Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer.
Obesity and associated metabolic disorders have been implicated in liver carcinogenesis; however, there are little data on the role of obesity-related biomarkers on liver cancer risk. We studied prospectively the association of inflammatory and metabolic biomarkers with risks of hepatocellular carcinoma (HCC), intrahepatic bile duct (IBD), and gallbladder and biliary tract cancers outside of the liver (GBTC) in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Over an average of 7.7 years, 296 participants developed HCC (n=125), GBTC (n=137), or IBD (n=34). Using risk-set sampling, controls were selected in a 2:1 ratio and matched for recruitment center, age, sex, fasting status, and time of blood collection. Baseline serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), C-peptide, total high-molecular-weight (HMW) adiponectin, leptin, fetuin-a, and glutamatdehydrogenase (GLDH) were measured, and incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for lifestyle factors, diabetes, hepatitis infection, and adiposity measures, higher concentrations of CRP, IL-6, C-peptide, and non-HMW adiponectin were associated with higher risk of HCC (IRR per doubling of concentrations=1.22; 95% CI=1.02-1.46; P=0.03; 1.90; 95% CI=1.30-2.77; P=0.001; 2.25; 95% CI=1.43-3.54; P=0.0005; and 2.09; 95% CI=1.19-3.67; P=0.01, respectively). CRP was associated also with risk of GBTC (IRR=1.22; 95% CI=1.05-1.42; P=0.01). GLDH was associated with risks of HCC (IRR=1.62; 95% CI=1.25-2.11; P=0.0003) and IBD (IRR=10.5; 95% CI=2.20-50.90; P=0.003). The continuous net reclassification index was 0.63 for CRP, IL-6, C-peptide, and non-HMW adiponectin and 0.46 for GLDH, indicating good predictive ability of these biomarkers.


CONCLUSIONS
Elevated levels of biomarkers of inflammation and hyperinsulinemia are associated with a higher risk of HCC, independent of obesity and established liver cancer risk factors.
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.
Krasimira
K
Aleksandrova
Heiner
H
Boeing
Ute
U
Nöthlings
Mazda
M
Jenab
Veronika
V
Fedirko
Rudolf
R
Kaaks
Annekatrin
A
Lukanova
Antonia
A
Trichopoulou
Dimitrios
D
Trichopoulos
Paolo
P
Boffetta
Elisabeth
E
Trepo
Sabine
S
Westhpal
Talita
T
Duarte-Salles
Magdalena
M
Stepien
Kim
K
Overvad
Anne
A
Tjønneland
Jytte
J
Halkjaer
Marie-Christine
MC
Boutron-Ruault
Laure
L
Dossus
Antoine
A
Racine
Pagona
P
Lagiou
Christina
C
Bamia
Vassiliki
V
Benetou
Claudia
C
Agnoli
Domenico
D
Palli
Salvatore
S
Panico
Rosario
R
Tumino
Paolo
P
Vineis
Bas
B
Bueno-de-Mesquita
Petra H
PH
Peeters
Inger Torhild
IT
Gram
Eiliv
E
Lund
Elisabete
E
Weiderpass
J Ramón
JR
Quirós
Antonio
A
Agudo
María-José
MJ
Sánchez
Diana
D
Gavrila
Aurelio
A
Barricarte
Miren
M
Dorronsoro
Bodil
B
Ohlsson
Björn
B
Lindkvist
Anders
A
Johansson
Malin
M
Sund
Kay-Tee
KT
Khaw
Nicholas
N
Wareham
Ruth C
RC
Travis
Elio
E
Riboli
Tobias
T
Pischon
D000328:Adult; D000368:Aged; D001661:Biliary Tract Neoplasms / Q000097:blood / Q000453:epidemiology* / Q000473:pathology*; D015415:Biomarkers / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000453:epidemiology* / Q000473:pathology*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D015994:Incidence; D007249:Inflammation / Q000097:blood / Q000453:epidemiology / Q000473:pathology; D008113:Liver Neoplasms / Q000097:blood / Q000453:epidemiology* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors
D015415:Biomarkers