Gallstone disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Humans have a long history with gallstones with the earliest recording being noted at least 7000 years ago. Autopsies performed on the earliest mummies in Egypt were discovered to have gallstones. Gallstones became easier to visualize in 1895 with the introduction of the plain x-ray film. In 1924 and 1970, IV cholecystography and percutaneous transhepatic cholangiography were developed respectively.

Gallstone disease has been noted as far back as when Egyptian pharaohs ruled. Autopsies performed on mummies found gallstones present within the body cavities.^[1]

• From 1895 to 1924, plain film was developed to better detect radiopaque stones.^[2]
• From 1924 to 1960, contrast media was introduced which inspired the invention of IV cholecystography.
• From then on, in 1970, percutaneous transhepatic cholangiography, scintigraphy, and sonography were invented.
• By 1980, the notion that gallbladder stones could be treated medically was introduced.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Gallstone disease may be classified according to the chemical analysis of gallstone. In this way, there are 3 subtypes: pure cholesterol, pure bilirubin stones and mixed.

• Gallstone disease may be divided into 3 subtypes according to chemical analysis of gallstones :^[1][2]
  • Pure cholesterol
  • Bilirubin
  • Mixed or composite:
    • Mixed cholesterol
    • Calcium carbonate
    • Calcium palmitate
    • Calcium phosphate
    • Black phosphate

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Studies have shown that gallstone formation is mostly due to bile supersaturation. In the United States, patients that present with gallbladder stones mostly have cholesterol stones. Cholesterol stones form when the concentration of cholesterol in the bile is much higher than the concentration of cholesterol that can be dissolved in the bile. Normally cholesterol is metabolized in the body and excess cholesterol is disposed of in the bile. There is a balance between pronucleating (crystallization-promoting) and antinucleating (crystallization-inhibiting) forces, so that gallstones don’t form. When pronucleating forces take the upper hand, gallstones will form. On the other hand, moderate intake of wine and the consumption of whole grain bread may decrease the risk of developing gallstones.

• The most common type of gallstone is a cholesterol stone.^{[1][2][3][4][5]}
• When pronucleating proteins are present, such as mucin, the bile becomes hypersaturated with cholesterol and cholesterol stones form.
• Gallstone disease can also be caused by a lack of motility in the muscular wall of the gallbladder or excessive sphincter contraction, that prevents bile secretion.
• In this way the bile stagnates within the gallbladder and promotes the formation of stones.

• Cholesterol stones are the most common type of gallstone.
• The quantity of cholesterol is balanced within the body.
• Cholesterol is an important organic molecule that is needed for incorporation within cell membranes and to produce steroid hormones in the body.

• Less commonly, gallstones can be composed of bilirubin and are sometimes referred to as “pigment stones”.^[8]
• Bilirubin is a byproduct of red blood cell breakdown and so are usually found in patients with hemoglobin disorders.
• Pigment stones are formed via two main pathways:
  • Infection of the biliary tree with bacteria that can release hydrolytic enzymes and form insoluble calcium salts.
  • Non-bacterial, non-enzymatic hydrolysis of bilirubin conjugates such as what may happen in patients with Gilbert’s syndrome and chronic hemolysis.

• There is a lack of evidence that supports a true pathology to explain how mixed stones are formed.^[2]
• However, there have been theories that include a combination of several mechanisms including supersaturation, infection and hypomotility of the gall bladder.

The conditions associated with gallstone disease include:^[9][10]

• Diabetes mellitus type 2
• Obesity
• Pregnancy
• Gallbladder cancer
• Gallbladder polyps
• Primary sclerosing cholangitis
• Porcelain gallbladder
• Rapid weight loss
• Constipation
• Eating fewer meals
• Low intake of:
  • Fish
  • Magnesium
  • Folate
  • Whole grain bread
  • Fiber
  • Vitamin C

• On gross pathology, commonly multiple small stones are found and less commonly a solitary stone is seen.^[11]

• On microscopic analysis, characteristic findings include:^[12]
  • Transmural thickening of the gall bladder wall
  • Neutrophilia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Common causes of gallstone disease include increasing age, oral contraceptive pills, pregnancy, diabetes, and obesity. Life threatening causes include conditions causing hepatic and biliary cirrhosis.

Life threatening causes of gallstones include:^[1]

• Biliary cirrhosis
• Cystic fibrosis
• Liver cirrhosis

Most common causes of gallstones include:^[2][3][4]Closing </ref> missing for <ref> tag^[5][6]

• Aging
• Combined oral contraceptive pill
• Diabetes
• Drug induced
  • Clofibrate
  • Atazanavir
  • Ceftriaxone
  • Clofibrate
  • Febuxostat
  • Lanreotide
  • Leflunomide
  • Proton pump inhibitors
  • Somatostatin
• Obesity
• Pregnancy
• Crohn’s disease

Less common causes of gallstones include:^[2][3][4]

• Fasting
• Hemolytic anemia
• Inflammatory bowel disease
• William’s syndrome
• Ulcerative colitis
• Sickle cell disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Gallstone disease must be differentiated from other diseases that cause right upper quadrant pain including gastroesophageal reflux disorder, peptic ulcer disease,hepatitis,sphincter of Oddi dysfunction,appendicitis, bile duct stricture, chronic pancreatitis, irritable bowel syndrome, ischemic heart disease, pyelonephritis, ureteral calculi and complications of gallstone disease include: acute cholecystitis, choledocholithiasis, acute pancreatitis, and acute cholangitis.

• Gallstone disease can manifest in a variety of clinical forms.
• The presence of biliary colic is an important diagnostic feature to distinguish between gallstones and non-biliary stone disorders.
• Patients who present with biliary colic are more likely to have gallstones detected on imaging. ^[1]
• However, it is important to note that biliary colic can be concomitant in patients with other biliary disorders such as acute cholecystitis, choledocholithiasis, sphincter of Oddi dysfunction, and functional gallbladder disorder.^[2][3]

The differential diagnosis of diseases presenting with abdominal pain, fever and jaundice is discussed below.

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

To review a differential diagnosis for abdominal pain, click here

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

The third National Health and Nutrition Examination Survey found that 630 per 100,000 and 1420 per 100,000 men and women aged 20 to 74 respectively in the United States had gallstone disease. In the United States, every year about 1-3% (3 to 9 million people/year) of the population develop gallstones. Gallstone disease has an overall higher incidence in females than males of the Caucasian, Hispanic and Native American nations. Whilst a lower incidence was found in Eastern European, African American, and Japanese populations.

The third National Health and Nutrition Examination Survey found that 630 per 100,000 and 1420 per 100,000 men and women aged 20 to 74 respectively in the United States had gallstone disease.^[1]

• In the United States, every year about 1-3% (3 to 9 million people/year) of the population develop gallstones.^[2]
• The incidence of choledocholithiasis is higher internationally, mainly because of parasitic infestation with liver flukes such as Clonorchis sinensis not found in the United States.

• Patients of age groups between 20 – 74 develop gallstone disease.^[1]
• The most common age group is between 40-69 years of age.

• Gallstone disease usually affects individuals of the Western Caucasian, Hispanic and Native American races.^[3][4][5][6]
• Eastern European, African American and Japanese individuals are less likely to develop Gallstone disease.

• Females are more commonly affected by gallstone disease than males.^{[1][9][10][11][12]}
• This may be due to increased estrogen levels and the use of oral contraceptive pills within the female population, which increase biliary cholesterol secretion.
• The female to male ratio is approximately 2.5 to 1.

• In Japanese men of the Sumo wrestling profession, a high incidence of gallstones was found with an increasing body mass index.^[13]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Common risk factors in the development of gallstone disease include age, sex, pregnancy, and oral contraceptives and estrogen replacement therapy. Less common risk factors include rapid weight loss, prolonged total parenteral nutrition and hepatic and biliary cirrhosis.

• Common risk factors in the development of gallstone disease include:^{[1][2][3][4][3][5]}
  • Age
    • Age is the most important risk factor.
    • The most common age for developing gallstones was found to be between ages 40 – 69 years.
    • Cholelithiasis rarely exists in children unless in a hemolytic state.
  • Gender
    • A higher incidence is noted in women across all age groups.
  • Race
    • Gallstone disease is common amongst Pima Indians, North Americans and Chileans. Japanese have the lowest incidence.
  • Pregnancy
    • Cholesterol gallstone incidence in pregnant women is very common, paarticularly in multiparous women.
  • Diabetes Mellitus Type 2
    • Uncontrolled diabetes mellitus will cause motility problems in the gallbladder.
  • Obesity
    • Obesity is related to a high fat or high cholesterol diet.

• Less common risk factorsin the development of gallstone disease include:^{[6][7][8][9][10]}
  • Rapidly weight loss and gastric bypass surgery
  • Long-term octreotide
  • Long-term total parenteral nutrition (TPN)
  • Drug induced e.g. Ceftriaxone^[11]
  • Prolonged fasting
  • Presence of Crohn’s disease
  • Cystic fibrosis
  • Liver cirrhosis
  • Extensive bowel resection
  • Spinal cord injury
  • Use of medications such as
    • Chlorpromazine
    • Octreotide
    • Clofibrate

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Periodic screening for gallstones is not currently indicated. However, it has been suggested that screening diabetic patients for gallstones and treating them earlier is good practice for avoiding a future cholecystectomy or possible complications.

• There is no screening program in place for the detection of gallstones at present.^[1][2]
• However, it has been suggested that screening diabetic patients for gallstones and treating them earlier is good practice for avoiding a future cholecystectomy or possible complications.
• A Taiwanese study also concluded that annual screening for gallstones could be valuable both medically and economically.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Gallstone disease patients should not undergo an elective cholecystectomy until symptoms develop, since almost 55% of patients will remain asymptomatic. Also, the complications of asymptomatic gallstones are almost negligible unless symptoms develop. The complications of gallstone disease include acute cholecystitis, obstructive jaundice, acute cholangitis and acute pancreatitis. The prognosis after laparoscopic cholecystectomy is excellent with morbidity and mortality rates being as low as 0.5 and 10% respectively.

• Gallstone disease usually develops in the third decade of life, and can start asymptomatically.^[1]
• Symptoms of biliary colic may develop such as abdominal pain, fever and, jaundice.
• If left untreated, only 10% of patients with gallstone disease may progress to develop symptoms.

• Common complications of gallstone disease include:^[2]
  • Acute cholecystitis
  • Gallbladder perforation
  • Obstructive jaundice
  • Choledocholithiasis with or without acute cholangitis
  • Gallbladder fistula
  • Cholangiocarcinoma
  • Gallstone pancreatitis
  • Gallstone ileus

• Elective cholecystectomy has a mortality rate and morbidity rate of 0.5% and 10% respectively.^[3]
• Emergent cholecystectomy has a mortality rate and morbidity rate of 3-5% and 30-50% respectively.
• The risk of developing an incisional hernia after a laparoscopic cholecystectomy is about 8% in patients over 50 years of age.
• Patients with gallstones in the gallbladder have an associated choledocholithiasis (stone in the common bile duct) in 10-15% of the time.

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