Gallstones, composed mostly of cholesterol or Ca++ bilirubinate, accumulate in the gallbladder or elsewhere in the biliary tree. Their significance lies in their ability to obstruct biliary flow, leading to pain, poor tolerance of fatty meals, retention of biliary constituents, and potential liver injury if left untreated. In susceptible individuals, mechanisms that prevent nucleation of saturated bile are defective, allowing small crystals to form and grow into gallstones. Human bile is often supersaturated with cholesterol, increasing the risk of stone formation, especially during prolonged fasting. Middle-aged obese women, particularly those who have borne children, have a higher prevalence of cholesterol gallstones, possibly due to the estrogen's ability to increase hepatic cholesterol secretion. In severe cases of gallstone disease, surgical removal of the gallbladder is performed, typically using laparoscopy. Endoscopic retrieval of small gallstones lodged in the biliary tree can also be attempted by inserting a small snare through the sphincter of Oddi. 

Bile is secreted from the gallbladder in response to signals that relax the sphincter of Oddi and contract the smooth muscle surrounding the gallbladder epithelium. Cholecystokinin plays a critical role in mediating this response. Intrinsic neural reflexes and vagal pathways, some of which are stimulated by cholecystokinin binding to vagal afferents, also contribute to gallbladder contractility. This results in the ejection of a concentrated bolus of bile into the duodenal lumen, aiding in lipid uptake through mixed micelles. The bile acids are later reclaimed and reenter the enterohepatic circulation, while the other components of bile are mostly lost in stool, facilitating their excretion from the body. 

The liver is responsible for excreting bilirubin, a potentially toxic metabolite of heme. Bilirubin acts as an antioxidant and helps eliminate excess heme released from senescent red blood cells. The majority of bilirubin production comes from red blood cells, with smaller amounts originating from heme-containing proteins in other tissues. Bilirubin can cross the blood-brain barrier and, when present in excessive levels, can lead to brain dysfunction, neuronal cell death, activation of astrocytes and microglia, and even fatality if left untreated. Bilirubin and its metabolites provide color to bile, feces, and to a lesser extent urine. In cases of liver disease, the accumulation of bilirubin in the circulation results in the common symptom of jaundice, characterized by yellowing of the skin and conjunctiva.
Humansareunusuallysusceptibletogallstones, whichrepresentprecipitatedbileconstituentsthataccumulateinthegallbladderorelsewhereinthebiliarytree.GallstonesarecomposedpredominantlyofcholesterolorCa++ bilirubinate(cholesterolvs.pigmentstones,respectively).Theirsignificanceliesintheirpropensitytoobstructbiliaryflowandtherebyresultinpain,poortoleranceoflargefattymeals,retentionofbiliaryconstituents,and(ifleftuntreated)liverinjury.Insusceptibleindividuals,mechanismsthatnormallypreventnucleationofsaturatedbileareeitherdefectiveorovercome,andsmallcrystalsformandcangrowintogallstones.Humanbileisoftensupersaturatedintermsofitscholesterolcontent,thusincreasingtheriskforstoneformation,particularlyduringprolongedfasting.Cholesterolgallstonesareespeciallycommoninmiddle-agedwomenwhoareobese,particularlythosewhohavebornechildren.Thisincreasedprevalenceisapparentlydueatleastinparttotheabilityofestrogentoincreasehepaticcholesterolsecretion.Inseverecasesofgallstonediseasethegallbladdermayberemovedsurgically,whichisusuallyaccomplishedlaparoscopically.SmallgallstonesthathavelodgedinthebiliarytreecansometimesberetrievedendoscopicallybyinsertingasmallsnarethroughthesphincterofOddifromanendoscope.
Bile is secreted from the gallbladder in response to signals that simultaneously relax the sphincter of Oddi and contract the smooth muscle that encircles the gallbladder epithelium (
Fig. 32.12 ). A critical mediator of this response is cholecystokinin. In addition, intrinsic neural reflexes and vagal pathways, some of which themselves are stimulated by the ability of cholecystokinin to bind to vagal afferents, also contribute to gallbladder contractility. The net result is ejection of a concentrated bolus of bile into the duodenal lumen, where the constituent mixed micelles can aid in lipid uptake. Then, when no longer needed, the bile acids are reclaimed and reenter the enterohepatic circulation to begin the cycle again. However, the other components of bile are largely lost in stool, thus providing for their excretion from the body.
Bilirubin Formation and Excretion by the Liver
The liver is also important for excretion of bilirubin, which is a metabolite of heme that is potentially toxic to the body. Bilirubin is an antioxidant and also serves as a way to eliminate the excess heme released from the hemoglobin of senescent red blood cells. Indeed, red blood cells account for 80% of bilirubin production, with the remainder coming from additional heme-containing proteins in other tissues such as skeletal muscle and the liver. Bilirubin can cross the blood-brain barrier and, if present in excessive levels, results •Fig. 32.12 Neurohumoralcontrolofgallbladdercontractionandbiliarysecretion.ThepathwayalsoinvolvesrelaxationofthesphincterofOdditopermitoutflowofbileintotheduodenum.ACh,acetylcholine;CCK,cholecystokinin;NO,nitricoxide;VIP,vasoactiveintestinalpolypeptide.
in brain dysfunction secondary to neuronal cell death and the activation of astrocytes and microglia; it can be fatal if left untreated. Bilirubin and its metabolites are also notable for the fact that they provide color to bile, feces, and to a lesser extent urine. By the same token, when bilirubin accumulates in the circulation as a result of liver disease, it is responsible for the common symptom of jaundice, or yellowing of the skin and conjunctiva.