Cholelithiasis

Etiology

There are three main pathways in the formation of gallstones: 

• Cholesterol supersaturation: Normally, bile can dissolve the amount of cholesterol excreted by the liver. But if the liver produces more cholesterol than bile can dissolve, the excess cholesterol may precipitate as crystals. Crystals are trapped in gallbladder mucus, producing gallbladder sludge. With time, the crystals may grow to form stones and occlude the ducts which ultimately produce the gallstone disease.
• Excess bilirubin: Bilirubin, a yellow pigment derived from the breakdown of red blood cells, is secreted into bile by liver cells. Certain hematologic conditions cause the liver to make too much bilirubin through the processing of breakdown of hemoglobin. This excess bilirubin may also cause gallstone formation.
• Gallbladder hypomotility or impaired contractility: If the gallbladder does not empty effectively, bile may become concentrated and form gallstones.

Depending on the etiology, gallstones have different compositions. The three most common types are cholesterol gallstones, black pigment gallstones, and brown pigment gallstones. Ninety percent of gallstones are cholesterol gallstones.

Each stone has a unique set of risk factors. Some risk factors for the development of cholesterol gallstones are obesity, age, female gender, pregnancy, genetics, total parenteral nutrition, rapid weight loss, and certain medications (oral contraceptives, clofibrate, and somatostatin analogs).

Approximately 2% of all gallstones are black and brown pigment stones. These can be found in individuals with high hemoglobin turnover. The pigment consists of mostly bilirubin. Patients with cirrhosis, ileal diseases, sickle cell anemia, and cystic fibrosis are at risk of developing black pigment stones. Brown pigments are mainly found in the Southeast Asian population and are not common in the United States. Risk factors for brown pigment stones are intraductal stasis and chronic colonization of bile with bacteria.[4][5][6][7]

Patients with Crohn disease and those with ileum disease (or resection) are not able to reabsorb bile salts and this increases the risk of gallstones.

Epidemiology

Cholelithiasis is quite common and can be found in approximately 6% of men and 9% of women. The highest prevalence of cholelithiasis arises in Native American populations. Gallstones are not as common in Africa or Asia. The epidemic of obesity has likely magnified the rise of gallstones.

Despite how prevalent gallstones may be, more than 80% of people remain asymptomatic. Biliary pain, however, will develop annually in 1% to 2% of individuals previously asymptomatic. Those who started to develop symptoms may continue to have major complications (cholecystitis, choledocholithiasis, gallstone pancreatitis, cholangitis) occur at a rate of 0.1% to 0.3% yearly.

Pathophysiology

Cholesterol gallstones are formed mainly due to over secretion of cholesterol by liver cells and hypomotility or impaired emptying of the gallbladder. In pigmented gallstones, conditions with high heme turnover, bilirubin may be present in bile at higher than normal concentrations. Bilirubin may then crystallize and eventually form stones.

Symptoms and complications of cholelithiasis result when stones obstruct the cystic duct, bile ducts or both. Temporary obstruction of the cystic duct (as when a stone lodges in cystic duct before the duct dilates and the stone returns to gallbladder) results in biliary pain but is usually short-lived. This is known as cholelithiasis. More persistent obstruction of cystic duct (as when a large stone gets permanently lodged in the neck of the gallbladder) can lead to acute cholecystitis. Sometimes a gallstone may get pass through the cystic duct and get lodged and impacted the common bile duct, and causes obstruction and jaundice. This complication is known as choledocholithiasis.

If gallstones pass through the cystic duct, common bile duct and get dislodged at the ampulla of the distal portion of the bile duct, acute gallstone pancreatitis may result from backing up of fluid and increase pressure in pancreatic ducts and in situ activation of pancreatic enzymes. Occasionally, large gallstones do perforate the gallbladder wall and create a fistula between the gallbladder and small or large bowel, producing bowel obstruction or ileus.

History and Physical

Patients with gallstone disease typically present with symptoms of biliary colic (intermittent episodes of constant, sharp, right upper quadrant (RUQ) abdominal pain often associated with nausea and vomiting), normal physical examination findings, and normal laboratory test results. It may be accompanied by diaphoresis, nausea, and vomiting.

• Biliary colic is usually caused by the gallbladder contracting in response to some form of stimulation, forcing a stone through the gallbladder into the cystic duct opening, leading to increased gallbladder wall tension and pressure which often result in pain known as biliary colic. As the gallbladder relaxes, the stones often fall back into the gallbladder, and the pain subsides within 30 to 90 minutes.
• Fatty meals are a common trigger for gallbladder contraction. The pain usually starts within an hour after a fatty meal and is often described as intense and dull, and may last from 1 to 5 hours. However, an association with meals is not universal, and in a significant proportion of patients, the pain is nocturnal. The frequency of recurrent episodes is variable, though most patients do not have symptoms on a daily basis.
• A thorough physical exam is useful to distinguish biliary pain due to acute cholecystitis, uncomplicated cholelithiasis or other complications.  
• In uncomplicated biliary colic, the patient is afebrile and has an essentially benign abdominal examination without rebound or guarding.

Acute cholecystitis occurs when persistent stone dislodged the cystic duct causes the gallbladder to become distended and inflamed. The patient may also present with fever, pain in the right upper quadrant and tenderness over the gallbladder (this is known as Murphy's sign).

When fever, persistent tachycardia, hypotension, or jaundice are present, it requires a search for complications of cholelithiasis, including cholecystitis, cholangitis, pancreatitis, or other systemic causes.

Choledocholithiasis is a complication of gallstones when stones obstruct the common bile duct it impedes the flow of bile from the liver to the intestine. Pressure rises resulting in elevation of liver enzymes and jaundice.

Cholangitis is triggered by the colonization of bacteria and overgrowth in static bile above an obstructing common duct stone. This produces purulent inflammation of the liver and biliary tree. Charcot's triad consists of severe RUQ tenderness with fever and jaundice and is classic for cholangitis. Surgical removal of the stone obstruction with intravenous antibiotics is required to treat this condition.

Evaluation

Initial labs to evaluate gallstones often include CBC, CMP, PT/PTT, lipase, amylase, Alk Phos, total bilirubin, urine analysis.

Ultrasound remains the first line and best imaging modality to diagnose gallstones. A systematic review estimated that the sensitivity was 84% and specificity was 99%, better than other modalities. Either radiology ultrasound study or point-of-care ultrasound can be used to detect biliary disease. Several studies in the literature have shown that point-of-care ultrasound by clinicians is accurate and reliable in diagnosing or excluding biliary disease. Gallstones on ultrasound have the appearance of hyperechoic structures within the gallbladder with distal acoustic shadowing. Sludge in gallbladder may also be seen, with an appearance of hyperechoic layering within the gallbladder. Sludge, unlike stones, does not cast acoustic shadowing.  If the following additional signs are noted, suspicion should be raised for acute cholecystitis:  thickened anterior gallbladder wall (greater than 3 mm), the presence of pericholecystic fluid or positive sonographic Murphy's sign. Additionally, common bile duct (CBD) measurements can be obtained by ultrasound, and if increased, can suggest choledocholithiasis. The normal range of CBD is four mm in patients up to 40 years of age, with additional 1 mm allowed for every additional decade of life.  Post-Cholecystectomy patients are allowed up to 10 mm diameter since the common duct become the bile reservoir once the gallbladder is removed.

If an ultrasound study is equivocal for ruling out acute cholecystitis, then a nuclear medicine cholescintigraphy scan, also known as a HIDA scan can be performed. In a normal healthy gallbladder, a radioactive tracer injected into a peripheral vein is circulated to the liver where it enters the biliary tree and gets taken up into the gallbladder within 4 hours. A diseased gallbladder with cystic duct obstruction will prevent the tracer from entering the gallbladder. HIDA scan has a sensitivity of up to 97% and specificity of 94% for the diagnosis of acute cholecystitis.

CT imaging of the abdomen does not add to increased sensitivity or specificity for diagnosing gallstones or cholecystitis. It can be helpful in determining if CBD dilatation is present, and can detect pancreatic inflammation or complications (masses, pseudo-cysts, necrotizing features). CT imaging is also useful if RUQ ultrasound excludes biliary disease and other causes of abdominal pain are being sought.

Additionally, tests such as endoscopic or magnetic retrograde cholangiopancreatography (ERCP/MRCP) are sometimes useful when working up patients with jaundice and dilated CBD or suspected cholangitis, but are usually obtained after an ultrasound. ERCP is an invasive test, requiring the use of contrast dye but also has the advantage of allowing intervention if pathology is found (e.g., stenting, stone extraction, biopsy).  MRCP, on the other hand, is non-invasive and does not require contrast dye.

Treatment / Management

Management of gallstones can be divided into two categories: asymptomatic gallstones and symptomatic gallstones.

Asymptomatic gallstones require the patient to be counseled regarding symptoms of biliary colic and when to seek medical attention. Cholelithiasis without complications can be treated acutely with oral or parenteral analgesia in the emergency department or urgent care center once the diagnosis has been established and alternative diagnoses excluded. Patients should also be offered dietary advice to reduce the chance of recurrent episodes and referred to a general surgeon for elective laparoscopic cholecystectomy. Today, laparoscopic cholecystectomy is the standard of care and most patients are managed as outpatients.

Patients with symptoms and workup consistent with acute cholecystitis will require admission to hospital, surgical consult and intravenous antibiotics.  Patients with choledocholithiasis or gallstone pancreatitis will also require admission to hospital, gastrointestinal (GI) consultation and ERCP or MRCP. Patients with acute ascending cholangitis are usually ill-appearing and septic. They often also require aggressive resuscitation and ICU-level care in addition to surgical intervention to drain an infection in the biliary tract.[8][9][10](A1)

Medical treatment with ursodeoxycholic acid is an option but not practical. The patient must have stones less than 1 cm with high cholesterol content. But the therapy can take 9-12 months to dissolve the stone in only 50% of cases.

Extracorporeal shockwave lithotripsy for non-calcified gallstones is another option.

Differential Diagnosis

• Acute Pancreatitis

• Appendicitis

• Bile Duct Strictures

• Bile Duct Tumors

• Diabetic ketoacidosis

• Emergent Treatment of Gastroenteritis

• Esophageal spasm

• Gallbladder Cancer

• Gastroesophageal reflux disease (GERD)

• Hepatitis

• Irritable bowel syndrome

• Pancreatic Cancer

• Pancreatitis (acute or chronic)

• Peptic Ulcer Disease

Prognosis

Data suggest that only 50% of patients with gallstones develop symptoms. The mortality rate following elective laparoscopic cholecystectomy is less than 1%. However, emergency cholecystectomy is associated with high mortality rates. Other problems include stones in the bile duct after surgery, incisional hernia, and injury to the bile duct. A few percentages of patients develop post-cholecystectomy pain.

Complications

• Pancreatitis
• Bile duct stones
• Acute cholecystitis
• Gallbladder empyema, necrosis
• Gallbladder cancer
• Cholecystoenteric fistula