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Q.- What are gall stones? How is cholesterol metabolism related to gall stone formation ? Discuss in  detail about the biochemical basis, clinical manifestations, diagnosis and treatment of this problem.

Answer- Stones in the gall bladder (Gall stones)- (Figure-1)

A gallstone is a crystalline concretion formed within the gallbladder by accretion of bile components.


















Figure-1- Showing stones in the gall bladder.


The two main types of stones are cholesterol stones and pigmented stones.

Mixed type are also there which typically contain cholesterol, bile pigments, calcium ions and organic materials  (Calcium carbonate, palmitate phosphate), (Figure-4)

a) Cholesterol stones

Eighty percent of gallstones in the Western world are a result of cholesterol precipitation from the bile, a condition known as Cholelithiasis (Figure-2)











Figure-2-showing cholesterol stones.

Bile is a controlled mixture of cholesterol, bile acids, and phospholipids (with small amounts of bile pigments), and if cholesterol levels are elevated or bile acids/salts lowered, the ratio of the three major components changes leaving cholesterol less protected against the aqueous environment and more likely to precipitate. Bile salt (ionized, deprotonated form) and bile acid (neutral, protonated form) are to solubilize cholesterol thus preventing precipitation of cholesterol crystals and facilitating cholesterol excretion.

Causes of cholesterol stone formation

  • Excess HMG-CoA reductase activity, the rate-limiting enzyme in cholesterol biosynthesis; this condition is typically seen in the obese.
  • Alternatively, reduced levels of acyl- CoA: cholesterol acyl Transferase [ACAT],  the enzyme that esterifies cholesterol within cells, or
  •  Reduced levels of cholesterol 7α-hydroxylase can cause elevation of cholesterol. The initial and rate-limiting step of bile acid synthesis is oxidation of cholesterol to 7a-hydroxycholesterol by a mixed function oxidase from the cytochrome P450 super family, cholesterol 7a-hydroxylase (CYP7A1).
  • Deoxycholate, a secondary bile acid synthesized by intestinal bacteria, inhibits CYP7A1. Therefore, high levels of deoxycholate resulting from prolonged exposure of bile acids to intestinal bacteria may result in high levels of cholesterol in bile.
  • Due to impaired entero-hepatic circulation (ileal resection)
  • Infections (cause conversion of lecithin to lysolecithin), phospholipids  are less available to keep cholesterol soluble

When the bile becomes over saturated with cholesterol; the excess forms solid particles (cholesterol crystals). These microscopic crystals accumulate in the gallbladder, where they clump and grow into gallstones.

b) Pigmented stones are usually made of bilirubin and appear dark in color (Figure-3). These microscopic crystals accumulate in the gallbladder, where they clump and grow into gall stones. 











Figure-3-Showing Pigment stones

The stones may stay in the gallbladder or pass into bile ducts. Stones can block the cystic duct, common bile duct, or ampulla of Vater. Any stricture of the bile ducts can lead to a blockage or slow bile flow. Bacterial infections can develop when bile flow is slowed or blocked.











Figure-4- Showing mixed stones

Sometimes microscopic particles of cholesterol, calcium compounds, bilirubin, and other materials accumulate but do not form stones. This material is called biliary sludge. Sludge develops when bile remains in the gallbladder too long, for example, as it does during pregnancy. Gallbladder sludge usually disappears when its cause resolves, for example, when pregnancy ends. Sludge, however, can evolve into gallstones or pass into the biliary tract and block the ducts.

Incidence of Gall stones

Gallstones are more common in women than in men and increase in incidence in both sexes and all races with aging. In the United States, over 10% of men and 20% of women have gallstones by age 65 years; the total exceeds 20 million people. Although cholesterol gallstones are less common in black people, cholelithiasis attributable to hemolysis occurs in over a third of individuals with sickle cell anemia.

Risk factors

1) Genetic mutations that predispose persons to gallstones have been identified.

2) Obesity is a risk factor for gallstones, especially in women.

3) Rapid weight loss also increases the risk of symptomatic gallstone formation.

4) There is evidence that glucose intolerance and elevated serum insulin levels (insulin resistance syndrome) are risk factors for gallstones, and a high-intake of carbohydrate and high dietary glycemic load increase the risk of cholecystectomy in women. A low-carbohydrate diet and physical activity may help prevent gallstones.

5) Consumption of caffeinated coffee appears to protect against gallstones in women, and a high intake of polyunsaturated and monounsaturated fats reduces the risk of gallstones in men on an energy-balanced diet.

6) A high-fiber diet reduces the risk of cholecystectomy in women.

7) Hypertriglyceridemia may promote gallstone formation by impairing gallbladder motility.

8) The incidence of gallstones is high in individuals with Crohn’s disease; approximately one-third of those with inflammatory involvement of the terminal ileum have gallstones due to disruption of bile salt resorption that results in decreased solubility of the bile. T

8)The incidence of cholelithiasis is also increased in patients with diabetes mellitus  

9) The prevalence of gallbladder disease is increased in men (but not women) with cirrhosis and hepatitis C virus infection.

Clinical Manifestations

a) About 80% of people with gallstones do not have any symptoms for many years, if ever, particularly if the gallstones remain in the gallbladder.

b) Pain-Gallstones may cause pain. Pain develops when the stones pass from the gallbladder into the cystic duct, common bile duct, or ampulla of Vater and block the duct. Then the gallbladder dilates, causing pain called biliary colic. The pain is felt in the upper abdomen, usually on the right side. Eating a heavy meal can trigger biliary colic, but simply eating fatty foods does not. Gallstones do not cause belching or bloating. Nausea occurs only when biliary colic occurs.

Although most episodes of biliary colic resolve spontaneously, pain returns in 20 to 40% of people each year, and complications may develop. Between episodes, people feel well.

c) Inflammation-If the blockage persists, the gallbladder becomes inflamed .When the gallbladder is inflamed  infection may develop. The inflammation usually causes fever.

d) Blockage– Blockage of a bile duct can cause the ducts to dilate (Figure-5). It can also cause fever, chills, and jaundice. This combination of symptoms indicates that a serious infection called acute cholangitis has developed.












Figure -5- Showing Obstruction of Common bile duct by Gall stones

e) Septicemia- Bacteria can spread to the bloodstream and cause serious infections elsewhere in the body. Also, abscess can develop in the liver.

f) Pancreatitis-Stones that block the ampulla of Vater also can block the pancreatic duct, causing pancreatitis.

g) Perforation and Peritonitis-Inflammation of the gallbladder caused by gallstones can erode the gallbladder wall, sometimes resulting in perforation. Perforation results in leakage of the gallbladder contents throughout the abdominal cavity, causing severe peritonitis.

h) Gall stone ileus– A large gallstone that enters the small intestine can cause intestinal blockage, called a gallstone ileus. Though rare, this complication is more likely to occur in older people.


Diagnosis is   made by the characteristic pain in the upper abdomen. Sometimes gallstones are detected when an imaging test such as ultrasonography is done for other reasons.

Ultrasonography is essential. It is 95% accurate in detecting gallstones in the gallbladder. It is less accurate in detecting stones in the bile ducts, but it may show that the blockage has caused the ducts to dilate. Other diagnostic tests may be necessary.

They include magnetic resonance imaging (MRI) of the bile and pancreatic ducts, computed tomography (CT), and endoscopic retrograde cholangiopancreatography .

Blood test results are usually normal unless stones block the bile ducts. Then, the liver tests are abnormal, suggesting cholestasis. Results often include an increase in bilirubin and certain liver enzymes.


Gallstones that do not cause symptoms (silent gallstones) do not require treatment. If gallstones do cause pain, changing the diet (for example, to a low-fat diet) does not help.

Gallstones in the Gallbladder

If gallstones cause disruptive, recurring episodes of pain, surgical removal of the gallbladder cholecystectomy is recommended. Laparoscopic cholecystectomy is the treatment of choice for symptomatic gallbladder disease.  Removal of the gallbladder prevents episodes of biliary colic yet does not affect digestion. No special dietary restrictions are required after surgery.

Cheno- and ursodeoxycholic acids are bile salts that when given orally for up to 2 years dissolve some cholesterol stones and may be considered in occasional, selected patients who refuse cholecystectomy.

Gallstones in the Bile Ducts

Stones in the bile ducts are removed during endoscopic retrograde cholangiopancreatography (ERCP).



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