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==Diagnosis==
==Diagnosis==
Cholestasis can be suspected when there is an elevation of both [[5'-nucleotidase]] and [[alkaline phosphatase]] (ALP) enzymes. With a few exceptions, the optimal test for cholestasis would be elevations of serum [[bile acid]] levels. However, this is not normally available in most clinical settings. The [[gamma-glutamyl transferase]] (GGT) enzyme was previously thought to be helpful in confirming a hepatic source of ALP; however, GGT elevations lack the necessary specificity to be a useful confirmatory test for ALP. Normally GGT and ALP are anchored to membranes of [[hepatocytes]] and are released in small amounts in hepatocellular damage. In cholestasis, synthesis of these enzymes is induced and they are made soluble. GGT is elevated because it leaks out from the bile duct cells due to pressure from inside bile ducts.{{cn|date=March 2019}} In a later stage of cholestasis [[aspartate transaminase]] (AST), [[alanine transaminase]] (ALT) and [[unconjugated bilirubin]] may be elevated due to hepatocyte damage as a secondary effect of cholestasis.
Cholestasis can be suspected when there is an elevation of both [[5'-nucleotidase]] and [[alkaline phosphatase]] (ALP) enzymes.<ref name=":02">{{Cite book|url=https://www.worldcat.org/oclc/525070586|title=Cholestatic liver disease|date=2008|publisher=Humana|others=Keith D. Lindor, Jayant A. Talwalker|isbn=978-1-59745-118-5|location=Totowa, N.J.|oclc=525070586}}</ref> With a few exceptions, the optimal test for cholestasis would be elevations of serum [[bile acid]] levels.<ref>{{Cite book|last=Neil.|first=McIntyre,|url=http://worldcat.org/oclc/23766801|title=Oxford textbook of clinical hepatology|date=1991|publisher=Oxford University Press|isbn=0-19-261968-3|oclc=23766801}}</ref> However, this is not normally available in most clinical settings, thus necessitating the use of other biomarkers. If 5’ nucleosidase and ALP enzymes are elevated, imaging studies are used to differentiate intrahepatic cholestasis from extrahepatic cholestasis.<ref name=":02" /> Common imaging techniques include [[CT scan|computed tomography]] (CT) scan, [[ultrasound]], and [[magnetic resonance imaging]] (MRI). After this, additional imaging, laboratory testing, and biopsies may be conducted to identify the cause and extent of cholestasis.<ref name=":02" />

=== Biomarkers ===
ALP enzymes are found abundantly within the bile canaliculi and bile. If a duct is obstructed, tight junctions permit migration of the ALP enzymes until the polarity is reversed and the enzymes are found on the whole of the cell membrane.<ref name=":02" /> Serum ALP levels exceeding 2-3 times the upper baseline value may be due to a variety of liver diseases.<ref name=":12">{{Cite book|last=Claude.|first=Cecil, Russell L. (Russell La Fayette), 1881-1965. Goldman, Lee (Physician) Bennett, J.|url=http://worldcat.org/oclc/45544383|title=Cecil textbook of medicine.|date=2000|publisher=W.B. Saunders|isbn=0-7216-7996-X|oclc=45544383}}</ref> However, an elevation that exceeds 10 times the upper baseline limit is strongly indicative of either intrahepatic or extrahepatic cholestasis and requires further investigation.<ref name=":12" /> Cholestasis can be differentiated from other liver disorders by measuring the proportion of ALP to serum aminotransferases, where a greater proportion indicates a higher likelihood of cholestasis.<ref name=":02" /> Typically, aminotransferase enzymes are localized within hepatocytes and leak across the membrane upon damage.<ref>{{Cite journal|last=McGill|first=Mitchell R.|date=2016-12-15|title=The past and present of serum aminotransferases and the future of liver injury biomarkers|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318690/|journal=EXCLI Journal|volume=15|pages=817–828|doi=10.17179/excli2016-800|issn=1611-2156|pmc=5318690|pmid=28337112}}</ref> However, measurement of serum aminotransferase levels alone is not a good marker to determine cholestasis. In up to a third of patients, ALP levels may be elevated without the presence of cholestasis.<ref name=":12" /> As such, other biomarkers should be measured to corroborate findings.

Measurement of 5’ nucleosidase levels may be used to identify cholestasis in conjunction with ALP. 5’ nucleosidase is highly expressed on the sinusoidal and canalicular membranes of the liver.<ref name=":02" /> Whereas levels of ALP may rise within a few hours after the onset of cholestasis, 5’ nucleosidase levels may take a few days.<ref>{{Cite journal|date=1967-10|title=AN ASSESSMENT OF 5′-NUCLEOTIDASE AS A LIVER-FUNCTION TEST|url=http://dx.doi.org/10.1093/oxfordjournals.qjmed.a067123|journal=QJM: An International Journal of Medicine|doi=10.1093/oxfordjournals.qjmed.a067123|issn=1460-2393}}</ref> Given that many labs cannot measure 5’ nucleosidase and ALP levels, [[Gamma-glutamyltransferase|gamma-glutamyl transferase]] (GGT) may be measured in some cases.<ref name=":02" /> Abnormal GGT elevation may be attributable to a variety of factors.<ref>{{Cite journal|last=Gowda|first=Shivaraj|last2=Desai|first2=Prakash B.|last3=Hull|first3=Vinayak V.|last4=Math|first4=Avinash A. K.|last5=Vernekar|first5=Sonal N.|last6=Kulkarni|first6=Shruthi S.|date=2009-11-22|title=A review on laboratory liver function tests|url=https://pubmed.ncbi.nlm.nih.gov/21532726|journal=The Pan African Medical Journal|volume=3|pages=17|issn=1937-8688|pmc=2984286|pmid=21532726}}</ref> As such, GGT elevations lack the necessary specificity to be a useful confirmatory test for cholestasis.<ref name=":02" />

[[Bilirubin]] is made through the breakdown of red blood cells and maybe in the unconjugated or conjugated form, depending on if it is bound to a protein.<ref>{{Cite journal|last=Fevery|first=Johan|date=2008-04-10|title=Bilirubin in clinical practice: a review: Bilirubin in clinical practice|url=https://onlinelibrary.wiley.com/doi/10.1111/j.1478-3231.2008.01716.x|journal=Liver International|language=en|volume=28|issue=5|pages=592–605|doi=10.1111/j.1478-3231.2008.01716.x}}</ref> Bilirubin is excreted into the bile in the conjugated form. An abnormal elevation of bilirubin (hyperbilirubinemia) may be a result of low bilirubin reuptake, overproduction, or a variety of other factors.<ref name=":02" /> Importantly, conjugated hyperbilirubinemia is present in 80% of patients with extrahepatic cholestasis and 50% of patients with intrahepatic cholestasis.<ref name=":12" /> Given that many patients with hyperbilirubinemia may not have cholestasis, the measurement of bilirubin levels is not a good diagnostic tool for identifying cholestasis.<ref name=":02" /> In a later stage of cholestasis [[aspartate transaminase]] (AST), [[alanine transaminase]] (ALT) and [[unconjugated bilirubin]] may be elevated due to hepatocyte damage as a secondary effect of cholestasis.

=== Imaging ===
After determination using biomarkers, a variety of imaging studies may be used to differentiate between intrahepatic or extrahepatic cholestasis. Ultrasound is often used to identify the location of the obstruction.<ref>{{Cite journal|last=Pérez Fernández|first=T.|last2=López Serrano|first2=P.|last3=Tomás|first3=E.|last4=Gutiérrez|first4=Mª L.|last5=Lledó|first5=J. L.|last6=Cacho|first6=G.|last7=Santander|first7=C.|last8=Fernández Rodríguez|first8=C. M.|date=2004-01|title=Diagnostic and therapeutic approach to cholestatic liver disease|url=http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S1130-01082004000100008&lng=en&nrm=iso&tlng=en|journal=Revista Española de Enfermedades Digestivas|language=en|volume=96|issue=1|doi=10.4321/S1130-01082004000100008|issn=1130-0108}}</ref> Typically, patients should be fasting to enlarge the gall bladder to better visualize the blockage location.<ref name=":02" /> Ultrasound is often insufficient in determining the level of biliary obstruction or its cause, given that it is prone to picking up bowel gas which may interfere with readings.<ref name=":02" /><ref>{{Cite journal|last=Andrzejewska|first=Magdalena|last2=Grzymisławski|first2=Marian|date=2018|title=The role of intestinal ultrasound in diagnostics of bowel diseases|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894446/|journal=Przegla̜d Gastroenterologiczny|volume=13|issue=1|pages=1–5|doi=10.5114/pg.2018.74554|issn=1895-5770|pmc=5894446|pmid=29657604}}</ref> CT scans are not impacted by bowel gas and may be more suitable for overweight patients.<ref name=":02" /> Typically, the cause of cholestasis and magnitude of obstruction is better diagnosed with CT compared to ultrasound.<ref>{{Cite journal|last=Reddy|first=Sarathchandra I|last2=Grace|first2=Norman D|date=2002-02|title=Liver imaging: A hepatologist's perspective|url=http://dx.doi.org/10.1016/s1089-3261(03)00077-1|journal=Clinics in Liver Disease|volume=6|issue=1|pages=297–310|doi=10.1016/s1089-3261(03)00077-1|issn=1089-3261}}</ref> MRI scans provide similar information to CT scans but are more prone to interference from breathing or other bodily functions.<ref>{{Cite journal|last=Ladd|first=Mark E.|last2=Bachert|first2=Peter|last3=Meyerspeer|first3=Martin|last4=Moser|first4=Ewald|last5=Nagel|first5=Armin M.|last6=Norris|first6=David G.|last7=Schmitter|first7=Sebastian|last8=Speck|first8=Oliver|last9=Straub|first9=Sina|last10=Zaiss|first10=Moritz|date=2018-12|title=Pros and cons of ultra-high-field MRI/MRS for human application|url=https://linkinghub.elsevier.com/retrieve/pii/S007965651830013X|journal=Progress in Nuclear Magnetic Resonance Spectroscopy|language=en|volume=109|pages=1–50|doi=10.1016/j.pnmrs.2018.06.001}}</ref>

Although CT, ultrasound, and MRI may help differentiate intrahepatic and extrahepatic cholestasis, the cause and extent of obstruction is best determined by [[cholangiography]].<ref name=":02" /> Potential causes of extrahepatic cholestasis include obstructions outside the wall of the lumen, those outside the duct, and obstructions found in the duct lumen.<ref name=":02" /> Endoscopic retrograde cholangiography may be useful to visualize the extrahepatic biliary ducts.<ref>{{Cite journal|last=Singla|first=Sumit|last2=Piraka|first2=Cyrus|date=2014-12|title=Endoscopic retrograde cholangiopancreatography|url=http://dx.doi.org/10.1002/cld.441|journal=Clinical Liver Disease|volume=4|issue=6|pages=133–137|doi=10.1002/cld.441|issn=2046-2484}}</ref> In case of anatomical anomalies, or if endoscopic retrograde cholangiography is unsuccessful, percutaneous transhepatic cholangiography may be used.<ref name=":02" /> CT or MRI-based cholangiography may also be useful, particularly in cases where additional interventions are not anticipated.<ref name=":02" />


===Histopathology===
===Histopathology===

Revision as of 05:37, 3 November 2021

Cholestasis
Micrograph showing bile (yellow) stasis in liver tissue, i.e. cholestasis. H&E stain.
SpecialtyGastroenterology

Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malignancy, and metabolic types of cholestasis which are disturbances in bile formation that can occur because of genetic defects or acquired as a side effect of many medications.

Signs and symptoms

  • Itchiness (pruritus). Pruritus is the primary symptom of cholestasis and is thought to be due to interactions of serum bile acids with opioidergic nerves. In fact, the opioid antagonist naltrexone is used to treat pruritus due to cholestasis.
  • Jaundice. Jaundice is an uncommon occurrence in intrahepatic (metabolic) cholestasis, but is common in obstructive cholestasis.
  • Pale stool. This symptom implies obstructive cholestasis.
  • Dark urine[citation needed]

Causes

Possible causes:

Drugs such as gold salts, nitrofurantoin, anabolic steroids, chlorpromazine, prochlorperazine, sulindac, cimetidine, erythromycin, estrogen, and statins can cause cholestasis and may result in damage to the liver.[citation needed]

Mechanism

Bile is secreted by the liver to aid in the digestion of fats. Bile formation begins in bile canaliculi that form between two adjacent surfaces of liver cells (hepatocytes) similar to the terminal branches of a tree. The canaliculi join each other to form larger and larger structures, sometimes referred to as the canals of Hering, which themselves join to form small bile ductules that have an epithelial surface. The ductules join to form bile ducts that eventually form either the right main hepatic duct that drains the right lobe of the liver, or the left main hepatic duct draining the left lobe of the liver. The two ducts join to form the common hepatic duct, which in turn joins the cystic duct from the gall bladder, to give the common bile duct. This duct then enters the duodenum at the ampulla of Vater.

In cholestasis, bile accumulates in the hepatic parenchyma.[1]

Diagnosis

Cholestasis can be suspected when there is an elevation of both 5'-nucleotidase and alkaline phosphatase (ALP) enzymes.[2] With a few exceptions, the optimal test for cholestasis would be elevations of serum bile acid levels.[3] However, this is not normally available in most clinical settings, thus necessitating the use of other biomarkers. If 5’ nucleosidase and ALP enzymes are elevated, imaging studies are used to differentiate intrahepatic cholestasis from extrahepatic cholestasis.[2] Common imaging techniques include computed tomography (CT) scan, ultrasound, and magnetic resonance imaging (MRI). After this, additional imaging, laboratory testing, and biopsies may be conducted to identify the cause and extent of cholestasis.[2]

Biomarkers

ALP enzymes are found abundantly within the bile canaliculi and bile. If a duct is obstructed, tight junctions permit migration of the ALP enzymes until the polarity is reversed and the enzymes are found on the whole of the cell membrane.[2] Serum ALP levels exceeding 2-3 times the upper baseline value may be due to a variety of liver diseases.[4] However, an elevation that exceeds 10 times the upper baseline limit is strongly indicative of either intrahepatic or extrahepatic cholestasis and requires further investigation.[4] Cholestasis can be differentiated from other liver disorders by measuring the proportion of ALP to serum aminotransferases, where a greater proportion indicates a higher likelihood of cholestasis.[2] Typically, aminotransferase enzymes are localized within hepatocytes and leak across the membrane upon damage.[5] However, measurement of serum aminotransferase levels alone is not a good marker to determine cholestasis. In up to a third of patients, ALP levels may be elevated without the presence of cholestasis.[4] As such, other biomarkers should be measured to corroborate findings.

Measurement of 5’ nucleosidase levels may be used to identify cholestasis in conjunction with ALP. 5’ nucleosidase is highly expressed on the sinusoidal and canalicular membranes of the liver.[2] Whereas levels of ALP may rise within a few hours after the onset of cholestasis, 5’ nucleosidase levels may take a few days.[6] Given that many labs cannot measure 5’ nucleosidase and ALP levels, gamma-glutamyl transferase (GGT) may be measured in some cases.[2] Abnormal GGT elevation may be attributable to a variety of factors.[7] As such, GGT elevations lack the necessary specificity to be a useful confirmatory test for cholestasis.[2]

Bilirubin is made through the breakdown of red blood cells and maybe in the unconjugated or conjugated form, depending on if it is bound to a protein.[8] Bilirubin is excreted into the bile in the conjugated form. An abnormal elevation of bilirubin (hyperbilirubinemia) may be a result of low bilirubin reuptake, overproduction, or a variety of other factors.[2] Importantly, conjugated hyperbilirubinemia is present in 80% of patients with extrahepatic cholestasis and 50% of patients with intrahepatic cholestasis.[4] Given that many patients with hyperbilirubinemia may not have cholestasis, the measurement of bilirubin levels is not a good diagnostic tool for identifying cholestasis.[2] In a later stage of cholestasis aspartate transaminase (AST), alanine transaminase (ALT) and unconjugated bilirubin may be elevated due to hepatocyte damage as a secondary effect of cholestasis.

Imaging

After determination using biomarkers, a variety of imaging studies may be used to differentiate between intrahepatic or extrahepatic cholestasis. Ultrasound is often used to identify the location of the obstruction.[9] Typically, patients should be fasting to enlarge the gall bladder to better visualize the blockage location.[2] Ultrasound is often insufficient in determining the level of biliary obstruction or its cause, given that it is prone to picking up bowel gas which may interfere with readings.[2][10] CT scans are not impacted by bowel gas and may be more suitable for overweight patients.[2] Typically, the cause of cholestasis and magnitude of obstruction is better diagnosed with CT compared to ultrasound.[11] MRI scans provide similar information to CT scans but are more prone to interference from breathing or other bodily functions.[12]

Although CT, ultrasound, and MRI may help differentiate intrahepatic and extrahepatic cholestasis, the cause and extent of obstruction is best determined by cholangiography.[2] Potential causes of extrahepatic cholestasis include obstructions outside the wall of the lumen, those outside the duct, and obstructions found in the duct lumen.[2] Endoscopic retrograde cholangiography may be useful to visualize the extrahepatic biliary ducts.[13] In case of anatomical anomalies, or if endoscopic retrograde cholangiography is unsuccessful, percutaneous transhepatic cholangiography may be used.[2] CT or MRI-based cholangiography may also be useful, particularly in cases where additional interventions are not anticipated.[2]

Histopathology

Under a microscope, the individual hepatocytes will have a brownish-green stippled appearance within the cytoplasm, representing bile that cannot get out of the cell. Canalicular bile plugs between individual hepatocytes or within bile ducts may also be seen, representing bile that has been excreted from the hepatocytes but cannot go any further due to the obstruction. When these plugs occur within the bile duct, sufficient pressure (caused by bile accumulation) can cause them to rupture, spilling bile into the surrounding tissue, causing hepatic necrosis. These areas are known as bile lakes, and are typically seen only with extra-hepatic obstruction.[citation needed]

Management

Extrahepatic cholestasis can usually be treated by surgery. Pruritus in cholestatic jaundice is treated by antihistamines, ursodeoxycholic acid, and phenobarbital. Nalfurafine hydrochloride can also treat pruritus caused by chronic liver disease and was recently approved in Japan for this purpose.[citation needed]

See also

References

  1. ^ Kumar (2015). Robbins and Cotran Pathologic Basis of Disease (9 ed.). Elsevier. pp. 821–881.
  2. ^ a b c d e f g h i j k l m n o p q Cholestatic liver disease. Keith D. Lindor, Jayant A. Talwalker. Totowa, N.J.: Humana. 2008. ISBN 978-1-59745-118-5. OCLC 525070586.{{cite book}}: CS1 maint: others (link)
  3. ^ Neil., McIntyre, (1991). Oxford textbook of clinical hepatology. Oxford University Press. ISBN 0-19-261968-3. OCLC 23766801.{{cite book}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  4. ^ a b c d Claude., Cecil, Russell L. (Russell La Fayette), 1881-1965. Goldman, Lee (Physician) Bennett, J. (2000). Cecil textbook of medicine. W.B. Saunders. ISBN 0-7216-7996-X. OCLC 45544383.{{cite book}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  5. ^ McGill, Mitchell R. (2016-12-15). "The past and present of serum aminotransferases and the future of liver injury biomarkers". EXCLI Journal. 15: 817–828. doi:10.17179/excli2016-800. ISSN 1611-2156. PMC 5318690. PMID 28337112.
  6. ^ "AN ASSESSMENT OF 5′-NUCLEOTIDASE AS A LIVER-FUNCTION TEST". QJM: An International Journal of Medicine. 1967-10. doi:10.1093/oxfordjournals.qjmed.a067123. ISSN 1460-2393. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Gowda, Shivaraj; Desai, Prakash B.; Hull, Vinayak V.; Math, Avinash A. K.; Vernekar, Sonal N.; Kulkarni, Shruthi S. (2009-11-22). "A review on laboratory liver function tests". The Pan African Medical Journal. 3: 17. ISSN 1937-8688. PMC 2984286. PMID 21532726.
  8. ^ Fevery, Johan (2008-04-10). "Bilirubin in clinical practice: a review: Bilirubin in clinical practice". Liver International. 28 (5): 592–605. doi:10.1111/j.1478-3231.2008.01716.x.
  9. ^ Pérez Fernández, T.; López Serrano, P.; Tomás, E.; Gutiérrez, Mª L.; Lledó, J. L.; Cacho, G.; Santander, C.; Fernández Rodríguez, C. M. (2004-01). "Diagnostic and therapeutic approach to cholestatic liver disease". Revista Española de Enfermedades Digestivas. 96 (1). doi:10.4321/S1130-01082004000100008. ISSN 1130-0108. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Andrzejewska, Magdalena; Grzymisławski, Marian (2018). "The role of intestinal ultrasound in diagnostics of bowel diseases". Przegla̜d Gastroenterologiczny. 13 (1): 1–5. doi:10.5114/pg.2018.74554. ISSN 1895-5770. PMC 5894446. PMID 29657604.
  11. ^ Reddy, Sarathchandra I; Grace, Norman D (2002-02). "Liver imaging: A hepatologist's perspective". Clinics in Liver Disease. 6 (1): 297–310. doi:10.1016/s1089-3261(03)00077-1. ISSN 1089-3261. {{cite journal}}: Check date values in: |date= (help)
  12. ^ Ladd, Mark E.; Bachert, Peter; Meyerspeer, Martin; Moser, Ewald; Nagel, Armin M.; Norris, David G.; Schmitter, Sebastian; Speck, Oliver; Straub, Sina; Zaiss, Moritz (2018-12). "Pros and cons of ultra-high-field MRI/MRS for human application". Progress in Nuclear Magnetic Resonance Spectroscopy. 109: 1–50. doi:10.1016/j.pnmrs.2018.06.001. {{cite journal}}: Check date values in: |date= (help)
  13. ^ Singla, Sumit; Piraka, Cyrus (2014-12). "Endoscopic retrograde cholangiopancreatography". Clinical Liver Disease. 4 (6): 133–137. doi:10.1002/cld.441. ISSN 2046-2484. {{cite journal}}: Check date values in: |date= (help)

External links

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