Gallstones are common in the United States, especially among the Hispanic population. They are common among the fatty fertile females in their forties. The gallstones are mostly asymptomatic that do not need treatment except in certain high-risk groups. The symptomatic patients present with right upper quadrant abdominal pain and cholecystectomy is the primary treatment option in these patients.
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gallstones

Image: “Opened gall bladder containing numerous gallstones.” by Emmanuelm at en.wikipedia. License: CC BY 3.0


Background

Gallstones are the stones in the gall bladder that are formed when bile fluid becomes hardened inside the gallbladder.

Biliary colic is the pain in right upper quadrant of the abdomen that results when a gallstone temporarily impacts the cystic duct during a contraction.

Acute cholecystitis occurs when there is a prolonged obstruction of the cystic duct and secondary bacterial infection of the gallbladder resulting in right upper quadrant abdominal pain, fever, and abdominal tenderness.

The majority of gallstones are cholesterol based and are asymptomatic. When symptomatic, the most common presentation 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.

The treatment is surgical removal of the gallbladder (cholecystectomy). The current consensus is to treat symptomatic gallstones only. However, in certain populations, a prophylactic cholecystectomy is offered, such as children with sickle cell disease.

Pathophysiology of Biliary Disease

Bile is formed by the liver and is stored and concentrated in the gallbladder, which contracts after fatty meals to deliver the bile into the intestine. Bile is mainly composed of cholesterol, bile salts, phospholipids and inorganic acids and helps in fat emulsification and absorption in the small intestine.

Precipitation of bile salts and cholesterol gives rise to gall stones. Formation of a nadir of insoluble cholesterol or mucus 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 mucus 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 gallstones to pancreatitis and intestinal obstruction.

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.

diagram showing the position of the bile ducts

Image: “Diagram Showing the Position of the Bile Ducts.” by Cancer Research UK uploader. License: CC BY-SA 4.0

 

Epidemiology of Gallstones

While gallstones are found among all age groups, they are more common in Females, who are Fertile, obese (Fatty) and in their Forties (the 4 Fs). 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, only 20% of the patients are symptomatic and approximately 2% of people are expected to become symptomatic per year. Because of this low risk, asymptomatic patients are not surgically treated.

The prevalence of gallstone increases with age and 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.

People who are at an increased risk of dyslipidemia such as the obese, diabetics, having the sedentary lifestyle and those who attempt to lose weight rapidly, are also all at an increased risk of gallstones.

Additionally, gallstones are more common in certain races, such as Native Americans, Hispanics, followed by North Americans, Europeans and, finally, Asian populations. Finally, certain drugs have been linked to an increased risk of gallstones, such as fibrates and chronic use of proton pump inhibitors.

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.

Etiologies of cholesterol gallstones

Cholesterol gallstones are formed when bile cholesterol concentration increases. These patients are 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 have excessive cholesterol biosynthesis. Additionally, diabetics are known to have hypertriglyceridemia, which predisposes them to cholesterol gallstones.

Older age and higher estrogen states have been linked to a decreased cholesterol 7-alpha hydroxylase enzyme activity, which results in the diminished conversion of cholesterol to bile acid and eventually, cholesterol becomes less soluble in the bile and stones form.

Interruption of the enterohepatic circulation could happen after gastrointestinal surgery or overnight fasting.

Etiologies of pigment gallstones

Pigment gallstones are the result of excessive bilirubin, unlike cholesterol gallstones. 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.

red blood cells in sickle cell disease

Image: “Photomicrograph of normal-shaped and sickle-shape red blood cells from a patient with sickle cell disease.” by Gregory Kato – Own work. License: CC BY-SA 4.0

  • 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.

Clinical Presentation of Gallstones

The majority of patients with gallstones are asymptomatic but these patients can have non-related gastrointestinal symptoms such as heartburn, bloating, constipation or diarrhea and gallstones are incidentally identified on an ultrasonography.

Symptomatic patients, on the other hand, are more likely to present with right-sided upper quadrant abdominal pain that describes a more specific picture of biliary colic. Biliary colic results when a stone temporarily impacts the cystic duct during a contraction. The pain reaches maximum intensity in the right upper quadrant in 20 minutes after the ingestion of a fatty meal and eventually resolves in one to two hours. It is intense and not truly colicky in nature. 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 are the markers of gallbladder inflammation that 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.

Diagnostic Workup of Gallstones Disease

Laboratory investigations can help exclude an acute inflammatory process but are 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

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.

Ultrasonography

Transabdominal ultrasonography is the best imaging modality to diagnose gallbladder stones. It is non-invasive, cheap, sensitive and specific. Gallbladder stones are echogenic on ultrasonography and have an acoustic shadow as seen in the figure.

ultrasound image of gallbladder stone gallstone

Image: “Ultrasound Image of Gallbladder Stone.” by © Nevit Dilmen. License: CC BY-SA 3.0

In addition to its role in the diagnosis of gallstones, 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.

Abdominal plain x-ray

Gallstones as seen on plain x-ray.

Image: “Gallstones as seen on plain x-ray.” by James Heilman, MD – Own work. License: CC BY-SA 3.0

The majority of gallstones are radiolucent but around two-thirds of pigment gallstones can be seen on abdominal x-rays due to higher calcium content.

Abdominal x-rays also help exclude other differential diagnoses, such as renal stones, calcific pancreatitis, and intestinal obstruction.

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 choledocholithiasis

Image: “MRCP: (a) gallbladder with gallstones, (b) stones in the bile duct, (c) pancreatic duct, (d) fluid in duodenum.” by Hellerhoff – Own work. License: CC BY-SA 3.0

MRCP has an excellent sensitivity for the diagnosis of gallstones anywhere in the biliary tract. However, it is currently reserved for patients with complicated common bile duct disease or when there is high clinical suspicion but the ultrasonography is negative, due to being expensive and the need for specialized software. 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 often used in patients with common bile duct stones. It 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 the medical dissolution of gallstones is high and is up to 50%.

Surgical intervention for gallstones

Cholecystectomy

Image: “Pictures of my cholecystectomy in progress taken through the laparoscope.” by User:Pschemp. License: CC BY-SA 3.0

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 four 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 a few cases, removal of the common bile duct stones during the surgery is not possible. In this occasion, endoscopic sphincterotomy and ERCP are indicated to extract common bile duct stones. ERCP can also be used in the acutely ill patient and not only in elective cases.

Complications of Gallstones

Acute Cholangitis

Cholangitis is the inflammation (infection) of the biliary tree after obstruction irrespective of the cause of obstruction. Charcot triad is very helpful for its diagnosis that consists of 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.

Acute pancreatitis

Gallstones are one of the most common causes of acute 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 resulting in the inflammation of the pancreas.

Porcelain gallbladder

The chronic gallstones irritate the gallbladder wall leading to extensive calcium deposition. This brittle gallbladder with high calcium content is called porcelain gallbladder and has a high association with gallbladder adenocarcinoma. It is often an incidental finding and cholecystectomy is usually performed due to a higher risk of cancer.

Mirizzi syndrome

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.

Conclusion

Gallstones are common in fatty fertile females in their forties (4-Fs). 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.

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