Age is a major risk factor for the formation of gallstones, or cholelithiasis. While it is unclear as to the reasons for this increased prevalence, 38% of women and 22% of men have gallstones by age 90.1 More than half the cases (50% to 70%) of acute cholecystitis, defined as inflammation, and possibly infection, of the gallbladder, occur in seniors.1 Ethnicity and race also play a role. White individuals, Mexican Americans, and Native Americans are known to have a relatively high prevalence of gallstones.2 Among Native Americans, the prevalence of cholelithiasis reaches as high as 80% in women and 70% in men by age 50.1 Prevalence in Mexican Americans is similar to that in Native Americans.2 A somewhat lower risk is observed in Asians and Africans and their descendants.2 Other risk factors, including female gender and medications, may be found in TABLE 1.
The gallbladder, located under the liver, aids in the digestive process by storing bile and secreting it into the small intestine when food enters; bile is produced by the liver and is made up of several substances, including cholesterol, bilirubin, and bile salts.3 Gallstones develop insidiously. While most gallstones remain asymptomatic and are often found accidentally upon abdominal imaging, approximately 500,000 individuals develop symptomatic gallstones each year in the United States.1 The human and health care system burden of cholelithiasis is reflected in the serious complications of the condition (TABLE 2) that may result in severe pain, inflammation, systemic infection, and malignancy.1 Approximately 7,000 deaths are attributable to acute complications secondary to cholelithiasis, such as acute pancreatitis.2 Furthermore, although cholecystectomy is a relatively safe and common surgical procedure, rare complications result in several hundred deaths each year.2
Highly prevalent in the geriatric population, acute cholecystitis may occur in the presence or absence of gallstones, although it is almost always due to gallstones. Its severity varies from mild edema to severe inflammation, and even to necrosis or perforation of the gallbladder at its most catastrophic.1,4 Classic manifestations of acute cholecystitis include continuous and severe abdominal pain (especially in the right upper quadrant or epigastrum) radiating to the back or shoulder, often after eating a fatty meal; also commonly seen are chills, fever, nausea, and vomiting.1 Presentation in the elderly may be atypical; that is, fever, nausea, and vomiting may be absent in the elderly in more than 50% of cases.1 Furthermore, these signs may also be absent in more than one-third of seniors even in the presence of gangrene or perforation of the gallbladder.1
The prevalence of choledocholithiasis (gallstones entering the common bile duct) increases with age.1 Choledocholithiasis, which occurs as a result of gallbladder contraction, can potentially obstruct the common bile duct and cause jaundice, ascending cholangitis (inflammation or infection of a bile duct), liver abscess, and pancreatitis.1 Biliary colic (TABLE 2) is the term used for the classic signs and symptoms of biliary obstruction.
Gallstone Composition
There are two main types of gallstones. In the U.S., more than 80% of gallstones contain cholesterol as their major constituent; they are usually yellow-green in color.1,3 Black pigment stones, which are composed of unconjugated bilirubin in the form of crystallized calcium bilirubinate, account for approximately 10% to 20% of gallstones in the U.S.; they develop in the setting of excess bilirubin in bile.1 In addition, cholesterol gallstones may become colonized with bacteria causing inflammation of gallbladder mucosa; enzymes from bacteria and leukocytes alter bilirubin conjugates and fatty acids, resulting in an accumulation of calcium bilirubinate and other calcium salts and producing mixed gallstones.2
Postmenopausal Estrogen Use and Gallbladder Disease
Gallbladder disease is commonly cited as a complication of oral estrogen therapy.5 The increased risk of cholelithiasis in women is associated with increased biliary cholesterol excretion by estrogen.1 However, while estrogen therapy is thought to promote gallstone formation and cholecystitis, most data are derived from observational studies rather than randomized trials.6
Cirillo et al conducted two randomized, double-blind, placebo-controlled trials at 40 U.S. clinical centers to determine the effect of estrogen therapy in healthy postmenopausal women on gallbladder disease outcomes.6 The data indicate that there is an increased risk for cholecystitis, cholelithiasis, and cholecystectomy among women taking oral estrogen (0.625 mg/day of conjugated equine estrogens [CEE]) or estrogen-progestogen therapy (CEE plus 2.5 mg/day of medroxyprogesterone acetate).6 Cirillo et al concluded that these data suggest an increase in the risk of biliary tract disease among postmenopausal women using estrogen therapy. Further, the researchers suggest that morbidity and cost associated with these outcomes may need to be considered in the decision-making process regarding the use of estrogen therapy.
Another study (the prospective cohort Million Women Study), conducted by Liu et al, set out to determine whether transdermal hormone replacement therapy reduces the risk of gallbladder disease in postmenopausal women as compared with oral therapy.7 The results showed that compared with never-users of hormone replacement therapy, current users were more likely to be admitted for gallbladder disease; however, risks were substantially lower with transdermal therapy than with oral therapy.7 The researchers concluded that gallbladder disease is common in postmenopausal women and that use of hormone replacement therapy increases the risk; the use of transdermal therapy rather than oral therapy over a 5-year period could avoid one cholecystectomy in every 140 users.7
In light of these data, pharmacists developing a pharmaceutical care plan for postmenopausal hormone replacement therapy should consider the lowest effective dose for the shortest duration, carefully and individually weighing treatment goals and risks for each patient.5 Estrogen therapy delivered via a transdermal patch as an alternative to oral therapy for women at high risk for cholelithiasis should be considered.
Diagnostic Tests and Procedures
Gallstones are suspected in patients experiencing biliary colic (TABLE 2). An abdominal ultrasound or a CT scan is used to create an image of the gallbladder and analyzed to check for gallstones.8 Abdominal ultrasonography is the method of choice for the detection of gallstones with sensitivity and specificity; it is noninvasive, easily tolerated, widely available, and inexpensive.1,4 To check the bile ducts for gallstones, tests may include a hepatobiliary iminodiacetic acid scan, MRI or endoscopic retrograde cholangiopancreatography (ERCP).8 If gallstones are discovered using ERCP, they can be removed during the procedure.8 Additionally, blood tests may be used to check for infection, jaundice, pancreatitis, or other complications caused by gallstones.8 For a detailed discussion of diagnostic investigations, refer to Reference 1.
Treatment
The treatment of gallstones depends upon the stage of disease.2 Most patients consider asymptomatic gallstones that never cause clinical illness not to be worth the discomfort, expense, and risk of elective surgery; however, asymptomatic gallstones in diabetic patients must be removed.4 Surgical intervention with cholecystectomy is usually indicated for symptomatic gallstones, although medical dissolution may be considered in some cases.2 In patients who are too sick to tolerate cholecystectomy, and to clear stones from the common bile duct, additional interventions may be of value to address acute complications of gallstones.2
Surgery: Treatment of gallstones usually involves surgery to remove the gallbladder, which has traditionally been done as an open cholecystectomy.3 More recently, the laparoscopic cholecystectomy procedure is used in most cases, since it is less invasive and is associated with fewer complications.3
Medication: Ursodeoxycholic acid (ursodiol), a gallstone dissolution agent, is used in two ways:
1) At a dose of 8-10 mg/kg/day orally in 2 to 3 divided doses (use beyond 24 months is not established) for chemodissolution of bile duct stones in patients with established cholesterol gallstones 2,4,9; complications may occur until dissolution is completed, which does not occur for many patients2; after treatment discontinuation, new gallstones develop in 50% of patients by 5 years.4
2) At a dose of 600 mg daily (300 mg orally bid) for 16 weeks for the prevention of gallstones in obese patients experiencing rapid weight loss (i.e., from very low-calorie diets or by bariatric surgery), which is associated with a high risk of new cholesterol gallstones. The incidence of gallstones is reduced by 80% in this setting.2,4,9
Ursodiol should not be administered with aluminum-based antacids; if aluminum-based antacids are necessary, administer 2 hours after ursodiol.9 Recommended monitoring parameters include alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST) at initiation, at 1 and 3 months, and every 6 months thereafter, and a sonogram.9 Patients should be instructed to take ursodiol with food; comply with frequent blood work necessary to follow drug effects; and report any persistent nausea, vomiting, or abdominal pain.9 As there have been no specific clinical studies in the elderly, it is recommended to start ursodiol at the lowest recommended dose, with scheduled monitoring.9
Conclusion
Gallstones continue to form throughout adult life. Increasing age is a major risk factor for their formation, with the prevalence of gallstones being greatest at advanced age. While the majority of gallstones remain asymptomatic, seniors have a high risk for acute cholecystitis with atypical presentation, even when gangrene or perforation has occurred. Pharmacists should be familiar not only with the risk factors for cholelithiasis, including advanced age and medications, but with the diagnostic techniques and current options for treatment as well.
REFERENCES
1. Rice JC, Barancin C, Benson M, et al. Hepatic, biliary, and pancreatic disease. In: Halter JB, Ouslander JG, Tinetti ME, et al, eds. Hazzard's Geriatric Medicine and Gerontology. 6th ed. New York, NY: McGraw-Hill; 2009:1065-1073.
2. Cholelithiasis. EMedicine. WebMD. http: emedicine.medscape.com/4. Beers MH, Porter RS, Jones TV, et al. The Merck Manual of Diagnosis and Therapy. 18th ed. Whitehouse Station, NJ: Merck Research Laboratories; 2006:240-243.
5. Kalantaridou SN, Davis SR, Calis KA. Hormone therapy in women. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; 2008:1351-1368.
6. Cirillo DJ, Wallace RB, Rodabough RJ, et al. Effect of estrogen therapy on gallbladder disease. JAMA. 2005;293(3):330-339.
7. Liu B, Beral V, Balkwill A, et al. Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study. BMJ. 2008;337:a386.
8. Gallstones. MayoClinic.com.
www.mayoclinic.com/health/
9. Semla TP, Beizer JL, Higbee MD. Geriatric Dosage Handbook. 15th ed. Hudson, OH: Lexi-Comp, Inc; 2009.
10. Dorland's Pocket Medical Dictionary. 28th ed. New York, NY: Elsevier Saunders; 2009.
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