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Internal Medicine

Gallstone disease (GD)

Chronic recurrent hepatobiliary disease, the basis for which is the impaired metabolism of cholesterol, bilirubin and bile acids, which is characterized by the formation of gallstones in the hepatic bile duct, common bile duct, or gallbladder.

Introduction

Gallstones are solid stones that are produced in the gallbladder when there’s an imbalance in the composition of bile. The main types of gallstones are cholesterol stones, bilirubin stones, and brown stones.

Chronic recurrent hepatobiliary disease, the basis for which is the impaired metabolism of cholesterol, bilirubin and bile acids, which is characterized by the formation of gallstones in the hepatic bile duct, common bile duct, or gallbladder.

  • M/C gall-bladder pathology (10-15% western population)

Epidemiology

Cholelithiasis prevalence:

Worldwide prevalence of gallstones in females based on ultrasonographic surveys: Prevalence is inordinately high in American Indians and their admixtures, and also Northern Europeans; somewhat lower in European and American whites; intermediate in Asians and black Americans, and quite low in black Africans. | Stinton, L. M., & Shaffer, E. A. (2012). Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut and liver, 6(2), 172–187. https://doi.org/10.5009/gnl.2012.6.2.172

Gallbladder cancer prevalence:

Incidence of gallbladder cancer worldwide: Carcinoma of the gallbladder is more common in certain ethnic groups: native American Indians, white Hispanics from North and South America, and those from northern India and Eastern Europe.198 Elsewhere in the world, the incidence is low at <2/100,000. | National Cancer Institute. Surveillance, Epidemiology and End Results (SEER) Program. Available from http://seer.cancer.gov/).

Gallstones

Gallstones are hardened deposits of the digestive fluid bile, that can form within the gallbladder.

Risk factors for gallstone formation:

“Fat and fertile, female and forty” & 6 Fs for gallstone formation
  • Female
  • Fertile (Pregnancy)
  • Fat
  • Forty + (Age)
  • Family (Aboriginals > Hispanics > Whites)
  • Farmacology (Octreotide, ceftriaxone)
Risk Factors for Gallstone Disease | TPN, total parental nutrition. | Stinton, L. M., & Shaffer, E. A. (2012). Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut and liver, 6(2), 172–187. https://doi.org/10.5009/gnl.2012.6.2.172

Gallbladder sludge:

Thickened gallbladder mucoprotein with tiny entrapped cholesterol crystals; usual precursor of gallstones
  • Risk factors:
    • Pregnancy
    • Prolonged total parenteral nutrition (TPN)
    • Starvation, or rapid weight loss
    • Antibiotic (ceftriaxone)

Composition of gallstones:

Three main categories of gallstones can be identified according to their predominant chemical composition, cholesterol and pigment stones
Types of Gallbladder and Biliary Tract Stones: Characteristics and Clinical Associations | TPN, total parental nutrition. | Stinton, L. M., & Shaffer, E. A. (2012). Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut and liver, 6(2), 172–187. https://doi.org/10.5009/gnl.2012.6.2.172

Pure cholesterol stones & Mixed stones:

Pure cholesterol stones contain 90% cholesterol while mixed stones contain varying proportions of cholesterol, bilirubin and other substances such as calcium carbonate, calcium phosphate and calcium palmitate; 80% cases in west.

Cholesterol gallstones form when the cholesterol concentration in bile exceeds the ability of bile to hold it in solution, so that crystals form and grow as stones. Three types of abnormalities have been considered to be responsible for cholesterol gallstone formation:

  1. Cholesterol supersaturation: Excessive cholesterol biosynthesis (main lithogenic mechanism in obese persons)
  2. Defective conversion of cholesterol to bile acids: Due to low activity of cholesterol 7α hydroxylase (rate limiting enzyme for bile acid biosynthesis and cholesterol elimination) resulting in excessive cholesterol secretion (in non-obese)
  3. Interruption of enterohepatic circulation of bile acids: Leads to a higher cholesterol/phospholipid ratio in the vesicles secreted by the liver. Estrogen treatment also reduces the synthesis of bile acid in women
Diagram of gallstone formation by taking into account the above impaired bile production and excretion processes. | Reshetnyak V. I. (2012). Concept of the pathogenesis and treatment of cholelithiasis. World journal of hepatology, 4(2), 18–34. https://doi.org/10.4254/wjh.v4.i2.18

Pigment stones:

Pigment stones occur when RBCs are being destroyed, leading to excessive bilirubin in the bile. They contain at least 90% bilirubin; 80% cases in Asia while 2% incidence in the West
  • Brown pigment stones (calcium bilirubinate): Intraductal stasis and chronic colonization of bile with bacteria.
    • Mainly found in the Southeast Asian population
  • Black pigment stones (bilirubin, calcium and/or tribasic phosphate): Cirrhosis or chronic hemolytic conditions (thalassemias, hereditary spherocytosis, and sickle cell disease)
Human gallbladder stones. Pure cholesterol stones with spherical shape and morular surface (a), oval shape and smooth surface (b), multiple stones (c). The cut surface is shown with a brownish centre and radial disposition of cholesterol monohydrate crystals (d). Pure pigment stones are shown as debris (e). Mixed stones are shown as multifaceted concernments (f). Note that the black pigment surface and the inner centre are made of a small amount of solid cholesterol crystals (arrow) Black horizontal line=1 cm. | Portincasa, P., Molina-Molina, E., Garruti, G., & Wang, D. Q. (2019). Critical Care Aspects of Gallstone Disease. Journal of critical care medicine (Universitatea de Medicina si Farmacie din Targu-Mures), 5(1), 6–18. https://doi.org/10.2478/jccm-2019-0003

Complications:

The critical feature of gallstones is that they are not all symptomatic. Sometimes they may migrate near the opening of the cystic duct and block the flow of bile. This can lead to tension in the gallbladder, which results in the classic biliary colicky pain. If the cystic duct is obstructed for more than a few hours, it can lead to inflammation of the gallbladder wall (cholecystitis). Sometimes the gallstone may move into the bile duct and cause obstruction, leading to jaundice and abdominal pain. Patients who have chronic gallstones may develop progressive fibrosis and loss of motor function of the gallbladder.
Problems caused by gallstones | Sanders, G., & Kingsnorth, A. N. (2007). Gallstones. BMJ (Clinical research ed.), 335(7614), 295–299. https://doi.org/10.1136/bmj.39267.452257.AD
  • Acute/chronic cholecystitis (36%)
  • Acute/chronic acalculous cholecystitis
  • Acute cholangitis
  • Recurrent pyogenic cholangitis
  • Biliary enteric fistula and gallstone ileus:
  • Choledocholithiasis
  • Cholestatic jaundice
  • Acute biliary pancreatitis
  • Cholesterolosis and gallbladder polyps
  • Gallbladder carcinoma and porcelain gallbladder

Clinical features

Asymptomatic cholelithiasis:

Gallstones develop problems related to gallstones at a rate of 1%-4% a year
cholelithiasis
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Biliary colic:

Biliary colic is 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. Biliary colic and cholecystitis share a spectrum of symptoms, and no exact time course or definition exists to separate them.
  • Intermittent episodes of constant, sharp, right upper quadrant (RUQ) abdominal pain
  • Associated with nausea and vomiting
  • Fatty meals are a common trigger for gallbladder contraction
Symptoms and signs of biliary colic and acute cholecystitis | Sanders, G., & Kingsnorth, A. N. (2007). Gallstones. BMJ (Clinical research ed.), 335(7614), 295–299. https://doi.org/10.1136/bmj.39267.452257.AD

Acute cholecystitis:

Occurs when persistent stone dislodged the cystic duct causes the gallbladder to become distended and inflamed.
  • Biliary colic + fever, RUQ pain
  • Murphy’s sign: tenderness over the gallbladder

Choledocholithiasis:

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:

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 (classic for cholangitis):
    1. Severe RUQ tenderness
    2. Fever + rigors
    3. Jaundice

Mirizzi’s syndrome:

Obstruction leading to jaundice due to compression of the common hepatic duct by a stone in the neck of the gall bladder or cystic duct

Pancreatitis:

Gallstone migration theory: Transitory obstruction of the biliopancreatic duct (the common channel) in ampulla, initiates premature activation of enzymes in the pancreas, leading to pancreatitis
  • Classically constant epigastric pain, radiating through to the back, and relieved by bending forwards
  • Vomiting (profuse)

Gallstone ileus:

Small bowel obstruction caused by an impaction of a gallstone within the lumen of the small intestine
  • M/C site: Terminal 2ft of ileum
  • Riggler’s triad (on abdominal radiograph):
    1. Small bowel obstruction
    2. Gallstone outside the gallbladder
    3. Pneumobilia: Air in the bile ducts
(A) Plain abdominal radiograph of a 90-year-old man with acute retrosternal pain showing air–fluid levels, predominantly in the small bowel, and pneumobilia (arrowhead). (B) Computed tomography scan showing an ectopic gallstone impacted in the lumen of the small bowel (arrow). | Roothans, D., & Anguille, S. (2013). Rigler triad in gallstone ileus. Canadian Medical Association Journal, 185(14), E690 LP-E690. https://doi.org/10.1503/cmaj.121432

Bouveret’s syndrome:

Rare form of gallstone ileus secondary to an acquired fistula between the gallbladder and either the duodenum or stomach

Gallbladder cancer:

Rare complication accounting for 0.3% of patients with gallstone disease

Diagnosis

Physical examination:

  • Murphy’s sign: RUQ pain in acute phase exacerbated during inspiration by examiner’s right subcostal palpation
  • Palpable abdominal mass: Omentum wall falls off inflamed gallbladder
  • Courvoisier’s sign: Palpable non-tender gallbladder

Lab investigations:

  • Total bilirubin
  • Gamma-glutamyltransferase (γ-GT)
  • Alkaline phosphatase (AP)
  • Alanine aminotransferase/aspartate aminotransferase (ALT/AST)
  • Lipase

RUQ abdominal ultrasound:

Investigation of choice; can detect stones ≥ 2 mm as well as sludge and gallbladder polyps.
  • Gallbladder wall thickening (> 3 mm)
  • Postacoustic shadow seen (D/D gallbladder polyps, where its not seen)
  • Pericholecystic fluid
  • Positive sonographic Murphy’s sign
  • Wall echo shadow (WES) sign: Seen in chronic cholecystitis
Sonographic appearance of acute cholecystitis in cholelithiasis | Gutt, C., Schläfer, S., & Lammert, F. (2020). The Treatment of Gallstone Disease. Deutsches Arzteblatt international, 117(9), 148–158. https://doi.org/10.3238/arztebl.2020.0148

Abdominal radiograph:

10% stones are radiopaque and can be seen on X-ray
  • Mercedes benz sign

Hepatobiliary iminodiacetic acid (HIDA) scan:

Nuclear imaging for acute cholecystitis
  • Non-visualization of gallbladder

Magnetic resonance cholangiopancreatography (MRCP)

Investigation of choice for suspected CBD stone

Endoscopic retrograde cholangiopancreatogram (ERCP):

gold-standard test if a CBD stone is identified on MRCP
  • M/C complication: Pancreatitis

Percutaneous transhepatic cholangiogram (PTHC):

Useful in diagnosing common bile duct stones if an ERCP is not possible

Differential diagnosis:

  • Common:
    • Appendicitis
    • Perforated peptic ulcer
    • Acute pancreatitis
  • Rare:
    • Acute pyelonephritis
    • Myocardial infarction (MI)
    • Pneumonia (right-lower lobe)

Management

Treatment for cholelithiasis is indicated only in the presence of symptoms.

Algorithm for the diagnosis and treatment of gallstones. AP, alkaline phosphatase; ALT, alanine aminotransferase; CDL, choledocholithiasis; ERC, endoscopic retrograde cholangiography; EUS, endosonography; GT, glutamyltransferase; MRC, magnetic resonance cholangiography | Gutt, C., Schläfer, S., & Lammert, F. (2020). The Treatment of Gallstone Disease. Deutsches Arzteblatt international, 117(9), 148–158. https://doi.org/10.3238/arztebl.2020.0148

Asymptomatic cholelithiasis:

Asymptomatic cholelithiasis is usually not an indication for cholecystectomy.

Biliary colic:

As a rule, treatment for cholelithiasis is indicated only in the presence of symptoms. There is usually no indication for cholecystectomy in asymptomatic patients unless they are found to have gallstones >3 cm, polyps >1 cm, or porcelain gallbladder.
  • Nonsteroidal anti-inflammatory drugs
  • Spasmolytics (if severe)

Cholecystectomy:

Treatment of choice for both uncomplicated symptomatic cholelithiasis and proven gallbladder sludge with the characteristic biliary pain.

Cholecystectomy aims to prevent/reduce renewed biliary pain; avoidance of later and elimination of existing complications of cholelithiasis; and prevention of gallbladder cancer in high-risk patients.

Tokyo consensus guidelines 2018 (TG18):

flowchart for the treatment of acute cholecystitis (AC)
TG18 flowchart for the management of acute cholecystitis Grade I. λ, CCI 5 or less and/or ASA class II or less (low risk); µ, CCI 6 or greater and/or ASA class III or greater (not low risk); ▵, in case of serious operative difficulty, bail‐out procedures including conversion should be used. | ASA‐PS American Society of Anesthesiologists physical status. | Okamoto, K., Suzuki, K., Takada, T., Strasberg, S.M., Asbun, H.J., Endo, I., Iwashita, Y., Hibi, T., Pitt, H.A., Umezawa, A., Asai, K., Han, H.‐S., Hwang, T.‐L., Mori, Y., Yoon, Y.‐S., Huang, W.S.‐W., Belli, G., Dervenis, C., Yokoe, M., Kiriyama, S., Itoi, T., Jagannath, P., Garden, O.J., Miura, F., Nakamura, M., Horiguchi, A., Wakabayashi, G., Cherqui, D., de Santibañes, E., Shikata, S., Noguchi, Y., Ukai, T., Higuchi, R., Wada, K., Honda, G., Supe, A.N., Yoshida, M., Mayumi, T., Gouma, D.J., Deziel, D.J., Liau, K.‐H., Chen, M.‐F., Shibao, K., Liu, K.‐H., Su, C.‐H., Chan, A.C.W., Yoon, D.‐S., Choi, I.‐S., Jonas, E., Chen, X.‐P., Fan, S.T., Ker, C.‐G., Giménez, M.E., Kitano, S., Inomata, M., Hirata, K., Inui, K., Sumiyama, Y. and Yamamoto, M. (2018), Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis. J Hepatobiliary Pancreat Sci, 25: 55-72. https://doi.org/10.1002/jhbp.516
TG18 flowchart for the management of acute cholecystitis Grade II. α, antibiotics and general supportive care successful; ϕ, antibiotics and general supportive care fail to control inflammation; λ, CCI 5 or less and/or ASA‐PS class II or less (low risk); µ, CCI 6 or greater and/or ASA‐PS class III or greater (not low risk); ※, performance of a blood culture should be taken into consideration before initiation of administration of antibiotics; †, a bile culture should be performed during GB drainage; ▵, in case of serious operative difficulty, bail‐out procedures including conversion should be used. | ASA‐PS American Society of Anesthesiologists physical status, CCI Charlson comorbidity index, GB gallbladder, LC laparoscopic cholecystectomy. | Okamoto, K., Suzuki, K., Takada, T., Strasberg, S.M., Asbun, H.J., Endo, I., Iwashita, Y., Hibi, T., Pitt, H.A., Umezawa, A., Asai, K., Han, H.‐S., Hwang, T.‐L., Mori, Y., Yoon, Y.‐S., Huang, W.S.‐W., Belli, G., Dervenis, C., Yokoe, M., Kiriyama, S., Itoi, T., Jagannath, P., Garden, O.J., Miura, F., Nakamura, M., Horiguchi, A., Wakabayashi, G., Cherqui, D., de Santibañes, E., Shikata, S., Noguchi, Y., Ukai, T., Higuchi, R., Wada, K., Honda, G., Supe, A.N., Yoshida, M., Mayumi, T., Gouma, D.J., Deziel, D.J., Liau, K.‐H., Chen, M.‐F., Shibao, K., Liu, K.‐H., Su, C.‐H., Chan, A.C.W., Yoon, D.‐S., Choi, I.‐S., Jonas, E., Chen, X.‐P., Fan, S.T., Ker, C.‐G., Giménez, M.E., Kitano, S., Inomata, M., Hirata, K., Inui, K., Sumiyama, Y. and Yamamoto, M. (2018), Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis. J Hepatobiliary Pancreat Sci, 25: 55-72. https://doi.org/10.1002/jhbp.516
TG18 flowchart for the management of acute cholecystitis Grade III. ※, performance of a blood culture should be taken into consideration before initiation of administration of antibiotics; #, negative predictive factors: jaundice (TBil ≥2), neurological dysfunction, respiratory dysfunction; Φ, FOSF: favorable organ system failure = cardiovascular or renal organ system failure which is rapidly reversible after admission and before early LC in AC; *, in cases of Grade III, CCI (Charlson comorbidity index) 4 or greater, ASA‐PS 3 or greater are high risk; †, a bile culture should be performed during GB drainage; Ψ, advanced center = intensive care and advanced laparoscopic techniques are available; ▵, in case of serious operative difficulty, bail‐out procedures including conversion should be used. | GB gallbladder, LC laparoscopic cholecystectomy, PS performance status | Okamoto, K., Suzuki, K., Takada, T., Strasberg, S.M., Asbun, H.J., Endo, I., Iwashita, Y., Hibi, T., Pitt, H.A., Umezawa, A., Asai, K., Han, H.‐S., Hwang, T.‐L., Mori, Y., Yoon, Y.‐S., Huang, W.S.‐W., Belli, G., Dervenis, C., Yokoe, M., Kiriyama, S., Itoi, T., Jagannath, P., Garden, O.J., Miura, F., Nakamura, M., Horiguchi, A., Wakabayashi, G., Cherqui, D., de Santibañes, E., Shikata, S., Noguchi, Y., Ukai, T., Higuchi, R., Wada, K., Honda, G., Supe, A.N., Yoshida, M., Mayumi, T., Gouma, D.J., Deziel, D.J., Liau, K.‐H., Chen, M.‐F., Shibao, K., Liu, K.‐H., Su, C.‐H., Chan, A.C.W., Yoon, D.‐S., Choi, I.‐S., Jonas, E., Chen, X.‐P., Fan, S.T., Ker, C.‐G., Giménez, M.E., Kitano, S., Inomata, M., Hirata, K., Inui, K., Sumiyama, Y. and Yamamoto, M. (2018), Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis. J Hepatobiliary Pancreat Sci, 25: 55-72. https://doi.org/10.1002/jhbp.516

Gallstone ileus:

2-stage surgery: Simultaneously occurring choledocholithiasis and cholelithiasis should be treated separately. The first step is endoscopic removal of the bile duct stones, followed (within 72 h) by cholecystectomy.
  1. 1st surgery: Ileus (obstruction) relieved only
  2. 2nd surgery: Fistula repaired with cholecystectomy

ERCP:

For biliary pancreatitis and suspected coexisting acute cholangitis, administration of antibiotics followed (within 24 h) by ERC with sphincterotomy and stone extraction
  • M/C complication of ERCP: Pancreatitis

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