Pathophysiology of Biliary Disease
Bile is formed by the liver for fat emulsification and absorption in the small intestine. It is mainly composed of cholesterol, bile salts, phospholipids and inorganic acids. Bile is stored and concentrated in the gall bladder, which contracts after fatty meals to deliver the bile into the intestine.
Precipitation of bile salts and cholesterol gives rise to gall stones. Formation of a nadir of insoluble cholesterol or mucous is the primary step followed by multiple layers of precipitation until the stone is formed. This may be due to either over-concentration of bile, or over-secretion of mucous or bile stasis.
Bile stasis is clinically significant in diabetic patients who have intestinal hypomobility, comatose patients in the ICU or under total parental nutrition, pregnant women and those with oral contraceptive use.
20% of the population will have biliary complaints and 20% of patients will have serious complications, ranging from gall stones to pancreatitis and intestinal obstruction.
The majority of gallstones are cholesterol based. The current consensus is to mainly treat symptomatic gallstones and to offer prophylactic cholecystectomy in certain populations, such as children with sickle cell disease.
The most common presentation of patients with gallstones is recurrent right-upper quadrant abdominal pain that is associated with nausea and vomiting and could have a temporal relationship with high-fat content food intake.
Ultrasonography is the main method to diagnose gallstones, while cholescintigraphy and oral cholecystography provide additional information that could affect the clinical judgement.
Gallstones form when fluid bile becomes hardened inside the gallbladder.
The size of gallstones plays an important role in the symptomatology of the patient. Larger stones result in the typical right-upper quadrant pain experienced in gallstones, while smaller ones tend to lodge down and block the pancreatic duct causing pancreatitis.
In order for the fluid bile to solidify, an imbalance in the chemical content of the bile has to occur.
While gallstones are found among all age groups, they are more common in women in their middle ages. In one study, it was estimated that 25% of women older than 60 years are expected to have gallstones.
Despite this high prevalence of gallstones, symptoms only occur in up to 20% of the patients with gallstones. Approximately, 2% of people with gallstones are expected to become symptomatic per year and, because of this low risk, many argue that asymptomatic patients should not be surgically treated.
Types of gallstones
- Cholesterol stones are the most common gallstones. They develop in women more often than in men, with risk factors like obesity, cystic fibrosis, use of oral contraceptives, clofibrate and malabsorption.
- Pure cholesterol stones are solitary, white in color and larger than 2.5 cm.
- Mixed cholesterol stones with 50% cholesterol are multiple, small and laminated into layers of dark and light pigment stones.
- Pigment stones are less common.
- Black stones are formed of polymerization of calcium bilirubinate inside the gall bladder. The excess bile pigment is common in patients with hemolytic anemia and alcoholic liver disease.
- Brown stones are common inside the ducts from bacterial enzymes that precipitate bile pigment. They can be associated with duodenal diverticula.
Epidemiology of Gallstones
Approximately 25% of the middle-aged population have gallstones and only 20% of them are symptomatic. Age is an important non-modified risk factor for gallstones. The risk of gallstones is 10 times higher in the older than younger population.
One hypothesis to explain this link with age is the fact that the majority of gallstones are cholesterol based and that the activity of the enzyme cholesterol 7-alpha hydroxylase decreases with age. This enzyme is responsible for bile acid synthesis from cholesterol.
Women are twice as likely to develop gallstones. This is thought to be due to a higher cholesterol blood level that is related to high estrogen states, such as in pregnancy or when on combined oral contraceptives. This gender-related difference in risk tends to diminish with age, especially when postmenopausal women are compared to age-matched men.
Additionally, gallstones are more common in certain races, such as native Americans, Hispanics, followed by North Americans, Europeans and, finally, Asian populations. These race differences cannot be explained by diet or environmental factors and point towards a possible genetic factor.
People who are at an increased risk of dyslipidemia such as the obese, diabetics and those who attempt to lose weight rapidly, are also all at an increased risk of gallstones. Additionally, sedentary life style and western diets that are rich in fat are associated with gallstones disease.
Finally, certain drugs have been linked to an increased risk of gallstones, such as fibrates and chronic use of proton pump inhibitors. Ceftriaxone, a cephalosporin antibiotic, is also associated with an increased risk of gallstones formation.
Pathogenesis and Etiologies of Gallstones Disease
The majority of gallstones are formed of mainly cholesterol and calcium salts. Regardless, other types of gallstones, such as pigment stones and mixed stones, are related to different etiologies.
Cholesterol gallstones are the most common type of gallstones, and are usually formed when biliary cholesterol concentration exceeds the ability of bile to hold in the liquid form.
Once a cholesterol crystal forms, more cholesterol and calcium is deposited and, eventually, a stone is formed. These stones cause biliary fluid sluggish and eventually lead to more stones formation.
In order for cholesterol to be soluble, it has to be associated with bile salts, and a high cholesterol content would eventually oversaturate the available bile salts and render the extra cholesterol insoluble.
Etiologies of cholesterol gallstones
In order for bile cholesterol concentration to increase, the patient is expected to have excessive cholesterol biosynthesis, the inability to convert cholesterol to bile acids, or an interruption of the enterohepatic circulation.
Obese people and patients with genetic predisposition to hyperlipidemia, such as familial hypercholesterolemia, fit in the first mechanism for cholesterol stones formation, excessive cholesterol biosynthesis. Additionally, diabetics are known to have hypertriglyceridemia, which predisposes them to cholesterol gallstones.
Older age has been linked to a decreased cholesterol 7-alpha hydroxylase enzyme activity, which results in diminished conversion of cholesterol to bile acid and eventually cholesterol becomes less soluble in the bile and stones form. Higher estrogen states are also thought to decrease this enzyme’s activity.
Interruption of the enterohepatic circulation could happen after gastrointestinal surgery or overnight fasting.
Pathogenesis of pigment gallstones
While the first type of gallstones is due to excessive cholesterol concentration in the bile, pigment stones are the result of excessive bilirubin. Excessive bilirubin is associated with hemolysis, cirrhosis, and infection with beta-glucuronidase producing bacteria. Pigment stones are more likely to be calcified and visible on plain x-ray.
Etiologies of pigment gallstones
Black pigment stones result from chronic hemolytic diseases, such as thalassemia, sickle cell disease and hereditary spherocytosis. Cirrhosis can also cause black pigment gallstones.
Brown pigment stones, on the other hand, are usually the result of beta-glucuronidase bacterial infections of the gallbladder. Beta-glucuronidase hydrolyzes conjugated bilirubin and renders it as unconjugated bilirubin. Unconjugated bilirubin is more likely to form calcium salts, which are not soluble and form gallstones. Brown pigment stones are also more common in Asians populations.
Gallbladder sludge as a precursor for gallstones
Gallbladder sludge is defined as a thickened gallbladder bile that has a large number of cholesterol crystals, high biliary protein content and increased biliary cholesterol concentrations.
In some patients, gallbladder sludge can occur before gallstones and can eventually lead to other complications, such as acute pancreatitis. Pregnancy, parenteral nutrition, prolonged fasting, ceftriaxone and rapid weight loss are risk factors for gallbladder sludge formation.
Clinical Presentation of Gallstones
Because the majority of patients with gallstones are asymptomatic, it helps to understand if less specific symptoms could occur in this population. Patients with asymptomatic gallstones often have other gastrointestinal problems and gallstones are incidentally identified on an ultrasonography.
Patients with asymptomatic gallbladder stones can have non-related gastrointestinal symptoms such as heartburn, bloating, constipation or diarrhea. Dyspepsia can be also described after the intake of fatty foods.
Symptomatic patients, on the other hand, are more likely to describe a more specific picture of biliary colic. Biliary colic results when a stone temporarily impacts the cystic duct during a contraction.
The pain happens approximately one hour after the ingestion of a fatty meal, is intense and not truly colicky in nature. The pain reaches maximum intensity in the right upper quadrant in 20 minutes and eventually resolves in one to two hours.
Less specific symptoms include vomiting, nausea, dyspepsia and fat intolerance. Physical examination is important in patients with biliary colic to differentiate them from acute cholecystitis cases.
Tenderness and rebound tenderness, markers of gallbladder inflammation, are unlikely in biliary colic where inflammation is not implicated. Fever is also more specific of cholecystitis, rather than biliary colic.
Acute cholecystitis occurs when there is a prolonged obstruction of the cystic duct and secondary bacterial infection of the gallbladder. Chronic gallbladder stones put the patient at an increased risk of gallbladder wall fibrosis and cancer.
Complications of Gallstones
Cholangitis is the infection of the biliary tree after obstruction irrespective of the cause of obstruction. Charcot triad is very helpful for diagnosis. Patients will present with fever, right upper quadrant pain and jaundice. Reynolds pentad of hypotension and altered mental status with the triad is a bad prognostic indicator for severe biliary infection.
Organisms migrating to the biliary tree from the intestine through the portal vein or the biliary tract are responsible for the conditions. E. coli, pseudomonas, proteus, klebsiella and enteric streptococci can be isolated.
Impaction of a gall bladder stone in the cystic duct can cause external compression and subsequent obstruction of either the common bile duct or the hepatic duct. Obstruction of both ducts can result in necrosis of the wall, fistula or scar formation and obstructive jaundice will develop.
Gallstones are one of the most common causes of pancreatitis. It can be due to the obstruction of the pancreatic duct by a stone in the bile duct or back flow of the bile into the pancreatic duct causing activation of pancreatic enzymes.
Acute acalcular cholecystitis
This is defined as an inflammation of the bladder without stone obstruction. The condition is common among patients who have severe burns, ICU admission, trauma and coma.
Symptoms vary according to the case and may include fever and leukocytosis. Some patients may have infection with gas forming clostridium species which can be seen on x-ray as emphysematous cholecystitis. High index of suspicion in vulnerable patients is a must to avoid gangrene and perforation of the bladder.
Primary biliary cirrhosis/cholangitis, PBC
Elevation of alkaline phosphatase is an early sign followed by symptoms of obstructive jaundice. Patients will present with jaundice, itching and other autoimmune disease symptoms. Autoimmune obstruction develops in the hepatic small bile ducts and progresses to cirrhosis. Anti-mitochondrial antibodies are the mainstay for diagnosis. Biopsy of the bile ducts will show cytotoxic T lymphocyte infiltration and destruction.
This is similar in clinical presentation to primary biliary cirrhosis, but shows a different serology. Antinuclear antibody is positive rather than antimitochondrial antibodies in PBC. Antinuclear fluorescent antibodies and anti-smooth muscle antibodies are also positive. Both diseases have the same presentation and the same management plans.
Primary sclerosing cholangitis, PSC
Common with other autoimmune diseases e.g. Crohn’s disease and ulcerative colitis. It is believed to be an autoimmune inflammation to the biliary tree leading to fibrosis and sclerosis of the ducts. Patients may present with itching, jaundice and sometimes cirrhosis.
Tumors of the biliary tract
- Gall bladder cancer: the most common of all biliary tract tumors. It can mimic the clinical picture of acute calculus obstruction. Porcelain gall bladder with calcification of the wall due to chronic inflammation is a predisposing factor.
- Cholangiocarcinoma: risk factors include asbestos, primary sclerosing cholangitis and chronic cholestasis. Pathologically, adenocarcinoma types of cells arise from the lining epithelium of bile ducts.
- Ampullary carcinoma: the least common. The tumor arises from the ampulla of Vater which can precipitate an acute attack of pancreatitis.
Patients with biliary tract tumors present with general symptoms of malignancy e.g. weight loss, fatigue, anorexia and fever. Late specific manifestations e.g. jaundice and itching from obstruction, will indicate a bad prognosis as cases present late after liver metastases.
Cysts of the biliary tract
Dilatation of the intrahepatic and/or extrahepatic biliary ducts is thought to be due to regurgitation of pancreatic enzymes into the biliary tree. Patients will present with different manifestations from jaundice and abdominal pain to the complication of malignancy, pancreatitis, liver abscess and stones.
Diagnostic Workup of Gallstones Disease
Laboratory investigations can help exclude an acute inflammatory process, but is usually unhelpful in simple biliary colic. Abdominal x-rays, ultrasonography, computed tomography, magnetic resonance imaging and nuclear scintigraphy, are all used in the diagnostic workup of patients with gallstones.
Laboratory investigations in gallstones disease
Hematologic testing is essential when complicated gallstones disease is suspected, such as in the case of empyema or acute cholecystitis.
Acute cholecystitis is associated with neutrophils leukocytosis in two thirds of the patients. Liver enzymes might be slightly impaired in acute cholecystitis. Amylase levels and lipase are also important to exclude acute pancreatitis, especially if the ultrasonography shows small gallbladder stones.
Common bile duct stones, another complication of gallstones, result in an increase in alanine and aspartate aminotransferases levels at first and followed by an increase in bilirubin. A serum bilirubin level above 3 mg/dL is usually associated with a common bile duct stone.
Abdominal plain x-ray
Abdominal x-rays are also important in the diagnosis of gallstones, especially if pigment stones are suspected due to a known history of sickle cell disease, for instance.
Gallstones are visible on plain x-ray only in a third of the patients with gallstones in general, and in two thirds of patients with pigment stones.
Abdominal x-rays also help exclude other differential diagnoses, such as renal stones, calcific pancreatitis and intestinal obstruction.
Transabdominal ultrasonography is the best imaging modality to diagnose gallbladder stones due to being non-invasive, cheap, sensitive and specific. Usually, a stone that is greater than 2 mm in diameter is going to be visible on an ultrasonography, making this test very sensitive.
In addition to its role in the diagnosis of biliary colic, ultrasonography also helps in the exclusion of acute cholecystitis. Increased wall thickening of more than 5 mm, pericholecystic fluid and gallbladder distension are markers of acute cholecystitis and their absence can help exclude this complication.
Gallbladder stones are echogenic on ultrasonography and have an acoustic shadow as seen in the figure.
Endoscopic and laparoscopic ultrasound are also emerging techniques to visualize the common bile duct non-invasively or during laparoscopic cholecystectomy respectively, to exclude common bile duct stones with virtually a 100% sensitivity.
Computed tomography (CT) scan
CT abdominal scanning is used to exclude other causes of abdominal pain when one is not certain about gallstones as the etiology. It has a low sensitivity for gallstones and is expensive if compared to the more specific and faster ultrasonography scan.
Magnetic resonance cholangiopancreatography (MRCP)
MRCP has an excellent sensitivity for the diagnosis of gallstones anywhere in the biliary tract but, due to being expensive and the need for specialized software, it is currently reserved for patients with complicated common bile duct disease or when cholecystitis and gallstones are highly suspected but the ultrasonography is negative. The figure demonstrates multiple common bile duct stones on an MRCP study.
Technetium-99m (99m Tc) hepatoiminodiacetic acid (HIDA)
HIDA scintigraphy is only useful in patients with acute cholecystitis with an obstructed cystic duct. A recent meta-analysis showed that patients with a positive HIDA scan result and a negative ultrasonography will always benefit from a cholecystectomy.
Endoscopic retrograde cholangiopancreatography (ERCP)
ERCP is used in patients with common bile duct stones and not in simple biliary colic cases. ERCP is both diagnostic and interventional where the stones can be extracted from the common bile duct.
Treatment Options for Gallstones
Asymptomatic gallstones should not be offered medical treatment unless they have mild biliary colic and are in a high-risk group for surgical intervention. Any patient with symptomatic gallstones should be offered a cholecystectomy unless surgery poses a high risk. Medical treatment at the emergency department should mainly include pain control.
Treatment of asymptomatic gallstones
People with asymptomatic gallstones should not be offered a surgical intervention. Pregnant women and diabetics are at an increased risk of gallstones disease complications and, if asymptomatic gallstones are identified, it should be followed-up closely.
Despite this, certain patients with asymptomatic gallstones should undergo a cholecystectomy. For example, patients with stones larger than 2 cm in diameter, gallbladder wall calcification, patients with spinal cord injuries and, in sickle cell disease, asymptomatic gallstones are indicated for a cholecystectomy.
Ursodeoxycholic acid (ursodiol) can be used to dissolve pure cholesterol stones in asymptomatic patients, or in patients who cannot undergo surgical intervention. Treatment with ursodiol is successful with small stones and should be attempted for at least 6 months. Unfortunately, the recurrence rate after medical dissolution of gallstones is high and is up to 50%.
Surgical intervention for gallstones
Cholecystectomy is indicated in any patient with symptomatic gallstones unless that patient’s age or history of chronic disease puts him at high risk.
Traditional open cholecystectomy uses a large subcostal incision to remove the gallbladder, which is associated with an increased recovery time and postoperative complications when compared to the modern laparoscopic technique.
Laparoscopic cholecystectomy involves 4 very small abdominal incisions and can be done in an outpatient setting. If the surgeon cannot catch the escaped gallstones during laparoscopic cholecystectomy, or adhesions and bleeding complications occur, conversion to open cholecystectomy might be required.
Cholecystostomy is indicated in patients with empyema or who are not stable enough to undergo cholecystectomy. Once the patient is stable again, elective cholecystectomy is offered. Cholecystostomy uses a tube that passes through the gallbladder to drain pus.
In few cases, removal of the common bile duct stones during the surgery is not possible. In this occasion, endoscopic sphinecterotomy and ERCP are indicated to extract common bile duct stones. ERCP can be also used in the acute ill patient and not only in elective cases.
Diet and exercise
Caffeine intake in one study has been reported to be associated with a lower risk of gallstone formation. Regular exercise is thought to lower the risk of gallstones disease and the need for a cholecystectomy in the future. Obese people who want to lose weight rapidly are encouraged to take ursodeoxycholic acid as a prophylaxis against gallstone disease.
Gallstones are more common in middle-aged females, patients with certain hemolytic conditions, the obese and diabetics.
While the majority of the cases are asymptomatic, only 2% of asymptomatic gallstones are expected to become symptomatic per year.
Asymptomatic gallstones should not be treated except for certain populations that are known to be at high risk for the development of symptomatic disease and complications, while symptomatic patients should undergo a cholecystectomy. Laparoscopic cholecystectomy is superior to open cholecystectomy but, in a few cases, the surgeon might need to convert to an open procedure.
Finally, patients with symptomatic gallstones, who are not possible candidates for surgical intervention, should be prescribed a gallstone dissolution agent if the stones are expected to be purely made of cholesterol.