Cholelithiasis (Gall stones) : Causes, Pathophysiology, Symptoms and Treatment
Cholelithiasis (gall stones) is the presence of one or more gallstones known as calculi in the gallbladder. Cholelithiasis is caused by precipitation of substances contained in bile, mainly cholesterol and bilirubin.
There are three main factors contributing to the formation of gallstones:
- Abnormalities in the composition of bile,
- Stasis of bile, and
- Inflammation of the gallbladder.
The gallbladder is a small pear-shaped organ that is located next to the liver. The major function is to act as a store and to concentrate the bile produced in the liver. When fat is consumed in the diet the gallbladder contracts to release bile back into the digestive tract for fat digestion. Conditions affecting the biliary system are;
- Cholelithiasis is the presence of gallstones in the gallbladder.
- Choledocholithiasis is the presence of one or more gallstones in the common bile duct
- Cholecystitis is inflammation of the gallbladder from obstruction of the cystic duct or common bile duct (choledocholithiasis or common bile duct stone)
- Cholangitis is an infection of the biliary tree.
After the appendix, the gall bladder is the second intra-abdominal organ that most commonly requires surgery.
Gall stones are more common in females than in male counterparts. Its prevalence increases with increasing age.
Stages of development
Gall stones have four stages of development
- The lithogenic stage when the conditions that favor gallstone formation are present,
- Asymptomatic stage
- Symptomatic stage
- Complicated cholelithiasis
You may have heard of gallbladder colic. This is a kind of pain caused by a stone temporarily obstructing the cystic duct or common bile duct (CBD).
Pathophysiology of cholelithiasis:
Three types of gallstones exist.
- Cholesterol (most common),
- Pigment-calcium bilirubinate and,
- Mixed stones.
These account for about 80 percent of all the cases of cholelithiasis.
They comprise of either pure cholesterol stones or mixed cholesterol stones which have cholesterol and calcium.
In a normal person, cholesterol is brought to the liver from chylomicrons or from other tissues in the form of low-density lipoproteins.
One of the functions of the liver is to regulate plasma cholesterol by either synthesizing it when it's low or eliminating it from the body when it accumulates to excess levels.
Cholesterol synthesis is from acetate under the influence of an enzyme known as HMG CoA (3-hydroxy 3-methylglutaryl coenzyme A
Like we have already mentioned, the liver regulates cholesterol levels by elimination. This elimination takes place in three different ways.
- As cholesterol
- As bile salt or as
- Cholesterol esters.
Once the cholesterol has been brought to the gallbladder it is kept in a soluble form in the vesicles.
During some instances such as extreme fasting the concentration of this cholesterol in the gall bladder exceeds its solubility limit. As a result of this supersaturation, crystals start forming. Together with the stasis in the gallbladder, it forms a biliary sludge which is a thickened gallbladder mucoprotein with tiny trapped cholesterol crystals
Biliary sludge is often a precursor of gallstones. It consists of Calcium bilirubinate (a polymer of bilirubin), cholesterol microcrystals, and mucin. Over time the crystals grow, aggregate and fuse to form microscopic stones.
Most of the sludge is does not result in any symptoms and disappears when the primary condition resolves.
This process is exacerbated by mucin and inhibited by ursodeoxycholic acid which is a bile salt, drugs such as NSAIDs and caffeine. This is the reason a dose of aspirin with a cup of coffee can help in cholelithiasis.
An increase in the cholesterol concentration or a decrease in the bile salt concentration results in supersaturation of bile with cholesterol, and the formation of a liquid crystalline phase of cholesterol.
Normally, bile salts (ursodeoxycholic and chenodeoxycholic), lecithin, and phospholipids help to maintain cholesterol as a solute in the bile. When bile is supersaturated with cholesterol, it crystallizes and forms a nidus for stone formation.
It should be noted that any factor that increases plasma and bile cholesterol levels exacerbates the production of sludge in the gallbladder. These conditions are for example obesity, diabetes mellitus, cystic fibrosis, female gender, and pregnancy.
How does pregnancy lead to increased plasma and bile cholesterol?
Also, some drugs such as clofibrate and other fibrate hypolipidemic drugs can deplete bile salts and increase the hepatic elimination of cholesterol increases the risk of cholesterol cholelithiasis. Somatostatin analogs also reduce gallbladder emptying.
The sludge can be reabsorbed or continue to form gallstones over a period of 8 years to 12 years.
Another type of gallstones are pigmented stones
Pigment stones result from bilirubin production. To begin with, bilirubin is a product derived from the breakdown of heme. Normally bilirubin is first solubilized by a process known as conjugation in the liver.
This conjugation leads to the formation of diglucuronide which is stable and water-soluble. But is some circumstances a small portion of bilirubin remains unconjugated and forms an insoluble salt or precipitate with calcium.
Gallstones can result through three pathways that are;
- Increased bilirubin is secondary to hemolytic anemia. This causes accumulation of too much-unconjugated bilirubin.
- The second way is by the development of insoluble bilirubin due to glucuronidases like in the case of obstruction allowing accumulation of glucuronidase containing bacteria.
- The third mechanisms are liver cirrhosis. Cirrhotic patients have reduced glucuronidase inhibitors. This causes too much accumulation of unconjugated bilirubin because the liver has failed in its conjugation function.
Black pigment stones
Once the unconjugated bilirubin forms an insoluble salt, calcium bilirubinate it then crystallizes to form a gallstone. This deposition results in the accumulation of multiple small black stones. As various oxidation takes place bilirubin precipitates to form a jet-black color.
Black pigment stones are small, hard gallstones composed of Calcium bilirubinate and inorganic Calcium salts. Factors that accelerate stone development include alcoholic liver disease, chronic hemolysis, and older age.
Another kind of pigmented stone is brown pigment stone.
brown pigment stone.
Normally bile is sterile but if there is an obstruction like in the case of biliary stricture it may become colonized by bacteria. The colonizing bacteria, in turn, hydrolyzes the conjugated bilirubin back to unconjugated bilirubin leading to precipitation of calcium bilirubinate crystals.
Bacteria also have the ability to hydrolyze lecithin to release fatty acids that also combine with calcium to form a brown pigment stone mostly de novo in the bile duct.
The Brown pigment stones are characteristically soft and greasy. They consist of bilirubinate and fatty acids (specifically Calcium palmitate or stearate). This kind of stone forms during infection, inflammation or a parasitic infestation.
Black stones are usually common in individuals with hemolytic disorders whereas Brown pigment stones are common in the intrahepatic or extrahepatic duct and are associated with gallbladder infections.
infection of cholesterol gallstones with bacteria elicits gallbladder mucosal inflammation. Lytic bacterial enzymes and leucocytes hydrolyze conjugated bilirubin and fatty acids. As a result, cholesterol stones may accumulate a large amount of calcium bilirubinate and other calcium salts producing a mixed stone.
On a plain x-ray film, these stones form an eggshell appearance due to the calcium rim on their surface.
Symptoms and Signs of cholelithiasis
Most gallstones are asymptomatic.
The remainder has symptoms ranging from biliary-type pain (biliary colic) to cholecystitis to life-threatening cholangitis.
Pain due to cholelithiasis is of two types
- Obstructive pain or
- Inflammatory pain.
Like its name, obstructive pain results when the neck of the gallbladder becomes obstructed by a stone and gallbladder contraction continues under the influence of cholecystokinin and neural reflexes from the duodenum.
The bare nerve endings detect this tension and since they pass centrally via the coeliac plexus, the resultant pain is dull and poorly located. It tends to extend to the right of the epigastrium and back to the mid-scapular space.
This obstructive pain has a fairly rapid onset as pressure increases. The pain is invariably associated with nausea and vomiting. And lasts for a number of hours and relieved when the stone dislodges or passes from the cystic duct to the bile duct.
Obstruction of bile flow by a stone at the ampulla of Vater may lead to abdominal pain and jaundice known as obstructive jaundice. Stasis above the obstructing bile stone becomes infected by bacteria which then spread rapidly back up the ductal system to the liver producing a condition known as ascending cholangitis.
The second type of pain associated with cholelithiasis is inflammatory pain
Since bile is usually sterile, a sterile inflammatory response can develop if the stone is not dislodged followed by infective cholecystitis.
The most common bacteria involved are Escherichia coli,Klebsiella and streptococcus feacalis.
Inflammation may involve the parietal peritonitis and the somatic afferents of the dermatome segment changing the patient’s perception of pain.
This kind of pain moves to the right hypochondriac, it is sharp and localized, exacerbated by movement or deep breathing.
The sharpness is due to the dense innervation of the peritoneum by the somatic nervous system.
On examination, There is positive Murphy’s sign and guarding on the right hypochondriac.
Biliary colic is the most common symptom.
Stones occasionally traverse the cystic duct without causing symptoms. However, most gallstone migration leads to cystic duct obstruction, which, even if transient, causes biliary colic.
Biliary colic begins in the right upper quadrant but can occur elsewhere in the abdominal regions. This kind of pain is poorly localized, especially in diabetic patients and elderly individuals. It may radiate into the back or down the arm.
Nonspecific GI symptoms, such as gas, bloating, and nausea may be present.
Usually mild jaundice, deep jaundice is suggestive of choledocholithiasis
Itchiness of the body
Dark urine and pale stool
Risk factors for cholelithiasis
There are 5 F's for remembering the risk factors; Fair, fat, fertile, female of forty.
- Female sex
- Dietary influence-fatty diet
- Increased risk in pregnancy
- Oral contraceptive-high estrogen content
- Estrogen replacement therapy
- Rapid weight loss
- Increased hemolysis -sickle cell, thalassemia
- Chronic alcoholism with liver cirrhosis
- Formation of stones increases with age
- Infections (including parasitic)-pigment stones
- Terminal ileal resection, and jejunoileal bypass
- Other illnesses predispose people to gallstone formation.
- Burns, Total parenteral nutrition, Paralysis, ICU care and
- Major trauma
Investigations in Cholelithiasis
- Abdominal x-ray-show radioopaque stones if present
- Abdominal ultrasound
- MRCP(magnetic resonance cholangiopancreatography)
- Rarely ERCP-diagnostic and therapeutic.
- CT-scan, tumors are better shown
- PTC-Percutaneous transhepatic cholangiography
- MR Angiography
- Full hemogram-white blood cell levels and differential
- Liver function tests-Alkaline phosphatase and GGT, AST and ALT
- Bilirubin –Total and Direct
- Coagulation screen-, PTI, INR
- (INR acceptable for surgery ). Patients need to be given vitamin k prophylaxis 10 mg IM
Complications of cholelithiasis
- cholecystitis(chronic or acute)
- Acute pancreatitis
- Acute cholangitis
- Obstructive jaundice
Management of Cholelithiasis
3.ERCP and sphincterotomy
3.Cholecystectomy –open or laparoscopic
Medical therapy entails
1.Gallstone dissolution therapy.
Cholesterol gallstones can be dissolved by decreasing the cholesterol saturation of bile. The naturally occurring bile salt chenodeoxycholic acid and the synthetic ursodeoxycholic acid, when given by mouth, achieve this.
M.O.A - reducing the hepatic synthesis of cholesterol rather than by expanding the bile acid pool.
Ursodeoxycholic acid is more efficient at reducing the cholesterol saturation of bile. The unexplained benefit is that some patients experience relief of their symptoms without much change in the size of the stones.
This dissolution therapy can only be used for non-calcified stones within a functioning gallbladder. Less than 20 percent of patients are suitable candidates. The therapy is unsuitable for patients with acute symptoms and is less effective in obese patients and in stones >15 mm.
Chenodeoxycholic acid is given at a dose of (10-15 mg/kg/day) and ursodeoxycholic acid (8-12 mg/kg/day) and up to( 15 mg/kg/day in obese patients).
While on treatment, liver function is carefully monitored and the stones are measured at 6 months.
If there has been no reduction in size there is no point in continuing with treatment. Eighty percent of small stones dissolve in 6 months, but larger stones require up to 2 years of treatment.
Recurrence common hence the therapy is useful in patients who are poor anesthetic risks or who refuse surgery.
2.Extracorporeal shock wave lithotripsy
This technique of treatment entails the fragmentation of both gallbladder and common bile duct stones using high energy sound.
Munich criteria for lithotripsy
1-Functioning gallbladder >50% emptying.
2-Stones must be radiolucent.
3-Stones should be less than 30 mm in diameter or 40ml in volume.
4-Should not be more than three (ideally only one).
These criteria restrict the use of extracorporeal shock wave lithotripsy to between 5 percent and 10 percent of patients.
Patients are partly immersed in a water bath or placed in contact with a water cushion. An electromagnetic impulse, a piezoelectric generator or a high-voltage spark from an underwater electrode produces a shock wave that is transmitted through water. The acoustic impedance of most body tissue is similar to that of water, while stones have different impedance.
The wave, guided by ultrasound or fluoroscopy to focus directly at the stone, penetrates the body with only slight attenuation. When the wave reaches the stone, tear and shear forces develop, disintegrating it.
Patients generally take an oral gallstone-dissolving drug such as ursodiol -for one week before lithotripsy and continue it for at least three months after the disappearance of stone fragments.
3.ERCP Endoscopic Retrograde Cholangiopancreatography and Sphincterotomy
Endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy offer effective minimally invasive effective procedure as the procedure of choice.
4.Cholecystectomy -Open or Laparoscopic
Open cholecystectomy involves dissecting the Calots triangle as the first step in cholecystectomy
Borders of calots triangle are cystic duct laterally, CBD medially and the inferior aspect of the liver superiorly
The cystic artery crosses the triangle from left to right, running behind the bile duct and arising from the right hepatic artery.
Once the cystic duct and artery have been definitely identified, the cystic artery is ligated in continuity and divided between ligatures. The cystic duct is dissected as far as it is necessary to expose a sufficient length for easy cannulation for operative cholangiography. Any stones in the cystic duct are milked back into the gallbladder and the cystic duct is ligated close to the gallbladder.
The dissection of the gallbladder from the liver can begin either at the fundus or in the region of the cystic duct.
Complications of open cholecystectomy
This procedure can lead to sudden hemorrhage is usually from the cystic artery.
If this cant is controlled by clamping then occluding the hepatic artery with the fingers and thumb of the left hand placed across the entrance of the lesser sac (Pringle's maneuver).
Laparoscopic cholecystectomy is rapidly replacing open cholecystectomy.
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