concretions formed by the precipitation of cholesterol or bilirubin and other substances around a nidus of material. They usually form in the gallbladder, but may form in the bile ducts.
Types of Gallstones
(1) Cholesterol gallstones
- ~80% of all gallstones. Result from precipitation of cholesterol microcrystals from supersaturated bile, typically in patients with abnormalities of cholesterol metabolism. May be as much as 50% calcium carbonate. 80% of cholesterol gallstones are radiolucent, only sufficient calcium carbonate renders radiopaque.
(2) Pigment (black) gallstones
- ~10% of all gallstones. Result from precipitation of calcium bilirubinate and related polymers, typically in patients with hemolytic anemias or cirrhosis.
(3) Mixed gallstones
– remainder of gallstones have variable content of cholesterol, bilirubin, and calcium carbonate.
Into bile as: cholesterol and lecithin vesicles, mixed micelles
Cholesterol and lecithin vesicles – cholesterol alone is virtually insoluble in aqueous solutions. Lecithin is hydrophobic too, but combines with cholesterol to form liquid crystal vesicles.
Mixed micelles – composed of cholesterol, lecithin and bile acids. By combining with bile acids, cholesterol becomes two million-fold more soluble. This happens by the cholesterol sandwiching between lecithin and bile acid, both of which have a greater number of polar groups directed outward the water interface. The cholesterol is then maintained in the lipid interior of the water soluble mixed micelle.
The degree of cholesterol solubility is determined by the relative concentrations all the three constituents. If the ratio is disturbed and there is insufficient lecithin and bile acids to maintain the structure of the micelle cholesterol supersaturation and precipitation can result.
General factors associated with cholesterol gallstone formation:
Heredity
, Sex (3x more frequent in women), Age (with age
ß in 7-a hydroxylase results in ß conversion of cholesterol to bile acids), Geography (0% in African Masai to 70% in American Indian), Obesity (in rapid weight loss the ratio of cholesterol in comparison to lecithin and bile acids increases, thus resulting in cholesterol precipitation), Drugs (estrogens, oral contraceptives, and clofibrate increase the biliary secretion of cholesterol and double the risk of gallstone formation), Delayed gallbladder emptying (following truncal vagotomy, or in diabetes), Disease involving or resection of the terminal ileum (results in impaired bile salt absorption).
Pathophysiologic mechanisms of cholesterol gallstone formation:
Hepatic cholesterol hypersecretion
– an increase in the content of free cholesterol in hepatocytes by:
Increased plasma lipoprotein uptake
Increased synthesis of cholesterol from up-regulation of HMG CoA reductase
Decreased catabolism of cholesterol to bile salts from decreased 7-
a hydroxylase activity
Decreased storage of cholesterol esters from decreased acylcoenzyme A cholesterol acyltransferase (ACAT) activity.
Hyposecretion of bile acids
Inability to eliminate cholesterol with 7-
a hydroxylase, because enzyme isn’t being controlled properly.
Impaired recycling of bile – liver doesn’t make enough bile and therefore must reuse it over and over.
Increased GI bile salt loss from ileal disease or resection.
Defective vesicle formation
– cholesterol is packaged into lecithin vesicles in the Golgi, this assembly may fail with lecithin deficiency.
Gallbladder hypomotility
–stasis of bile flow can result in stone formation due to primary smooth muscle defect
Presence of nucleation factors
– nucleation is the process of cholesterol precipitation and stone formation.
Glycoproteins may play a role.
Mucus may trap cholesterol crystals which serve as a nidus for nucleation.
Steps in cholesterol gallstone formation:
Supersaturation of bile by cholesterol
Formation of solid crystals of cholesterol
Cholesterol nucleation
Microscopic stone growth
Þ macroscopic stone growth
Pigment gallstones
Pathophysiologic mechanisms:
Defective gallbladder mucosal Na+/H+ exchange
Þ increase in bile pH, increase in concentrations ionized bilirubin, calcium, and carbonate Þ precipitates of calcium bilirubinate or calcium carbonate.
Hydrolysis of conjugated bilirubin
– to water insoluble unconjugated form by bacterial b -glucuronidase or by hydrolytic enzymes of hepatic, pancreatic or gallbladder origin. Results in calcium bilirubinate precipitation.
Natural history of gallstones
~20% of men and 35% of women >75 y/o have gallstones, most asymptomatic, most never require treatment.
the longer the stones are present, the more likely they will become symptomatic (10% at 5 yrs, 15% at 10 yrs).
90% of symptomatic patients present with RUQ pain with radiation to right scapula.
Mortality associated with gallstone disease is low, and is most frequently associated with a complication of gallbladder.
in patients with symptomatic gallbladder disease, recurrent attack is 50% 1st yr, 75% in 3 yrs, 90% in five yrs.
these patients also have increased mortality rate and cancer risk (1%).
Clincial Manifestations of Gallstone Disease
Once formed, gallstones may:
remain in the gallbladder without causing symptoms (asymptomatic cholelithiasis)
obstruct the cystic duct, resulting in gallbladder distention, inflammation and pain.
Migrate through the cystic duct into the common bile duct.
Migrate into ampulla of Vater and obstruct the pancreatic duct, causing acute pancreatitis.
Silently pass into the duodenum and out in the stool.
Other Gallbladder Problems
Cholecystitis
Pathogenesis:
Acute (calculous) Cholecystitis
– 90% of the time by gallstone in cystic duct. Gallbladder distends, blood supply and lymphatic drainage compromised, bugs in the gallbladder grow Þ inflammation and pain.
Acute Acalculous Cholecystitis
– same symptoms as above but no stone is found upon removal of gallbladder. Seen in 5-12% of removed gallbladders. Disease is result of ischemic compromise to gallbladder.
Chronic Cholecystitis
– longstanding stones in gallbladder Þ recurrent mild inflammation Þ thickening of gallbladder wall and infiltration of mononuclear inflammatory cells. Results in decreased ability to concentrate bile.
Clinical Diagnosis:
ultrasound – visualize the stone (>2mm diameter).
99m-technetium labeled biliary contract agent (HIDA) – is injected IV, taken up by liver, excreted in bile, concentrate in gallbladder. If gallbladder doesn’t appear on scan Þ acute cholecystitis.
Choledocholithiasis
(gallstones in common bile duct (CBD))
Pathogenesis: gallstones get lodged in CBD because can’t pass ampulla of Vater. Intermittent/persistent obstruction to bile flow Þ obstructive jaundice.
Complications: Bile gets infected due to bug growth on the lodged stones. Though this is not clinically significant, infection can spread to extrahepatic and intrahepatic biliary tree (ascending cholangitis) Þ fever, RUQ pain, sepsis, jaundice. CBD must be drained immediately.
Clinical Diagnosis:
ultrasound – CBD dilation and echogenic stones in distal CBD.
Endoscopic retrograde cholangiopancreatography (ERCP) – endoscope inside catheter into mouthÞ duodenumÞ to ampulla of vater; inject material into CBD and pancreatic duct. Visualize block. If present, can use sphincterotome to split open ampulla of Vater permitting passage of stone without need for surgery.
Inflammatory disorders of the biliary tree
Sclerosing cholangitis
Etiology: unknown.
Clinical: Progressive inflammation and fibrosis of intra- and extrahepatic bile ducts.
65% of time occurs in association with ulcerative colitis.
Disease of young males, characterized by: recurrent fever, jaundice, abdominal pain.
Diagnosis: cholangiogram (x-ray of the bile ducts).
Treatment: Liver transplant.
Biliary tract neoplasms
Carcinoma of the gallbladder
20% of all GI cancers.
More common in women (3:1), with peak incidence in the 7th decade.
90% of patients have associated cholelithiasis, and possible chronic cholecystitis (causal factor).
>50% of patients have greater than a 1 yr history of biliary tract disease (one of most rapidly fatal forms of carcinoma).
Five year survival rate is 1%.
Cholangiocarcinoma
(Carcinoma of the bile ducts)
rare.
more common in men, with peak incidence in the 5th-7th decade.
Increased risk: choledochal cysts, ulcerative colitis, chronic biliary infection with Clonorchis sinensis and Giardia lamblia.
Klatskin tumors
– located in CBD between cystic duct junction and the confluence of the right and left hepatic ducts. These tumors are slow growing with infrequent distal metastases. Clinical suspicion with onset of obstructive jaundice and weight loss.