Abstract
Background
Methods
Results
Conclusions
Keywords
1. Introduction
2. Methods
2.1 Search strategy
2.2 Eligibility criteria
2.3 Data extraction
2.4 Statistical methods for meta-analysis
2.5 Statistical methods for PAR calculations
where is aflatoxin attributable risk fraction in the population including exposed and unexposed individuals, Pi is the proportion of the population in stratum i that is exposed, and Wi is the proportion of diseased individuals (cases) in stratum i. We use adjusted ORi in stratum i as an approximation of RRi.
where Pc is the proportion of cases exposed in the combined population based on detection limits for aflatoxin biomarkers in the studies, and HBsAg positivity-adjusted OR is used as an approximation of RR. For each AFpop, we calculated 95% confidence intervals (CI) using the method described in Daly.
3. Results
3.1 Literature search

3.2 Study characteristics
No | Source | Location/period | Sex | Age, yrs | No of cases (% exposed) | No of controls (% exposed) | Measure/range of exposure, detection limit | Adjusted ORs/RRs | Adjustment for covariates |
---|---|---|---|---|---|---|---|---|---|
1 | Qian et al., 1994 6 (cohort of 18,244 middle-aged men) | China, 1986–1992 | M | 45–64 | 50 cases (36%) | 267 matched controls (12%) | AFB1-N7-Gua adduct (detectable vs non-detectable, 0.07 ng aflatoxins/ml urine | 9.1 (2.9–29.2) | HBsAg positivity, cigarette smoking |
50 cases (72%) | 267 matched controls (41%) | Multiple urinary biomarker (detectable vs non-detectable, 0.01fmol/μg) | 5.0 (2.1–11.8) | ||||||
2 | Chen et al., 1996 18 (7 township cohort nested case-control study) | Taiwan, 1991–1992 | F/M | 36–65 | 20 cases (65%) | 86 matched controls (37%) | AFB1-albumin adducts (detectable Vs non-detectable, 0.01fmol/μg) | 5.5 (1.2–24.5) | HBsAg, anti-HCV, family history of liver cancer cirrhosis |
3 | Chen et al., 1996 19 (nested case-control in cohort of 4841 male HBsAg individuals) | Taiwan, 1988–1992 | M | 30–65 | 32 cases (37.5% low exposure) | 73 matched controls (33% low exposure) | AFB1-albumin adducts (Low Vs Non-detectable, 0.01fmol/μg) | 1.6 (0.6–4.0) | Cigarette smoking, alcohol consumption |
32 cases (19% high exposure) | 73 matched controls (6.8% high exposure) | AFB1-albumin adducts (High Vs Non-detectable, 0.01fmol/μg) | 3.8 (1.0–14.5) | ||||||
4 | Wang et al., 1996 7 (7 township cohort nested case-control study | Taiwan, 1991–1995 | F/M | 30–64 | 52 cases (60%) | 168 matched controls (37%) | AFB1-albumin adducts (detectable vs non-detectable, 0.01fmol/μg) | 1.6 (0.4–5.5) | HBsAg positivity |
38 cases (53%) | 137 matched controls (45%) | Urinary aflatoxin metabolite (high vs low, 0.01fmol/μg) | 3.8 (1.1–12.8) | ||||||
5 | Zhang et al., 1997 22 (Hospital-based case-control study) | China, 1994–1995 | F/M | 18–88 | 152 cases (33%) | 115 non-hepatic patient controls (2%) | Corn consumption history from dietary questionnaire | (1:1 pair-matched) 16.44 (1.67–61.65) | HBV infection, individual history of liver diseases, family history of liver diseases, and peanut consumption |
152 cases (89%) | 115 non-hepatic patient controls (49%) | Peanut consumption history from dietary questionnaire | 3.51 (1.45–8.47) | HBV infection, individual history of liver diseases, family history of liver diseases, and corn consumption | |||||
6 | Yu et al., 1997 21 (nested case-control of a cohort of 4841 male HBsAg individuals) | Taiwan, 1988–1994 | M | 30–65 | 42 cases (29%) | 43 matched controls (14%) | AFB1-N7-gua, (below 0.21 ng/ml Vs 0.21–0.36 ng/ml, 0.05 ng aflatoxin/ml urine) | 5.3 (1.1–25.2) | Education level, ethnicity, habitual alcohol drinking and cigarette smoking status |
42 cases (14%) | 43 matched controls (16%) | AFB1-N7-gua (below 0.21 ng/ml Vs > 0.36 ng/ml, 0.05 ng aflatoxin/ml urine) | 2.8 (0.6–12.9) | ||||||
42 cases (24%) | 43 matched controls (23%) | AFM1 (below 1.61 ng/ml Vs 1.61–2.85 ng/ml, 0.05 ng aflatoxin/ml urine) | 1.9 (0.5–7.2) | ||||||
42 cases (55%) | 43 matched controls (35%) | AFM1 (below 1.61 ng/ml Vs > 2.85 ng/ml, 0.05 ng aflatoxin/ml urine) | 6.0 (1.2–29.0) | ||||||
7 | Lunn et al., 1997 20 (case-control study) | Taiwan, 1984–1995 | F/M | 105 cases (80%) | 37 controls (43%) | AFB1-DNA adducts | Corrected OR: 3.9 (1.4–11.5) | n/a | |
8 | Kirk et al., 2000 23 (case-control study) | The Gambia, 1997–1998 | F/M | 20–73 | 53 cases (36%) | 53 matched controls (5.7%) | Ser-249 P53 mutation | 16.4 (3.0–90.5) | Age, sex, recruitment site and HBsAg positivity |
9 | Sun et al., 2001 25 (7 township cohort nested case-control study, HBsAg individuals) | Taiwan, 1991–1997 | F/M | 30–64 | 75 cases (64%) | 140 matched controls (46%) | Aflatoxin-albumin adducts (detectable vs non-detectable, 0.01fmol/μg) | 2.0 (1.1–3.7) | Sex, age and residence |
10 | Omer et al., 2001 24 (case-control study) | Sudan 1996–1998 | F/M | 20–70 | 115 cases | 199 matched controls | Peanut butter consumption > 300 g/mo Vs Peanut butter consumption < 70 g/mo | 3.3 (1.4–8.1) | Age and hepatitis |
11 | Ming et al., 2002 26 (Hospital-based cohort, 145 HBsAg individuals) | Qidong, China | M | 27–74 | 31 cases | 145 HBsAg + carriers follow up | AFM1 (>3.6 ng/l) | 3.5 (1.5–8.1) | Age, HCV, family history of HCC |
12 | Huang et al., 2003 27 (case-control study) | Qidong, China | F/M | 19–87 | 25 cases (40%) | 30 controls (6.7%) | Ser 249 TP 53 mutation | 22.1 (3.2–91.7) | Sex, age, recruitment site and HBsAg positivity |
13 | Omer et al., 2004 8 (case-control study) | Sudan, 1996–1998 | F/M | 20–70 | 114 cases (46%) | 198 matched controls (26%) | Peanut butter consumption > 300 g/mo Vs Peanut butter consumption < 70 g/mo | n/a | age |
14 | Kirk et al., 2005 5 (case-control study) | Gambia, | F/M | 186 cases (40%) | 348 matched controls (3.4%) | Ser-249 TP53 mutation | 20.3 (8.19–50.0) | Adjusted for study group, season of recruitment and daily groundnut intake | |
15 | Long et al., 2009 28 (hospital-based case-control) | China, 2006–2008 | F/M | 12.1% < 35, 77.8% 35–65, 10.1% > 65 | 618 cases (28%) | 712 matched control (29%) | AFB1-adduct: Low (⩽ 1·00 μmol/mol DNA) Vs Medium (1.01–2.00 μmol/mol DNA), (0.25 μmol/mol DNA) | 2.11 (1.54–2.90) | Age, sex, ethnicity, HBsAg, anti-HCV, and AFB1 –exposure years |
618 cases (47%) | 712 matched controls (17%) | AFB1-adduct: Low (⩽ 1.00 μmol/mol DNA) Vs High (⩾2.01 μmol/mol DNA) (0.25 μmol/mol DNA) | 6.23 (4.48–8.67) | ||||||
16 | Wu et al., 2009 30 (7 township cohort nested case-control study) | Taiwan 1991–2004 | F/M | 30–64 yr | 230 cases (93%) | 1052 matched controls (95%) | AFB1-albumin adduct(fmol/mg): Non-detectable Vs Detectable (0·01fmol/μg or 1fmol/ml) | 0.99 (0.48–2.02) | HBsAg, anti-HCV, habitual smoking, alcohol drinking, BMI and the batch of aflatoxin biomarker assay |
230 cases (33%) | 1052 matched controls (33%) | AFB1-albumin adduct(fmol/mg): Below the mean (<59·8) vs. Above the mean (⩾59·8), | 1.54 (1.01–2.36) | ||||||
198 cases (88%) | 904 matched controls (88%) | Urinary AFB1 metabolites (fmol/ml): Non-detectable Vs Detectable (0.01fmol/μg or 1fmol/ml) | 1.70 (0.89–3.25) | ||||||
198 cases (57%) | 904 matched controls (44%) | Urinary AFB1 metabolites: Below the mean Vs Above the mean | 1.76 (1.18–2.58) | ||||||
17 | Szymanska et al., 2009 29 (nested case-control study) | China, 1989–1998 | M | 30–59 | 126 cases (67%) | 123 matched controls (68%) | AF-albumin Detectable Vs non-detectable (3 pg/mg) | 0.90 (0.52–1.56) | In HBV individuals |
Risk factor | Study population | Study area (n of studies) | Cases/controls a If there was a series of follow-up studies in the same cohort need to be combined, only the numbers of cases and controls from the largest follow-up study were counted, although different odds ratios from different follow-up studies were combined to assess the effect. All the cases and controls were only counted once, and as well as in calculations presented in Tables 4 and 5. | Odds ratio, 95% CI | Model | Heterogeneity |
---|---|---|---|---|---|---|
Aflatoxin only | General population with HBsAg+ adjustment | China 4 , 6 , 22 , 27 , 28 | 634 cases/913 controls | 5.99 (3.70–9.69) | Fixed | Q = 4.86, P = 0.18, I2 = 38.32 |
Taiwan 3 , 7 , 18 , 30 | 198 cases/904 controls | 2.01 (1.40–2.89) | Fixed | Q = 3.19, P = 0.20, I2 = 37.29 | ||
Sub-Saharan Africa 2 , 23 , 24 | 168 cases/252 controls | 4.62 (2.12–10.08) | Fixed | Q = 2·69, P = 0·1, I2 = 62·82 | ||
Summary 9 | 1000 cases/2069 controls | 4.75 (2.78–8.11) | Random | Q = 32.73, P < 0·000, I2 = 75.56 | ||
General population with HBsAg+ adjustment after adjust heterogeneity | Summary 8 , 5 , 6 , 7 , 8 , 18 , 22 , 27 , 28 | 840 cases/1302 controls | 5.72 (4.42–7.40) | Fixed | Q = 8.40, P = 0.30, I2 = 16.66 | |
General population with HBsAg+ adjustment by only including Wu et al. as follow-up for cohort in Taiwan | Summary 7 , 5 , 6 , 8 , 22 , 27 , 28 , 30 | 1000 cases/2069 controls | 4.88 (2.62–9.10) | Random | Q = 32.55, P < 0.000, I2 = 81.57 | |
General population with HBsAg+ adjustment by taking the average effect of the series of Taiwan Studies | Summary 7 | 1000 cases/2069 controls | 4.92 (2.74–8.82) | Random | Q = 29.48, P < 0.000, I2 = 79.65 | |
HBsAg+ individuals | China 3 , 6 , 26 , 29 | 189 cases/268 controls | 2.00 (0.84–4.75) | Random | Q = 10·66, P = 0·005, I2 = 81·24 | |
Taiwan 6 , 7 , 19 , 20 , 21 , 25 , 30 | 254 cases/310 controls | 1.81 (1.29–2.56) | Fixed | Q = 8.38, P = 0.14, I2 = 40.35 | ||
Sub-Saharan Africa 2 , 5 , 8 | 128 cases/56 controls | 6.48 (0.22–194) | Random | Q = 6.54, P = 0.01, I2 = 84.71 | ||
Summary 11 d Seven studies7,15,17,21,22,25,26 reported adjusted ORs on aflatoxin-related HCC risk in HBsAg+ individuals. Four studies5,6,8,16 (including two studies conducted in Sub-Saharan Africa countries) did not provide adjusted ORs directly, but provided data to calculate the unadjusted ORs. We calculated the unadjusted ORs for each of these studies and combined them with ORs from other studies with eligible data, thus we can include the effects of studies in Sub-Saharan Africa population. In subgroup analysis, the large variation of summarised ORs of aflatoxin-related HCC in HBsAg+ individuals may be explained by combining the unadjusted ORs. The heterogeneity was significant when studies were combined to examine the association between aflatoxin exposure and HCC risk in the general population and in HBsAg+ individuals. | 571 cases/634 controls | 2.39 (1.50–3.82) | Random | Q = 27.99, P = 0.002, I2 = 64.27 | ||
HBsAg+ individuals after adjust heterogeneity | Summary 9 , 5 , 6 , 7 , 8 , 19 , 20 , 21 , 25 , 26 | 377 cases/383 controls | 2.90 (2.09–4.01) | Fixed | Q = 11.16, P = 0.19, I2 = 28.29 | |
HBsAg+ individuals by only including most recent follow-up studies in a cohort of Taiwan | Summary 8 , 5 , 6 , 8 , 20 , 21 , 26 , 29 , 30 | 571 cases/634 controls | 2.27 (1.24–4.14) | Random | Q = 24.33, P = 0.001, I2 = 71.23 | |
HBsAg+ individuals by only combing studies with adjusted ORs | Summary | 332 cases/538 controls | 2.10 (1.25–3.52) | Random | Q = 16.40, P = 0.012, I2 = 63.42 | |
HBsAg+ individuals by taking the average effect of all follow-up studies in the same cohort | Summary 8 | 571 cases/634 controls | 2.35 (1.38–3.99) | Random | Q = 23·17, P = 0·002, I2 = 69.79 | |
HBsAg− individuals | China 1 , 6 | 18 cases/ 236 controls | 3·4 (1·13–10·25) | / | / | |
Taiwan 3 , 7 , 20 , 30 | 81 cases/664 controls | 5·00 (2·22–11·28) | Fixed | Q = 3·69, P = 0·16, I2 = 45·79 | ||
Sub-Saharan Africa 2 , 5 , 8 | 122 cases/391 controls | 8·40 (4·15–16·99) | Fixed | Q = 8·40, P = 0·19, I2 = 42·63 | ||
Summary 6 | 221 cases/1291 controls | 5·91 (3·66–9·55) | Fixed | Q = 7·51, P = 0·19, I2 = 33·42 | ||
HBsAg− individuals excluding Wu et al. 30 | Summary 5 | 172 cases/769 controls | 6·37 (3·74–10·86) | Fixed | Q = 7·11, P = 0·13, I2 = 43·71 | |
HBV only | General population | Summary 6 , 5 , 6 , 7 , 8 , 20 , 30 | 244 cases/1072 controls | 11·2 (7·48–16·7) | Fixed | Q = 2·37, P = 0·80, I2 = 0·00 |
General population after adjusted heterogeneity | Summary 5 , 5 , 6 , 7 , 8 , 20 | 171 cases/638 controls | 11·3 (6·75–18·9) | Fixed | Q = 2·36, P = 0·67, I2 = 0·00 | |
Aflatoxin and HBV infection combined effects | General population | Summary 6 , 5 , 6 , 7 , 8 , 20 , 30 | 554 cases/1456 controls | 54·1 (21·3–137·7) | Random | Q = 13·65, P = 0·02, I2 = 63·36 |
General population after adjust heterogeneity | Summary 5 , 5 , 6 , 7 , 8 , 20 | 452 cases/847 controls | 73·0 (36·0–148·3) | Fixed | Q = 3·48, P = 0·48, I2 = 0·00 |
3.3 Aflatoxin exposure and HCC risk by HBsAg Status
3.4 Sensitivity analysis

3.5 Multiplicative model of effects between aflatoxin exposure and chronic HBV infection

3.6 PAR of HCC from aflatoxin exposure in each study population
Studies | Exposure measurement | PAR for aflatoxin attributable HCC risk in HBsAg+ | PAR for aflatoxin attributable HCC risk in HBsAg− | PAR for aflatoxin attributable HCC risk in general study population adjusted by HBsAg+ |
---|---|---|---|---|
Qian et al., 1994 6 (Shanghai, China) | Multiple urinary aflatoxin metabolites | 40% (24–47%) | 3.6% (0.3–5.6%) | 9.0% (5.9–10.4%) |
Chen et al., 1996 18 (Taiwan) | AFB1 albumin adducts | n/a | n/a | 10% (2.5–12%) |
Chen et al., 1996 19 (Taiwan) | AFB1 albumin adducts 6 Low vs undetectable | 4.2% (0–13%) | n/a HBV individuals only | n/a HBV individuals only |
AFB1 albumin adducts 6 High vs undetectable | 4.5% (0–11%) | n/a HBV individuals only | n/a HBV individuals only | |
Sum = 8·7% (0–24%) | n/a HBV individuals only | n/a HBV individuals only | ||
Wang et al., 1996 7 (Taiwan) | AFB1 albumin adducts | 31% (0–51%) | 0 (0–2.3%) | 5% (0–11%) |
Urinary aflatoxin metabolites | 41% (8.1–54%) | 1% (0–4.1%) | 11% (1.4% - 13.7%) | |
Lunn et al., 1997 20 (Taiwan) | AFB1-DNA adduct | 31% (0–75%) | 44% (29%-47%) | n/a |
Yu et al., 1997 21 (Taiwan) | 1.61–2·85 ng/ml AFM1 vs non-detectable) | 2.1% (0–7.2%) | n/a HBV individuals only | n/a HBV individuals only |
>2·85 ng/ml AFM1 vs non-detectable) | 19% (2.2–25%) | n/a HBV individuals only | n/a HBV individuals only | |
Sum = 21% (2.2–32%) | n/a HBV individuals only | n/a HBV individuals only | ||
Zhang et al., 1997 22 (Henan, China) | Corn consumption | n/a | n/a | 17·5% (8–18.4%) |
Peanut consumption | n/a | n/a | 36% (16–45%) | |
Kirk et al., 2000 23 (The Gambia) | Ser 249 TP53 mutation | n/a | n/a | 17% (12–18%) |
Omer et al., 2001 24 (Sudan) | Average peanut butter consumption | n/a | n/a | 23% (11–29%) |
Sun et al., 2001 (Taiwan) 25 | AFB1 albumin adducts | 12% (1.7% - 20%) | n/a HBV individuals only | n/a HBV individuals only |
Ming et al., 2002 26 (Qidong, China) | AFM1 | 57% (16–72%) | n/a | n/a |
Huang et al. 2003 27 (Qidong, China) | Ser 249 TP53 mutation | n/a | n/a | 17% (13–18%) |
Omer et al., 2004 8 (Sudan) | Average peanut butter consumption | 5.4% (0–62%) | 20% (9.0–25%) | n/a |
Kirk et al., 2005 5 (The Gambia) | Ser 249 TP53 mutation | 63% (39–67%) | 12% (6.3–17%) | 13% (12–14%) 6 |
Wu et al., 2009 30 (Taiwan) | AFB1 albumin adducts | 3.7% (0–11%) | 1.7% (0–4.6%) | 2.1% (0.06–3.4%) |
urinary aflatoxin metabolites | 3.1% (0–11.7%) | 4.7% (1.2–6.7%) | 4.4% (1.6–6.3%) | |
Szymanska et al., 2009 29 (Qidong, China) | AFB1 albumin adducts | 0 (0–14%) | n/a HBV individuals only | n/a HBV individuals only |
Long et al., 2009 28 (Guangxi, China) | AFB1-DNA adduct medium vs low | n/a | n/a | 6.8% (4.5–8.5%) |
AFB1-DNA adduct high vs low | n/a | n/a | 19% (17–20%) | |
Total | n/a | n/a | 26% (22–29%) |
Study population | Total exposed cases (n1) | Total sample size (n2) | Pc (n1/n2) | Summarised OR (95% CI) | PAR (95% CI) | |
---|---|---|---|---|---|---|
General population adjusted by HBV status (6, 7, 18, 22–24, 27, 28, 30) | China | 475 | 1588 | 0.299 | 5.99 (3.70–9.69) | 25% (22–27%) |
Taiwan | 113 | 1102 | 0.103 | 2.01 (1.40–2.89) | 5.2% (2.9–6.7%) | |
Sub-Saharan Africa | 82 | 340 | 0.241 | 4.62 (2.12–10.08) | 19% (13–22%) | |
Summary | 670 | 3030 | 0.221 | 4·75 (2·78–8.11) | 17% (14–19%) | |
General population adjusted by HBV status after excluding Wu et al. 2009 30 | Summary | 583 | 2103 | 0.277 | 5.72 (4.42–7.40) | 23% (21–24%) |
Study population | Total HBsAg+ (or HBsAg−) (n1) | Total HCC cases in HBsAg+ (or HBsAg−) (n2) | Total exposed HBsAg+ (or HBsAg−) (n3) | Proportion of HCC cases in HBsAg+ (or HBsAg−) (W1) | Proportion of exposed HBsAg+ (or HBsAg−) (P1) | Summarised OR (95%CI) | PAR (95% CI) | |
---|---|---|---|---|---|---|---|---|
HBV+ population (5–8, 19–21, 25, 26, 29, 30) | China | 457 | 189 | 276 | 0.414 | 0.604 | 2.00 (0.84–4.75) | 16% (0–29%) |
Taiwan | 564 | 254 | 314 | 0.450 | 0.557 | 1.81 (1.29–2.56) | 14% (6.3–21%) | |
Sub-Saharan Africa | 184 | 128 | 76 | 0.696 | 0.413 | 6.48 (0.22–194) | 48% (0–69%) | |
Summary | 1205 | 571 | 666 | 0.473 | 0.553 | 2.39 (1.50–3.82) | 21% (10–29%) | |
HBV+ population after excluding Szymanska et al. 2009 29 and Wu et al(30) | China | 208 | 63 | 108 | 0.303 | 0.519 | 3.01 (1.86–4.88) | 16% (9–20%) |
Taiwan | 368 | 186 | 216 | 0.505 | 0.587 | 2.59 (1.63–4.13) | 24% (14–33%) | |
Summary | 760 | 377 | 400 | 0.496 | 0.526 | 2.90 (2.09–4.01) | 25% (18–30%) | |
HBV− population (5–8, 20, 30) | Taiwan | 745 | 81 | 332 | 0.109 | 0.446 | 5.00 (2.22–11.28) | 7% (3.8–8·9%) |
Sub-Saharan Africa | 513 | 122 | 113 | 0.238 | 0.220 | 8.40 (4.15–16.99) | 15% (9.7–19%) | |
Summary | 1632 | 227 | 617 | 0.139 | 0.353 | 5.91 (3.66–9.55) | 8.8% (6.7–10%) |
4. Discussion
Conflict of interest statement
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Footnotes
☆This work was funded by the National Cancer Institute (5R01CA153073-02) of the United States National Institutes of Health.