Gallbladder disease affects an estimated 20 million Americans and is now the leading surgical procedure in the United States (Hoffman, 2014). Research as far back as 1975 reported on the necessity of administering Vitamin B6 to prevent excretion of tryptophan metabolites resulting from use of oral contraceptives in woman. More than 99 percent of women age 15-44 have used some form of contraceptive (Guttmacher, 2014) and oral contraceptives account for an estimated 17 percent, about 10 million American woman. Recent studies now link oral contraceptives as the leading risk factor in gallbladder disease in woman who have ever used oral contraceptives. Nutritional scientists identify vitamin B6 deficiencies as the principle cause of gallbladder disorders associated with oral contraceptive use. Supplementation with live source B6 is essential for the prevention of gallbladder disorders and disease in woman taking oral contraceptives.
Oral contraceptives became a popular form of birth control in the United States during the 1970’s. In 2010 an estimated 27.5 percent or 10,540,000 women between the age of 15 and 44 were using oral contraceptives (Guttmacher, 2014). Ironically, the escalation in contraceptive use corresponds to an increase in gallbladder disease with an estimated total of 20 million Americans have some form of gallbladder disease (Hoffman, 2014).
Early research in 1975 by Brown and Rose et al found the use of oral contraceptive drugs increased requirements for vitamin B6 to prevent excess urinary secretion of tryptophan metabolites (Bermond, 1982). Recent studies have identified that oral contraceptives pose a risk of gallstones (Wang, 2011) the leading cause of gallbladder disease. In addition, other variables associated with raising the risk factor of gallbladder disease include obesity, heredity (Mexican, Native Americans and northern European), age (over 60), gender and slow intestinal transit (Hoffman, 2014).
According to Hoffman (2014), medical school students are taught to identify patients with gallbladder disease using the five F’s, “fair, fat, forty, fertile and female.” National failure to recommend B6 supplementation when prescribing birth control pills, combined with other risk factors has resulted in a generation of woman suffering from gallbladder disorders as well as other vitamin B6 deficiency disorders.
The purpose of this paper is to explore the evidence based research and examine the etiology of relationships involved in the effects of oral contraceptives on the function of the gallbladder and how vitamin B6 deficiency contributes to the formation of gallstones in the gallbladder. We will discuss the function of the gallbladder focusing on the importance of bile flow, examine research explaining the importance of vitamin B6 for fatty acid digestion and present the latest research linking birth control pills to gallbladder disease. This cumulative research shows that oral contraceptives are a risk factor to gallstones, the leading cause of gallbladder disease among woman.
In Chinese medicine the gallbladder is the decision organ essential for metabolism of dietary fats and cholesterol and elimination of toxic waste. Anatomically, the gallbladder, shown in Figure 1, is a small sac connected to the liver which stores bile (made in the liver) and released into the bile duct of the small intestines to digest and absorb dietary fats. Bile has three main functions. Bile salts are cholesterol derivatives and acids which emulsify fats by breaking them down into tiny particles (Marieb, 2013) so they can be enzymatically digested and absorbed in the small intestine for fuel. Bile salts also control cholesterol levels by dissolving them and precipitating excess levels. Birru and Warren et al (2014) found the molar ratio of lipids to bile salts is essential for dilution of liposomes and absorption in the gut lumen. Either too much cholesterol in the diet or insufficient bile salts allows cholesterol to crystalize and form gall stones (Marieb, 2013).
Bile also carries toxins out of the liver as conjugated bilirubin. Toxins in the blood circulate through the liver where they are condensed through a cycle of detoxification and filtration. The condensed chemotoxic waste product (Johnson, 2014), is released into the bile and enters the small intestine where it is metabolized by bacteria and eliminated as waste (Marieb, 2014) through feces.
Inadequate bile function interferes with the absorption and metabolism of essential fat soluble vitamins A, D, E, and K (Johnson, 2014). For example, malabsorption of vitamin D, a fat soluble hormone, will interfere with absorption of calcium (Marshall, 2012) in the intestines. Thus, individuals with poor gallbladder function are at risk of developing osteoporosis (Marshall, 2012). Inadequate bile also interferes with cholesterol metabolism, essential for hormonal function. It not only raises cholesterol level (Marshall, 2012) but precipitates the formation of gallstones within the gallbladder. It also interferes with the formation of DHA discussed shortly.
Common symptoms of inadequate gallbladder function are dry hair and skin, facial wrinkles, brittle nails, weight gain around the middle and poor sleep (Marshall, 2014). Other symptoms, include anxiety, depression, adrenal fatigue ( Bartoszewshi, 2012), constipation, gas, bloating, burping after fatty meals and foul smelling stool (Johnson, 2014) and poor close range vision (Marshall, 2008).
Vitamin B6 and Metabolism:
Vitamin B6 (pyridoxine) is a water soluble vitamin that supports numerous essential metabolic processes essential for healthy gallbladder function. B6 keeps bile salts in suspension (Johnson, 2014) and acts as a coenzyme to break down fats, carbohydrates and proteins (Weil, 2014) so that food, especially fats, can be digested and absorbed. Gregory and Park et al (2013) found that even marginal vitamin B6 deficiency has widespread metabolic perturbation. The pyridoxal 5-phosphate serves as a coenzyme in the metabolism of amino acids, carbohydrates, organic acids and neurotransmitters (Gregory, 2013).
Vitamin B6 was also shown to reduce homocysteine levels in individuals with osteoporosis. Ebesunun and Umahoin, et al (2014) found that changes in total homocysteine, folic acid and vitamins B12 and B6 impair collagen cross linking contributing to low bone mineral density. The mechanism of action of vitamin B6 and gallbladder function is complex, relatively new and expanding. Recent research indicates that Vitamin B6 deficiency interferes with the metabolism of n-6, n-3 polyunsaturated fatty acids (PUFA’s) and impairs the metabolism of PUFA’s from linoleic acid to EPA and DHA production.
Zhao and Ralat, et al (2013) found vitamin B-6 restriction alters PUFA’s synthesis, particularly of n-6 and n-3 PUFA’s. Tsuge and Hotta et al (2000) found B6 deficiency reduces the production of DHA, the substance than protects every cell membrane in the body including the myelin sheath of the nervous tissue of body and brain. Choi and Cho (2008) found insufficient fatty acid metabolism results in reduced fuel storage capacity and utilization as indicated by lower liver glycogen and plasma protein levels and reduced muscle triglyceride levels.
Oral Contraceptives and Gallbladder Disease:
Cholecystectomy, the surgical removal of the gallbladder is the most common type of surgery performed in the United States. An estimated 20 million Americans have gallbladder disease (Hoffman, 2014). Oral contraceptives and other estrogen replacement therapies reduce vitamin B6 levels in the liver resulting in insufficient bile production and the formation of gallstones, the leading cause of gallbladder disorders. Researchers at Tufts University found that 75 percent of women taking oral contraceptives were deficient in B6 (Bartoszewski, 2012).
In gallbladder disease bile in the gallbladder thickens and becomes concentrated resulting in a built up of cholesterol and bile salts which results in either inflammation (cholecystitis) or gallstones (cholelithiasis) (Etminan and Delaney et al, 2011). Gallstones are shown in the upper right side of Figure 2. Figure 3 at right shows gallstones within the gallbladder. Gallstones restrict bile flow resulting in excruciating pain.
Figure 2: The New York Times Company 2007 Figure 3: Wikepedia 2014
In 2011 a large cohort study from 1997-2009 of 2.7 million women was conducted to determine whether oral contraceptives raised the risk of cholecystectomy (Etminan et al 2011). They found a statistically significant increase in the risk of gallbladder disease associated with certain oral contraceptives. In a similar study, Wang and Shen et al (2011) found that “oral contraceptives are an important contributor to gallbladder disease” in patients with a body mass index over 30. Obesity and oral estrogen replacement are both high risk factors to developing gallbladder disease as cholesterol becomes supersaturated (Hoffman, 2014).
Park and Andreotti et al (2009) from China found that biliary tract cancers encompass tumors originating in the gallbladder, extra hepatic bile duct and ampulla of Vater. They found gallstones are the predominant risk factor for all three anatomic sub sites. Apart from gallstones, the etiology of biliary tract cancer is poorly understood but gallbladder cancer is one of the few cancers predominant in females and it is hypothesized to be related to steroid hormone metabolism (Park et al. 2009). In further support of this hypothesis, several hormonal factors, including high parity, young first pregnancy, use of oral contraceptive and obesity have been reported to increase the risk of gallbladder cancer in women.
In this population-based study in China, common variants in genes involved in steroid hormone biosynthesis, metabolism and transport were associated with biliary tract cancers and biliary stones. Of two biomarkers analyzed the effects of þ 6 on gallbladder cancer and gallstone risks were limited to women who used oral contraceptives. These results, Park et al (2009), support the hypothesis that variants in hormone-related genes could play a role in the etiology of biliary tract cancer and stones.
It is widely recognized and documented for the past 40 years that oral contraceptives interfere with the absorption of vitamin B6. The synthesis of vitamin B6 in the liver appears to be affected leading to chronic vitamin B6 deficiency and disturbance in fatty acid metabolism. Vitamin B6 is essential to keep bile salts in suspension and to prevent formation of gallstones. Recently, studies have linked gallbladder disease with the formation of gallstones resulting from oral contraceptive use. Apparently gallstones take years to develop which partially explain the delay in action.
Nutritional science recommends Vitamin B6 supplementation of 60 mg per day for all women taking birth control pills to maintain fat metabolism and a healthy gallbladder function. According to Marshall, 2012, just 6 months of birth control usage will impact vitamin B6 metabolism so that a woman is required to take B6 for the rest of their life. Further research is needed to evaluate the complex mechanism of action of vitamin B6 and metabolic disturbances in fatty acid metabolism to further aid in the prevention of gallbladder disease.
Bartoszewski, M. (2012, July). Why you must take a vitamin B- complex if on birth control. In Natural News. Retrieved November 2014, from http://www.naturalnews.com/036590_b_vitamins_birth_control_nutritional_deficiencies.html
Bermond, P. (1982). Therapy of side effects of oral contraceptive agents with vitamin B6. Acta Vitaminol Enzymol, 4, 45-54. Abstract retrieved from PMID: 6889807
Birru, W., Warren, D., Ibrahim, A., Williams, H., Benameur, H., Porter, C., . . . Pouton, C. (2014). Digestion of phospholipids after secretion of bile into the duodenum changes the phase behavior of bile components. Molecular Pharmacy, 11(8), 2825-34. doi:10.1021/mp500193g
Bordoni, A., Hrelia, S., Lorenzini, A., Bergami, R., Cabrini, L., Biagi, P., & Tolomelli, B. (1998). Dual influence of aging and vitamin B6 deficiency on delta-6-desaturation of essential fatty acids in rat liver microsomes [Abstract]. Prostaglandins Leukot Essential Fatty Acids, 58, 417-20. doi:PMID: 10189072
Brown, R., Rose, D., Leklem, J., & Linkswiler, H. (1975). . Effects of oral contraceptives on tryptophan metabolism and vitamin B6 requirements in women. Acta Vitaminol Enzymol, 29, 151-7. Retrieved from PMID: 1244084
Choi, E., & Cho, Y. (2008). Vitamin B6 deficiency can reduce fuel storage and utilization in physically trained rats [Abstract]. International Journal of Vitamin Nutrient Research, 78, 64-69. doi:1024/0300-98188.8.131.52
Ebesunun, M., Umahoin, K., Alonge, T., & Adebusoye, L. (2014). Plasma homocysteine, B vitamins and bone mineral density in osteoporosis: a possible risk for bone fracture. Afr J Med Med Sci, 43(1), 41-7. Abstract retrieved from PMID: 25335377
Etminan, M., Delaney, J., Bressler, B., & Brophy, J. (2011). Oral contraceptives and the risk of gallbladder disease: a comparative safety study. Canadian Medical Association Journal, 183(8), 899-904. doi:10.1503/cmaj.110161
Gregory, J., Park, Y., Lamers, Y., Bandyopadhyay, N., Chi, Y., Lee, K., . . . Jones, D. (2013). Metabolomic analysis reveals extended metabolic consequences of marginal vitamin B-6 deficiency in healthy human subjects [Abstract]. PloS One, 8(6). doi:10.1371/journal.pone.0063544
Guttmacher. (2014, June). Who uses contraceptives? In Contraceptive Use in the United States. Retrieved June 2014, from Guttmacher Institute website: http://www.guttmacher.org/pubs/fb_contr_use.pdf
Hoffman, R. (2014). Gallbladder disease. In Intelligent Medicine. Retrieved November 2014, from Hoffman Center website: http://drhoffman.com/article/gallbladder-disease-2/
Marieb, E., & Hoehn, K. (2013). The digestive system. In Human Anatomy and Physiology (pp. 881-882). Glenville, IL: Pearson Education Inc.
Marshall, R. (2008, January 26). Gallbladder disorders: Hair, Skin, Eyes. In Best of Health Line Radio Library. Retrieved November 2014, from Health Line Radio website: http://www.tom’sgoodfiles.com
Park, S., Andreotti, G., Sakoda, L., Gao, Y., Rashid, A., Chen, J., . . . Hsing, A. (2009). Variants in hormone-related genes and the risk of biliary tract cancers and stones: a population-based study in China [Abstract]. Carcinogenesis, 4, 604-14. doi:10. 1093/carcin/bgp024
Tsuge, H., Hotta, N., & Hayakawa, T. (2000). Effects of vitamin B-6 on(n-3) polyunsaturated fatty acid metabolism. The Journal Of Nutrition, 130, 333S-334S. Abstract retrieved from PMID: 10721899
Wang, F., Shen, X., Guo, X., & Peng, Y. (2011). Oral contraceptives and risk of gallbladder disease [Abstract]. CMAJ, 183(13), 1517. doi:10.1503/cmaj.111-2065
Zhao, M., Ralat, M., da Silva, V., Garrett, T., Melnyk, S., James, S., & Gregory, J. (2013). Vitamin B-6 restriction impairs fatty acid synthesis in cultured human hepatoma (HepG2) cells [Abstract]. American Journal of Physiology and Endocrinology Metabolism, 304(4), E342-51. doi:10.1152/ajpendo.00359.2012