Cholecystectomy and increase in cancer

What is cholecystectomy? 

Cholecystectomy (koh-luh-sis-TEK-tuh-me) is a very common procedure (about 57000 each year in England) to remove the gallbladder. The gallbladder is a small, pouch-like organ in the upper right side of the abdomen that sits just below the liver; it stores bile made in the liver to emulsify fatty food for better absorption of lipids.

Why might you need a cholecystectomy? 

Although it may sound like the gallbladder is quite an important organ in the digestive system, you can live without it! Surgery is often recommended to patients with gallbladder complication. These problems could include:

- Gallstones (these are hardened cholesterol or bilirubin which can range in size from a grain of salt to a golf ball) in the gallbladder that are causing inflammation of the gallbladder (cholecystitis). This is due to gallstones blocking the cystic duct or the common bile duct (CBD). They do not usually cause symptoms but may include sudden sharp pain in the upper right-hand side of the abdomen which spreads towards your right shoulder, jaundice, feeling and being sick etc. 

- Large gallbladder polyps, which can turn cancerous. 

- Pancreas inflammation (pancreatitis) from gallstones in the CBD which is forcing pancreatic enzymes back into the pancreas causing irritation. 

- Possibility for cancer of the gallbladder. 

Increased risk of cancers from cholecystectomy. 

Though cholecystectomy is a very common procedure with minimal long-term risks that can take upto only 45 minutes to an hour on average and generally done to improve the patient’s quality of life, there is very little understanding of the link between cholecystectomy and its increase in digestive cancer like in the stomach, pancreas, small intestine, colon, oesophagus etc. Cholecystectomy relieves pain, improves digestion and reduces the risk of gallstones, lesser risk of bile reflux and lower the likelihood of pancreatitis. However, while cholecystectomy improves quality of life, there are concerns about potential long-term consequences, particularly an increased risk of certain cancers.

Removing the gallbladder means bile will just directly flow into the small intestine, instead of being stored somewhere. The internal pressure in the biliary tract is higher than the pressure of the Oddi sphincter, which leads to the long-term opening of the Oddi sphincter, resulting in the continuous discharge of bile. This changes the bile atmosphere in the gastrointestinal tract as removing the gallbladder now increases the intestinal exposure to bile. After cholecystectomy, all the hepatic bile enters the duodenum and the amount of enterohepatic circulation ((the process by which bile acids are recycled between the liver and intestine) of bile acids after cholecystectomy is twice that of healthy people. 

During this journey, anaerobic bacteria promote a multi-step process that converts hydrophilic primary bile acids into hydrophobic secondary bile acids (7α-dehydroxylation). These secondary bile acids include deoxycholic acids (used in the breakdown of submental fat or ‘double chin’) and lithocholic acid (acts as a detergent to solubilise fats for absorption). Depending on the concentration, hydrophobic secondary bile acids (SBA) can encourage apoptosis and DNA damage. It has also been found that deoxycholic acid has carcinogenic and mutagenic properties.

DCA (deoxycholic acids, an SBA), has also been found to have decreased the level of p53 (a protein that prevents cancer by regulating cell division and DNA repair) by stimulating extracellular signal-regulated kinases. The loss of p53 promotes the development of many tumours including adenocarcinomas of the colon. High levels of SBAs and deoxycholic acid (DCA) in faecal matter correlate with increased adenomatous polyp recurrence. Animal experiments have shown that the risk of colon cancer increases with increasing SBAs. A study conducted on the effect of cholecystectomy on colorectal tumours in mice induced by dimethylhydrazine (DMH) found that cholecystectomy could increase the S-phase cells of the colon mucosal epithelium in mice. This finding indicated that cholecystectomy could perhaps be linked to the occurrence of colon cancer within patients who had a history of cholecystectomy. 

One of the largest population- based cohort studies in Korea (123,295 patients) to examine the link between cholecystectomy and 24 types of cancer indicated that the incidence of developing cancer (in the colon, liver, pancreas, biliary tracts, oral cavity, thyroid and lung) was higher in subjects who underwent cholecystectomy. 

Numerous epidemiological studies have concluded that population with a high dietary fat intake have an elevated concentration of faecal secondary bile acids, mainly due to the increased production of bile acids to facilitate the digestion and absorption of fat. To further prove this point, studies were conducted on genetically normal mice (male and female) fed on 0.2% of the bile acid DAC for eight to ten months. This has led to faecal levels of DAC comparable to faecal levels of DAC in humans consuming a high-fat diet. Results have shown colonic tumours in 94% male mice including 54% with cancers, and in 91% of the female mice including 45% with cancer. In these mice, an increasing level of a type of oxidative DNA damage (biomarker - 8-OHdG) was observed and a decreasing level of the protein involved in repairing DNA damage (ERCC1) was noted, compared to mice fed the same diet without DAC. This is because on a high-fat diet more bile acids can enter the colon due to inefficient enterohepatic recirculation because of continuous production of bile and nowhere to store it. 

An increasing level of oxidative DNA damage (8-OHdG) can be explained - bile acids can disrupt cell membranes on colonic epithelial cells by their detergent action on membrane lipid components. This promotes reactive oxygen species which can damage DNA, such as DNA single strand breaks in human colon epithelial cells enough to trigger apoptosis of these cells. Studies were also conducted in colonic epithelial cells grown in a laboratory. This showed that repeated exposure to increasing concentrations of DAC caused the cells to undergo acquired resistance to apoptosis via natural selection - facilitating the progression to colon cancer.

It is important to note that the development of cancer in humans is a much longer process than in mice. This is because mice have about fivefold lower level of DNA repair activity than humans so could explain the earlier occurrence of colon cancer in mice. However, studies on animals to mimic the study of carcinogenicity of SBA in humans is inherently less time consuming and easier to study on animal model systems. Studies on animal models perhaps may not be representative of humans due controlling confounding factors like diet pattern, alcohol consumption, physical inactivity, comorbidity in humans. There have been studies that show opposing views on the issue. Studies conducted in Hungary and Japan have shown no statistical correlation between removal of the gallbladder and higher risk of colon cancer so cholecystectomy may not be an independent factor for colorectal cancer. It is important to carry out further research to understand physiological changes after cholecystectomy and whether it increases the occurrence and development of colon cancer.

*This blog has not been written to frighten patients who has a history of cholecystectomy, patients who might need or will have cholecystectomy done to improve their quality of life, or readers who has relations to patients who has had cholecystectomy. This is purely for educational purposes, not to contradict medical practices that has proven to be useful to patients worldwide. *

Written by Tasfiha

Moderated by Adelene

References: 

Bmj.com. (2021). Available at: https://bmjopen.bmj.com/content/13/8/e057138[Accessed 23 Jan. 2025].

NHS Choices (2019). Gallbladder removal. [online] NHS. Available at: https://www.nhs.uk/conditions/gallbladder-removal/ .

‌Chen, Z., Yu, C. and Li, Z. (2023). The effect of cholecystectomy on the risk of colorectal cancer: A systematic review and meta-analysis. Laparoscopic, Endoscopic and Robotic Surgery, 6(4), pp.134–141. doi:https://doi.org/10.1016/j.lers.2023.11.003.

Choi, Y.J., Jin, E.H., Lim, J.H., Shin, C.M., Kim, N., Han, K. and Lee, D.H. (2022). Increased Risk of Cancer after Cholecystectomy: A Nationwide Cohort Study in Korea including 123,295 Patients. Gut and Liver, [online] 16(3), pp.465–473. doi: https://doi.org/10.5009/gnl210009 .

‌Dong, Z., Shi, R., Li, P., Song, X., Dong, F., Zhu, J., Wu, R., Liang, Z., Du, M., Wang, J. and Yang, Z. (2023). Does postcholecystectomy increase the risk of colorectal cancer? Frontiers in Microbiology, [online] 14, p.1194419. doi:https://doi.org/10.3389/fmicb.2023.1194419.

‌Bernstein, H. and Bernstein, C. (2022). Bile acids as carcinogens in the colon and at other sites in the gastrointestinal system. Experimental Biology and Medicine, p.153537022211318. doi:https://doi.org/10.1177/15353702221131858.

Jiang, X., Jiang, Z., Cheng, Q., Sun, W., Jiang, M. and Sun, Y. (2022). Cholecystectomy promotes the development of colorectal cancer by the alternation of bile acid metabolism and the gut microbiota. Frontiers in Medicine, 9. doi:https://doi.org/10.3389/fmed.2022.1000563.