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A. Normal Bile Production [1] navigator

  1. Synthesized by Hepatocytes and Intestine [2]
    1. Transport blood constituents from basolateral surface to apical bile surface
    2. Synthesize primary bile acids from lipids and other metabolites
    3. Major primary bile acids are cholic and chenodeoxycholic acids
    4. Intestinal bacterial hydroxylate primary acids to form secondary bile acids
    5. Secondary bile acids include deoxycholic and lithocholic acids
  2. Bile acids have hydrophilic and hydrophobic domains
    1. Allows them to act as detergents
    2. Important for absorption of fat-soluble vitamins and lipids
  3. Bile salts and other biliary constituents concentrated in bile canaliculi
  4. Major transporter systems have been well studied in hepatocytes
  5. Basolateral (blood side) Channels and Transporters
    1. Na+/K+ ATPase
    2. K+ channel
    3. Na+/H+ exchanger (isoform 1)
    4. Na+/HCO3- transporter
    5. Na+ taurocholate cotransporter - conjugated bile salt uptake
    6. Organic anion-transporting polypeptide - amphipathic organic solutes
  6. Canalicular (bile side) Membrane Channels and Transporters
    1. Cl-/HCO3- Antiporter (anion exchanger, isorform 2)
    2. Cl- channel
    3. Multidrug resistance 1 P glycoprotein (MDR1) - organic cations, xenobiotics, cytotoxins
    4. Multidrug resistance 3 P glycoprotein (MDR3) - phospholipid transporter
    5. MDR associated protein 2 (MRP2) - organic anion transporter, conjugated bilirubin
    6. Canalicular bile-Salt Export Pump (BSEP, sister of P-glycoprotein, SPGP)
    7. Glutathione (GSH) transporter - into bile, stimulates bile flow independent of bile salts
  7. Cholangiocyte transporters are less well understood
    1. Cystic Fibrosis Transmembrane Regulator (CFTR) - apical chloride channel
    2. Cl-/HCO3- Antiporter
    3. Organic-solute transporters
  8. Bilirubin Metabolism [3,6]
    1. Most bilirubin from hemoglobin breakdown from red blood cells (RBC)
    2. Heme moiety is degraded by heme oxygenase yielding biliverdin and carbon monoxide
    3. Biliverdin is reduced to bilirubin by biliverdin reductase
    4. Bilirubin enters the liver and normally undergoes conjugation so it can be excreted
    5. Conjugated bilirubin enters intestinal lumin
    6. Bacteria can deconjugate bilirubin in the intestine leading to reabsorption
    7. This liver-intestine cycle is called enterohepatic recirculation
    8. Jaundice is due to failure to sufficiently excrete bilirubin
    9. Jaundice usually defined as serum bilirubin >2.5-3mg/dL along with clinical appearance

B. Liver Damage in Chronic Cholestasis [2]navigator

  1. Due to effects of high levels of hydrophobic bile acids in liver
  2. Lithocholic acid and precursor chenodeoxycholic acid are hepatotoxic
  3. Likely cause disruption of hepatocyte membranes [16]
    1. Both apoptosis and necrosis occur
    2. Toxic bile salts appear to induce ligand independent activation of Fas pathway
    3. Caspase 8 is cleaved and activates downstream effector caspases
    4. In addition, Magnesium influex is stimulated, and cathepsin B is activated
    5. Mitochondrial dysfunction also occurs in response to elevated levels of toxic bile salts
    6. Mitochondria release cytochrome c, which activates caspase 9 pathway
  4. Damage also likely contributed by immunologic injury to cholestatic areas
  5. Ursodeoxycholic acid therapy can reduce some of these effects in various diseases

C. Common Symptoms navigator

  1. Pruritus
  2. Jaundice and scleral icterus due to hyperbilirubinemia (bilirubin >3mg/dL) [7]
  3. May progress to cirrhosis
    1. Ascites
    2. Varices
    3. Coagulopathy

D. Differential Diagnosis of Cholestasis [3,7]navigator

  1. Drug Induced Cholestasis
    1. Tetracyclines
    2. Oral contraceptives
    3. Erythromycin
    4. Chlorpromazine
    5. Amoxicillin-clavulanate
    6. Rifampicin
    7. Trimethoprim-sulfamethoxazole
    8. Drug induced granulomatous hepatitis
  2. Gallstones
    1. Chronic gallstones
    2. Acute cholecystitis
    3. Acute bacterial (ascending) cholangitis
  3. Inflammatory Disease
    1. Primary Biliary Cirrhosis - decrease in Cl-/HCO3- antiporter
    2. Sclerosing Cholangitis - increase in organic anion transporter mRNA
  4. Infectious
    1. Parasitic infection
    2. Secondary syphilis [7]
    3. HIV associated cholangiopathy
    4. Epstein-Barr Virus (very uncommon as primary cholestatic picture)
  5. Biliary Congestion / Obstruction
    1. Biliary Sludge [11]
    2. Post-operative cholestasis
    3. Neoplasm: pancreatic cancer, cholangiocarcinoma [15]
    4. Gallstones (as above) - very common
    5. Parenteral nutrition
    6. Chronic (including home-based) parenteral nutrition [14]
    7. Lymphoma associated cholestasis (bile duct compression) [21]
    8. Increases in MDR 1 and MDR 3 are seen in biliary obstruction
    9. These increases are correlated with serum bilirubin concentrations
  6. Hepatic Steatosis (Fatty Liver) [8,13,19]
    1. Classified as alcoholic or non-alcoholic
    2. Likely most common liver disease overall
    3. Non-alcoholic type mainly associated with obesity and type II diabetes
    4. Metabolic syndrome / type 2 diabetes associated with 4-11X increased fatty liver risk [20]
    5. Other causes: tetracyclines, pregnancy (fatty liver of pregnancy)
    6. All causes are exacerbated by increased alcohol intake
    7. Diagnosis usually by specific ultrasonographic criteria
    8. Ultrasound criteria: hepatorenal echo contrast and liver brightness (required); deep attenuation and vascular blurring also seen
    9. Liver biopsy required for definitive diagnosis
    10. No specific tratment, but diabetes control and weight loss strongly advocated
  7. Pregnancy-Related
    1. Hyperemesis Gravidarum
    2. Intrahepatic cholestasis of pregnancy
    3. Primary biliary cirrhosis
    4. Gallstones may occur as well (usually with severe pain)
  8. Familial [1]
    1. Progressive Familial Intrahepatic Cholestasis (PFIC) - 3 types
    2. PFIC Type 1: mutation in P type ATPase, chromosome 18q21-22
    3. PFIC Type 2: mutation in sister of P-glycoprotein (SPGP) chromosome 2q24
    4. PFIC Type 3: mutation in MDR 3 chromosome 7q21
    5. Benign recurrent intrahepatic cholestasis - mutation in P type ATPase, PFIC 1 locus
    6. Extrahepatic Biliary Atresia - increase in organic anion transporter
  9. Biliary Atresia
    1. Congenital malformation of unknown cause
    2. All or part of extrahepatic bile ducts are obliterated
    3. ~25% of cases have biliary splenic malformation
    4. Fatal if not treated
    5. Frequency is about 1 in 16,700 live births
    6. Kasai portoenterostomy is the surgical treatment of choice
    7. Ten year survival is >90% if the procedure is done properly
  10. Vanishing Bile-Duct Syndrome [21]
    1. Rare entity with progressive loss of small intrahepatic bile ducts
    2. Cholestasis with marked progressive hyperbilirubinemia, modest enzyme increases
    3. Progressive disease and often death
    4. Associated with immune, infectious, vascular, or paraneoplastic diseases
    5. Also associated with adverse drug effects
    6. Clear association with Hodgkin lymphoma, likely paraneoplastic (tumor mass not found)
  11. Idiopathic [2]
    1. Congenital ductopenia (Alagille's syndrome)
    2. Acquired Ductopenia
    3. Histology shows decrease in intrahepatic bile ducts in >50% of portal tracts
    4. Cholestatic features, marked fibrosis or cirrhosis

E. Laboratory Evaluation navigator

  1. Alkaline Phosphatase Elevations
    1. Usually with little or no AST, ALT elevations
    2. Liver (heat stable) and bone (heat labile) produce most of body's alkaline phosphate
    3. Gallstone Related - Cholelithiasis usually with jaundice, acute cholecystitis
    4. Inflammatory disease - primary biliary cirrhosis, sclerosing cholangitis
    5. Steatosis: fatty liver (see above) [18,19]
    6. Cholangiocarcinoma
    7. Granulomatous diseases produce heat labile alkaline phosphatase (such as sarcoid)
  2. 5'-Nucleotidase (5'NT)
    1. 5'NT is highly specific for liver cholestasis (obstruction)
    2. Produced by biliary ductal cells; not produced by bone
    3. Currently recommended for identifying etiology of alkaline phosphatase elevations
  3. Gamma-glutamyl transferase (GGT)
    1. Generally less specific than 5'NT and is inducible with many drugs
    2. GGT levels very low in PFIC Type 1, elevated in PFIC Type 3
  4. Bilirubin [3]
    1. Direct bilirubin measures conjugated (glucuronidated) form
    2. Cholestatic liver disease is characterized by elevated conjugated bilirubin
    3. Indirect bilirubin elevations are due to increased heme loads (usually due to hemolysis)
    4. Highly elevated bilirubin levels always have direct and indirect components
    5. Direct bilirubin >50% of total is usually due to liver dysfunction
  5. Other Measures of Liver Function
    1. Prothrombin Time - measures mainly Factor VII production by liver (synthetic function)
    2. Albumin - measures synthetic function over longer period (t1/2 about 2 weeks)
    3. Transferrin - levels can reflect 2-3 day synthetic function (also acute phase reactant)
  6. Autoantibodies
    1. Primary biliary cirrhosis - ~95% ANA+, usually with anti-mitochondrial antibodies
    2. Sclerosing cholangitis - 70% p-ANCA+, ~25% ANA+ (often found with IBD)
  7. Neoplasia Differential [15]
    1. Insulin-like growth factor 1 (IGF-1) levels elevated in cholangiocarcioma
    2. Biliary IGF-1 highly elevated in cholangiocarciona but not in pancreatic cancer or gallstones
    3. Serum vascular endothelial growth factor (VEGF) levels about 3X elevated in either cancer compared with benign biliary abnormalities
  8. Livery biopsy may be required to confirm diagnosis and assess chronic damage [17]

F. Post-Operative Cholestasisnavigator

  1. Presentation
    1. Jaundice; bilirubin may be quite high (>10mg/dL; primarily direct)
    2. Low level transaminase elevation
    3. Mild alkaline phosphatase and amylase increase
    4. Pruritis may be prominant
  2. Etiology
    1. Hypotension / Hypoxia during anesthesia
    2. Intravascular volume depletion
    3. High bilirubin loads from blood transfusions and hemolysis
    4. Biliary sludge likely plays a role in cholestasis [11]
    5. Nothing by mouth (NPO) and/or TPN - both cause gall bladder stasis
  3. Treatment
    1. Supportive care
    2. Cholestyramine for removal of bilirubin
    3. Cholecystokinin or amino acids IV to improve gall bladder emptying [11]
    4. Naloxone may improve pruritis associated with cholestasis [10]

G. Biliary Sludge [11]navigator

  1. Clinical Symptoms
    1. Abdominal Pain
    2. Pancreatitis
    3. Progression to gallstones
    4. Cholecystitis
  2. Composition
    1. Cholesterol monohydrate crystals and/or calcium bilirubinate granules
    2. These are suspended in gallbladder mucus along with various proteins
    3. Ceftriaxone, a cephalosporin antibiotic, can also be a component of sludge
    4. Bilirubin usually found in unconjugated, least soluble form as calcium salt
    5. In patients on total parenteral nutrition, sludge has mainly calcium bilirubinate
    6. In pregnant women, cholesterol monohydrate crystals predominante
    7. Specific biliary proteins may play a role in increasing cohesion / viscosity
  3. Risk Factors
    1. Pathogenesis of sludge similar to gallstones
    2. Critical Illness
    3. Fasting for 5-10 days can induce sludge
    4. Parenteral nutrition [14] - cholestatic liver disease is common
    5. Pregnancy
    6. Ceftriaxone
    7. Octreotide (somatostatin analog)
    8. Bone marrow transplantation - up to 67% of persons 3-5 days post transplant
  4. Diagnosis
    1. Ultrasonography is usual method for screening
    2. However, standard ultrasound has ~55% sensitivity for sludge
    3. Endoscopic ultrasonography is ~95% sensitive
    4. Direct microscopic examination of sludge is most sensitive and specific method
    5. Sample of gallbladder contents obtained by endoscopy after cholecystokinin (CCK) dose
    6. Gallbladder will dump contents in response to CCK and duodenal aspirates obtained
    7. Sample is prepared and viewd under the microscope for crystals
  5. Clinical Course
    1. About 10% of cases develop gallstones
    2. Abdominal pain occurs in ~50% of patients (may persist for years)
    3. Majority of cases appear to be self resolving
  6. Treatment
    1. Similar to that for gallstones
    2. Only symptomatic patients whould be treated
    3. Reversible factors should be sought and eliminated
    4. Cholecystectomy may be required if sludge persists
    5. Ursodeoxycholic acid may reduce sludge and symptoms [2]
  7. Prevention
    1. Ursodeoxycholic acid (Actigal®) - also reduces risk of gallstones [2]
    2. Cholecystokinin (CCK) - in patients on total parenteral nutrition

H. Biliary Tract Emergenciesnavigator

  1. Entities
    1. Acute Cholecystitis
    2. Ascending Cholangitis
    3. Acute Pancreatitis
  2. Pathophysiology
    1. Occur due to obstruction in biliar treat
    2. Usually caused by stones formed originally in the gall bladder
    3. Stone migration with various duct obstruction
    4. Cystic duct obstruction: cholecystitis
    5. Common bile duct obstruction: cholangitis
    6. Pancreatic duct obstruction: pancreatitis
    7. Neoplastic disease can also extrinsically constrict ducts
  3. Complications
    1. Cholestasis
    2. Liver abscess
    3. Pancreatic pseudocyst, abscess
    4. Complications of therapeutic procedures
  4. Treatment Options [9]
    1. Laparoscopic exploration of common bile duct - as well tolerated as endoscopy
    2. Endoscopic procedures - generally well tolerated; complications depend on disease [4]
    3. Percutaneous drainage procedures
    4. Open surgical procedures
    5. Piperacillin (single dose) prophylaxis does not reduce post-ERCP cholangitis [5]

References navigator

  1. Trauner M, Meier PJ, Boyer JL. 1998. NEJM. 339(17):1217 abstract
  2. Kowdley KV. 2000. Am J Med. 108(6):481 abstract
  3. Roche SP and Kobos. 2004. Am Fam Phys. 69(2):299 abstract
  4. Freeman ML, Nelson DB, Sherman S, et al. 1996. NEJM. 335(13):909 abstract
  5. Van den Hazel SJ, Speelman P, Dankert J, et al. 1996. Ann Intern Med. 125(6):442 abstract
  6. Dennery PA, Seidman DS, Stevenson DK. 2001. NEJM. 344(8):581 abstract
  7. Greenstone CL, Saint S, Moseley RH. 2007. NEJM. 356(23):2407 (Case Discussion) abstract
  8. Tolman KG, Fonseca V, Tan MH, Dalpiaz A. 2004. Ann Intern Med. 141(12):946 abstract
  9. Rhodes M, Sussman L, Cohen L, Lewis MP. 1998. Lancet. 351(9097):159 abstract
  10. Moreno A, Carreno V, Cano A, Gonzalez C. 1997. NEJM. 336(12):835 abstract
  11. Ko CW, Sekijima JH, Lee SP. 1999. Ann Intern Med. 130(4):301 abstract
  12. Joshi N, Caputo GM, Weitekamp MR, Karchmer AW. 1999. NEJM. 341(25):1906 abstract
  13. Bellentani S, Saccoccio G, Masutti F, et al. 2000. Ann Intern Med. 132(2):112 abstract
  14. Cavicchi M, Beau P, Crenn P, et al. 2000. Ann Intern Med. 132(7):525 abstract
  15. Alvaro D, Macarri G, Mancino MG, et al. 2007. Ann Intern Med. 147(7):451 abstract
  16. Rust C and Gores GJ. 2000. Am J Med. 108(7):567 abstract
  17. Bravo AA, Sheth SG, Chopra S. 2001. NEJM. 344(7):495 abstract
  18. Clark JM and Diehl AM. 2003. JAMA. 289(22):3000 abstract
  19. Angulo P. 2002. NEJM. 346(16):1221 abstract
  20. Hamaguchi M, Kojima T, takeda N, et al. 2005. Ann Intern Med. 143(10):723
  21. Schmitt A, Gilden DJ, Saint S, Moseley RH. 2006. NEJM. 354(5):509 (Case Discussion) abstract