Gallbladder Disease

Introduction

The gallbladder is a small sack like structure attached to the under surface of the liver, located in the right upper quadrant of the abdomen. The purpose of the gallbladder is to store and concentrate bile. Bile is a green liquid made by the liver composed of water, cholesterol, bile salts and lecithin. Bile assists in the breakdown and absorption of fats from food. When you eat, especially when you eat fatty foods, the gallbladder is stimulated to contract and empty its contents into the intestine. When bile mixes with food, it emulsifies fats and certain vitamins such as A, D, E, and K aiding in absorption. If the gallbladder has concentrated the bile too much, stones can form. This is a condition called cholelithiasis. Most gallstones are asymptomatic but about ten percent of people will develop symptoms. In the presence of stones, when the gallbladder contracts one of those stones may block the opening of the gallbladder. When this happens, the pressure builds up causing distention and pain. Gallstones can range from a few millimeters to several centimeters in size. Most stones are composed of cholesterol but may also be calcified bilirubin. The second most common form of gallbladder disease occurs in the absence of stones. In this condition the most common cause is the deposition of small crystals of cholesterol within the muscular wall of the gallbladder leading to swelling, inflammation and ultimately dysfunction and pain.

Signs and Symptoms

Symptoms of gallbladder disease generally occur after eating fatty, deep fried or spicy foods but can be brought on by almost any food. After eating, most people describe a pressure type pain in the epigastria and right upper quadrant of the abdomen. This pain will frequently radiate to the back or the right shoulder. It is generally accompanied by a feeling of being very bloated, the need to burp or belch and sometimes even nausea and vomiting. Diarrhea and fecal urgency after eating are also associated with chronic gallbladder disease. These same symptoms can occur in acalculous cholecystitis; inflammation of the gallbladder in the absence of stones. When symptoms are mild, most people think they are suffering from dyspepsia, sour stomach, gas, or the effects of over eating.

Risk Factors

While anyone can develop gallbladder disease there are known risk factors. Genetics certainly plays a role in this process. It is not uncommon to see multiple family members with this condition. Other risk factors include: Obesity, female gender, pregnancy, middle age, diet and ironically rapid weight loss.
Risk Factors in Women
Women are much more likely than men to develop gallstones. Gallstones occur in nearly 25% of women in the U.S. by age 60 and as many as 50% by age 75. In most cases, they are asymptomatic. In general, women are probably at increased risk because estrogen stimulates the liver to remove more cholesterol from blood and divert it into the bile.
Pregnancy:
Pregnancy increases the risk for gallstones, and pregnant women with stones are more likely to have symptoms than non-pregnant women. Hormonal changes associated with pregnancy, especially increased estrogen levels, predispose women to gallstone formation. If symptoms occur early in pregnancy, many surgeons advocate laparoscopic cholecystectomy just after the first trimester. If symptoms occur in the third trimester it is generally best to postpone surgery until after delivery. This is because surgery at this stage requires open surgery which can complicate normal delivery.
Hormone Replacement Therapy:
Several large studies have shown that use of hormone replacement therapy may increase the risk of developing symptomatic gallstones. A 2005 Journal of the American Medical Association study found that while all types of HRT raise the risks, estrogen alone has higher risks than combined estrogen and progesterone therapy. Estrogen has an effect on the liver and raises triglycerides, a fatty acid that increases the risk for cholesterol stones.
Risk Factors in Men
About 20% of men have gallstones by the time they reach age 75. Men who consume a diet high in foods containing iron, such as meat and seafood, are at increased risk for developing gallstones. Gallstones are not associated with diets high in alternative iron sources such as beans, lentils, and enriched grains. Men who have their gallbladders removed are more likely to have more severe disease and subsequently more likely to experience operative complications as compared to women.
Risks in Children
Gallstone disease is relatively rare in children. When gallstones occur in this age group they are more likely to be pigment stones. Girls do not seem to be more at risk than boys are. The following conditions may put children at higher risk:

• Spinal injury
• History of abdominal surgery
• Sickle-cell anemia
• Impaired immune system
• Intravenous nutrition

Ethnicity
Because gallstones are related to diet, particularly fat intake, the incidence of gallstones varies widely among nations and regions. Hispanics and Northern Europeans have a higher risk for gallstones than people of Asian and African descent. Native North and South Americans, such as Pima Indians in the U.S. and native populations in Chile and Peru, are especially prone to developing gallstones. In areas such as southern Arizona Pima women have an 80% chance of developing symptomatic gallstones during their lifetime. Such cases are most likely due to a combination of genetic and dietary factors. In these regions it is not unusual for children to develop symptomatic gallstones requiring surgery.
Genetics
Having a family member or close relative with gallstones may increase the risk of gallstones. Up to one-third of cases of painful gallstones may be related to genetic factors. Studies indicate that the disease is complex and may result from the interaction between genetics and environment. Some studies suggest immune and inflammatory mediators may play key roles.
Diabetes
People with diabetes are at higher risk for gallstones and have a higher than average risk for acalculous gallbladder disease (without stones). People with diabetes tend to have more advanced disease because of visceral neuropathy. The same process that affects peripheral nerves, affects nerves of the gastro-intestinal tract which allows gallbladder disease to progress undetected. Gallbladder disease may also progress more rapidly in patients with diabetes.

Obesity and Weight Changes

Obesity:
Being overweight is a significant risk factor for gallstones. In such cases, the liver over-produces cholesterol, which is delivered into the bile and causes it to become supersaturated. Some evidence suggests that specific dietary factors (saturated fats and refined sugars) are the primary culprit in these cases, although studies are conflicting. Animal studies, however, suggest that obesity itself, not any particular foods, triggers the process leading to cholesterol super saturation and the formation of stones.
Weight Cycling:
Rapid weight loss or cycling (dieting and then putting weight back on) further increases cholesterol production in the liver, and results in increased risk for gallstone formation. Individuals on an ultra low calorie diet that lose more the 25% of their body weight or lose more than 3 pounds a week are at very high risk of developing gallstones.

• The risk for gallstones is as high as 12% after 8 -16 weeks of restricted-calorie diets.
• The risk is more than 30% within 12 -18 months after gastric bypass surgery.

Bariatric Surgery
Patients who have radical weight loss surgery such as the Roux-en-Y, duodenal switch or sleeve gastrectomy are at high risk of developing symptomatic gallstones. For this reason, many centers request the patient undergo cholecystectomy before or during their bariatric procedure. This is because of the rapid and uncontrolled weight loss. Patients who have the Lap-Band surgery however have only about a 1% chance of developing symptomatic gallstones.

When to Seek Medical Advice

Generally people experience symptoms for quite some time before seeking professional help. Many people try over the counter antacids, gas preparations or even self induced vomiting to relieve the symptoms with little success. The factor that prompts people to seek help most often is an extremely intense attack which is unrelenting. Frequently these symptoms are so severe that people may fear they are having a heart attack and go the emergency room.

Diagnosis

The diagnosis of gallbladder disease is generally made with ultrasound which will frequently demonstrate stones. Blood work can also be helpful if liver enzymes or bilirubin are elevated. In the absence of stones a functional study of the gallbladder called a HIDA scan may be obtained. During this study a tracer that is taken up by the gallbladder is administered. The gallbladder is then stimulated to contract by injecting the same hormone that is secreted after eating. The study then measures how well the gallbladder contracts and whether any symptoms are elicited. A reduced ejection fraction and reproduction of symptoms is generally interpreted as a positive test.

Treatment Options

The most reliable and definitive treatment for disease of the gallbladder is its surgical removal. This is most commonly performed laparoscopically using a small TV camera, though on rare occasions open surgery may be necessary. In the past treatments to help dissolve gallstones or break them up using ultrasound have been explored but these have had only very limited success.
Laparoscopic Cholecystectomy
During this surgery the abdomen is filled with carbon dioxide gas, a small TV camera known as a laparoscope is inserted. Several other small incisions are made through which instruments are inserted. Watching the surgery on a monitor, the surgeon first identifies the cystic duct and artery. The surgeons of Advanced Surgery of Idaho then inject die into the cystic duct and obtain a special X-ray of the bile ducts called a cholangiogram. This identifies any stones that may have passed into the bile duct and more decisively delineates the anatomy reducing the chance of injury to the ducts. (Link to Cholangiogram pictures) The gallbladder is then removed from the under surface of the liver with electrocautery, placed in a plastic bag and extracted. The gas is then evacuated and the wounds closed. This procedure is usually done on an outpatient basis. While gallbladder surgery is very safe, any surgery has the risk of bleeding or infection. Possible risks of gallbladder surgery include bile leak, injury to the liver, bile ducts or intestine. Though rare, these complications may require major open surgery to correct. Insert Video (Reserve space for Lap Chole video)
Dissolution Therapy
Oral dissolution therapy uses bile acids in pill form to dissolve gallstones and may be used in conjunction with lithotripsy, although both techniques are rarely used at present. Ursodiol, (trade name Actigall) is the standard oral bile acid dissolution drug. Long-term treatment appears to reduce the risk of biliary pain and acute cholecystitis. The treatment is only modestly effective since gallstones recur in the majority of patients. Patients most likely to benefit from oral dissolution therapy are those with small stones that have high cholesterol content. Patients who probably will not benefit from this treatment include obese patients and those with gallstones that are calcified or composed of bile pigments. Less than 30% of patients would actually be candidates for oral dissolution therapy. Because of side effects, compliance is often a problem. The treatment can take up to 2 years and can cost thousands of dollars per year.
Extracorporeal Shock Wave Lithotripsy
Gallstone fragmentation by extracorporeal shock wave lithotripsy (ESWL) may be an appropriate therapy for some patients who cannot undergo surgery, but it is no longer widely used. The treatment works best on solitary stones that are less than two centimeters in diameter. The patient typically sits in a tub of water while high energy ultrasound shock waves are directed through the abdominal wall toward the stones. The shock waves travel through the soft tissues of the body and break up the stones. The stone fragments may then be small enough to pass through the bile duct and into the intestines. Lithotripsy is generally combined with oral dissolution treatment to help dissolve the fragmented pieces of the original gallstone. Complications include acute cholecystitis and pancreatitis, usually occurring within a month of treatment. In addition, not all of the fragments may clear the bile duct requiring ERCP and sphincterotomy. About 35% of patients who are left with fragments are at risk for further problems, which can be severe. The chance of recurrence is high with this procedure, and in one study, almost half of patients eventually required surgery. Elderly people may have a lower risk for recurrence than younger adults, which may make this a good choice for some.
Percutaneous Cholecystostomy
Percutaneous cholecystostomy is a procedure that may be used in seriously ill patients with severe gallbladder infection who cannot tolerate immediate surgery. It is also the standard treatment for critically ill patients with acute acalculous cholecystitis. A drainage catheter is inserted through the skin and into the gallbladder to relieve the pressure. This drainage catheter is usually left in place for up to 8 weeks. After that time laparoscopic or open cholecystectomy may be performed. Without cholecystectomy recurrence rates are high, especially in the presence of stones.

Complications

The complications of non treated cholecystitis include severe scarring of the gallbladder possibly precluding laparoscopic surgery, gangrene with perforation, and possibly life threatening pancreatitis. While rare, cancer of the gallbladder is possible, occurring about once per 1000 cases. This is most often associated with long standing disease or calcification of the gallbladder.

Complications of Acute Cholecystitis
The most serious complication of acute cholecystitis is infection, and is extremely dangerous and life-threatening if it spreads to other parts of the body or gets into the bloodstream. This can lead to a condition called sepsis which is life threatening. Symptoms include fever, rapid heartbeat, fast breathing, and mental confusion. Among the conditions that can lead to gallbladder sepsis are the following:

• Gangrene or Abscesses If acute cholecystitis is untreated and becomes very severe, inflammation can cause abscesses or destroy enough tissue in the gallbladder to lead to gangrene. Studies have reported this complication in between 2 - 30% of cases. The highest risk is in men over 50 with a history of heart disease and individuals with diabetes.
• Perforated GallbladderDelay in treatment of acute severe cholecystitis can result in perforation of the gallbladder, which is a life-threatening condition. This condition is most common in people with diabetes. The risk for perforation increases with a condition called emphysematous cholecystitis, in which gas forms in the gallbladder wall as the result of infection. Once the gallbladder has been perforated, pain may temporarily decrease. This is a dangerous and misleading event, however, since peritonitis (widespread abdominal infection) develops afterward.
• Empyema Pus in the gallbladder (empyema) occurs in 2 - 3% of patients with acute cholecystitis. Patients usually experience severe abdominal pain for more than 7 days. Ultrasound or CT scan will usually demonstrate a thickened gallbladder wall, fluid around the gallbladder and surrounding inflammation. The condition can be life threatening, particularly if infection spreads to other parts of the body.
• Choledocholithiasis This is a situation where gallstones are pushed out of the gallbladder into the common bile duct. The stones can then obstruct the bile duct leading to an infection of the bile duct known as cholangitis. If antibiotics are administered immediately, the infection clears up in 75% of patients. If cholangitis does not improve, the infection may spread and become life-threatening. If a stone blocks the pancreatic duct, this can back up the digestive enzymes into the pancreas causing pancreatitis. Both of these conditions can be life threatening. Either surgery or a procedure known as endoscopic sphincterotomy is required to open and drain the ducts.
• Gallbladder Cancer
  Cancer of the gallbladder is found in about one out of every one thousand gallbladders removed. Gallstones are present in about 80% of people with gallbladder cancer. Calcification of the gallbladder called porcelain gallbladder is associated with a high incidence of cancer. Symptoms of gallbladder cancer usually do not appear until the disease has reached an advanced stage and may include weight loss, anemia, recurrent vomiting, and a lump in the abdomen. When the cancer is caught at an early stage, removal of the gallbladder results in a 5-year survival rate of 68%. If cancer has spread to the liver, more extensive surgery or other treatments are required and have dismal results.

Gallbladder Polyps
Polyps are sometimes detected during diagnostic tests for gallbladder disease. Small gallbladder polyps (up to 10 mm) pose little or no risk, but large ones (greater than 15 mm) pose some risk for cancer, so the gallbladder should be removed. Patients with polyps 10 - 15 mm have a lower risk, but they should still discuss removal of their gallbladder with their doctor.

Do it Yourself

Once gallstones form there is little that one can do to relieve or prevent symptoms. Many people try over the counter antacids, gas preparations or even self induced vomiting with little relief. Strict dietary modification eliminating fatty, deep fried and spicy foods can minimize the frequency and severity of gallbladder attacks. A diet of plain rice, potatoes or soup is generally well tolerated. The only real treatment is surgical removal of the gallbladder.
Preventing Gallstones
Fats, particularly saturated fats found in meats, butter, and other animal products, have been associated with gallstone formation and attacks. Some studies have found a lower risk for gallstones in people who consume foods containing monounsaturated fats found in olive and canola oils. Omega-3 fatty acids, found in canola, flaxseed, and fish oil, also have health benefits. Fish oil may be of particular benefit in patients with high triglyceride levels by improving the emptying actions of the gallbladder. High intake of fiber has been associated with a lower risk for gallstones. Studies suggest that people may be able to reduce their risk of gallstones by eating more nuts such peanuts, walnuts and almonds. A diet high in fruits and vegetables and plant protein such as that found in soybeans also lowers the risk.

High-intake of sugar has been associated with an increased risk for gallstones. Diets that are high in carbohydrates such as pasta and bread can also increase risk, since carbohydrates are converted to sugar in the body.

A few studies have reported a lower risk for gallstones with alcohol consumption. Even small amounts (1 ounce per day) have been found to reduce the risk of gallstones in women by 20%. Moderate intake (defined as 1 - 2 drinks a day) also appears to have heart protection benefits. Pregnant women, people who can't drink moderately, and people with liver disease should not drink at all.

Ascorbic acid (vitamin C) appears to help break cholesterol down in bile. Vitamin C deficiencies have been associated with a higher risk for gallstones.

In one study, men who drank 2 or more cups of regular coffee daily (either instant, filtered, or espresso) had a 40% lower risk of developing gallbladder disease over 10 years than men who did not drink coffee regularly. Those who drank more than 4 cups had the lowest risk.

Preventing Gallstones during Weight Loss
Avoiding rapid weight loss helps to reduce the risk of gallstones. People who undergo certain types of weight loss procedures are at high risk for developing gallstones (See gallstones and bariatric surgery). Taking the medication Actigall during weight loss may reduce the risk for people who are very overweight and lose weight quickly. This medication is ordinarily used to dissolve existing gallstones. Xenical, a drug for treating obesity, may protect against gallstone formation during weight loss. The drug appeared to reduce bile acids and other components involved in gallstone production.

Exercising regularly and vigorously may reduce the risk of gallstones and gallbladder disease, even in people who are overweight. Studies are reporting a lower risk for gallstones in both men and women who exercise. Active sports exercise appears to be most protective for both men and women. A 1999 study of women reported that exercise reduced gallstone risk regardless of whether the women lost weight or not. Some evidence suggests that, in addition to controlling weight, exercise helps reduce cholesterol levels in the biliary tract, which could help prevent gallstones.

The Effects of Cholesterol-Lowering Drugs
Although it would be reasonable to believe that agents used to lower cholesterol would protect against gallstones, they do not appear to provide a significant benefit. One study however, reported a weak association between the statin drugs (Mevacor, Pravachol, Zocor, Lipitor, and Crestor) and a lower risk of gallstone formation.

More information is available at the National Institutes of Health website.

References:
Grunhage F, Lammert F. Gallstone disease. Pathogenesis of gallstones: A genetic perspective. Best Pract Res Clin Gastroenterol. 2006;20(6):997-1011.

Myers JA, Fischer GA, Sarker S, Shayani V. Gallbladder disease in patients undergoing laparoscopic adjustable gastric banding. Surg Obes Relat Dis. 2005;1(6)561-563.

Portenier DD, Grant JP, Blackwood HS, Pryor A, McMahon RL, Demaria E. Expectant management of the asymptomatic gallbladder at Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2007.

Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Fruit and vegetable consumption and risk of cholecystectomy in women. Am J Med. 2006;119(9):760-767.

Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Heme and non-heme iron consumption and risk of gallstone disease in men. Am J Clin Nutr. 2007;85(2):518-522.

Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Weight cycling and risk of gallstone disease in men. Arch Intern Med. 2006;166(21):2369-2374.

Wittenburg H, Lammert F. Genetic predisposition to gallbladder stones. Semin Liver Dis. 2007;237(1):109-121.

Sabiston Textbook of Surgery. Elsevier publishing 2008

National Institutes of Health Website