Surveillance for hepatocellular carcinoma in chronic viral hepatitis: Is it time to personalize it?

Table 1 Patients for whom surveillance of hepatocellular carcinoma is recommended according to society guidelines

Cirrhotic patients regardless of etiology, Child-Pugh stage A-B[12-14]
Cirrhotic patients regardless of etiology, Child-Pugh stage C awaiting liver transplantation[12-14]
Asian male hepatitis B carriers over the age of 40 yr[12-14]
Asian female hepatitis B carriers over the age of 50 yr[12-14]
Hepatitis B carriers with a family history of HCC[12-14]
Non-cirrhotic F3 patients, regardless of etiology, may be considered for surveillance based on an individual risk assessment[14]

HCC: Hepatocellular carcinoma.

Table 2 Hepatocellular carcinoma prediction risk scores for chronic hepatitis B patients

Risk scores	Cohort: Patients/ratio of cirrhosis	Study population	Antiviral treatment	Variables	External validation
GAG-HCC (Yuen et al[26], 2009)	Training: 820/15%; Validation: -	Asian (Hong Kong)	No	Age; Gender; HBV-DNA; Cirrhosis	Asian, Caucasian
CU-HCC (Wong et al[27], 2010)	Training: 1055/38%; Validation: 428/16%	Asian (Hong Kong)	No	Age; Albumin; Bilirubin; HBV-DNA; Radiologic cirrhosis	Asian, Caucasian
REACH-B (Yang et al[29], 2011)	Training: 3584/0; Validation: 1505/18%	Asian (Taiwan)	No	Age; Gender; ALT; HBeAg status; HBV-DNA concentration	Asian, Caucasian
REACH-BII(Lee et al[30], 2013)	Training: 2227/0; Validation: 1113/0	Asian (Taiwan)	No	Age; Gender; ALT; HBeAg/HBV-DNA/HBsAg/Genotype status	- (Internal only)
mREACH-B (Lee et al[31], 2014)	Training: 192/46.9%; Validation: -	Asian (South Korea)	ETV	Gender; ALT; HBeAg status; LSM value	Asian
LSM-HCC (Wong et al[33], 2014)	Training: 1035/32%; Validation: 520/31%	Asian (Hong Kong)	No	Age; Albumin; HBV-DNA concentration; LSM value	Asian
RWS-HCC (Poh et al[34], 2016)	Training: 583/13.7%; Validation: 3353/NA	Asian (Singapore)	No	Age; Sex; Cirrhosis; AFP	Asian, Caucasian
PAGE-B (Papatheodoridis et al[39], 2016)	Training: 1325/20%; Validation: 490/48%	Caucasians (Europe)	ETV/TDF	Age; Gender; Platelet count	Asian, Caucasian
mPAGE-B (Kim et al[42], 2018)	Training: 2001/19%; Validation: 1000/20%	Asian (South Korea)	ETV/TDF	Age; Gender; Platelet count; Albumin	Asian
HCC-RESCUE (Sohn et al[44], 2017)	Training: 990/39%; Validation: 1071/35%	Asian (South Korea)	ETV	Age; Gender; Cirrhosis	Asian
APA-B (Chen et al[45], 2017)	Training: 883/36%; Validation: 442/236%	Asian (Taiwan)	ETV	Age; Platelet; AFP	Asian
HCC-ESC (Fung et al[35], 2018)	Training: 723/NA; Validation: -	Asian (Hong Kong)	No	Age; Gender; Cirrhosis; Hypoalbuminemia; HBV-DNA; ALT	-
CAMD (Hsu et al[46], 2018)	Training: 23851/26.4%; Validation: 19321/7.1%	Asian (Taiwan)	ETV/TDF	Age; Gender; Diabetes; Cirrhosis	Asian
AGED (Fan et al[36], 2019)	Training: 628/0%; Validation: 1663/0%	Asian (China)	No	Age; Gender; HBeAg status; HBV-DNA	- (Internal only)
AASL-HCC (Yu et al[47], 2019)	Training: 944/39%; Validation: 298/39%	Asian (South Korea)	ETV/TDF	Age; Gender; Albumin; Cirrhosis	Asian
REAL-B (Yang et al[48], 2020)	Training: 5365/20.2%; Validation: 2683/22.1%	Asian (Multiethnicity)	Yes (not specified)	Age; Gender; Alcohol use; Diabetes; Platelet count; Cirrhosis; AFP	- (Internal only)
HCC-ESCAVT (Lim et al[49], 2020)	Training: 769/41.5%; Validation: 1061/26.1%	Asian (South Korea)	ETV/TDF	Gender; Cirrhosis; Fibrosis-4 index	- (Internal only)

GAG-HCC: The guide with age, gender, hepatitis B virus DNA, core promoter mutations, and cirrhosis risk score; CU-HCC: Chinese University-hepatocellular carcinoma risk score; REACH-B: The risk estimation for hepatocellular carcinoma in chronic hepatitis B score; RWS: Real-world score; APA-B: Age, platelet, alpha-fetoprotein-B score; CAMD: Cirrhosis, age, male gender, diabetes score; AFP: Alpha-fetoprotein, ALT: Alanine aminotransferase, HBeAg: Hepatitis B e Antigen, HBV: Hepatitis B virus, LSM: Liver stiffness measurement.

Table 3 Hepatocellular carcinoma prediction risk scores for chronic hepatitis C patients

Ref.	Cohort: Patients/ratio of cirrhosis	Study population	Variables	External validation
Lok et al[56], 2009	Training: 1050/41%; Validation: -	North America (United States HALT-C cohort)	Age; Race (Black); ALP; Esophageal varices; Ever smoked; Platelet count	-
Masuzaki et al[58], 2009	Training: 866/22.6%; Validation: -	Asian (Japan)	LSM	-
Chang et al[59], 2012	Training: 871/27.9%; Validation: -	Asian (Taiwan)	Age; Platelet count; AFP; Fibrosis stage	-
El-Serag HB et al[57], 2014	Training: 11721/100%; Validation: 52135/0	North America (United States Veterans Administration)	Age; ALT; Platelet; AFP	-
Ganne-Carrié et al[60],2016	Training: 720/100%; Validation: 360/100%	Caucasian (France)	Age; Past excessive alcohol intake; Platelet count; GGT; SVR status	-
Shiha et al[63], 2020 (GES)	Training: 2372/73.1%; Validation 1: 687/61.5%; Validation 2: 1314/70.6%	Egypt	Age; Gender; Fibrosis stage; Albumin; Alpha-feto protein	Egypt

AFP: Alpha-fetoprotein, ALP: Alkaline phosphatase, ALT: Alanine aminotransferase, GGT: Gamma-glutamyl transferase, LSM: Liver stiffness measurement, SVR: Sustained virologic response.

Table 4 Hepatocellular carcinoma prediction risk scores regardless of etiology

Risk scores	Cohort: Patients	Study population	Variables	External validation
ADRESS-HCC, (Flemming et al[64], 2014)	Training: 17124/100%; Validation:17808/100%	North America (United States)	Age; Diabetes; Race; Etiology of liver disease; Gender; Child-Pugh Score	- (Internal only)
THRI, (Sharma et al[65], 2017)	Training: 2079/100%; Validation: 1144/100%	Caucasian (Canada)	Age; Gender; Etiology of liver disease; Platelet count	Asian, Caucasian
TDS, (Li et al[68], 2018)	Training: 21149/NA; Validation:10574/NA	Asian (Taiwan)	Age; Gender; Smoking status; HbA1c; Glutamic-pyruvic transaminase; Cirrhosis; Hepatitis B virus; Hepatitis C virus; Anti-diabetic medication; Anti-hyperlipidemic medicaiton; Total/HDL cholesterol ratio	- (Internal only)
aMAP, (Fan et al[69], 2020)	Training: 3688/19.3%; Validation cohorts: 13686/11.4%-100%	Multicenter (Asian + Caucasian)	Age; Gender; Albumin-bilirubin score; Platelet count	Asian, Caucasian

THRI: Toronto hepatocellular carcinoma risk index; ADRESS: Age, diabetes, race, etiology of cirrhosis, sex, and severity; HbA1c: Hemoglobin A1c; HDL: High-density lipoprotein.

Table 5 Algorithmic approaches using the combination of serologic and clinical parameters for hepatocellular carcinoma risk prediction

Risk scores	Cohort: Patients/ratio of cirrhosis	Study population	Variables	External validation
GALAD score (Johnson et al[72], 2014)	HCC case: 670/90%; CLD control: 339/97%	Caucasian (England)	AFP; AFP-L3; DCP	Asian, Caucasian
Doylestown algorithm (Wang et al[76], 2016)	Training HCC case: 165/100%; CLD control: 195/100%; Validation 1 HCC case: 432/100%; CLD control: 438/100%; Validation 2 HCC case: 113/100%; CLD control: 586/100%; Validation 3 HCC case: 425/100%; CLD control: 804/100%	North America (United States)	Age; Gender; ALT; ALP; AFP; Fucosylated kininogen	North America (United States)
GALADUS score (Yang et al[75], 2019)	Training HCC case: 111/98%; CLD control: 180/85%; Validation HCC case: 233/100%; CLD control: 412/100%	North America (United States)	AFP; AFP-L3; DCP; Ultrasonography	North America (United States)
HES algorithm (Tayob et al[78,79], 2019)	HCC case: 4804/100%; CLD control: 33627/100%	North American (United States Veterans Administration)	Age; Rate of AFP change; ALT; Platelet count; Etiology of cirrhosis	-

AFP: Alpha-fetoprotein; AFP-L3: Alpha-fetoprotein-L3; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; DCP: Des-gamma-carboxy-prothrombin, HCC: Hepatocellular carcinoma; CLD: Chronic liver disease.