J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://www.jocmr.org

Original Article

Volume 15, Number 7, July 2023, pages 343-359

Protein Induced by Vitamin K Absence or Antagonist-II Versus Alpha-Fetoprotein in the Diagnosis of Hepatocellular Carcinoma: A Systematic Review With Meta-Analysis

Figure 2. Risk of bias and applicability concerns graph: reviewing authors’ judgements about each domain presented as percentages across included studies.

Figure 3. Forest plot for sensitivity and specificity of PIVKA-II. PIVKA-II: protein induced by vitamin K absence or antagonist-II.

Figure 5. Summary receiver operating characteristic curve of the diagnostic accuracy of PIVKA-II (a) and AFP (b). AFP: α-fetoprotein; PIVKA-II: protein induced by vitamin K absence or antagonist-II.

Figure 6. Funnel plot of the pooled DOR of PIVKA-II (a) and AFP (b) for diagnosis of HCC. AFP: α-fetoprotein; DOR: diagnostic odds ratio; HCC: hepatocellular carcinoma; PIVKA-II: protein induced by vitamin K absence or antagonist-II.

**Table 1.** Characteristics of the Studies Included in the Meta-Analysis
Study and year of publication	Country	Sample size of HCCs/controls	Type of controls	Median or mean age of HCC/control (years)	Cut-off value of PIVKA-II	Cut-off value of AFP	Etiology of HCC	Sensitivity of PIVKA-II/AFP	Specificity of PIVKA-II/AFP
AFP: α-fetoprotein; AIH: autoimmune hepatitis; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; NASH: nonalcoholic steatohepatitis; PIVKA-II: protein induced by vitamin K absence or antagonist-II.
Abd El Gawad et al 2014 [17]	Egypt	40/20	Cirrhosis + healthy controls	59/57	1.2 ng/mL	40.5 ng/mL	Mixed	97.5%/82.5%	90%/85%
Beneduce et al 2008 [18]	Italy	33/31	Healthy controls	61/55	2 ng/mL	20 ng/mL	HCV	39%/48%	100%/100%
Caviglia et al 2020 [19]	Italy	149/200	Cirrhosis	67/61	> 73 mAU/mL	> 9.7 ng/mL	Mixed	68%/72%	84%/66%
Cerban et al 2019 [20]	Romania	101/52	Cirrhosis	60.3/59.4	> 63 mAU/mL	> 18.9 ng/mL	Mixed	81.36%/52.54%	60.61%/93.94%
Chan et al 2022 [21]	China	168/208	Disease controls	62.86/52.18	28.4 ng/mL	20 ng/mL	Mixed	86.9%/51.8%	83.7%/98.1%
Chen et al 2020 [22]	China	110/250	Chronic hepatitis B + cirrhosis + healthy controls	55.62/54.29	51 mAU/mL	5.65 ng/mL	HBV	85%/84.1%	93.3%/70.90%
Choi 2013 [13]	South Korea	90/78	Benign liver disease	59.7/55.6	40 AU/L	10 ng/mL	Mixed	62.2%/78.9%	94.9%/84.6%
Cui et al 2003 [23]	China	120/90	Cirrhosis	59/56	40 mAU/mL	20 ng/mL	Mixed	53.3%/58.3%	85.6%/63.3%
Durazo et al 2008 [24]	USA	144/96	Cirrhosis + chronic hepatitis	54.2/45.85	84 mAU/mL	25 ng/mL	Mixed	87%/69%	85%/87%
Ekmen et al 2020 [25]	Turkey	66/46	Cirrhosis	54.53/54.45	2.63 ng/mL	6.08 ng/mL	Mixed	71%/77%	83%/77%
Ertle et al 2012 [26]	Germany	164/422	Viral hepatitis, cirrhosis, other chronic liver diseases such as NASH, AIH and others	64/48.8	5 ng/mL	10 ng/mL	Mixed	63.4%/54.9%	94.5%/94.5%
Feng et al 2021 [27]	China	168/153	Healthy controls	ND	35.60 mAU/mL	17.76 ng/mL	Mixed	83.93%/64.29%	91.50%/90.20%
Fujiyama et al 1992 [28]	Japan	200/197	Cirrhosis + chronic hepatitis + hemangioma + liver cysts	60.7/52.6	0.11 AU/mL	150 ng/mL	Mixed	54%/54%	98%/95.9%
Gentile et al 2017 [29]	Italy	56/104	HCV without HCC	70/66	> 36 mAU/mL	> 12 ng/mL	HCV	78.6%/60%	66.3%/77.2%
Grazi et al 1995 [30]	Italy	111/116	Postnecrotic cirrhosis + liver metastases from colorectal cancer + benign liver lesions + tumors not affecting the liver without hepatic metastases, and other diseases	60.9/49.9	0.09 AU/mL	20 ng/dL	Mixed	53.3%/54.9%	88.1%/97.4%
Guan et al 2022 [31]	China	139/345	ND	60.6/56.2	40 mAU/mL	20 ng/mL	Nonalcoholic fatty liver	74.8%/52.5%	91.0%/97.4%
Hadi et al 2022 [32]	Malaysia	40/123	Liver cirrhosis + non-cirrhotic high-risk patients	64.5/56.5	36.7 mAU/mL	14.2 ng/mL	Mixed	90%/75%	82.1%/93.5%
Huang et al 2017 [33]	China	132/450	Viral hepatitis + liver cirrhosis + metastatic hepatic carcinoma + other benign liver diseases + healthy individuals	53.7/47.45	≥ 40 mAU/mL	≥ 20 ng/mL	Mixed	80%/68%	89%/91%
Ismail et al 2017 [34]	Egypt	66/83	Malignant tumors or benign liver lesions	59/46	28 ng/mL	20 ng/mL	Mixed	90.9%/68.2%	97.6%/91.6%
Jang et al 2016 [35]	France	208/193	Cirrhosis	61.02/57.85	> 10 ng/mL	> 20 ng/mL	Mixed	51%/62%	91.2%/90.2%
Ji et al 2016 [36]	China	236/285	Hemangiomas of liver, metastatic hepatic carcinoma and liver cirrhosis + healthy control	51/50.22	40 mAU/mL	20 ng/mL	Mixed	82.63%/67.80%	89.12%/91.23%
King et al 1989 [37]	South Africa	98/120	Hepatic metastases + amoebic hepatic abscesses + chronic hepatic parenchymal disease	46.7/54.77	> 1.5 mU/mL	> 20 ng/mL	Mixed	67.3%/83.7%	84.2%/90.8%
Lee et al 2021 [38]	China	158/62	Chronic hepatitis B	ND	ND	ND	HBV	68.4%/57.6%	98.4%/93.5%
Lim et al 2015 [39]	South Korea	361/276	Cirrhosis	58/55	40 mAU/mL	20 ng/mL	Mixed	62.9%/56.8%	90.8%/82.8%
Liu et al 2022 [40]	China	105/172	HCV-infected patients	60.8/55.8	40 mAU/mL	20 ng/mL	HCV	78.1%/56.2%	89.0%/90.1%
Loglio et al 2020 [41]	Italy	64/148	HBV-infected patients	66/60	> 48 mAU/mL	> 4.2 ng/mL	HBV	64%/56%	91%/94%
Marrero et al 2003 [42]	USA	55/104	Cirrhosis and chronic hepatitis	56.2/51	125 mAU/mL	11 ng/mL	Mixed	89%/77%	95%/79%
Marrero et al 2009 [43]	USA	419/417	Cirrhosis	60.5/55	150 mAU/mL	20 ng/mL	Mixed	74%/59%	70%/90%
Morota et al 2011 [44]	USA	70/156	Cirrhosis + hepatitis + normal	ND	123.9 AU/L	15.3 mg/L	Mixed	84.3%/62.9%	88.1%/92.3%
Nomura et al 1999 [45]	Japan	36/49	Cirrhosis	ND	ND	20 ng/mL	Mixed	27.8%/58.3%	95.9%/75.5%
Park et al 2016 [46]	South Korea	79/77	Cirrhosis	62.33/55.59	> 40 mAU/mL	>10 ng/mL	Mixed	70.89%/68.35%	70.13%/81.82%
Peng et al 2022 [47]	China	148/143	Cirrhosis	55/51	> 199.9 mAU/mL	> 619.3 ng/mL	HBV	78.65%/49.44%	99.30%/98.60%
Pote et al 2014 [48]	France	85/43	Cirrhosis	57.8/54.8	42 mAU/mL	5.5 ng/mL	Mixed	73%/61%	81%/50%
Qi et al 2019 [49]	China	120/89	Chronic liver disease	56/47	33.080 mAu/mL	11.880 ng/mL	Mixed	83.5%/73.6%	71.6%/80.7%
Seo et al 2015 [50]	South Korea	157/879	Chronic hepatitis B	57/45	40 mAU/mL	10 ng/mL	HBV	73.9%/67.5%	89.7%/90.3%
Sharma et al 2010 [12]	India	70/38	Cirrhosis	58.84/47.92	9.2 ng/mL	13.02 ng/mL	Mixed	80%/72.9%	92.1%/65.8%
Shimizu et al 2022 [51]	Japan	56/34	Cirrhosis	62/61	40 mAU/mL	20 ng/mL	Mixed	46.4%/58.9%	97.1%/85.3%
Si et al 2020 [52]	China	266/167	Benign liver disease and healthy individuals	ND	41.74 mAU/mL	21.8 ng/mL	HBV	81.2%/51.5%	88.5%/89.7%
Song et al 2014 [53]	China	550/604	Malignant disease + chronic liver disease + benign disease + healthy participants	51/41.5	86 mAU/mL	21 ng/mL	Mixed	71.50%/68.00%	86.30%/93.20%
Song et al 2020 [54]	China	88/112	Chronic HBV + cirrhosis	ND	44 mAU/mL	5 ng/mL	Mixed	55.7%/65.9%	94.6%/88.4%
Sterling et al 2009 [55]	Canada	74/298	Healthy participants	54.9/52.1	> 200 ng/mL	20 ng/mL	HCV	56.3%/60.8%	100%/71.1%
Suehiro et al 1993 [56]	Japan	185/90	Cholangiocellular carcinoma + cirrhosis	ND	ND	ND	Mixed	35.1%/65.4%	95.3%/71.8%
Takikawa et al 1992 [57]	Japan	116/253	Cirrhosis	ND	0.1 AU/mL	20 ng/mL	Mixed	52.8%/70.1%	98.8%/75.5%
Tian et al 2022 [58]	China	145/57	Benign liver disease	58.9/48.1	38.91 mAU/mL	5.6 ng/mL	Mixed	92.4%/88.3%	96.5%/98.2%
Viggiani et al 2016 [59]	Italy	60/60	Benign liver disease	39 - 86/26 - 84	47 mAU/mL	20 mAU/mL	Mixed	60%/55%	90%/55%
Volk et al 2007 [60]	USA	84/169	Cirrhosis	59/53	150 mAU/mL	23 ng/mL	Mixed	86%/69%	93%/91%
Wang et al 2005 [61]	Taiwan	61/66	Chronic hepatitis and cirrhosis	63/54.5	40 mAU/mL	20 ng/mL	Mixed	77%/59%	86.4%/77.3%
Wang et al 2019 [62]	China	176/359	Chronic hepatitis B	53/49	162.22 mAU/mL	145.65 ng/mL	HBV	51.3%/64.8%	93.6%/77.2%
Wang et al 2020 [63]	China	234/396	Chronic hepatitis B	54/48	87.63 mAU/mL	499.80 ng/mL	HBV	86.80%/52.10%	90.20%/91.40%
Xu et al 2021 [64]	China	308/120	Benign liver disease + cirrhosis	51.4/44.56	40 mAU/mL	25 ng/mL	Mixed	89.0%/86.8%	91.7%/87.6%
Yoon et al 2009 [65]	South Korea	106/100	Non-HCC	54.5/ND	40 mAU/mL	20 ng/mL	Mixed	51.9%/57.5%	97%/88%
Yu et al 2015 [66]	China	134/505	Liver diseases + other cancers + healthy controls	49.6/50.93	200 mAU/mL	195.2 ng/mL	Mixed	64.2%/60.4%	90.8%/89.6%
Zhang and Huang 2022 [67]	China	228/103	Cirrhosis	56/58	25.3 ng/mL	7 ng/mL	Mixed	70.18%/63.16%	82.50%/85.44%

Table 1. Characteristics of the Studies Included in the Meta-Analysis

Study and year of publication

Country

Sample size of HCCs/controls

Type of controls

Median or mean age of HCC/control (years)

Cut-off value of PIVKA-II

Cut-off value of AFP

Etiology of HCC

Sensitivity of PIVKA-II/AFP

Specificity of PIVKA-II/AFP

AFP: α-fetoprotein; AIH: autoimmune hepatitis; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; NASH: nonalcoholic steatohepatitis; PIVKA-II: protein induced by vitamin K absence or antagonist-II.

Abd El Gawad et al 2014 [17]

Egypt

40/20

Cirrhosis + healthy controls

59/57

1.2 ng/mL

40.5 ng/mL

Mixed

97.5%/82.5%

90%/85%

Beneduce et al 2008 [18]

Italy

33/31

Healthy controls

61/55

2 ng/mL

20 ng/mL

HCV

39%/48%

100%/100%

Caviglia et al 2020 [19]

Italy

149/200

Cirrhosis

67/61

> 73 mAU/mL

> 9.7 ng/mL

Mixed

68%/72%

84%/66%

Cerban et al 2019 [20]

Romania

101/52

Cirrhosis

60.3/59.4

> 63 mAU/mL

> 18.9 ng/mL

Mixed

81.36%/52.54%

60.61%/93.94%

Chan et al 2022 [21]

China

168/208

Disease controls

62.86/52.18

28.4 ng/mL

20 ng/mL

Mixed

86.9%/51.8%

83.7%/98.1%

Chen et al 2020 [22]

China

110/250

Chronic hepatitis B + cirrhosis + healthy controls

55.62/54.29

51 mAU/mL

5.65 ng/mL

HBV

85%/84.1%

93.3%/70.90%

Choi 2013 [13]

South Korea

90/78

Benign liver disease

59.7/55.6

40 AU/L

10 ng/mL

Mixed

62.2%/78.9%

94.9%/84.6%

Cui et al 2003 [23]

China

120/90

Cirrhosis

59/56

40 mAU/mL

20 ng/mL

Mixed

53.3%/58.3%

85.6%/63.3%

Durazo et al 2008 [24]

USA

144/96

Cirrhosis + chronic hepatitis

54.2/45.85

84 mAU/mL

25 ng/mL

Mixed

87%/69%

85%/87%

Ekmen et al 2020 [25]

Turkey

66/46

Cirrhosis

54.53/54.45

2.63 ng/mL

6.08 ng/mL

Mixed

71%/77%

83%/77%

Ertle et al 2012 [26]

Germany

164/422

Viral hepatitis, cirrhosis, other chronic liver diseases such as NASH, AIH and others

64/48.8

5 ng/mL

10 ng/mL

Mixed

63.4%/54.9%

94.5%/94.5%

Feng et al 2021 [27]

China

168/153

Healthy controls

35.60 mAU/mL

17.76 ng/mL

Mixed

83.93%/64.29%

91.50%/90.20%

Fujiyama et al 1992 [28]

Japan

200/197

Cirrhosis + chronic hepatitis + hemangioma + liver cysts

60.7/52.6

0.11 AU/mL

150 ng/mL

Mixed

54%/54%

98%/95.9%

Gentile et al 2017 [29]

Italy

56/104

HCV without HCC

70/66

> 36 mAU/mL

> 12 ng/mL

HCV

78.6%/60%

66.3%/77.2%

Grazi et al 1995 [30]

Italy

111/116

Postnecrotic cirrhosis + liver metastases from colorectal cancer + benign liver lesions + tumors not affecting the liver without hepatic metastases, and other diseases

60.9/49.9

0.09 AU/mL

20 ng/dL

Mixed

53.3%/54.9%

88.1%/97.4%

Guan et al 2022 [31]

China

139/345

60.6/56.2

40 mAU/mL

20 ng/mL

Nonalcoholic fatty liver

74.8%/52.5%

91.0%/97.4%

Hadi et al 2022 [32]

Malaysia

40/123

Liver cirrhosis + non-cirrhotic high-risk patients

64.5/56.5

36.7 mAU/mL

14.2 ng/mL

Mixed

90%/75%

82.1%/93.5%

Huang et al 2017 [33]

China

132/450

Viral hepatitis + liver cirrhosis + metastatic hepatic carcinoma + other benign liver diseases + healthy individuals

53.7/47.45

≥ 40 mAU/mL

≥ 20 ng/mL

Mixed

80%/68%

89%/91%

Ismail et al 2017 [34]

Egypt

66/83

Malignant tumors or benign liver lesions

59/46

28 ng/mL

20 ng/mL

Mixed

90.9%/68.2%

97.6%/91.6%

Jang et al 2016 [35]

France

208/193

Cirrhosis

61.02/57.85

> 10 ng/mL

> 20 ng/mL

Mixed

51%/62%

91.2%/90.2%

Ji et al 2016 [36]

China

236/285

Hemangiomas of liver, metastatic hepatic carcinoma and liver cirrhosis + healthy control

51/50.22

40 mAU/mL

20 ng/mL

Mixed

82.63%/67.80%

89.12%/91.23%

King et al 1989 [37]

South Africa

98/120

Hepatic metastases + amoebic hepatic abscesses + chronic hepatic parenchymal disease

46.7/54.77

> 1.5 mU/mL

> 20 ng/mL

Mixed

67.3%/83.7%

84.2%/90.8%

Lee et al 2021 [38]

China

158/62

Chronic hepatitis B

HBV

68.4%/57.6%

98.4%/93.5%

Lim et al 2015 [39]

South Korea

361/276

Cirrhosis

58/55

40 mAU/mL

20 ng/mL

Mixed

62.9%/56.8%

90.8%/82.8%

Liu et al 2022 [40]

China

105/172

HCV-infected patients

60.8/55.8

40 mAU/mL

20 ng/mL

HCV

78.1%/56.2%

89.0%/90.1%

Loglio et al 2020 [41]

Italy

64/148

HBV-infected patients

66/60

> 48 mAU/mL

> 4.2 ng/mL

HBV

64%/56%

91%/94%

Marrero et al 2003 [42]

USA

55/104

Cirrhosis and chronic hepatitis

56.2/51

125 mAU/mL

11 ng/mL

Mixed

89%/77%

95%/79%

Marrero et al 2009 [43]

USA

419/417

Cirrhosis

60.5/55

150 mAU/mL

20 ng/mL

Mixed

74%/59%

70%/90%

Morota et al 2011 [44]

USA

70/156

Cirrhosis + hepatitis + normal

123.9 AU/L

15.3 mg/L

Mixed

84.3%/62.9%

88.1%/92.3%

Nomura et al 1999 [45]

Japan

36/49

Cirrhosis

20 ng/mL

Mixed

27.8%/58.3%

95.9%/75.5%

Park et al 2016 [46]

South Korea

79/77

Cirrhosis

62.33/55.59

> 40 mAU/mL

>10 ng/mL

Mixed

70.89%/68.35%

70.13%/81.82%

Peng et al 2022 [47]

China

148/143

Cirrhosis

55/51

> 199.9 mAU/mL

> 619.3 ng/mL

HBV

78.65%/49.44%

99.30%/98.60%

Pote et al 2014 [48]

France

85/43

Cirrhosis

57.8/54.8

42 mAU/mL

5.5 ng/mL

Mixed

73%/61%

81%/50%

Qi et al 2019 [49]

China

120/89

Chronic liver disease

56/47

33.080 mAu/mL

11.880 ng/mL

Mixed

83.5%/73.6%

71.6%/80.7%

Seo et al 2015 [50]

South Korea

157/879

Chronic hepatitis B

57/45

40 mAU/mL

10 ng/mL

HBV

73.9%/67.5%

89.7%/90.3%

Sharma et al 2010 [12]

India

70/38

Cirrhosis

58.84/47.92

9.2 ng/mL

13.02 ng/mL

Mixed

80%/72.9%

92.1%/65.8%

Shimizu et al 2022 [51]

Japan

56/34

Cirrhosis

62/61

40 mAU/mL

20 ng/mL

Mixed

46.4%/58.9%

97.1%/85.3%

Si et al 2020 [52]

China

266/167

Benign liver disease and healthy individuals

41.74 mAU/mL

21.8 ng/mL

HBV

81.2%/51.5%

88.5%/89.7%

Song et al 2014 [53]

China

550/604

Malignant disease + chronic liver disease + benign disease + healthy participants

51/41.5

86 mAU/mL

21 ng/mL

Mixed

71.50%/68.00%

86.30%/93.20%

Song et al 2020 [54]

China

88/112

Chronic HBV + cirrhosis

44 mAU/mL

5 ng/mL

Mixed

55.7%/65.9%

94.6%/88.4%

Sterling et al 2009 [55]

Canada

74/298

Healthy participants

54.9/52.1

> 200 ng/mL

20 ng/mL

HCV

56.3%/60.8%

100%/71.1%

Suehiro et al 1993 [56]

Japan

185/90

Cholangiocellular carcinoma + cirrhosis

Mixed

35.1%/65.4%

95.3%/71.8%

Takikawa et al 1992 [57]

Japan

116/253

Cirrhosis

0.1 AU/mL

20 ng/mL

Mixed

52.8%/70.1%

98.8%/75.5%

Tian et al 2022 [58]

China

145/57

Benign liver disease

58.9/48.1

38.91 mAU/mL

5.6 ng/mL

Mixed

92.4%/88.3%

96.5%/98.2%

Viggiani et al 2016 [59]

Italy

60/60

Benign liver disease

39 - 86/26 - 84

47 mAU/mL

20 mAU/mL

Mixed

60%/55%

90%/55%

Volk et al 2007 [60]

USA

84/169

Cirrhosis

59/53

150 mAU/mL

23 ng/mL

Mixed

86%/69%

93%/91%

Wang et al 2005 [61]

Taiwan

61/66

Chronic hepatitis and cirrhosis

63/54.5

40 mAU/mL

20 ng/mL

Mixed

77%/59%

86.4%/77.3%

Wang et al 2019 [62]

China

176/359

Chronic hepatitis B

53/49

162.22 mAU/mL

145.65 ng/mL

HBV

51.3%/64.8%

93.6%/77.2%

Wang et al 2020 [63]

China

234/396

Chronic hepatitis B

54/48

87.63 mAU/mL

499.80 ng/mL

HBV

86.80%/52.10%

90.20%/91.40%

Xu et al 2021 [64]

China

308/120

Benign liver disease + cirrhosis

51.4/44.56

40 mAU/mL

25 ng/mL

Mixed

89.0%/86.8%

91.7%/87.6%

Yoon et al 2009 [65]

South Korea

106/100

Non-HCC

54.5/ND

40 mAU/mL

20 ng/mL

Mixed

51.9%/57.5%

97%/88%

Yu et al 2015 [66]

China

134/505

Liver diseases + other cancers + healthy controls

49.6/50.93

200 mAU/mL

195.2 ng/mL

Mixed

64.2%/60.4%

90.8%/89.6%

Zhang and Huang 2022 [67]

China

228/103

Cirrhosis

56/58

25.3 ng/mL

7 ng/mL

Mixed

70.18%/63.16%

82.50%/85.44%

**Table 2.** Comparison of Diagnostic Accuracy of PIVKA-II and AFP
Marker	Sensitivity (95% CI)	Specificity (95% CI)	NLR (95% CI)	PLR (95% CI)	DOR (95% CI)	AUC (95% CI)
AFP: α-fetoprotein; AUC: area under the ROC curve; CI: confidence interval; DOR: diagnostic odds ratio; NLR: negative likelihood ratio; PIVKA-II: protein induced by vitamin K absence or antagonist-II; PLR: positive likelihood ratio.
PIVKA-II	0.71 (0.70 - 0.72)	0.90 (0.89 - 0.90)	0.30 (0.27 - 0.35)	7.18 (5.96 - 8.66)	27.12 (21.14 - 37.79)	0.89 (0.88 - 0.90)
AFP	0.64 (0.63 - 0.65)	0.87 (0.87 - 0.88)	0.42 (0.39 - 0.45)	5.08 (4.20 - 6.15)	12.94 (10.35 - 16.18)	0.78 (0.77 - 0.79)

Table 2. Comparison of Diagnostic Accuracy of PIVKA-II and AFP

Marker

Sensitivity (95% CI)

Specificity (95% CI)

NLR (95% CI)

PLR (95% CI)

DOR (95% CI)

AUC (95% CI)

AFP: α-fetoprotein; AUC: area under the ROC curve; CI: confidence interval; DOR: diagnostic odds ratio; NLR: negative likelihood ratio; PIVKA-II: protein induced by vitamin K absence or antagonist-II; PLR: positive likelihood ratio.

PIVKA-II

0.71 (0.70 - 0.72)

0.90 (0.89 - 0.90)

0.30 (0.27 - 0.35)

7.18 (5.96 - 8.66)

27.12 (21.14 - 37.79)

0.89 (0.88 - 0.90)

AFP

0.64 (0.63 - 0.65)

0.87 (0.87 - 0.88)

0.42 (0.39 - 0.45)

5.08 (4.20 - 6.15)

12.94 (10.35 - 16.18)

0.78 (0.77 - 0.79)

**Table 3.** Meta-Regression Analysis of Potential Sources of Heterogeneity
Factor	PIVKA-II	AFP
AFP: α-fetoprotein; PIVKA-II: protein induced by vitamin K absence or antagonist-II.
Ethnicity	0.335	0.105	-0.061	0.673
Etiology	0.185	0.287	-0.084	0.500
Sample size	-0.026	0.930	0.014	0.949

Table 3. Meta-Regression Analysis of Potential Sources of Heterogeneity

Factor

PIVKA-II

AFP

Coefficient

P value

Coefficient

P value

AFP: α-fetoprotein; PIVKA-II: protein induced by vitamin K absence or antagonist-II.

Ethnicity

0.335

0.105

-0.061

0.673

Etiology

0.185

0.287

-0.084

0.500

Sample size

-0.026

0.930

0.014

0.949

**Table 4.** Subgroup Analysis of the Diagnostic Accuracy of PIVKA-II and AFP
Moderator	Subgroups	PIVKA-II	AFP
AFP: α-fetoprotein; AUC: area under the ROC curve; CI: confidence interval; DOR: diagnostic odds ratio; HBV: hepatitis B virus; HCV: hepatitis C virus; PIVKA-II: protein induced by vitamin K absence or antagonist-II.
Ethnicity	Africa	0.817 (0.756 - 0.868)	0.897 (0.849 - 0.933)	10,415 (6,314 - 17,179)	0.968 (0.945 - 0.986)	0.784 (0.721 - 0.839)	0.906 (0.860 - 0.941)	34,544 (19,580 - 60,945)	0.940 (0.934 - 0.946)
	Europe	0.634 (0.604 - 0.662)	0.875 (0.857 - 0.892)	12,082 (8,798 - 16,591)	0.812 (0.804 - 0.824)	0.603 (0.574 - 0.633)	0.852 (0.833 - 0.870)	9,145 (4,753 - 17,595)	0.706 (0.697 - 0.714)
	Asia	0.716 (0.703 - 0.728)	0.906 (0.899 - 0.913)	30,759 (23,184 - 40,809)	0.910 (0.045 - 0.921)	0.643 (0.629 - 0.655)	0.879 (0.872 - 0.887)	13,858 (10,441 - 17,676)	0.799 (0.784 - 0.808)
	America	0.777 (0.747 - 0.804)	0.859 (0.838 - 0.878)	53,251 (15,058 - 188,31)	0.912 (0.903 - 0.923)	0.632 (0.599 - 0.665)	0.848 (0.826 - 0.867)	12,366 (7,213 - 21,202)	0.733 (0.721 - 0.749)
Etiology	Mixed	0.706 (0.694 - 0.718)	0.885 (0.887 - 0.893)	24,933 (18,697 - 33,250)	0.901 (0.897 - 0.911)	0.657 (0.645 - 0.669)	0.874 (0.866 - 0.882)	12,967 (9,893 - 16,995)	0.785 (0.778 - 0.796)
	HCV	0.675 (0.616 - 0.731)	0.911 (0.885 - 0.932)	31,639 (7,453 - 134,31)	0.845 (0.831 - 0.853)	0.575 (0.513 - 0.635)	0.790 (0.755 - 0.822)	6,865 (3,346 - 14,083)	0.665 (0.650 - 0.670)
	HBV	0.749 (0.724 - 0.772)	0.917 (0.905 - 0.927)	40,281 (23,256 - 69,770)	0.912 (0.904 - 0.924)	0.588 (0.561 - 0.615)	0.873 (0.859 - 0.886)	13,718 (9,209 - 20,434)	0.820 (0.809 - 0.831)
Sample size	≤ 100	0.711 (0.686 - 0.735)	0.893 (0.879 - 0.907)	27,398 (17,183 - 43,685)	0.903 (0.891 - 0,910)	0.678 (0.652 - 0.702)	0.823 (0.806 - 0.840)	10,350 (6,626 - 16,169)	0.773 (0.764 - 0,779)
	> 100	0.714 (0.702 - 0.725)	0.896 (0.889 - 0.902)	27,279 (20,162 - 36,907)	0.890 (0.881 - 0.896)	0.631 (0.619 - 0.643)	0.844 (0.877 - 0.891)	14,678 (11,381 - 19,930)	0.796 (0.789 - 0.802)

Table 4. Subgroup Analysis of the Diagnostic Accuracy of PIVKA-II and AFP

Moderator

Subgroups

PIVKA-II

AFP

Sensitivity (95% CI)

Specificity (95% CI)

DOR (95% CI)

AUC (95% CI)

Sensitivity (95% CI)

Specificity (95% CI)

DOR (95% CI)

AUC (95% CI)

AFP: α-fetoprotein; AUC: area under the ROC curve; CI: confidence interval; DOR: diagnostic odds ratio; HBV: hepatitis B virus; HCV: hepatitis C virus; PIVKA-II: protein induced by vitamin K absence or antagonist-II.

Ethnicity

Africa

0.817 (0.756 - 0.868)

0.897 (0.849 - 0.933)

10,415 (6,314 - 17,179)

0.968 (0.945 - 0.986)

0.784 (0.721 - 0.839)

0.906 (0.860 - 0.941)

34,544 (19,580 - 60,945)

0.940 (0.934 - 0.946)

Europe

0.634 (0.604 - 0.662)

0.875 (0.857 - 0.892)

12,082 (8,798 - 16,591)

0.812 (0.804 - 0.824)

0.603 (0.574 - 0.633)

0.852 (0.833 - 0.870)

9,145 (4,753 - 17,595)

0.706 (0.697 - 0.714)

Asia

0.716 (0.703 - 0.728)

0.906 (0.899 - 0.913)

30,759 (23,184 - 40,809)

0.910 (0.045 - 0.921)

0.643 (0.629 - 0.655)

0.879 (0.872 - 0.887)

13,858 (10,441 - 17,676)

0.799 (0.784 - 0.808)

America

0.777 (0.747 - 0.804)

0.859 (0.838 - 0.878)

53,251 (15,058 - 188,31)

0.912 (0.903 - 0.923)

0.632 (0.599 - 0.665)

0.848 (0.826 - 0.867)

12,366 (7,213 - 21,202)

0.733 (0.721 - 0.749)

Etiology

Mixed

0.706 (0.694 - 0.718)

0.885 (0.887 - 0.893)

24,933 (18,697 - 33,250)

0.901 (0.897 - 0.911)

0.657 (0.645 - 0.669)

0.874 (0.866 - 0.882)

12,967 (9,893 - 16,995)

0.785 (0.778 - 0.796)

HCV

0.675 (0.616 - 0.731)

0.911 (0.885 - 0.932)

31,639 (7,453 - 134,31)

0.845 (0.831 - 0.853)

0.575 (0.513 - 0.635)

0.790 (0.755 - 0.822)

6,865 (3,346 - 14,083)

0.665 (0.650 - 0.670)

HBV

0.749 (0.724 - 0.772)

0.917 (0.905 - 0.927)

40,281 (23,256 - 69,770)

0.912 (0.904 - 0.924)

0.588 (0.561 - 0.615)

0.873 (0.859 - 0.886)

13,718 (9,209 - 20,434)

0.820 (0.809 - 0.831)

Sample size

≤ 100

0.711 (0.686 - 0.735)

0.893 (0.879 - 0.907)

27,398 (17,183 - 43,685)

0.903 (0.891 - 0,910)

0.678 (0.652 - 0.702)

0.823 (0.806 - 0.840)

10,350 (6,626 - 16,169)

0.773 (0.764 - 0,779)

> 100

0.714 (0.702 - 0.725)

0.896 (0.889 - 0.902)

27,279 (20,162 - 36,907)

0.890 (0.881 - 0.896)

0.631 (0.619 - 0.643)

0.844 (0.877 - 0.891)

14,678 (11,381 - 19,930)

0.796 (0.789 - 0.802)