Common disorders of the biliary system

Cholelithiasis

The main roles of the gallbladder are to store and concentrate bile, and to secrete mucus. Disturbance in the natural balance of the contents of the gallbladder or inflammation of the gallbladder mucosa can create a pro-lithogenic environment. The presence of calculi within the gallbladder is referred to as cholelithiasis. The vast majority of individuals with cholelithiasis are asymptomatic. However, the conversion rate from asymptomatic to symptomatic is estimated between 2 – 4% per year. There are three types of gallstones that are encountered. The most prominent types of stones in the Western world are cholesterol and mixed stones. However, in the Asian subcontinent, pigment stones are the most prominent of the three. 

Risk factors for cholelithiasis

Modifiable risk factors associated with cholelithiasis include (but are not limited to):

• Obesity and high fat diet – increased cholesterol can lead to oversaturation and cholesterol precipitation within the gallbladder.
• Oral contraceptive use – cholestatic effect of progesterones.
• Pregnancy – similar concept to oral contraceptive use.

The non-modifiable risk factors are as follows:

• Ethnicity – highest in individuals of Hispanic and Native American populations, as well as in people of Northern European descent. It is relatively less commonly seen in those of African and Asian descent.
• Increasing age – cholesterol gallstone formation increases with age, while pigment stones may occur in younger individuals with parasitic infections or haemolytic anaemias. 
• Being female – high levels of estrogen (particularly during the reproductive period) increases the production of cholesterol by increasing the activity of the HMG CoA reductase enzyme.
• Hemolytic anaemia – increased concentration of unconjugated bilirubin, thus promoting pigment stone formation.
• Cholestasis –allows for precipitation and crystallization of cholesterol and unconjugated bilirubin.

The presence of certain risk factors may also help to predict the type of gallstones that will form. For example, obesity and pregnancy are more likely to cause cholesterol stone formation, while hemolytic anemias and biliary tract infection can result in pigment stone formation.

Formation of gallstones

Cholesterol Stones

Cholesterol by itself is insoluble in water and requires bile salts and lecithin to carry it through the gastrointestinal tract and into the cells. While in the gallbladder, bile salts, lecithin and cholesterol exist as micelles. However, if the bile becomes supersaturated with cholesterol, or the concentration of bile salts should fall, then the micelles will change from a vesicular to a unilamellar configuration and cholesterol will then precipitate and begin to form crystals (nucleation). Other factors such as excessive mucus secretion from the gallbladder or hypomotility of the organ (due to low cholecystokinin or vagal stimulation) also have lithogenic effects.

Cholesterol stones often contain organic and inorganic calcium salts, phosphates and some amount of bilirubin. If the cholesterol accounts for more than 50% of the stones’ composition, then they are cholesterol stones. If the percentage composition ranges between 30 – 50%, then they are referred to as mixed stones. Grossly, pure cholesterol stones are round and may be faceted (i.e. have flat surfaces) because of the tight packing of numerous stones within the gallbladder. The pure stones are yellow, but range from grey to white as the percentage of cholesterol decreases. Only about 10 – 20% of these stones have enough inorganic calcium salts to show up on plain film radiography. In other words, most of these stones are radiolucent.

Pigment stones

Pigmented stones contain less than 30% cholesterol, and can be grouped as either black or brown stones. They are primarily comprised of unconjugated bilirubin polymers and a variety of inorganic calcium salts. In addition to the risk factors stated above, pigment stones are also more commonly seen in patients with ileal dysfunction or resection. A defective ileum (e.g. in Crohn’s disease) reduces the absorptive capacity of the small intestines. Therefore the concentration of bile salts may fall faster than they can be replaced by the hepatocytes.

The presence of a biliary tree infection also predisposes individuals to forming pigmented stones. The biliary tree is normally a sterile area. The microbes (e.g. C. sinensis, E. coli, A. lumbricoides) that can colonize the tract also produce β-glucuronidase enzymes, which then oxidize water-soluble bilirubin glucuronides to the insoluble form. Increasing the unconjugated bilirubin levels above the carrying capacity of the micelles creates a pro-lithogenic, saturated environment.

The type of pigmented stones that are formed varies based on the location of the lithogenic event. Black stones tend to form within the sterile gallbladder, while brown stones are more commonly seen in larger infected ducts. Black stones tend to be relatively small (<1.5 cm); but the formation of larger stones often correlates to fewer stones within the gallbladder. These friable, speculated stones are usually made up of some carbonate and phosphate salts of calcium, mucinous materials secreted by the gallbladder, low concentration of cholesterol crystals, along with the chief component – unconjugated bilirubin polymers. Brown stones, which are made up of soapy calcium bilirubinate, along with palmate and stearate based calcium salts, have a greasy consistency, are soft, and appear laminated on gross inspection. 

Signs and symptoms of gallstones

Patients who have symptomatic gallstones often complain of a dull, right upper quadrant or epigastric pain that may be associated with Collins sign (pain radiating to the tip of the right scapula). The pain (biliary colic) is not relieved by positional changes (i.e. leaning forward), and often commences at night, waking the patient from sleep. It has a crescendo decrescendo pattern that commences following a greasy meal and intensifies over about 20 minutes. It subsequently decreases in intensity over a few hours until it resolves. The intensity of the pain may result in excessive sweating, nausea and vomiting. However, neither vomiting, nor passing flatus or stool, nor antacid use relieves the sensation of biliary colic. The term biliary colic is a bit of a misnomer, as the pain is constant and not intermittent like traditional colic. Other non-specific symptoms that are associated with (but not necessarily caused by) gallstones include bloating, belching, indigestion and fat intolerance.

Biliary colic results from impaction of a large enough stone at the opening of the cystic duct. Consequently, when gallbladder contraction is initiated by the release of cholecystokinin following the fatty meal, the contents of the gallbladder are trapped behind the impacted stone. This results in distension and increased wall tension of the gallbladder, causing the dull pain. As cholecystokinin levels fall, gallbladder contraction is reduced, the stone is likely to fall back into the gallbladder fundus, the pressure is released and the pain resolves. 

In extremely rare cases, a large gallstone can become impacted in Hartmann's pouch. The stone may then ulcerate through the gallbladder and compress the adjacent common bile duct, leading to a picture of obstructive jaundice. This phenomenon is referred to as Mirizzi syndrome.

In simple biliary colic, the peritoneum is not inflamed and there are no systemic features of disease. Therefore, patients will be afebrile and the Murphy’s sign (respiratory arrest during the inspiratory phase on deep palpation of the right upper quadrant as the inflamed gallbladder makes contact with the examiner’s hand) will be negative. An ultrasound assessment of the abdomen is likely to reveal calculi within the gallbladder. Plain radiography is only useful in the 10 - 20% of cases with radiopaque gallstones.

Complications of cholelithiasis

The primary sequelae of cholelithiasis are acute and chronic cholecystitis (discussed below). It is also possible for a small enough stone to pass through the cystic duct and become obstructed in the common bile duct, causing secondary choledocolithiasis. These stones may migrate further and cause obstruction at the hepatopancreatic duct and result in gallstone pancreatitis.

Cholecystoenteric fistula formation has been noted as complication of a large gallstone. After the stone erodes into the adjacent loops of bowel, it can pass into the small intestines and result in Bouveret syndrome (gastric outlet obstruction due to pyloric, or proximal duodenal obstruction by the gallstone) or gallstone ileus. 

Cholecystitis

Inflammation of the gallbladder (cholecystitis) is a well-documented complication of cholelithiasis (i.e. acute calculous cholecystitis). However, there are also scenarios where inflammation occurs in the absence of gallstones (i.e. acalculous cholecystitis). It can be classified as acute, chronic, or acute on chronic (chronic cholecystitis with episodes of acute exacerbation). 

Risk Factors of Cholecystitis

Symptomatic cholelithiasis is a known risk factor for developing calculous cholecystitis. Therefore, they share the same ethnic, gender, age, and environmental risk factors. 

On the other hand, acalculous cholecystitis is associated with a different set of risk factors. It is more common in patients who are critically ill, or have undergone major surgery. There is also a predilection for developing acalculous cholecystitis in burns patients and those on prolonged total parenteral nutrition, as well as extended fasting. Diabetes mellitus and AIDS defining illnesses such as cryptosporidiosis and cytomegalovirus have also been linked to acalculous cholecystitis.

Calculous cholecystitis

The symptoms of biliary colic are also present with acute calculous cholecystitis, but with increased intensity and duration. There is usually an aversion to eating, as this tends to precipitate symptoms. Patients will also be febrile, and Murphy’s sign will be positive. Additionally, Boas’ sign (increased sensitivity inferior to the right scapula) may also be demonstrated. A complete blood count may also reveal a leucocytosis. Patients often present on a spectrum ranging from sudden onset of severe symptoms that warrant surgical intervention, to mild symptoms that may resolve without treatment. However, recurrence is inevitable in the absence of surgical intervention. 

The presence of an obstructing stone in the cystic duct prevents bile from draining from the gallbladder. The cholestasis allows enough time for the phospholipases produced by the gallbladder epithelium to convert the lecithins to lysolecithins, which are toxic to the mucosa. Furthermore, the normal mucous production from gallbladder epithelium is impaired. Therefore the toxic compounds, along with native prostaglandins from the epithelium, cause irritation and inflammation of the mucosa. As the gallbladder continues to distend, the increased pressure obstructs venous (and eventually arterial) flow to the gland; leading to ischaemic injury. Subsequently, the gallbladder may become infected, resulting in the formation of an empyema of the gallbladder. Increased pressure and compromise of the walls may result in rupture of the organ and the formation of an abscess.

Acalculous cholecystitis

Unlike calculous cholecystitis, acalculous disease presents with subtle onset of symptoms or may be asymptomatic. The features are often masked by the other factors that predisposed the patient to the symptoms in the first place. Therefore, the clinician should have a high degree of suspicion and monitor the patient for features of cholecystitis as this condition can be fatal if left untreated. There is a higher rate of gallbladder perforation in patients with acalculous disease when compared to those with calculous cholecystitis.

In the absence of an obstructing stone, an ischaemic insult is the most likely cause of cholecystitis. There is little collateral supply to the gallbladder. Consequently, inflammation, wall edema, and hypoperfusion can result in vascular compromise of the organ. The build-up of biliary sludge (accumulation of mini cholesterol crystals) and increased mucus production can also cause obstruction of the cystic duct without gallstones. Patients on total parenteral nutrition are fed through large veins. Therefore, the stimulus for release of cholecystokinin is removed and bile stasis ensues. 

Chronic cholecystitis

While the pathogenesis remains unclear, chronic cholecystitis has a strong correlation with cholelithiasis. However, 10% of cases can arise from acute acalculous cholecystitis. The populations at risk of developing chronic cholecystitis are similar to those susceptible to gallstone and acalculous disease. The episodes are characterized by frequent, recurrent attacks of acute cholecystitis and its associated symptoms (pain, nausea, anorexia, vomiting, etc.).

Long standing exposure to supersaturated bile occurs in both calculous and acalculous cholecystitis. Therefore, it is this continuous inflammation that is thought to result in transformation from acute to chronic disease. Recurrent inflammation results in cellular damage and eventually, cell death. The gallbladder epithelium may heal with fibrosis and calcification, resulting in a hard, shrunken gallbladder known as a porcelain gallbladder. Histologically, there are usually significant outpouchings known as Rokitansky-Aschoff sinuses, found in the mucosal lining.

Complications of cholecystitis 

Several complications of the different types of cholecystitis were discussed above. Unfortunately, the most sinister complication to be aware of is the increased risk of gallbladder and biliary tree cancer that is associated with cholelithiasis and cholecystitis. Historically it has been thought that the development of a porcelain gallbladder is heavily associated with gallbladder cancer. However, more recent studies propose that there is a very slight (approximately 6%) risk of patients with porcelain gallbladder advancing into gallbladder cancer.

In most cases of cholecystitis, the inflamed gallbladder is also distended and palpable. However, Courvoisier cautioned that a patient with painless jaundice and an enlarged gallbladder is unlikely to have gallstones as the cause of their presentation. As such, a more concerning etiology should be considered.

Choledocholithiasis

Gallstones have been observed within the extrahepatic biliary tree. These stones may either arise primarily in the ductal system (brown pigment stones) or may migrate from the gallbladder into the ducts (secondary disease). When the stones are within the common bile duct, this condition is referred to as choledocholithiasis. Secondary choledocholithiasis is far more common than the primary counterpart. It usually occurs when a small enough stone enters the ductal system and becomes stuck along its passage. 

The cohort is split in half between asymptomatic and symptomatic individuals. The symptomatic group often has an antecedent history of biliary colic. Furthermore, they often present with a tetrad of acholic (pale) stools, dark urine, intermittent jaundice, and pruritus (excessive itching). These are the pathognomonic signs of obstructive jaundice. However, these features may also be present in other disorders such as a tumor at the head of the pancreas, periampullary tumor, or a tumor of the ampulla of Vater. Therefore, the clinician should get a better understanding of the progression of the jaundice. If the onset of jaundice was sudden and maintained intensity, then it is more likely to be due to stones. However, if the onset of jaundice was gradual, and deepened over time, then the obstruction is more likely to be due to a tumor. This concept is based on the notion that a stone would suddenly occlude the ducts, while a tumor would gradually increase in size over time. 

These patients are often tender in the right upper quadrant or epigastrium, and are afebrile. Ultrasound imaging can confirm the presence of a stone within the duct, and proximal dilatation of the ductal system. The disorder can lead to gallstone pancreatitis, biliary strictures, secondary biliary cirrhosis and ascending cholangitis.

Ascending cholangitis

Ascending cholangitis refers to an infected, obstructed biliary tree. While choledocholithiasis is a common cause of the disease, other factors such as biliary strictures, iatrogenic injury, and neoplasms can also create an environment that supports an infection. Gram-negative organisms such as E. coli, K. pneumoniae, and P. aeruginosa and gram-positive Enterococcus species are among the common infectious agents found in this condition. Anaerobic organisms like B. fragilis, and fungal microbes are far less common. 

Patients with ascending cholangitis present with Charcot’s triad, which includes obstructive jaundice, right upper quadrant pain, and a fever. In more severe cases, they also have altered mental status and hypotension, which is referred to as Reynolds’ pentad. Additionally, other general symptoms of nausea, vomiting, ileus, and abdominal distension may also be present. These individuals will require aggressive fluid resuscitation and intravenous antibiotics as part of the initial management.