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==Overview==
==Overview==
It has long been noted that gallbladder stone formation, and in particular cholesterol stones, are associated with bile supersaturation, and this still remains the most common cause for gallstone formation.<ref name="pmid17981556">{{cite journal |vauthors=Wang HH, Portincasa P, Wang DQ |title=Molecular pathophysiology and physical chemistry of cholesterol gallstones |journal=Front. Biosci. |volume=13 |issue= |pages=401–23 |year=2008 |pmid=17981556 |doi= |url=}}</ref>
 
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 in take of wine and the concumption of whole grain bread may decrease the risk of developing gallstones.<ref>{{cite journal |year=1995 |month=June |title=. |journal=European Journal Gastroenterology & Hepatology |volume=6 |pages=585-593 |accessdate= 2007-08-25}}</ref>


== Pathophysiology ==
== Pathophysiology ==
 
The most common type of gallstone is a cholesterol stone. 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. <ref name="pmid22570746">{{cite journal |vauthors=Stinton LM, Shaffer EA |title=Epidemiology of gallbladder disease: cholelithiasis and cancer |journal=Gut Liver |volume=6 |issue=2 |pages=172–87 |year=2012 |pmid=22570746 |pmc=3343155 |doi=10.5009/gnl.2012.6.2.172 |url=}}</ref><ref name="pmid12242178">{{cite journal |vauthors=Indar AA, Beckingham IJ |title=Acute cholecystitis |journal=BMJ |volume=325 |issue=7365 |pages=639–43 |year=2002 |pmid=12242178 |pmc=1124163 |doi= |url=}}</ref><ref>{{cite book | last = McPhee | first = Stephen | title = Pathophysiology of disease : an introduction to clinical medicine | publisher = McGraw-Hill Education Medical | location = New York | year = 2014 | isbn = 0071806008 }}</ref> <ref name="pmid17981556">{{cite journal |vauthors=Wang HH, Portincasa P, Wang DQ |title=Molecular pathophysiology and physical chemistry of cholesterol gallstones |journal=Front. Biosci. |volume=13 |issue= |pages=401–23 |year=2008 |pmid=17981556 |doi= |url=}}</ref>
In general, gallstone disease can 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. Rarely, the gallbladder may not fill properly with bile and so the bile is diverted from the gallbladder to the small bile duct. This exacerbates the hypomotility and accelerates stone formation.<ref name="pmid22570746">{{cite journal |vauthors=Stinton LM, Shaffer EA |title=Epidemiology of gallbladder disease: cholelithiasis and cancer |journal=Gut Liver |volume=6 |issue=2 |pages=172–87 |year=2012 |pmid=22570746 |pmc=3343155 |doi=10.5009/gnl.2012.6.2.172 |url=}}</ref><ref name="pmid12242178">{{cite journal |vauthors=Indar AA, Beckingham IJ |title=Acute cholecystitis |journal=BMJ |volume=325 |issue=7365 |pages=639–43 |year=2002 |pmid=12242178 |pmc=1124163 |doi= |url=}}</ref><ref>{{cite book | last = McPhee | first = Stephen | title = Pathophysiology of disease : an introduction to clinical medicine | publisher = McGraw-Hill Education Medical | location = New York | year = 2014 | isbn = 0071806008 }}</ref> The most common stone formed is made of cholesterol.  


===Pathogenesis of Specific Stones===
===Pathogenesis of Specific Stones===


====Cholesterol Stones====
====Cholesterol Stones====
* Cholesterol is an important organic molecule that is needed for incorporation within cell membranes and to produce steroid hormones in the body.  
*Cholesterol stones are the most common type of gallstone.
* The quantity of cholesterol must be balanced internally, when cholesterol if in excess the only way in which the body can rid itself of it is through the formation of bile.  
*Cholesterol is an important organic molecule that is needed for incorporation within cell membranes and to produce steroid hormones in the body.  
* The process of cholesterol gallstones formation begins with the presence of biliary sludge.<ref name="pmid22570746">{{cite journal |vauthors=Stinton LM, Shaffer EA |title=Epidemiology of gallbladder disease: cholelithiasis and cancer |journal=Gut Liver |volume=6 |issue=2 |pages=172–87 |year=2012 |pmid=22570746 |pmc=3343155 |doi=10.5009/gnl.2012.6.2.172 |url=}}</ref>  
*The quantity of cholesterol is balanced within the body.
** Biliary sludge is a viscous mixture that consists of glycoproteins, calcium deposits and cholesterol crystals in the gallbladder.
*When there is excess cholesterol in the body, the body will dispose of it by secreting it into the bile.
** Biliary sludge forms when anti-nucleating (crystallization-inhibiting) defence mechanisms fail to prevent cholesterol from precipitating or '''crystallizing''' in the bile whilst pro-nucleating (crystallization-promoting) mechanisms take the upper hand.
*When the cholesterol concentration reachs a certain level beyond that that can be secreted into the bile, biliary sludge will start to form.
** The sludge becomes hypersaturated and eventually stones form.<ref name="pmid17547709">{{cite journal |vauthors=Marschall HU, Einarsson C |title=Gallstone disease |journal=J. Intern. Med. |volume=261 |issue=6 |pages=529–42 |year=2007 |pmid=17547709 |doi=10.1111/j.1365-2796.2007.01783.x |url=}}</ref><ref name="pmid18579815">{{cite journal |vauthors=Strasberg SM |title=Clinical practice. Acute calculous cholecystitis |journal=N. Engl. J. Med. |volume=358 |issue=26 |pages=2804–11 |year=2008 |pmid=18579815 |doi=10.1056/NEJMcp0800929 |url=}}</ref>
*Biliary sludge is a viscous mixture that consists of mucin glycoproteins, calcium deposits and cholesterol crystals in the gallbladder.
*Over time, this sludge becomes more and more concentrated with cholesterol and eventually stones form.<ref name="pmid22570746">{{cite journal |vauthors=Stinton LM, Shaffer EA |title=Epidemiology of gallbladder disease: cholelithiasis and cancer |journal=Gut Liver |volume=6 |issue=2 |pages=172–87 |year=2012 |pmid=22570746 |pmc=3343155 |doi=10.5009/gnl.2012.6.2.172 |url=}}</ref><ref name="pmid17547709">{{cite journal |vauthors=Marschall HU, Einarsson C |title=Gallstone disease |journal=J. Intern. Med. |volume=261 |issue=6 |pages=529–42 |year=2007 |pmid=17547709 |doi=10.1111/j.1365-2796.2007.01783.x |url=}}</ref><ref name="pmid18579815">{{cite journal |vauthors=Strasberg SM |title=Clinical practice. Acute calculous cholecystitis |journal=N. Engl. J. Med. |volume=358 |issue=26 |pages=2804–11 |year=2008 |pmid=18579815 |doi=10.1056/NEJMcp0800929 |url=}}</ref>
 


====Pigment Stones====
====Pigment Stones====
* Occasionally, gallstones are composed of bilirubin and are sometimes referred to as "pigment stones".  
*Less commonly, gallstones can be composed of bilirubin and are sometimes referred to as "pigment stones".  
* Bilirubin is a byproduct of red blood cell breakdown and these stones are formed via two main pathways:
*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:
** An infection of the biliary tract which predisposes to stone formation.
  **Infection of the biliary tree with bacteria that can release hydrolytic enzymes and form insoluble calcium salts.
** Bile, which is normally recycled after its secretion back from the small bowel and to the liver, may be enterohepatically cycled extensively. This may also cause the formation of a bilirubin stone. Pigment stones are seen more often in the Asian and African continents.<ref name="pmid11930198">{{cite journal |vauthors=Myers RP, Shaffer EA, Beck PL |title=Gallbladder polyps: epidemiology, natural history and management |journal=Can. J. Gastroenterol. |volume=16 |issue=3 |pages=187–94 |year=2002 |pmid=11930198 |doi= |url=}}</ref>
  **Nonbacterial, nonenzymatic hydrolysis of bilirubin conjugates such as what may happen in patients with Gilbert's syndrome and chronic hemolysis.<ref name="pmid2022417">{{cite journal |vauthors=Trotman BW |title=Pigment gallstone disease |journal=Gastroenterol. Clin. North Am. |volume=20 |issue=1 |pages=111–26 |year=1991 |pmid=2022417 |doi= |url=}}</ref>


====Mixed Stones====
====Mixed Stones====


There is a lack of evidence that supports a true pathology to explain how mixed stones are formed. However, there have been theories that include a combination of the mechanisms mentioned above.<ref name="pmid12242178">{{cite journal |vauthors=Indar AA, Beckingham IJ |title=Acute cholecystitis |journal=BMJ |volume=325 |issue=7365 |pages=639–43 |year=2002 |pmid=12242178 |pmc=1124163 |doi= |url=}}</ref>  
There is a lack of evidence that supports a true pathology to explain how mixed stones are formed. However, there have been theories that include a combination of the mechanisms including supersaturation, infection and hypomotility of the gallbladder.<ref name="pmid12242178">{{cite journal |vauthors=Indar AA, Beckingham IJ |title=Acute cholecystitis |journal=BMJ |volume=325 |issue=7365 |pages=639–43 |year=2002 |pmid=12242178 |pmc=1124163 |doi= |url=}}</ref>  
   
   


Line 58: Line 61:
**[[Vitamin C]]<ref name="pmid29158491">{{cite journal |vauthors=Lv J, Yu C, Guo Y, Bian Z, Yang L, Chen Y, Li S, Huang Y, Fu Y, He P, Tang A, Chen J, Chen Z, Qi L, Li L |title=Gallstone Disease and the Risk of Type 2 Diabetes |journal=Sci Rep |volume=7 |issue=1 |pages=15853 |year=2017 |pmid=29158491 |doi=10.1038/s41598-017-14801-2 |url=}}</ref><ref>{{cite journal |author=R.M. Ortega |coauthors=M. Fernandez-Azuela, A. Encinas-Sotillos, P. Andres, and A. M. Lopez-Sobaler |year=1997 |month=February |title=Differences in diet and food habits between patients with gallstones and controls |journal=Journal of the American College of Nutrition |volume= 16 |pages=88-95 |accessdate= 2007-08-25}}</ref>  
**[[Vitamin C]]<ref name="pmid29158491">{{cite journal |vauthors=Lv J, Yu C, Guo Y, Bian Z, Yang L, Chen Y, Li S, Huang Y, Fu Y, He P, Tang A, Chen J, Chen Z, Qi L, Li L |title=Gallstone Disease and the Risk of Type 2 Diabetes |journal=Sci Rep |volume=7 |issue=1 |pages=15853 |year=2017 |pmid=29158491 |doi=10.1038/s41598-017-14801-2 |url=}}</ref><ref>{{cite journal |author=R.M. Ortega |coauthors=M. Fernandez-Azuela, A. Encinas-Sotillos, P. Andres, and A. M. Lopez-Sobaler |year=1997 |month=February |title=Differences in diet and food habits between patients with gallstones and controls |journal=Journal of the American College of Nutrition |volume= 16 |pages=88-95 |accessdate= 2007-08-25}}</ref>  


On the other hand, wine and whole grain bread may decrease the risk of gallstones.<ref>{{cite journal |year=1995 |month=June |title=. |journal=European Journal Gastroenterology & Hepatology |volume=6 |pages=585-593 |accessdate= 2007-08-25}}</ref>


==Gross Pathology==
==Gross Pathology==
* On gross pathology, multiple small stones are commonly found or less commonly a solitary stone is seen.  
*On gross pathology, commonly multiple small stones are found and less commonly a solitary stone is seen.  
* The smaller stones represent a higher morbidity since they can easily occlude the [[Bile duct|biliary tracts]].<ref>{{cite book | last = Ansert | first = Sandra | title = Textbook of diagnostic sonography | publisher = Elsevier | location = St. Louis, MO | year = 2018 | isbn = 978-0323353755}}</ref>
*The smaller stones represent a higher morbidity since they can easily occlude the [[Bile duct|biliary tracts]].<ref>{{cite book | last = Ansert | first = Sandra | title = Textbook of diagnostic sonography | publisher = Elsevier | location = St. Louis, MO | year = 2018 | isbn = 978-0323353755}}</ref>


==Microscopic Pathology==
==Microscopic Pathology==
 
*On microscopic analysis, characteristic findings include:
On microscopic histopathological analysis, variable evidences of inflammation can be noted transmurally including [[Neutrophil|neutrophils]], which are characteristic in gallstone disease.<ref>{{cite book | last = Fisher | first = M. M. | title = Gallstones | publisher = Springer US | location = Boston, MA | year = 1979 | isbn = 1461570662 }}</ref>
**Transmural thickening of gall bladder wall
**Neutrophilia<ref>{{cite book | last = Fisher | first = M. M. | title = Gallstones | publisher = Springer US | location = Boston, MA | year = 1979 | isbn = 1461570662 }}</ref>


==References==
==References==

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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]

Overview

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 in take of wine and the concumption of whole grain bread may decrease the risk of developing gallstones.[1]

Pathophysiology

The most common type of gallstone is a cholesterol stone. 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. [2][3][4] [5]

Pathogenesis of Specific Stones

Cholesterol Stones

  • Cholesterol stones are the most common type of gallstone.
  • Cholesterol is an important organic molecule that is needed for incorporation within cell membranes and to produce steroid hormones in the body.
  • The quantity of cholesterol is balanced within the body.
  • When there is excess cholesterol in the body, the body will dispose of it by secreting it into the bile.
  • When the cholesterol concentration reachs a certain level beyond that that can be secreted into the bile, biliary sludge will start to form.
  • Biliary sludge is a viscous mixture that consists of mucin glycoproteins, calcium deposits and cholesterol crystals in the gallbladder.
  • Over time, this sludge becomes more and more concentrated with cholesterol and eventually stones form.[2][6][7]


Pigment Stones

  • Less commonly, gallstones can be composed of bilirubin and are sometimes referred to as "pigment stones".
  • 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.
 **Nonbacterial, nonenzymatic hydrolysis of bilirubin conjugates such as what may happen in patients with Gilbert's syndrome and chronic hemolysis.[8]

Mixed Stones

There is a lack of evidence that supports a true pathology to explain how mixed stones are formed. However, there have been theories that include a combination of the mechanisms including supersaturation, infection and hypomotility of the gallbladder.[3]


Associated Conditions


Gross Pathology

  • On gross pathology, commonly multiple small stones are found and less commonly a solitary stone is seen.
  • The smaller stones represent a higher morbidity since they can easily occlude the biliary tracts.[11]

Microscopic Pathology

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

References

  1. ↑ European Journal Gastroenterology & Hepatology. 6: 585–593. 1995. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  2. ↑ 2.0 2.1 Stinton LM, Shaffer EA (2012). "Epidemiology of gallbladder disease: cholelithiasis and cancer". Gut Liver. 6 (2): 172–87. doi:10.5009/gnl.2012.6.2.172. PMC 3343155. PMID 22570746.
  3. ↑ 3.0 3.1 Indar AA, Beckingham IJ (2002). "Acute cholecystitis". BMJ. 325 (7365): 639–43. PMC 1124163. PMID 12242178.
  4. ↑ McPhee, Stephen (2014). Pathophysiology of disease : an introduction to clinical medicine. New York: McGraw-Hill Education Medical. ISBN 0071806008.
  5. ↑ Wang HH, Portincasa P, Wang DQ (2008). "Molecular pathophysiology and physical chemistry of cholesterol gallstones". Front. Biosci. 13: 401–23. PMID 17981556.
  6. ↑ Marschall HU, Einarsson C (2007). "Gallstone disease". J. Intern. Med. 261 (6): 529–42. doi:10.1111/j.1365-2796.2007.01783.x. PMID 17547709.
  7. ↑ Strasberg SM (2008). "Clinical practice. Acute calculous cholecystitis". N. Engl. J. Med. 358 (26): 2804–11. doi:10.1056/NEJMcp0800929. PMID 18579815.
  8. ↑ Trotman BW (1991). "Pigment gallstone disease". Gastroenterol. Clin. North Am. 20 (1): 111–26. PMID 2022417.
  9. ↑ Lv J, Yu C, Guo Y, Bian Z, Yang L, Chen Y, Li S, Huang Y, Fu Y, He P, Tang A, Chen J, Chen Z, Qi L, Li L (2017). "Gallstone Disease and the Risk of Type 2 Diabetes". Sci Rep. 7 (1): 15853. doi:10.1038/s41598-017-14801-2. PMID 29158491.
  10. ↑ R.M. Ortega (1997). "Differences in diet and food habits between patients with gallstones and controls". Journal of the American College of Nutrition. 16: 88–95. Unknown parameter |month= ignored (help); Unknown parameter |coauthors= ignored (help); |access-date= requires |url= (help)
  11. ↑ Ansert, Sandra (2018). Textbook of diagnostic sonography. St. Louis, MO: Elsevier. ISBN 978-0323353755.
  12. ↑ Fisher, M. M. (1979). Gallstones. Boston, MA: Springer US. ISBN 1461570662.

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