Gallbladder disease is one of the most common gastrointestinal disorders in developed countries. Gallbladder disease is typically manifested in the form of gallstones or gallbladder cancer. Gallstones affect 10-15% of people in developing countries, meaning 20-25 million Americans have or will have gallstones (Stinton and Shaffer, 2012). Though mortality rate is low; gallstones are responsible for about 1. 83% of the surgical deaths per year. The high prevalence rate means that there are still around 1000 gallstone related deaths per year in countries such as the United States and UK. Scollay et al. , 2011). Many factors contribute to Gallstones, both preventable and not including: ethnicity, age, gender, genetics, obesity, rapid weight loss, sedentary lifestyle, and diet (Stinton and Shaffer, 2012). There are two main types of gallstones, pigment and cholesterol gallstones. One of the main causes of cholesterol gallstones is thought to be a fatty diet (Castro-Torres et. al, 2015). Many physiological factors go into the formation of cholesterol gallstones.
The most widely recognized factor is imbalances in the secretion of biliary cholesterol. Cholesterol is secreted into the bile via micelles and liposomes, this process is mediated by proteins in the canalicular membrane of hepatocytes (Dikkers and Tietge, 2010). When excess cholesterol is available, phospholipids solubilize this cholesterol into vesicles. These crystals become trapped in the gallbladder, mucin then gels together with bilirubin salts, these elements agglomerate into macroscopic gallstones (Portincasa and Wang 2012).
The first paper (Kim et. al, 2012) explores n-3 polyunsaturated fatty acid (n-3 PUFA) and its role in preventing gallstones via suppressing mucin production and the benefits of coupling it with both Ursodeoxycholic acid (UDCA) and Ezetimibe (a cholesterol absorption inhibitor. ) The second paper (Castro-Torres et. al, 2012) focuses again on effects of ezetimibe in addition to the effects of a traditional Mexican remedy, 2 black radish root, on cholesterol gallstone prevention.
The third study (McConnell et. al, 2017) examines the effects of vegetarian and non-vegetarian diets on the development of gallstones; examining dietary components such as carbohydrate, fiber, protein, fat, and cholesterol intake. Lee’s study observed mice on six different diets: a regular diet (RD) consisting of healthy levels of fats, protein, cholesterol, and fiber, lithogenic diet (LD), RD+n-3 polyunsaturated fatty acid (n-3 PUFA), LD+n-3 PUFA, LD+ Ursodeoxycholic acid (UDCA), and LD +n-3 PUFA+UDCA.
The study explains that UDCA is the only established treatment to dissolve and prevent cholesterol gallstones (CG). UDCA works by decreasing a1 acid glycoprotein, hepatoglobin, immunoglobin A, IgG, y-glutamyl, transpeptidase, and aminopeptidase. The study found that mice on the RD and RD+n-3 PUFA showed no gallstones. Mice on the LD diet had increased instances of gallstones; however, mice on LD+n-3 PUFA+ UDCA showed a significant decrease in gallstone prevalence compared to LD, LD+n-3, and LD+UDCA.
It was also found that a LD resulted in hypertrophy of the gallbladder but when n-3 PUFA was added to the LD hypertrophy was suppressed. N-3 PUFA was shown to return gallbladder walls to their original state after the mucosal epithelium of gallbladder walls showed hypertrophic changes due to LD. A second factor examined in the study was levels of mucin mRNA. Excess levels of mucin are shown to increase likelihood of gallbladder disease. After n-3 PUFA treatment there was a significantly lower expression of mucin genes Muc2, Muc5ac, Mucc5b, and Much.
Though there is no clear evidence as to why the mucin genes are expressed in the first place; it is hypothesized that increased bile phospholipid production after n-3 PUFA treatment lowers cholesterol saturation index (CSI) and decreases chemical irritation to the mucosa of the gallbladder, this may result in decreased expression of mucin genes. The study showed that 3 western diets contain large amounts of n-6 polyunsaturated fat which negatively impacts hepatic lipogenesis. The ratio of n-3 to n-6 PUFA should be close to 3:1 as n-3 PUFA has antiinflammatory and anti-thrombotic properties that aid in gallbladder health.
The study suggests a diet high in foods with n-3 PUFA such as fish and fish oils, with little to no n-6 PUFA consumption. The final portion of the study briefly explored ezetimibe, a cholesterol absorption inhibitor. Ezetimibe was reported to reduce biliary cholesterol. As ezetimibe, n-3 PUFA, and UDCA all function via different mechanisms, the study recommends a combination of all three to more effectively prevent gallbladder disease (Kim et. al, 2012). Castro-Torres first focuses on the benefits of inhibiting proteins responsible for gallstone formation.
It is stated that proteins involved in gallstone formation include ATP binding cassette (ABC) such as: ABCB4, ABCB11, ABCG5, ABCG8, ABCC7, and Niemann-Pick C1L1. The study states that ezetimibe inhibits expression of Niemann-Pick protein in the small intestine decreasing intestinal absorption of cholesterol. When absorption in the small intestine is decreased, biliary cholesterol secretion is decreased, reducing the saturation of lipids in vesicles. This favors the activity of bile salts on cholesterol gallstones. Next examined was the effects of the traditional Mexican remedy for gallstones, black radish root.
The root is commonly juiced for consumption. Though some evidence suggests that juicing the root results in depletion of glucosinolates which is thought to be the active mechanism in the root that aids in gallstone treatment. The study was inconclusive on glucosinolates effect on gallstone treatment. Though treatment of gallstones with the root was proven to be two times more effective than treatment with UDCA. A tenfold dilution of the root in water was proven to be most effective, resulting in a decrease or complete disappearance of gallstones, and an overall 4 decrease in both cholesterol and triglycerides.
While a hundredfold dilution of the root only resulted in partial dissolving of gallstones, showing concentration of the root is directly proportional to its effectiveness. While the tenfold dilution of black radish root did result in a reduction on gallstones, cholesterol, and triglycerides, it did not result in significant improvement of hyperplasia in the epithelium of the gallbladder; this being another consequence of LD. Lithogenic diet (LD) is comparable to the typical western diet high in fats, cholesterol, and low in fiber (Castro-Torres et. l, 2012). McConnell’s study focused on the effects of vegetarian and non-vegetarian diets on gallstone development. The study examined 50,000 participants over an average of 14 years keeping a detailed log of the types of foods participants consumed and their body conditions. It was found that vegetarians generally consumed less refined sugars, and less fat. Vegetarian BMI was, on average, lower than non-vegetarian BMI. As BMI increases risk of gallstones also increases, this is due to supersaturation of cholesterol in bile.
In obese individuals’ biliary cholesterol, bile salts, and phospholipids are hyper-secreted, the rate of cholesterol secretion is greater than the secretion of biliary lipids resulting in cholesterol supersaturated bile and thus more instances of gallstones. It was also shown that individuals who consumed only vegetable protein were at a higher risk for gallstones than individuals who consumed only animal protein, while consuming only animal protein had no effect on risk of gallstone development.
Upon further investigation it was shown that diets with high carbohydrate consumption led to a greater risk of gallstone development, though this doesn’t explain why vegetarians would experience higher risk than those who consume animal protein. One hypothesis states that CCK, the main gastrointestinal polypeptide involved in gallbladder contraction, is poorly stimulated by 5 carbohydrates, but responds well to fats. Diets with animal proteins may contain more fat, thus resulting in higher motility of the gallbladder, which reduces the risk of gallstones (McConnell et. l, 2017). Prevention of gallstones isn’t as simple as one solution. As stated in Lee’s paper, likely the best remedy is a combination of many different measures. UDCA shows a reduction in gallstones long-term; whereas, the black radish root tends to work well short-term (Castro-Torres et. al, 2012).
Though elements such as UDCA and black radish root (which aid in riding the body of gallstones during early development) work best if n-3 PUFA is also added as n-3 PUFA aids in gallstone prevention by inhibiting expression of mucin genes (Kim et. l, 2012). The ideal treatment for gallstones includes n-3 PUFA, UDCA, and ezetimibe as they all use different mechanisms to treat gallstones. This in addition to a diet low in n-6 PUFA, carbohydrates, and cholesterol, is the current, ideal treatment for gallstones and gallstone prevention. Further investigations on protein inhibitors would also be useful along with further analysis on specific dietary components (such as cholesterol, carbohydrates, fats and proteins) effects on gallstone formation.