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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>


== Pathophysiology ==
Studies have shown that [[Gallstone disease|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 [[Metabolism|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.
==Pathophysiology==


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.  
*The most common type of gallstone is a [[cholesterol]] stone.<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><ref>{{cite journal |year=1995  |title=. |journal=European Journal Gastroenterology & Hepatology |volume=6 |pages=585-593 |accessdate= 2007-08-25}}</ref>
*When pronucleating proteins are present, such as [[mucin]], the [[bile]] becomes [[Supersaturation|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 of Oddi|sphincter]] contraction, that prevents [[bile]] secretion.
*In this way the [[bile]] stagnates within the gallbladder and promotes the formation of stones.


===Pathogenesis of Specific Stones===
===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.
* 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 Chemistry|organic]] molecule that is needed for incorporation within [[Cell membrane|cell membranes]] and to produce [[Steroid hormone|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>
** Biliary sludge is a viscous mixture that consists of glycoproteins, calcium deposits and cholesterol crystals in the gallbladder.
** 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.
** 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>


<br>
<div style="text-align: center;">'''Cholesterol Stones 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="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></div>
<br>
{| align="center"
|
{{Family tree/start}}
{{Family tree | | | | A01 | | | |A01=Excess [[cholesterol]] in body}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | B01 | | | |B01=The body will dispose of it by secreting it into the [[bile]]}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | C01 | | | |C01=[[Cholesterol]] [[concentration]] reaches a certain level beyond that that can be secreted into the bile}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | D01 | | | |D01=[[Biliary]] sludge starts to form}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | E01 | | | |E01=[[Biliary]] sludge is a [[Viscosity|viscous]] mixture that consists of [[mucin]] [[Glycoprotein|glycoproteins]], [[Calcium|calcium deposits]] and [[cholesterol]] crystals in the gallbladder}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | F01 | | | |F01=Over time, the sludge becomes more and more concentrated with [[cholesterol]]}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | G01 | | | |G01= Eventually forming gallstones}}
{{Family tree/end}}
|}
====Pigment Stones====
====Pigment Stones====
* Occasionally, gallstones are 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:


** An infection of the biliary tract which predisposes to stone formation.
*Less commonly, gallstones can be composed of [[bilirubin]] and are sometimes referred to as "pigment stones".<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>
** 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>
*[[Bilirubin]] is a byproduct of [[red blood cell]] [[Hemolysis|breakdown]] and so are usually found in patients with [[Hemoglobinopathy|hemoglobin disorders]].
*Pigment stones are formed via two main pathways:
**[[Infection]] of the [[biliary tree]] with [[bacteria]] that can release [[Hydrolysis|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 [[Hemolysis|chronic hemolysis]].


====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.<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>
*However, there have been theories that include a combination of several mechanisms including supersaturation, [[infection]] and hypomotility of the [[gall bladder]].


===Associated Conditions===  
==Associated Conditions==
The conditions associated with gallstone disease include:<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 |vauthors=Ortega RM, et al. |year=1997 |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>


*[[Diabetes mellitus type 2|Diabetes mellitus type 2]]
*[[Diabetes mellitus type 2|Diabetes mellitus type 2]]
*[[Obesity]]
*[[Obesity]]
*[[Pregnancy]]
*[[Pregnancy]]
*[[Cholangiocarcinoma|Gallbladder cancer]]
*[[Gallbladder cancer]]
*Gallbladder [[Polyp|polyps]]
*[[Gallbladder]] [[Polyp|polyps]]
*[[Primary sclerosing cholangitis|Primary sclerosing cholangitis]]
*[[Primary sclerosing cholangitis|Primary sclerosing cholangitis]]
*[[Porcelain gallbladder|Porcelain gallbladder]]
*[[Porcelain gallbladder|Porcelain gallbladder]]
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**Whole grain bread
**Whole grain bread
**Fiber
**Fiber
**[[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]]


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, commonly multiple small stones are found and less commonly a solitary stone is seen.<ref>{{cite book | last = Ansert | first = Sandra | title = Textbook of diagnostic sonography | publisher = Elsevier | location = St. Louis, MO | year = 2018 | isbn = 978-0323353755}}</ref>
* On gross pathology, multiple small stones are commonly found or 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>
[[Image:Gallstone.jpg|thumb|center|500px|Cholesterol gallstones are seen. Source: commons.wikimedia.org by Noortje123 from nl, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1805918]]


==Microscopic Pathology==
==Microscopic Pathology==


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>
*On microscopic analysis, characteristic findings include:<ref>{{cite book | last = Fisher | first = M. M. | title = Gallstones | publisher = Springer US | location = Boston, MA | year = 1979 | isbn = 1461570662 }}</ref>
**Transmural thickening of the gall bladder wall
**[[Neutrophilia]]


==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 intake of wine and the consumption of whole grain bread may decrease the risk of developing gallstones.

Pathophysiology

Pathogenesis of Specific Stones


Cholesterol Stones Formation[1][6][7]


 
 
 
Excess cholesterol in body
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The body will dispose of it by secreting it into the bile
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cholesterol concentration reaches a certain level beyond that that can be secreted into the bile
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biliary sludge starts to form
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biliary sludge is a viscous mixture that consists of mucin glycoproteins, calcium deposits and cholesterol crystals in the gallbladder
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Over time, the sludge becomes more and more concentrated with cholesterol
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eventually forming gallstones
 
 
 

Pigment Stones

Mixed Stones

  • 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.

Associated Conditions

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

Gross Pathology

  • On gross pathology, commonly multiple small stones are found and less commonly a solitary stone is seen.[11]
Cholesterol gallstones are seen. Source: commons.wikimedia.org by Noortje123 from nl, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1805918

Microscopic Pathology

  • On microscopic analysis, characteristic findings include:[12]

References

  1. ↑ 1.0 1.1 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.
  2. ↑ 2.0 2.1 Indar AA, Beckingham IJ (2002). "Acute cholecystitis". BMJ. 325 (7365): 639–43. PMC 1124163. PMID 12242178.
  3. ↑ McPhee, Stephen (2014). Pathophysiology of disease : an introduction to clinical medicine. New York: McGraw-Hill Education Medical. ISBN 0071806008.
  4. ↑ Wang HH, Portincasa P, Wang DQ (2008). "Molecular pathophysiology and physical chemistry of cholesterol gallstones". Front. Biosci. 13: 401–23. PMID 17981556.
  5. ↑ European Journal Gastroenterology & Hepatology. 6: 585–593. 1995. |access-date= requires |url= (help)
  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. ↑ Ortega RM, et al. (1997). "Differences in diet and food habits between patients with gallstones and controls". Journal of the American College of Nutrition. 16: 88–95. |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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