• Why is Gallbladder Cancer Mortality Decreasing in Some Countries but Increasing in Others?

Why is Gallbladder Cancer Mortality Decreasing in Some Countries but Increasing in Others?

Deaths from gallbladder and other biliary tract cancers are decreasing in most countries, but increasing in some high-income countries following decades of decline, researchers report in the March issue of Clinical Gastroenterology and Hepatology. These emerging trends may reflect lifestyle changes, such as increases in excess body weight.

Gallbladder cancer is unique. Fewer that 20% of patients with gallbladder cancer survive for 5 years, and it is one of only a few cancers that have higher incidence in women than in men. Some of the highest incidence rates have been observed in populations of the Americas with indigenous ancestry, including the Mapuche Indians of Chile, Alaska Natives, and Hispanics in Latin America and the United States. Geographic variation in the prevalence of gallstones, a primary risk factor for the disease, contributes to worldwide gallbladder cancer patterns.

Lindsey A. Torre et al investigated global patterns and trends in gallbladder and other biliary tract cancers, by sex, using the most recent available data from the World Health Organization mortality database. To limit bias due to misclassification of the cause of death among elderly populations, they included only data from patients 35 to 74 years old and excluded data from countries where death registration coverage was insufficient. Torre et al used joinpoint regression analysis to assess the temporal changes in mortality from gallbaldder and biliary cancers.

In their compilation of cross-sectional mortality data from 2009 through 2013 from 50 countries, Torre et al found that among women, there was a 26-fold variation in rates of mortality from gallbladder and other biliary tract cancers. Rates ranged from 0.8 deaths per 100,000 in South Africa to 21.2 deaths per 100,000 in Chile (see figure).

Among men, rates varied 16-fold, from 0.6 deaths per 100,000 in the United Kingdom and Ireland to 9.9 deaths per 100,000 in Chile.

Women had higher mortality than men in 22 of 48 countries for which the authors were able to make comparisons.

Over the past decade, rates of death from gallbladder and other biliary cancers decreased significantly in 36 of 45 countries among women and in 23 of 39 countries among men. Rates were decreasing in all included countries for women in Asia and Latin America and the Caribbean, although this pattern was not consistent for men.

Populations with the highest rates of death from gallbladder and other biliary cancers (men: Chile, Republic of Korea, Japan, and Czech Republic; women: Chile, Czech Republic, Republic of Korea, and Poland) had decreases ranging from 2% to greater than 3% annually.

However, rates increased for men and women in Croatia and Greece. Rates continued their long-term increase in Greece, by 1.4% annually in women and 4.7% annually in men from 1985 through 2012. Rates also began increasing in the mid-2000s, by 1.9% or more annually, in women in the United Kingdom and The Netherlands and in men in Germany.

Torre et al explain that unique risk factors might account for worldwide variations in gallbladder cancer rates. For instance, a genetic predisposition to gallstone formation among Chilean Hispanics and Mapuche Indians has been linked to high rates of gallbladder cancer in Chile. High rates in women in countries such as the Czech Republic, Poland, and Hungary might also be linked to a higher occurrence of gallstones in these countries. Women are more predisposed to cholelithiasis than men, which could account for their higher incidence of gallbladder cancers. The incidence of gallbladder cancers correlates with the prevalence of cholelithiasis, especially in Latin America. The high risk of disease in Chile also has been associated with aflatoxin exposure through the common consumption of ají rojo (red chili peppers).

Although no dietary factors have been linked consistently to risk of gallbladder and other biliary cancers, geographic variation in eating habits, including consumption of sweetened beverages or foods contaminated with mycotoxins, may contribute to geographic disparities.

Anomalous pancreaticobiliary duct junctions and choledochal cysts, congenital malformations of the biliary tree that appear to be most common among Asians, especially the Japanese, increase the risk of gallbladder cancer through a different carcinogenic pathway from gallstones and chronic gallbladder inflammation.

Risk factors for gallbladder and other biliary tract cancers include obesity, diabetes, and consumption of sucrose and sweetened beverages. Implicated toxins include mycotoxins or infections with Salmonella, Helicobacter, HBV, or HCV.

Use of statins might reduce the risk of gallstone disease and cancer by inhibiting hepatic cholesterol biosynthesis and biliary cholesterol secretion. Statins have been used widely in high-income countries since the 1990s and have helped reduce cardiovascular disease mortality. Although statin use may have contributed to recent decreases in gallbladder cancer mortality, rates began decreasing in many countries before widespread uptake of the drug.

It is not clear why mortality from gallbladder and other biliary tract cancers is increasing in Greece. The proportion of female gallbladder cancers associated with excess body weight in Greece (47%) is similar to that in other European countries, and lower than that in the United States (54%). Although body weight has been increasing in Greece, especially among men, the trends and prevalence of excess body weight are similar to those of other European countries, so could not account for the gallbladder cancer mortality trend. The recent increase in gallbladder mortality in the United Kingdom, The Netherlands, and Germany is believed to be due to the obesity epidemic.

In an editorial that accompanies the article, Tomonori Matsumoto and Hiroshi Seno write that the study is important because it elucidated the temporal trends in gallbladder and other biliary cancer deaths over several decades. It showed that mortality from these cancers has decreased significantly for decades in women in 80% of the countries and in men in more than 50% of the countries. However, this previous long-term decrease has leveled out or even reversed, as noted in some countries during the 2000s.

Matsumoto and Seno state that more research is neededespecially in countries such as Chile, Japan, and Greece, with the highest rates, male dominance, and increasing trends of gallbladder and other biliary cancers.

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