disease, 87%
received a nucleoside analogue (lamivudine or, since 2102,
entecavir). In Hong Kong, 15% of patients with HBV-related
HCC received lamivudine. Very few (o5%) of the European
patients received any form of antiviral therapy treatment. The
cohorts were recruited before the availability of directly acting
antivirals (DAAs) and there were few HBV-related cases.
The ALBI score. The ALBI score is a simple and objective measureof liver function and is applicable to HCC at all stages of chronic liverdisease unlike the C-P score that is conventionally restricted topatients with cirrhosis. It is based on serum bilirubin and albumin andwas derived from, and subsequently validated by, rigorous statisticalanalysis of over 6000 patients with HCC (Johnson et al, 2014).
The score is calculated from the formula,
ALBI score ¼ log10 bilirubin0:66 ðAlbumin0:085Þ
Where bilirubin is in mmol l  1 and albumin in g l  1.
Specific cutoffs are then applied to generate three prognostic
groups: ALBI score p  2.60 (ALBI grade-1), 4  2.60 top  1.39 (ALBI grade-2) and ALBI score 4  1.39 (ALBI grade-3).
The score and grade can be readily calculated from a ‘heat map’
given in the original publication (Johnson et al, 2014).
Statistical methods. All statistical analyses were undertaken using
Stata IC 12 (StataCorp., TX, USA). Survival was measured from thetime of treatment that was typically within 1 month of diagnosis.
For continuous variables with extreme skewness, an appropriate
transformation was applied. Correlations between the ALBI scoreand each of HVPG and ICG were analysed using the pairwise
correlation coefficient (r). The ALBI score and grade was calculated
for each cohort according to Johnson et al (2014) and discrimination between the grades was assessed by fitting Kaplan–Meier(KM) curves. The log-rank test was used to compare the survival
distributions between the different grades. Cox regression models
were fitted to derive hazard ratios and for testing the effect of ALBI
on survival after adjusting for other factors in a multivariable
model.
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Liver function in early hepatocellular carcinoma

Table 1. Characteristics of the cohorts (all patients undergoing curative treatments)
Europe (Germany, Spain and UK)

Japan

Hong Kong, China

Number of patients

749

1072

738

Accrual period

1994–2014

1990–2013

2004–2014% Ethnicity

92.3 (Caucasian)499% (Oriental)

499% (Oriental)

63.2 (56–70)
62.7 (±10.8)

67 (61–73)
66.6 (±8.9)

58 (52–65)
58.7 (±10.2)

Age (years)
Median (IQR)
Mean (±s.d.)% Male

80.6

71.6

83.1

n ¼ 712n ¼ 1072

n ¼ 738

515/144/52
73/20/7%
N ¼ 711864/180/27
81/17/2%
N ¼ 1071

700/36/02
95/05/00
N ¼ 738

75.3% (F3 and F4)
N ¼ 749

11/19/78/140/268
2.1/3.7/15.1/27.1/51.9%
N ¼ 516

30/62/81/54/180
7.4/15.2/19.9/13.3/44.2%
N ¼ 407

Child grade (A/B/C)n%N

Fibrosis stage (F0/F1/F2/F3/F4)n%N
Solitary tumours (%)

Tumour size (cm), median (IQR)% Macroscopic vascular invasion (presence)

AFP (4200 ng ml

1

), %

66.8

69.7

80.1

n ¼ 662n ¼ 1065

n ¼ 738

3 (2.3–4.3)

2.2 (1.6–3.4)

3 (2.2–5)

n ¼ 651n ¼ 1061

n ¼ 738

5.6

4.7

4.9

n ¼ 667n ¼ 1066

n ¼ 738
28.5

13.6

16.3

AFP (ng ml  1), median (IQR)

8.7 (4–51)

16 (6.2–80)

26 (5–289)

N

N ¼ 655

N ¼ 1050

N ¼ 738

316/317/74
45/45/10
N ¼ 707424/591/50
40/55/5
N ¼ 1065

501/231/6
68/31/01
N ¼ 738

ALBI grade (1/2/3)
n%N

Crude 90-day mortality rate per 100 patients(ALBI 1/2/3)

1.45/2.62/2.74

1.42/1.69/0

0.2/2.6/NA

N

276/305/73

424/591/50

501/231/6

ICG R15, median (IQR)

7.5 (4.1–11.2)

16.3 (10.7–26.0)

4.1 (2.4–6.9)

n ¼ 34n ¼ 969n ¼ 344

Transplantation %Resection %
RFA %
PEI %

42.6 (n ¼ 712)
30.6 (n ¼ 749)
24.2 (n ¼ 712)
5.2 (n ¼ 712)

0 (n ¼ 1072)
53.8 (n ¼ 1072)
24.9 (n ¼ 1072)
19.5 (n ¼ 1072)

0 (n ¼ 738)
62.7 (n ¼ 738)
37.3 (n ¼ 738)
0

Aetiology %N ¼ 698

N ¼ 1072

N ¼ 738HCVHBV
HCV þ HBV
Other

29.4
10.3
4.2
56.2

70.8
14.7
1.1
13.3

7.9
81.3
0
10.8

Resection (Child–Pugh A), months (95% CI)

67.5 (55.4, 72.3), n ¼ 179

89.3 (80.1, 104.7), n ¼ 591

Ablative (PEI, MWA and RFA), months (95% CI)
Transplantation, months (95% CI)

34.3 (30.8, 39.1), n ¼ 216
135.4 (100.6), n ¼ 302

54.8 (48.5, 63.3), n ¼ 495
NANot reached, 5-year survival ¼ 68.2%(62.5–73.3%), n ¼ 463
64.1 (56.6, 81.0), n ¼ 275
NAOverall median survival, months (95% CI)

69.5 (58.9, 75.4)

72.5 (67.3, 78.6)

103.1 (82.2)

n ¼ 708n ¼ 1072

n ¼ 738

Treatment

Median survival (months)

Abbreviations: AFP ¼ a-fetoprotein; HBV ¼ hepatitis B virus; HCV ¼ hepatitis C virus; ICG R15 ¼ indocyanine green retention rate at 15 min; IQR ¼ interquartile range; MWA ¼ microwave
ablation; NA ¼ not available; PEI ¼ percutaneous ethanol injection; RFA ¼ radiofrequency ablation.

RESULTS

Overall (Hong Kong, Japan and Europe), the 90-day mortality was
o3% (breakdown of this result according to ALBI grade is shown746

in Table 1). Based on histological examination of resected HCC
cases, 51.9% of Japanese and 44.2% of Hong Kong cases had
fibrosis stage 4 (cirrhosis); the figures for ‘severe’ fibrosis (stage
X3) were 79% and 57.5% respectively (Table 1). Of the patients inthe European cohort, 75% had stage 3 and 4 fibrosis. In a
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Liver function in early hepatocellular carcinoma

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multivariable Cox regression model that included age, gender,
tumour size, tumour number, AFP and vascular invasion, the ALBIscore remained a strong predictor of survival (Po0.0001), evenafter adjusting for tumour-related factors (Supplementary Table 1).
Within the entire group of 2559 patients, classification according
to ALBI resulted in three clear and non-overlapping groups withmedian survival figures of 106.3 (95% CI 96.3, 122.7), 53.7 (95% CI
48.2, 58.6) and 26.9 (95% CI 20.4, 33.4) months in ALBI grade-1,-2 and -3 respectively (Figure 1).
Patients undergoing orthotopic liver transplantation. There wasno significant difference in survival between the three ALBI grades
after liver transplantation (log-rank test, P ¼ 0.68). At 5 years,
survival for ALBI grade-1, -2 and -3 were 73.4% (95% CI 59.9,
83.1%), 67.3% (95% CI 58.1, 74.9%) and 73.3% (95% CI 58.0,
83.8%) respectively (Supplementary Figure 1).
Patients undergoing hepatic resection. Among the C-P grade A
patients, two clear and non-overlapping ALBI subgroups emergedin each of the Japanese (log-rank test, Po0.0001), Hong Kong(log-rank test, Po0.0001) and European (log-rank test,
P ¼ 0.0477) cohorts respectively (Figure 2). Survival was approximately twice as long in the ALBI grade-1 patients as in the ALBI
grade-2 patients (Figure 2). For instance, ALBI grade-1 patients
had median survival of 122.7 (95% CI 96.3, 148.7), not reached (or5-year survival at 72.8%, 95% CI 66.5, 78.0) and 71.1 months(95% CI 59.0, 120.4) in the Japanese, Hong Kong and European
patients respectively, whereas ALBI grade-2 survival was 71.2
(95% CI 56.2, 82.4), 44.5 (95% CI 28.6) and 42.3 months (95% CI
25.0, 69.5) in the same cohorts. The hazard ratio in ALBI grade-2
was twice that of ALBI grade-1 (Table 2). The better survival in
ALBI grade-1 patients persisted in the subgroup of patients
without tumour recurrence (Supplementary Figures 2a and b).
Among the Hong Kong patients, we assessed the impact of the
ALBI grade according to the extent of resection. From those who
underwent surgical resection (n ¼ 463), 263 and 200 received
minor and major (three hepatic segments or more) resections
respectively (Strasberg, 2005). In these patients, a clear distinction
between ALBI grade-1 and grade-2 persisted (log-rank test,
P ¼ 0.0002 and 0.0236 respectively) (Supplementary Figures 3a
and b). Following resection, in both Japan and Hong Kong, there
was a modest decrease in liver function (as assessed by ALBI) at 1
month followed by a return towards the preoperative score at 3 and6 months (Supplementary Figure 4).

European cohorts (log-rank test, P ¼ 0.0222, 0.0068 and 0.0011
respectively). In those cohorts, ALBI grade-1 median survivals
were 84.2 (95% CI 63.8), 89.3 (95% CI 66.7, 115.8) and 56.5
months (95% CI 36.0, 69.2), whereas for ALBI grade-2 these were56.1 (95% CI 48.6, 72.4), 59.2 (95% CI 47.2, 64.1) and 30.2 months(95% CI 27.4, 34.3) (Figure 3). The corresponding hazard ratios arealso shown in Table 2. Patients with ALBI grade-3 showed the least
survival in all three cohorts.
Survival by aetiology in patients undergoing curative treatment.
When patients undergoing curative treatment were classified

A

Japanese patients undergoing resection (with Child−Pugh A)

1.00

0.75

0.50

0.25

Log−rank test, P < 0.0001

0.00
0

B

60

80

ALBI grade-2

Hong Kong patients undergoing resection (with Child−Pugh A)

1.00

0.75

0.50

0.25
Log−rank test, P < 0.0001
0.00
0

20

40
Survival in months
ALBI grade-1

C

1.00

1.00

0.75

0.75

0.50

40
Survival in months
ALBI grade-1

Patients undergoing RFA or MWA. Among those undergoing
curative ablative therapies, ALBI grade-1 patients survived significantly longer than ALBI grade-2 in the Japanese, Hong Kong and
All patients undergoing resection and ablative treatment

20

60

80

ALBI grade-2

European patients undergoing resection (with Child−Pugh A)

0.50

0.25
0.25

Log−rank test, P = 0.0477

0.00
0

20

40
Survival in months
ALBI grade-1
ALBI grade-3

60

80

0.00
0

ALBI grade-2

Figure 1. Survival according to ALBI grade in all patients undergoing
resection and ablative treatment.

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20

40
Survival in months
ALBI grade-1

60

80

ALBI grade-2

Figure 2. Survival according to ALBI grade in C-P grade A patients
undergoing resection in (A) Japan, (B) Hong Kong and (C) Europe.

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Table 2. Median survival in the cohorts according to ALBI grade within each treatment
Treatment
All patients undergoing

Cohort

ALBI grade

N

Median survival inmonths (95% CI)

All

resection and ablative treatments
Patients undergoing resection

Japan(Child, Pugh A)
Hong Kong
EuropePatients undergoing RFA

JapanHong Kong

Europe5-year survival,% (95% CI)

Hazard ratio (95% CI),
P-value11124

106.3 (96.3, 122.7)

68.4 (65.0, 71.5)

1

2

983

53.7 (48.2, 58.6)

44.7 (40.9, 48.4)

2.0 (1.8, 2.3), Po0.0001

371

26.9 (20.4, 33.4)

11.1 (4.3, 21.6)

5.0 (3.8, 6.7), Po0.0001

1

325

122.7 (96.3, 148.7)

74.6 (68.5, 79.7)

1

2

211

71.2 (56.2, 82.4)

56.1 (48.1, 63.3)

1.9 (1.5, 2.5), Po0.0001

1

359

2

91

Not reached1

123

71.1 (59.0, 120.4)

60.0 (48.3, 69.8)

2

3942.3 (25.0, 69.5)

35.1 (16.9, 54.0)

44.5 (28.6)

72.8 (66.5, 78.0)

1

48.6 (34.9, 61.1)

2.4 (1.6, 3.7), Po0.0001
1
1.7 (1.0, 2.9), P ¼ 0.05

1

6584.2 (63.8)

67.0 (51.5, 78.5)

1

2

189

56.1 (48.6, 72.4)

48.0 (38.7, 56.7)

1.7 (1.1, 2.6), P ¼ 0.024

3

13

23.8 (10.1)0%

5.1 (2.2, 11.7), Po0.0001

1

14189.3 (66.7, 115.8)

61.6 (51.2, 70.5)

1

2

129

59.2 (47.2, 64.1)

45.7 (34.7, 56.1)

1.7 (1.1, 2.4), P ¼ 0.003

0%9.4 (3.3, 26.6), Po0.0001

35

7.4 (2.3)

1

61

56.5 (36.0, 69.2)

43.7 (27.4, 58.9)

1

2

89

30.2 (27.4, 34.3)

16.2 (8.4, 26.1)

2.0 (1.3, 3.0), P ¼ 0.002

3

1219.3 (7.8, 34.2)

13.8 (0.8, 44.3)

2.9 (1.4, 6.2), P ¼ 0.005

Abbreviations: CI ¼ confidence interval; RFA ¼ radiofrequency ablation.

according to viral status, it was apparent that HBV-positive
patients had a significantly better prognosis than HCV-positive
patients in the Japanese, Hong Kong and European cohorts (logrank test, Po0.0001, 0.0056 and 0.0029 respectively)(Supplementary Figure 5). In the same order of cohorts, HBVHCC median survival stood at 135.9 (95% CI 82.4, 168.1), 114.7(95% CI 87.5) and not reached (or 5-year survival at 75.9%, 95%
CI 61.7, 85.4), whereas HCV–HCC survival was 67.3 (95% CI 60.4,
74.5), 44.7 (95% CI 34.0, 69.8) and 71.9 months (95% CI 52.8,
90.2). In all, 68% of HBV–HCC patients fell into the ALBI grade-1
category as compared with only 33% of the HCV–HCC patients(Supplementary Table 2). It was notable that the survival curves
only separated at between 2 and 3 years. Severe fibrosis or cirrhosis(F3 and F4) was more common in the HCV patients (82.2%) thanin the HBV patients (65.2%) (Supplementary Table 3).
Median survival, 5-year survival and hazard ratio figures for allof the above are summarised in Table 2 and Supplementary
Table 4).
Correlation of ICG clearance and HVPG with ALBI score.
Because of skewness of the ICG distribution, an appropriate
transformation was used, in this case, the square root of each value.
Among the patients with measured ICG, a strong positive
correlation was observed with the ALBI score (r ¼ 0.6423,
n ¼ 1346, Po0.0001; Figure 4A). There was also a positive
correlation between HVPG and the ALBI score (r ¼ 0.55, n ¼ 52,
Po0.0001; Figure 4B).
DISCUSSIONInternational guidelines suggest that curative treatments, otherthan liver transplantation, should be confined to those with grade
A C-P score in order to avoid the short-term complications
associated with poor liver function (Schneider, 2004; Bruix andSherman, 2005; Seyama and Kokudo, 2009; Fan, 2010; Vauthey
et al, 2010; European Association For The Study Of The LiverEuropean Organisation For Research And Treatment Of Cancer,2012). Such guidelines are refined by estimation of serum bilirubinand HVPG or ICG clearance (Hemming et al, 1992; Bruix et al,
1996; Thalheimer et al, 2004), whereas HVPG is often substituted
748

for by ‘clinical evidence of portal hypertension’ (Berzigotti et al,2015; Roayaie et al, 2015).
The present data confirm, and greatly extend, our originalreport that within C-P A grade there are two distinct subgroups asclassified by the ALBI score. In all regions, among resectedpatients, survival was about twice as long among those with ALBI
grade-1 than for those with ALBI grade-2. The overall survival
results are remarkably consistent across regions. The rather worse
survival in the European patients may be attributable to different
practices when liver transplantation is an option. As expected, very
few patients (o1%) with ALBI grade-3 were subjected to surgicalresection. Similar results were obtained for those undergoing
ablative therapies with curative intent. The degree of discrimination within C-P A is all the more remarkable for the fact that noneof the clinical features related to the tumour itself that areperceived to influence survival (AFP, vascular invasion and tumoursize) are taken into account. This implies that a very significant
fraction of the mortality in HCC after potentially curative
therapies, even in C-P ‘A’ patients, is attributable to liver
dysfunction. The observation that clear separation between
survivals curves of ALBI grade-1 and ALBI grade-2 persists in
those patients without HCC recurrence (Supplementary Figure 2)
may be taken to imply that much of the increased mortality in
ALBI grade-2 is related to liver failure. There was little change inliver function after resection at 6 months, but we suspect that had
more prolonged follow-up been available, separation between ALBI
grade-1 and ALBI grade-2 would have become apparent. The
observation that surgical resection and ablative therapies, but nottransplant, are affected by the ALBI score would be expected if
ALBI reflects liver function.
Our data also demonstrate a further advantage of the ALBI
grade over the C-P scoring system in that it is equally applicable to
HCC patients without cirrhosis. The ALBI score gave clear
discrimination in each grade despite the fact that among patientswith HBV-related HCC only 47.2% had cirrhosis (fibrosis stage 4)
and even among the HCV patients the figure was only 56.6%.
Conventionally, the C-P scoring system is restricted to patientswith cirrhosis.
There is controversy concerning how to decide, in an individual
patient, whether the most appropriate treatment is transplantationor surgical resection (where that option exists) (Michel et al, 1997;
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Liver function in early hepatocellular carcinoma

A

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A

Japanese patients undergoing RFA

UK, Japan and Hong Kong cohorts

1.00

10

0.75

8
6

0.50

4

Log−rank tests:
ALBI 1 vs ALBI 2, P = 0.0222
ALBI 2 vs ALBI 3, P = 0.0019
ALBI 1 vs ALBI 3, P = 0.0002

0.25

2

0.00
0

20

40

0

60

Survival in months
ALBI grade-1
ALBI grade-3−5

ALBI grade-2

−4

B

B

Hong Kong patients undergoing RFA/MWA−3−2
ALBI score−10

UK cohort
20

1.00

15

0.50
Log−rank tests:
ALBI 1 vs ALBI 2, P = 0.0068
ALBI 2 vs ALBI 3, P = 0.0001
ALBI 1 vs ALBI 3, P < 0.0001

0.25

HVPG

0.75

10

5

0.00
0

20

40

60

Survival in months
ALBI grade-1
ALBI grade-3

C−5
ALBI grade-2

European patients undergoing RFA

0.75

0.50

Log−rank tests:
ALBI 1 vs ALBI 2, P = 0.0011
ALBI 2 vs ALBI 3, P = 0.2452
ALBI 1 vs ALBI 3, P = 0.0055

0.00
0

20

40

60

Survival in months
ALBI grade-1
ALBI grade-3

ALBI grade-2

Figure 3. Survival according to ALBI grade in patients undergoing RFA
and other ablative therapies in (A) Japanese, (B) Hong Kong and(C) European cohorts.

Sarasin et al, 1998; Figueras et al, 2000; Schwartz et al, 2007). It is
widely agreed that transplantation is the preferred choice among
patients with C-P B or C because such patients clearly have ahigher risk of death from the associated liver disease. However, as
noted above, we show that even within C-P ‘A’ there is a majordifference in mortality between ALBI grade-1 and ALBI grade-2.
Such information may influence the decision to transplant or
resect: resection being, perhaps, more appropriate in ALBI grade-1
and transplantation in ALBI grade-2. We cannot be certain aboutwww.bjcancer.com | DOI:10.1038/bjc.2016.33

−4

−3
−2
ALBI score−1

0

Figure 4. Raw data scatterplots showing with 95% CI correlation between
ALBI score and (A) sqrt(ICG) clearance (r ¼ 0.67, n ¼ 2190, Po0.0001)
and (B) WHPG (r ¼ 0.55, n ¼ 52, Po0.0001). WHPG = wedged hepatic
portal hepatic gradient.

1.00

0.25

0

the impact of postoperative antiviral therapy on our results.
Current evidence suggests that rates of recurrence/development of‘new’ tumours are probably decreased but definitive evidence is still
awaited (Lok, 2012; Urata et al, 2012; Kim and Gores, 2013; Yinet al, 2013).
The ability to assess liver dysfunction accurately with the ALBIscore before treatment may permit explanation of the findings ofFranssen et al (2014) that HBV-positive patients survive
significantly longer than those who are HCV positive. Analysis
of our large international data set confirmed this finding andsuggested that this may be attributable to differences in underlying
liver function. More patients in the HBV-positive group in all
regions were ALBI grade-1. This is consistent with the generalconsensus (and as shown in our results here; Supplementary
Table 3) that HCC arises largely in the cirrhotic (or at least severely
fibrotic) liver in HCV-positive patients, whereas it may also arise in
the HBV-positive livers before the stage of cirrhosis has beenreached (Shiratori et al, 1995; Grando-Lemaire et al, 1999; Kumar
et al, 2007; Schuppan and Afdhal, 2008).
All the above interpretations assume that the ALBI score is avalid measure of liver dysfunction. Our initial publication provided
circumstantial evidence that this was the case. Here, we adduce
three further pieces of supportive evidence. Firstly, there was apositive correlation with ICG clearance, an objective test ofliver function widely used in preoperative assessment. Secondly, ina smaller data set, there was also a correlation with HVPG,
another parameter used in preoperative assessment. Finally, wehypothesised that in patients undergoing liver transplantation,
749

BRITISH JOURNAL OF CANCER

preoperative liver function, as defined by the ALBI score, would
have no impact on survival and, indeed, this was the case.
We now have objective evidence that the ALBI score assesses
liver function in HCC patients. Although it is conventionallyconsidered that assessment of liver function before resection isimportant to exclude patients who might develop liver failure if toolarge a resection is undertaken, we show here that the liver function
also has a major impact on long-term survival. Such observations
may have major implications for decisions as to whether surgery
or liver transplantation is undertaken in HCC patients withcompromised liver function.
CONFLICT OF INTEREST

The authors declare no conflict of interest.

AUTHOR CONTRIBUTIONS

Study concept and design: PJJ, HT, JO’B, TK and PBSL; acquisitionof data: HT, PBSL, CCC, JO’B, SB, HR, WY, TT, MI, AV, NS, SLC,
BS and DM; analysis and interpretation of data: SB, HT, PBSL,
JO’B, FM and RPF; drafting of the manuscript: PJJ, SB, HT and
PBSL; critical revision of the manuscript for important intellectual
content: all; statistical analysis: SB, RF and FM; obtained
funding: none; administrative, technical or material support: none;
study supervision: PJJ.
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