Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide. The lack of effective biomarkers for the early detection of HCC results in unsatisfactory curative treatments. Here, metabolite biomarkers were identified and validated for HCC diagnosis. A total of 1,448 subjects, including healthy controls and patients with chronic hepatitis B virus infection, liver cirrhosis, and HCC, were recruited from multiple centers in China. Liquid chromatography–mass spectrometry–based metabolomics methods were used to characterize the subjects' serum metabolic profiles and to screen and validate the HCC biomarkers. A serum metabolite biomarker panel including phenylalanyl‐tryptophan and glycocholate was defined. This panel had a higher diagnostic performance than did α‐fetoprotein (AFP) in differentiating HCC from a high‐risk population of cirrhosis, such as an area under the receiver‐operating characteristic curve of 0.930, 0.892, and 0.807 for the panel versus 0.657, 0.725, and 0.650 for AFP in the discovery set, test set, and cohort 1 of the validation set, respectively. In the nested case–control study, this panel had high sensitivity (range 80.0%‐70.3%) to detect preclinical HCC, and its combination with AFP provided better risk prediction of preclinical HCC before clinical diagnosis. Besides, this panel showed a larger area under the receiver‐operating characteristic curve than did AFP (0.866 versus 0.682) to distinguish small HCC, and 80.6% of the AFP false‐negative patients with HCC were correctly diagnosed using this panel in the test set, which was corroborated by the validation set. The specificity and biological relevance of the identified biomarkers were further evaluated using sera from another two cancers and HCC tissue specimens, respectively. Conclusion: The discovered and validated serum metabolite biomarker panel exhibits good diagnostic performance for the early detection of HCC from at‐risk populations. (Hepatology 2018;67:662‐675).

Quiz Ref ID Worldwide, it has been estimated that more than 2.7 billion individuals were using solid fuels for domestic purposes in 2015, mostly in low- and middle-income countries including China, where an estimated 450 million people still heavily rely on solid fuels, which include biomass (eg, wood, charcoal, and dung) and coal.¹ When combusted indoors, solid fuels generate a large amount of pollutants such as fine particulate matter (PM_2.5).^2,3

China has seen rapid socio-economic and epidemiological changes over the past several decades. Economic growth plus shifts in environment, lifestyles and diet have increased life expectancy, but they have also led to a higher burden of chronic, non-communicable diseases. Stroke, coronary heart disease (CHD), cancer and diabetes account for 80% of the deaths and 70% of the disability-adjusted life-years lost in China.^1,2 In recent decades, epidemics of obesity and metabolic syndrome have grown rapidly in China, although the prevalence is still relatively low compared with Western countries.^3–7

Human exposure to silica dust is very common in both working and living environments. However, the potential long-term health effects have not been well established across different exposure situations. We studied 74,040 workers who worked at 29 metal mines and pottery factories in China for 1 y or more between January 1, 1960, and December 31, 1974, with follow-up until December 31, 2003 (median follow-up of 33 y). We estimated the cumulative silica dust exposure (CDE) for each worker by linking work history to a job–exposure matrix. We calculated standardized mortality ratios for underlying causes of death based on Chinese national mortality rates. Hazard ratios (HRs) for selected causes of death associated with CDE were estimated using the Cox proportional hazards model. The population attributable risks were estimated based on the prevalence of workers with silica dust exposure and HRs. The number of deaths attributable to silica dust exposure among Chinese workers was then calculated using the population attributable risk and the national mortality rate. We observed 19,516 deaths during 2,306,428 person-years of follow-up. Mortality from all causes was higher among workers exposed to silica dust than among non-exposed workers (993 versus 551 per 100,000 person-years). We observed significant positive exposure–response relationships between CDE (measured in milligrams/cubic meter–years, i.e., the sum of silica dust concentrations multiplied by the years of silica exposure) and mortality from all causes (HR 1.026, 95% confidence interval 1.023–1.029), respiratory diseases (1.069, 1.064–1.074), respiratory tuberculosis (1.065, 1.059–1.071), and cardiovascular disease (1.031, 1.025–1.036). Significantly elevated standardized mortality ratios were observed for all causes (1.06, 95% confidence interval 1.01–1.11), ischemic heart disease (1.65, 1.35–1.99), and pneumoconiosis (11.01, 7.67–14.95) among workers exposed to respirable silica concentrations equal to or lower than 0.1 mg/m³. After adjustment for potential confounders, including smoking, silica dust exposure accounted for 15.2% of all deaths in this study. We estimated that 4.2% of deaths (231,104 cases) among Chinese workers were attributable to silica dust exposure. The limitations of this study included a lack of data on dietary patterns and leisure time physical activity, possible underestimation of silica dust exposure for individuals who worked at the mines/factories before 1950, and a small number of deaths (4.3%) where the cause of death was based on oral reports from relatives. Long-term silica dust exposure was associated with substantially increased mortality among Chinese workers. The increased risk was observed not only for deaths due to respiratory diseases and lung cancer, but also for deaths due to cardiovascular disease. Please see later in the article for the Editors' Summary