Monica Acalovschi, MD
Frank Lammert, MD
Gallstones are formed in the biliary tract, mainly in the gallbladder. About 10-15% of gallstone patients have simultaneous gallbladder and common bile duct stones, whereas intrahepatic stones occur less frequently. According to the chemical composition, there are three major types of stones: cholesterol, pigment (bilirubin), and mixed stones.
There is a marked geographic variation in gallstone prevalence (Figure 1). In developed countries, more than 85% of gallstones are cholesterol stones. About 20 million people in the USA (15% of the population) have gallstones 1. The Third National Health and Nutrition Examination Survey (NHANES III) indicated a higher prevalence in Mexican-Americans than in non-Hispanic whites, and a lower prevalence in non-Hispanic blacks 2. An extraordinarily high prevalence was found in American Indians (specifically, the Pima tribe from Arizona) (Figure 1). In Europe, ultrasound studies revealed a prevalence of 9 - 21% and an incidence of 0.63/100 persons/year 3. A trend for increasing gallstone prevalence has been identified in Europe and North America by necroptic 4 and ultrasound studies 5, 6.
Figure 1: Worldwide prevalence of gallstones in females based on ultrasonographic surveys (Stinton LM, Shaffer EA, Gut and Liver 2012,; 6: 172-187).
This trend has also been demonstrated in Japan. Here, a higher gallstone prevalence (10%) than that previously described as well as an increased proportion of cholesterol stones has been documented by the Japan Gallstone Study Group 7. In South Eastern Asia, the prevalence of gallstones (mostly brown pigment) is low. Gallstone prevalence rates are even lower in Africa.
Mortality rates for GD decreased between 1979 and 2004 in the United States by 56% for gallstones as the underlying cause and by 71% for GD as the underlying or other cause (Figure 2). This was the greatest rate of decline for any common digestive disease in this time period 1. The trend is not the same with respect to morbidity rates. Although symptomatic and complicated stones represent only 20% of all gallstones, they lead to clinically relevant morbidity and complications as well as high costs of medical care. Complication rates are higher in older people and in some ethnic groups, and are also influenced by socio-economic factors 8, 9.
Figure 2: Gallstones: age-adjusted rates of death in the United States, 1979-2004 (Everhart JE & Ruhl CE, Gastroenterology 2009; 136: 1134-1144) (with permission from Elsevier).
In the United States, GD is the second most expensive digestive disease only surpassed by gastroesophageal reflux disease. In 2000, GD was the most common inpatient diagnosis, with 262,411 hospitalizations and 2004, there were 1.8 million ambulatory care visits with GD diagnosis 1. Every year about 700,000 cholecystectomies are performed in the United States 11, and 190,000 patients with GD undergo surgery in Germany 12. The health care costs of GD (~ 6.5 billion dollars/year) increased by 20% over the last three decades in the United States 1.
Cholesterol gallstones result from oversaturation of the bile with cholesterol, combined with accelerated nucleation of crystals and impaired gallbladder motility. Advanced age, gender and heredity are major risk factors for cholesterol lithogenesis (Table 1). Cholesterol GD results from the interaction between genetic susceptibility and “lithogenic” environmental factors. Based on twin studies, genetic susceptibility has been estimated to contribute about 25% of the total gallstone risk 13, 14. Variants of the cholesterol transporter ABCG5/G8 may account for one third of the genetic risk 15, 16.
Table 1: Risk factors for gallstone disease
Pigment gallstones form when bilirubin is excreted in excess into bile (black stones) or in association with bile duct infections (brown stones). The major risk factors for black stones are chronic haemolysis and liver cirrhosis, and patients with biliary infections or infestations are at risk for brown stones.
The GD prevalence is rising in the industrialized countries in Europe and America due to the changes in life style. A similar trend appears to be present in some developing countries. Apart from the aging of the population, key risk factors accounting for the increasing GD prevalence are environmental.
Obesity is a major risk factor for cholesterol GD, due to the increased hepatic cholesterol synthesis (via increased HMGCoA reductase activity) and biliary cholesterol excretion. The risk is higher in women and very high in morbidly obese individuals. Multiple weight cycling and rapid weight loss (e.g. after bariatric surgery) enhance the gallstone risk.
An increase of the body mass index between 1980 and 2008 has been documented worldwide, with great variations in different countries. In 2008, an estimated 1.46 billion adults were overweight, and of these, 500 millions were obese 17. The most dramatic obesity epidemic has been observed in the United States: in 1990 no state had an obesity prevalence equal to or higher than 15%; while in 2010 obesity was present in more than 25% of the adult population in half of the country’s states 18.
Type 2 diabetes is associated with an increased risk for GD. An increased cholesterol secretion into bile and gallbladder stasis, due to neuropathy, may explain the higher proportion of gallstone carriers among diabetics. Due to population growth, urbanization, aging and the increasing frequency of obesity and sedentary lifestyle, diabetes will continue to be a major health problem in developed countries and a growing problem in developing countries 19, 20. At the global level, the number of people with diabetes increased from 153 million in 1980 to 347 million in 2008 19. Accordingly, the age-standardized adult diabetes prevalence rate was significantly higher in 2008 (9.8% in men and 9.2% in women) than in 1980 (8.3% and 7.5%, respectively).
Metabolic Syndrome (MS)
The association between GD and obesity is now recognized as part of the MS, which includes central obesity, high triglyceride and low HDL-cholesterol levels, glucose intolerance, and hypertension. Hepatic insulin resistance stimulates cholesterol secretion into bile and impairs bile acid synthesis, favoring gallstone formation 21. Hepatic insulin resistance is associated with GD even in non-diabetic, non-obese individuals 22. The prevalence of MS is increasing up to epidemic proportions in many developed countries.
Non-alcoholic fatty liver disease (NAFLD)
NAFLD is the hepatic expression of the MS. Gallstones are more frequent in NAFLD patients than in the general population 23, 24, as NAFLD and cholesterol GD share common lifestyle and metabolic risk factors. The obesity epidemic will lead to an increased prevalence of NAFLD.
Although there is no correlation between cholesterol gallstones and total cholesterol levels in blood, GD is associated with low HDL-cholesterol and high triglyceride serum levels. Nearly all patients with hypertriglyceridemia have supersaturated bile, even if they are lean 25.
The change over time in gallstone prevalence suggests that there has been a similar change with respect to environmental risk factors. One of the main environmental exposures is nutrition. Chronic overnutrition with refined carbohydrates and reduced intake of dietary fibre might account for the increased cholesterol gallstone prevalence in Native Americans, European countries and urban centres in Eastern Asia (Japan). This increase is linked to obesity, slow intestinal transit, hypertriglyceridemia, and insulin resistance. Moderate alcohol consumption and coffee consumption seem to be protective factors for gallstone formation, or at least for the development of symptoms in gallstone carriers.
Decreased physical activity
Prospective studies have shown that sedentary behavior is associated with an increased risk of cholecystectomy, both in women and men 26. On the contrary, regular exercise improves - alone or most pronounced in association with low calorie diet - the metabolic profile associated with obesity and cholesterol gallstones, decreasing the lithogenic risk.
Liver cirrhosis and chronic hepatitis C virus (HCV) infection
End-stage liver disease is a well-known risk factor for GD. About 25-30% of cirrhotic patients have gallstones. Pigment lithogenesis is favored by chronic haemolysis and changes of liver metabolism. Cholesterol gallstones are also frequent in liver cirrhosis, in particular in cirrhotic patients with chronic HCV infection or NAFLD. Chronic HCV infection was shown to be an independent risk factor for GD both in patients with liver cirrhosis 27 and in chronic hepatitis 28. The prevalence of liver cirrhosis in HCV-infected patients has increased significantly over the past years 29. It will continue to increase, given the fact that the spread of HCV infection in the USA and Europe occurred mainly after the 1970s and long duration of infection is necessary for cirrhosis to develop.
Gallstones are highly prevalent in most developed countries, leading to high health care costs. In developing countries, there also exists a trend toward an increasing prevalence of the metabolic risk factors for GD. As long as the obesity and diabetes epidemics continue to spread around the world, an increase of gallstone prevalence rates is to be expected; and will parallel the aging populations in these countries.