Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract and the third most common gastrointestinal tract malignancy. About 178,100 new cases were diagnosed around the world in 2012, but the number of deaths from the disease was relatively high by comparison at 142,800.1 The incidence of GBC is especially high in South America, affecting 27 per 100,000 people.2 The high rates of GBC in South America and Asia including India, Pakistan, Korea, and Japan have been attributed to high rates of gallstones (GS) and chronic Salmonella infection, both of which are known risk factors for GBC.3 However, other risk factors, including those emanating from environmental exposure and heritable genetic traits and gender predisposition etc, have been focus of researchers for a long time so as to develop preventive strategies.
We read with great interest the recent article on association of aflatoxins with GBC published in Gastroenterology.4 In this case-control study of patients with GBC and GS versus patients with GS without cancer, the authors report an association between exposure to aflatoxin (based on plasma level of AFB1-lysine) with GBC, and based on which they further suggest that reducing aflatoxin exposure may reduce the incidence of GBC. Aflatoxins are secondary metabolites of Aspergillus flavus and Aspergillus parasiticus, and contaminate a variety of staple foods, particularly maize and groundnuts, in low-income countries. However, as per an estimate, approximately 4.5 billion of the world's population is exposed to aflatoxins,5 affecting many tropical countries comprising parts of Africa, Asia, and Latin America, but GBC is not as rampant disease in these geographical areas as compared with hepatocellular carcinoma, which has s more established connection with aflatoxin exposure based on the evidence from epidemiologic studies in exposed populations and mechanistic studies. In fact, GBC is a cancer type for which differences in incidence ratios point to variations in etiology in different populations.1
This study by Koshiol et al4 is based on the premise that GS are the strongest risk factor for GBC and this study allowed them to evaluate whether exposure to aflatoxin is associated with risk of GBC in the context of GS. It is important to note that in Asia, India has highest incidence of GS (10%–22%) as compared with China (5%) and Japan (5%).3 These data4 showing higher levels of aflatoxins adducts in the plasma of Chinese population with GS as a risk factor for GBC raises another pertinent question as to what makes patients with GS in India (another Asian country with higher GBC incidence, at 11,172 and 9450 cases of incidence and mortality in females has been reported just for 2012) less vulnerable for GBC as compared with their Chinese counterparts (27,699 cases of incidence and 22,475 cases of mortality in females), with incidence and mortality almost twice to that of India,6 even though China has lower incidence of GS in its population3 as compared with that of India? Does no association between aflatoxin exposure and patients with GBC in the Indian population as reported earlier in a recent study7 hold the key to the answer of this question?
Interestingly, the incidence of GBC has a specific geographic and ethnic variation in most populations; for example, in India GBC is most prevalent in northern and northeastern states of Uttar Pradesh, Bihar, Orissa, West Bengal, and Assam, with a 10 times lower incidence per 100,000 in South India compared with the North, the age-adjusted incidence rate for females being 0.8 in Chennai in the south and 8.9 in Delhi in the north.3,6 This stark difference in the incidence of GBC within a country where exposure to aflatoxins is almost similar suggests a need for further studies to explore the role of aflatoxins in a disease with as complex an etiology as GBC with more variables to be taken into considerations. Although this study4 explored the role of R249S mutation in the TP53 gene, which has been known to be associated with aflatoxin-related hepatocellular carcinoma, no association between GBC and this mutation was observed indicating the need for discovery of more genetic markers to serve as surrogate for aflatoxins’ exposure in the populations. Further studies in other populations using polymorphic variants of genes and proteins such as glutathione S-transferase and cytochrome-P450, known to be involved in the metabolism of aflatoxins as well as known genetic risk factors associated with GBC,8 are needed to generate more robust datasets after multivariate analyses so as to adjust for confounding factors, if any, which may otherwise distort the apparent exposure–disease relationship.