Gallstones (Cholelithiasis): Symptoms, Causes & Treatment

Cholelithiasis (Gallstones)

• Gallstones are formed from constituents of the bile (viz. cholesterol, bile pigments and calcium salts) along with other organic components.
• Accordingly, the gallstones commonly contain cholesterol, bile pigment and calcium salts in varying proportions.
• They are usually formed in the gallbladder but sometimes may develop within extrahepatic biliary passages, and rarely in the larger intrahepatic bile duct.

Gallstones  Risk Factors

• The incidence of gallstones varies markedly in different geographic areas, ages, gender, diet and various other risk factors.
• These factors which largely pertain to cholesterol stones can be summed up in the old saying that gallstones are common in the 4Fs acronym for fat, female, fertile (multipara) and forty’.

Some of the risk factors in lithogenesis are explained below:

1. Geography Gallstones are quite prevalent in almost the entire Western world. American Indians have the highest known prevalence. Black Africans and populations in the Eastern world are relatively free of cholelithiasis.

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2. Genetic factors There is an increased frequency of gallstones in first-degree relatives of patients with cholelithiasis.

• Patients of gallstone disease have increased secretion of dietary cholesterol in bile than in non-gallstone patients in spite of a high-cholesterol diet.
• Recently, a mutation in the CYP7A1 gene has been found that results in a deficiency of the enzyme, cholesterol 7-hydroxylase, which has a role in bile acid synthesis.
• This mutation is associated with hypercholesterolaemia and gallstones.

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3. Age There is a steady increase in the prevalence of gallstones with advancing age which may be related to increased cholesterol content in the bile.

• The incidence increases above the age of 40 and the presentation of the disease is usually in the 50s and 60s.

4. Sex Gallstones are twice more frequent in women than in men. In the United States, autopsy series have shown gallstones in about 20% of women and 8% of men above the age of 40.

• The incidence is higher in multiparous women than in nulliparous women.

5. Drugs Women on oestrogen therapy or on birth control pills have a higher incidence of gallstones. This is considered to be due to the production of more lithogenic bile as a result of the cholestatic effect of oestrogen.

• Similar is the influence of certain drugs used for lowering blood cholesterol such as clofibrate.

6. Obesity Obesity is associated with increased cholesterol synthesis and its excretion resulting in a higher incidence of gallstones in obese patients.

7. Diet Deficiency of dietary fibre content is linked to a higher prevalence of gallstones. Moderate consumption of alcohol, however, seems to protect against gallstones.

8. Gastrointestinal diseases Certain gastrointestinal disorders such as Crohn’s disease, ileal resection, ileal bypass surgery etc are associated with the interruption in enterohepatic circulation followed by gallstone formation.

9. Factors in pigment gallstones All the above factors apply largely to cholesterol stones.

• Pigment stones, whether pure or mixed type, are more frequently associated with haemolytic anaemias which lead to increased content of unconjugated bilirubin in the bile.
• Pigment stones are also more frequent in cirrhosis and hepatocellular disease.

Gallstones  Pathogenesis

The mechanism of gallstone formation ( lithogenesis) is explained separately below under 2 headings: firstly for cholesterol, mixed gallstones and biliary sludge; and, secondly for pigment gallstones as under:

Pathogenesis of Cholesterol, Mixed Gallstones and Biliary Sludge

• Cholesterol is essentially insoluble in water and can be solubilised by another lipid.
• Normally, cholesterol and phospholipids (lecithin) are secreted into bile as ‘bilayered vesicles’ but are converted into ‘mixed micelles by the addition of bile acids, the third constituent.
• If there is excess cholesterol compared to the other two constituents, unstable cholesterol-rich vesicles remain behind which aggregate and form cholesterol crystals.
• The formation of such lithogenic (stone-forming) bile is explained by the following mechanisms.

1. Supersaturation: of bile Several etiologic factors listed above favour increased secretion of cholesterol in the presence of normal bile acids and lecithin in the bile as the major mechanism for initiation of gallstone formation.

• These factors cause enhanced activity of the enzyme, HMG-CoA reductase, which normally regulates cholesterol synthesis and its hepatic uptake.
• Two other disturbances which may contribute to the supersaturation of the bile with cholesterol are as under:
  1. Reduced bile acid pool This causes rapid loss of the available bile acids into the small intestine and then into the colon, resulting in supersaturation of the bile with cholesterol.
  2. Increased conversion of cholic acid to deoxycholic acid This causes increased secretion of deoxycholate in the bile which is associated with hypersecretion of cholesterol into the bile.

• Mutation in the MDR3 gene has been found that causes a defect in phospholipid secretion from bile, resulting in cholesterol supersaturation of bile and cholesterol gallstone formation.
• Although supersaturation of the bile with cholesterol is an important pre-requisite for lithogenesis, this in itself is not sufficient for cholesterol precipitation.

2. Cholesterol nucleation Initiation of cholesterol stones occurs by nucleation of cholesterol monohydrate crystals.

• Accelerated nucleation of cholesterol monohydrate may occur either from pro-nucleating factors or from deficiency of anti-nucleating factors
  1. Pro-nucleating factors are mucin and non-mucin glycoproteins secreted by epithelial cells of the gallbladder.
  2. Anti-nucleating factors are apolipoproteins AI and AII, and some glycoproteins.
• Cholesterol monohydrate nucleation probably occurs in the mucin gel layer of the gallbladder followed by continued addition and precipitation of more crystals resulting in solid-state crystals.

3. Gallbladder hypomotility: Normally, the gallbladder is capable of emptying and clearing any sludge or debris which might initiate stone formation.

• This takes place under the influence of cholecystokinin secreted from the small intestine.
• However, the motility of the gallbladder may be impaired due to a decrease in cholecystokinin receptors in the gallbladder resulting in stasis of biliary sludge and lithogenesis.
• A defect in gallbladder emptying has been found to play a role in the recurrence of gallstone formation in patients who undergo biliary lithotripsy.

Pathogenesis of Pigment Gallstones

The mechanism of pigment stone formation is explained on the basis of the following factors:

1. Chronic haemolysis results in an increased level of unconjugated bilirubin in the bile.
2. Alcoholic cirrhosis.
3. Chronic biliary tract infection e.g. by parasitic infestations of the biliary tract such as by Clonorchis sinensis and Ascaris lumbricoides.
4. Demographic and genetic factors e.g. in rural settings and prevalence in Asian countries.

Types Of Gallstones

• As stated before, gallstones contain cholesterol, bile pigment and calcium carbonate, either in pure form or in various combinations.
• Accordingly, gallstones are of 3 major types—pure gallstones, mixed gallstones and combined gallstones. Mixed gallstones are the most common (80%) while pure and combined gallstones comprise 10% each.
• In general, gallstones are formed most frequently in the gallbladder but may occur in extrahepatic as well as intrahepatic biliary passages.
• Gallbladder containing pure stones shows no significant inflammatory reaction, whereas chronic cholecystitis is invariably present in gallbladder with either mixed or combined gallstones.
• The presence of calcium salts renders gallstones radio-opaque, while cholesterol stones appear as radiolucent filling defects in the gallbladder.
• The salient features of various types of gallstones are summarised and presented here

1. Pure Gallstones constitute about 10% of all gallstones. They are further divided into 3 types according to the component of bile forming them. These are as under

1. Pure cholesterol gallstones: They are usually solitary, oval and fairly large (3 cm or more) filling the gallbladder. Their surface is hard, smooth, whitish-yellow and glistening.

• On the cut section, the pure cholesterol stone shows radiating glistening crystals.
• It may result in the deposition of cholesterol within the mucosal macrophages of the gallbladder producing cholesterolosis which is an asymptomatic condition.
• Pure cholesterol stones are radiolucent but 10- 20% of them have calcium carbonate in them which renders them opaque.

2. Pure pigment gallstones: These stones are composed primarily of bile pigment, and calcium bilirubin, and contain less than 20% cholesterol.

• They are generally multiple, jet-black and small (less than 1 cm in diameter). They have mulberry-like external surfaces. They are soft and can be easily crushed. The gallbladder usually appears uninvolved.

3. Pure calcium carbonate gallstones: They are rare. Calcium carbonate gallstones are usually multiple, grey-white, small (less than 1 cm in diameter), faceted, fairly hard due to calcium content, and radio-opaque.

They, too, do not produce any change in the gallbladder wall.

2. Mixed Gallstones are the most common (80%) and contain more than 50% cholesterol monohydrate plus an admixture of calcium salts, bile pigments and fatty acids.

• They are always multiple, and multifaceted so that they fit together and vary in size from as tiny as sand grain to 1 cm or more in diameter.
• On section, they have distinct laminated structures with alternating dark pigment layers and pale-white layers revealing different combinations of cholesterol, bilirubin pigment and calcium carbonate, laid down in layers at different times.

Mixed gallstones are invariably accompanied by chronic cholecystitis.

3. Combined Gallstones: They comprise about 10% of all gallstones. Combined gallstones are usually solitary, large and smooth-surfaced.

• It has a pure gallstone nucleus (cholesterol, bile pigment or calcium carbonate) and an outer shell of mixed gallstone; or a mixed gallstone nucleus with a pure gallstone shell.
• Combined gallstones, too, are associated with chronic cholecystitis.

Gallstones Clinical Manifestations And Complications

• In about 50% of cases, gallstones cause no symptoms and may be diagnosed by chance during investigations for some other condition (silent gallstones).
• The future course in such asymptomatic silent cases is controversial, most surgeons advocate cholecystectomy while physicians advise watchful waiting.
• Follow-up studies, however, show that only about 10% of such cases develop symptoms. Symptomatic gallstone disease appears only when complications develop. These are as under.

1. Cholecystitis: The relationship between cholelithiasis and cholecystitis is well known but it is not certain which of the two comes first.

• Patients with gallstones develop symptoms due to cholecystitis which include typical biliary colic precipitated by fatty meal, nausea, vomiting, fever along with leucocytosis and high serum bilirubin.

2. Choledocholithiasis: Gallstones may pass down into the extrahepatic biliary passages and the small bowel, or less often they may be formed in the biliary tree.

• Patients with gallstones in the common bile duct frequently develop pain and obstructive jaundice. Fever may develop due to bacterial ascending cholangitis.

3. Mucocele and empyema: Mucocele or hydrops of the gallbladder is distension of the gallbladder by clear, watery mucinous secretion resulting from impacted stones in the neck of the gallbladder.

When it gets infected empyema is formed.

4. Biliary fistula: An uncommon complication of cholelithiasis is the formation of fistulae between one part of the biliary system and the bowel, and rarely between the gallbladder and the skin.

5. Gallstone ileus: A gallstone in the intestine may be passed in the faeces without causing symptoms. Occasionally, however, gallstones in the intestine may cause intestinal obstruction called gallstone ileus.

6. Pancreatitis: Obstructive cholecystitis may result in acute pancreatitis.

7. Gallbladder cancer: There is a small and doubtful risk of the development of cancer of the gallbladder in cases with cholelithiasis.

Cholelithiasis (Gallstones)

• Gallstones are formed from constituents of the bile (viz. cholesterol, bile pigments and calcium salts) along with other organic components.
• Gallstones are of 3 major types pure gallstones (cholesterol, bile and calcium-containing), mixed gallstones and combined gallstones.
• Mixed gallstones are the most common (80%) while pure and combined gallstones comprise 10% each.
• Major complications of gallstones are cholecystitis, choledocholithiasis, mucocele, empyema, biliary fistula, ileus, pancreatitis and gallbladder cancer.