Gallbladder Diseases: Research Looks to More Effective Treatments

What Are Gallstones?

More than 25 million people in the United States—up to 15 percent of the population—have gallstones, and one million people are diagnosed with gallstones each year. Gallstones develop when bile stored in the gallbladder hardens into stone-like chunks. Their sizes range from a grain of sand to a golf ball. Luckily, important advances have been made in the last few years in the understanding of gallstone disease and new remedies to treat it.

What Are the Different Kinds of Gallstones?

There are two types of gallstones: cholesterol stones and pigment stones.

•	Cholesterol stones: Accounting for about 80 percent of gallstones, cholesterol stones are yellow-green and made primarily of hardened cholesterol.
•	Pigment stones: Pigment stones are small dark stones made of bilirubin.

If gallstones get trapped in any of the ducts that carry bile from the liver to the small intestine—including the hepatic ducts, which carry bile out of the liver, and the cystic ducts, which take bile to and from the gallbladder—they can block the normal flow of bile, causing the gallbladder to become swollen. Gallstones can also block the pancreatic duct, which carries enzymes (chemicals that help the body digest food) out of the pancreas, leading to an extremely painful condition called gallstone pancreatitis. If any of these ducts remain blocked for a significant amount of time, the gallbladder, liver, or pancreas could become infected. Warning signs of a serious infection include fever, jaundice (yellowing of the skin and whites of the eyes), and persistent pain.

What Causes Gallstones?

Scientists don’t know what causes gallstones, but research has shown some factors that tend to increase people’s risk for developing them.

•	High cholesterol levels in the bile increase the risk for cholesterol stones
•	High amounts of bilirubin in the bile increase the risk for bilirubin (pigment) stones
•	Incomplete emptying of the gallbladder
•	Foods high in fat and cholesterol and low in fiber may increase the risk for gallstones, although scientists are not sure what exact role diet has in the formation of stones.

What Are the Symptoms of a Gallstone Attack?

Gallstone attacks, which often follow fatty meals, may occur during the night. Some people with gallstones have no symptoms (called “silent stones”). These silent stones do not interfere with gallbladder, liver, or pancreas function, and they do not require treatment.

The following symptoms may occur during a gallstone attack:

•	Steady pain in the upper abdomen that increases rapidly and lasts from 30 minutes to several hours
•	Pain in the back between the shoulder blades
•	Pain in the upper right shoulder
•	Nausea or vomiting
•	Abdominal bloating
•	Recurring intolerance of fatty foods
•	Colic
•	Belching
•	Gas
•	Indigestion.

If you have symptoms of a gallbladder attack and also experience sweating, chills, and fever, you should see your doctor immediately.

Cholecystitis

Cholecystitis occurs when the gallbladder becomes red and swollen. About 90 percent of cholecystitis cases are caused by gallstones that block the bile ducts. Because of this blockage, bile builds up and pushes on the walls of the gallbladder, causing inflammation. Other causes of cholecystitis include infection, severe illness, alcohol abuse, trauma, diabetes, or, rarely, a tumor.

What Are the Symptoms of Cholecystitis?

The primary symptom of cholecystitis is sudden intense pain in the upper right side of the abdomen, particularly after a fatty meal. Other symptoms include:

•	Nausea and vomiting
•	Recurrent painful attacks for several hours after meals
•	Pain that extends to the lower part of the right shoulder blade that may worsen with deep breaths
•	Shortness of breath due to pain while inhaling
•	Nausea
•	Vomiting
•	Stiff abdominal muscles, especially on the right side
•	Mild fever
•	Chills
•	Jaundice
•	Abdominal bloating.

Gallbladder Cancer

Gallbladder cancer is the fifth most common cancer of the gastrointestinal tract; about 7,000 people are diagnosed with the disease each year, and about 3,500 people die of gallbladder cancer each year.

Gallbladder cancer is twice as common in women as men, and white women are more likely than black women to develop the disease. Most people with gallbladder cancer are older than 70. Additionally, people of certain nationalities in certain areas are at a greater risk for gallbladder cancer. For example, in New Mexico, gallbladder cancer is diagnosed in five times as many Native Americans than it is in whites.

What Are the Symptoms of Gallbladder Cancer?

Unfortunately, gallbladder cancer is difficult to detect because the gallbladder is located behind other organs; the disease is usually not discovered until a person experiences symptoms of gallbladder cancer or the gallbladder is removed for other reasons.

Symptoms of gallbladder cancer are similar to those of other gallbladder diseases, and there may be no symptoms at all in the early stages of the disease. If you experience any of the following symptoms, visit your doctor immediately.

•	Pain above the stomach
•	Weight loss without trying
•	Fever
•	Yellowing of the skin (jaundice).

What Are the Different Stages of Gallbladder Cancer?

Treating gallbladder cancer depends on how far the disease has spread. There are three stages of the disease:

•	Localized. Cancer cells appear on the tissues on the wall of the gallbladder, and they can be completely removed with surgery.
•	Unresectable. Cancer cells have spread to the liver, stomach, pancreas, intestine, or lymph nodes. Surgery cannot remove all of the cancer.
•	Recurrent. The cancer cells have reappeared in the gallbladder after treatment.

Diagnosing Gallbladder Disease

If you are experiencing any of the symptoms of gallbladder disease, talk to your doctor. After a physical examination and a discussion of your medical history, he or she might order tests to rule out other diseases that have symptoms similar to those of gallbladder disease, including appendicitis, ulcers, irritable bowel syndrome, pancreatitis, and jaundice.

Many gallstones, especially silent stones, are found by accident during tests for other problems. If your doctor thinks you might have gallstones, he or she might order liver blood tests to examine signs of infection, obstruction, pancreatitis, or jaundice, which can occur if too much bile is in the liver.

Radiographic Tests

Your physician could also order radiographic tests, which use x-rays, to determine if you have gallstones.

•	Ultrasound. Ultrasound is the most sensitive and most common test to help physicians diagnose gallstones. During the test, sound waves bounce off the gallbladder and other structures inside your body to create an image. The sound waves will also pick up any hard objects, like gallstones.
•	Oral cholecystogram (OCG). During an OCG, the physician takes x-rays of the person’s gallbladder after the person swallows pills that contain dye.

Once gallstones have entered the bile duct, they are harder to detect with these tests because ultrasound is less sensitive in the bile duct and OCG can’t be used at all. To help identify any possible gallstones in the bile duct, your physician might recommend an endoscopic retrograde cholangiopancreatography, or ERCP. During this procedure, a physician inserts dye directly into the bile duct. Using a flexible swallowed endoscopy tube attached to a computer and TV monitor, he or she can locate and remove stones.

Your physician may recommend one of the following tests to detect gallstones:

•	Computed tomographic (CT) scan, a detailed cross-sectional x-ray image of the body, may help detect gallstones or other complications.
•	Magnetic resonance (MR) cholangiogram, the injection of dye into the bile ducts in order to examine the gallbladder and ducts on an x-ray, may detect blocked bile ducts.
•	Cholescintigraphy (HIDA scan) is used to detect obstruction or abnormal contractions of the gallbladder. During this test, a person is injected with a radioactive material that stimulates the gallbladder to contract.
•	Percutaneous transhepatic cholangiography (PTC), which involves using a needle with injection of dye into the bile ducts and x-ray to look for stones, also may detect gallstones.

Diagnosing Cholecystitis

Like gallstones, the symptoms of acute cholecystitis are similar to those of other illnesses, so it is sometimes hard to diagnose. If your doctor suspects that you might have cholecystitis, he or she may perform one or more of the following tests:

•	Abdominal ultrasound
•	Hepatobiliary scintigraphy, an imaging technique that allows the physician to examine the liver, bile ducts, gallbladder, and upper part of the small intestine
•	Cholangiography
•	CT scan.

Diagnosing Gallbladder Cancer

If you think you might have gallbladder cancer, talk to your doctor. After reviewing your symptoms and any possible risk factor you might have, he or she may give you a physical exam. During the physical, your doctor might check your abdomen for extra fluids, examine your skin and eyes for signs of jaundice, and look for swollen lymph nodes to help determine if the cancer has spread there.

Your physician could also recommend other diagnostic tests.

Blood Tests

Your doctor may order a blood test to measure the level of bilirubin in your blood. A high bilirubin level indicates possible gallbladder or liver problems. Your doctor could also order tests to detect levels of the chemicals alkaline phosphatase and aspartate aminotransferase and the tumor markers CEA and CA 19-9, which can indicate gallbladder cancer.

Diagnostic Tests

Your doctor could also recommend one of the following tests to help detect gallbladder cancer.

•	Ultrasound. Ultrasound can identify about one half of gallbladder cancers, and the pattern of sound wave echoes can help distinguish some types of benign tumors from malignant ones, as well as whether the cancer has invaded the liver.
•	CT scan. A CT scan can often determine the location of the cancer cells, and they are also used to determine how far the cancer has spread. CT scans also can be used to help guide a biopsy needle into a suspected tumor (or CT-guided needle biopsy).
•	MR imaging (MRI). MRI scans use radio waves and strong magnets instead of x-rays to produce detailed images of the body. The energy from the radio waves is absorbed and released in certain patterns depending upon the type of tissue (or diseased tissue) they enter. Although most doctors prefer CT scans as a first step at looking at the gallbladder, the MRI produces more detailed information.
•	Angiography. Angiography is an x-ray procedure used to examine blood vessels. A small amount of dye is injected into an artery to highlight blood vessels, and then x-ray images are taken to allow the doctor to see if blood flow to the area is blocked by a tumor or if there are any abnormal blood vessels in the gallbladder area. It can also reveal if a tumor has grown through the walls of blood vessels or the wall of the gallbladder.
•	Cholangiography.
•	ERCP.
•	Laparoscopy. During this procedure, a doctor inserts a thin lighted tube through an incision in the front of the abdomen to examine the gallbladder, liver, and area around the gallbladder to detect how much the cancer has spread.
•	Biopsy. During this procedure, a thin needle is inserted into the gallbladder to draw a sample of the tumor. The sample is then examined under a microscope to determine whether it is cancerous.

Treating Gallbladder Disease

Treating Gallstones

Researchers have developed new methods of treating gallbladder cancer during the last few years, but surgical removal of the gallbladder (a procedure known as cholecystectomy) remains the most popular therapy. Although newer nonsurgical treatments are useful in only some people, surgery can be used in nearly all people with gallstones.

Surgery

Each year, more than 500,000 Americans have gallbladder surgery.

•

Open cholecystectomy. During this procedure, the surgeon removes the gallbladder through a five- to eight-inch incision. People who undergo this procedure usually remain in the hospital for four or five days and then recover at home for a few weeks.

•

Laparoscopic cholecystectomy: Introduced in the United States in 1998, this technique is now used in 90 percent of all cholecystectomies. During this procedure, the surgeon makes several incisions in the belly button and inserts a tiny video camera that transmits a picture to the TV screen in the operating room, which guides the surgeon as he removes the gallbladder. Because abdominal muscles are not cut in this procedure, there is less pain, quicker recovery time, and fewer scars with this technique.

Nonsurgical Treatments

Your physician might not recommend surgery if you have cholesterol stones or if you have another medical condition that would make surgery difficult. Unfortunately, gallstones can appear after nonsurgical treatments.

•	Oral medications. Drugs made from bile acid—including ursodiol (Actigall) and chenodiol (Chenix)—dissolve the stones. These drugs work best on small cholesterol stones, and months or years of treatment may be necessary before all the stones are dissolved.
•	Contact dissolution therapy. When it’s injected directly into the gallbladder, a drug called methyl tertbutyl ether seems to dissolve stones. Some stones dissolve in as little as 1 to 3 days.
•	Extracorporeal shockwave lithotripsy (ESWL): This treatment uses shock waves to break up stones into smaller pieces that can pass more easily through bile ducts and avoid blockages. However, intense pain can follow treatment, and the long-term success rate is not known.

Treating Cholecystitis

Initial treatment for cholecystitis usually involves hospitalization, where the person is fed intravenously. Although cholecystitis may resolve itself without treatment, cholecystectomy (surgery to remove the gallbladder) may be necessary if inflammation is persistent. The surgery is performed as soon as possible after a person is diagnosed with cholecystitis.

Nonsurgical treatments of cholecystitis include medications to control pain, antibiotics to help wipe out the infection, and a low-fat diet.

Treating Gallbladder Cancer:

There are different options to treat gallbladder cancer. Ask your doctor which method is best for you.

Surgery

When gallbladder cancer has not spread to surrounding tissues, surgery is a common treatment. Your doctor may remove your gallbladder and, possibly, some of the surrounding lymph nodes. If the cancer has spread and cannot be removed or if it’s blocking the bile ducts, your doctor may perform surgery to relieve symptoms or perform a biliary bypass, which involves cutting the gallbladder or bile duct and sewing it to the small intestine. Your doctor may also insert a catheter into the gallbladder to drain excess bile.

Radiation

Radiation may be used alone or with surgery. Radiation for gallbladder cancer usually comes from an external machine (external-beam radiation therapy).

Chemotherapy

Chemotherapy, during which anticancer drugs are injected into the bloodstream, may be given along with radiation to make cancer cells more sensitive to the radiation (radiosensitizers).

Current Research

Gallstone Research

Scientists are researching whether a combination of different therapies, including lithotripsy and medications, may be more effective in dissolving gallstones that just one treatment option.

Cholecystitis Research

Scientists are trying to determine whether how quickly a person is diagnosed affects their treatment options. For example, a study published in American Family Physician about the effect of a delayed diagnosis on a person’s outcome found that people who didn’t see their doctor when they first had symptoms of cholecystitis were much more likely to require open surgery than those who sought medical help right away.

Gallbladder Cancer Research

Research on the causes, diagnosis, and treatment of gallbladder cancer is currently underway all over the world, including the following therapies:

•	Chemotherapy and radiation therapy: Scientists are looking into new ways of making radiation more effective. They’re also looking at new chemotherapy drugs and the use of old chemotherapy medications in combination with other treatments.
•	Immunotherapy: Experimental treatments that boost a patient’s immune response are being tested as a method to fight gallbladder cancer, including the use of interleukin-12 (IL-12).
•	Gene therapy: A protein from an altered form of the cold virus, ONYX-15, which can kill cancer cells, is being tested as a possible therapy for gallbladder cancer.

Towards the Future

Research on all gallbladder treatments continues to move forward, so new treatments are likely to be available in the future.

•	Chemotherapy medications. Researchers will study the effectiveness and safety of rebeccamycin analogue, a chemotherapy drug, in treating people who have advanced liver and/or gallbladder cancer.
•	Lithotripsy. Scientists are also studying how successfully lithotripsy treats single noncalcified gallstones that are 4 to 20 mm in diameter.

References

1. “Gallbladder Disease,” MEDLINEplus Medical Encyclopedia, National Library of Medicine (NLM), May 1, 2002.

2. “Gallstones,” The American Gastroenterological Association, 2002.

3. “About Cholecystectomy: Surgical Removal of the Gallbladder,” American College of Surgeons, 2003.

4. “Gallstones,” National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), March 2002.

5. “Acute Cholecystitis,” Journal of the American Medical Association, Jan. 1, 2003.

6. “Acute Cholecystitis (Gallstones),” MEDLINEplus Medical Encyclopedia, NLM, Nov. 18, 2002.

7. “What Are the Key Statistics for Gallbladder Cancer?” American Cancer Society (ACS), 2003.

8. “Gallbladder Cancer,” National Cancer Institute (NCI), Aug. 22, 2002.

9. “Treatment of Gallstone and Gallbladder Disease,” National Guideline Clearinghouse, May 2000.

10. “Cholelithiasis,” MEDLINEplus Medical Encyclopedia, Jan. 29, 2002.

11. “How Is Gallbladder Cancer Diagnosed?” ACS, 2003.

12. “Lithotripsy for the Treatment of Gallstones,” ClinicalTrials.gov, November 2002.

13. “Lithotripsy,” MEDLINEplus Medical Encyclopedia, NLM, Nov. 12, 2001.

14. “Cholecystitis Is Complicated by Delayed Diagnosis,” American Family Physician, March 1, 2000.

15. “What’s New in Gallbladder Cancer Research and Treatment?” ACS, 2003.

16. “Rebeccamycin Analogue in Treating Patients with Advanced Liver and/or Biliary Cancer,” ClinicalTrials.gov, February 2002.

Writer: Elizabeth Shimer
Clinical Reviewer: Patt Panzer, MD, MPH
Editors: Andrea King, Joanne Poeggel
Source of Material: Rockhill Communications, 14 Rock Hill Road Bala, Cynwyd, PA 19004, (610) 667-2040, http://www.rockhillcommunications.com
Date Written: 5/18/03
Date Last Revised: 5/30/03