Cholesterol gallstone formation is processed by two major steps: (1) metabolic abnormalities, genetics and defects of lipid metabolism, and (2) physical-chemical events, bile cholesterol supersaturation, cholesterol crystal nucleation, and crystal growth to macroscopic stones (Table 6.2). The gallbladder and intestines play a role in these processes.

Pigment stones are divided into two major types, black pigment stone and brown pigment stone. Black pigment stones consist dominantly of calcium bilirubinate, produced increasingly under hemolysis. Black pigment gallstones are composed mostly of polymerized shape of calcium bilirubinate and formed in noninfectious gallbladder. In contrast, brown pigment stones are formed, following biliary infection of anaerobic bacteria [59]. In principle, the risk factor is biliary secretion of excess bilirubin conjugates, resulting from hemolysis, ineffective erythropoiesis, or induced enterohepatic cycling of unconjugated bilirubin in association with gallbladder hypomotility caused by diabetes mellitus, total parenteral nutrition, and truncal vagotomy [60–63].

Black pigment stones consist of calcium phosphate and/or carbonate, whereas brown pigment stones are composed of amorphous calcium salts of long-chain saturated fatty acids. In addition, cholesterol is present in both types, with a higher proportion for brown pigment stones [64], especially intrahepatic stones [7]. Also, a mixed mucin glycoprotein matrix secreted by biliary epithelial cells promotes both types of pigment gallstones on the basis of biliary hypersecretion of bilirubin conjugates and endogenous biliary β-glucuronidase hydrolysis of bilirubin conjugates in gallbladder bile to precipitate as insoluble calcium salts. Further, reactive oxygen species, secreted by gallbladder mucosa when inflamed, promote precipitation of calcium bilirubinate polymers, and, therefore, its suppression is to be of therapeutic benefit in pigment gallstone treatment.

Gallstones cause certain typical symptoms: abdominal or back pain, fever, nausea and/or vomiting, and jaundice. Colic pain at the right upper quadrant is less frequent, and considerable cases remain asymptomatic. The typical history is to be as follows: a hypochondrial pain at the right side starts following oily meal, radiating to the right scapula or shoulder, and thereafter reaches a peak level within several hour. Usually gallstone-associated pain is improved by stone moving back to original position or passing through physiological strictures, but most patients find recurrent pain within 10 years after the first attack [65]. According to the Japanese Society of Gastroenterology Practice Guidelines for gallstone diseases 2009, asymptomatic gallstone patients are not recommended to undergo therapeutics, but recommended to a conservative follow-up (Fig. 6.5) [66]. Nevertheless, cases with gallbladder wall thickness or nonfunctioning, or hard condition for image assessment, can be subjected to prophylactic cholecystectomy. Patients with increased risk for gallbladder cancer, with large stones of diameter of >3 cm, and with chronic cholecystitis such as “porcelain gallbladder” are recommended to prophylactic cholecystectomy [67, 68].

Symptomatic gallstone patients need treatment, and laparoscopic cholecystectomy is to be a standard modality. The US National Institutes of Health consensus conference concluded that laparoscopic cholecystectomy is safe and cost-effective compared with open cholecystectomy [69]. For cases not indicated to surgery, optional treatments are oral dissolution for cholesterol gallstones; the indication is to be floating, radiolucent, diameter of <15 mm, CT score <60 HU, and functioning gallbladder [70–74]. A representative case is successfully treated by a combination of ursodeoxycholic acid (400 mg per day) and chenodeoxycholic acid (200 mg per day) that is shown in Fig. 6.6. UDCA monotherapy is also effective in mixed-type cholesterol gallstone dissolution as shown in Fig. 6.7. The underlying mechanism(s) of such an action of bile acids is understood as the enhancement of micelle formation by CDCA and liquid formation to dissolve cholesterol by UDCA (Fig. 6.8) [75, 76]. Extracorporeal shock wave lithotripsy (ESWL) can be considered for cholesterol gallstone, solitary, radiolucent, diameter of <20 mm, CT score <50 HU, and functioning gallbladder. Of the nonsurgical treatment, gallstone recurrence after treatment together with cost-benefit analysis is the weakness with less priority compared to laparoscopic cholecystectomy [77]. Bile acid adjuvant therapy is recommended for this technique in order to shorten a treatment period. On the other hand, cases complicated with acute cholecystitis are managed according to severity, periods after onset, and physical status; laparoscopic cholecystectomy with or without biliary drainage such as percutaneous transhepatic gallbladder drainage (PTGBD), percutaneous transhepatic gallbladder aspiration (PTGBA), endoscopic nasal gallbladder drainage (ENGBD) [78–86].

Recent investigations provide evidences to understand underlying mechanism(s) of gallstone formation process in the aspects of physiology, physical chemistry, molecular biology, and genetics of biliary lipid metabolism, supplying ideas of future strategies for prevention and/or nonsurgical therapeutics, instead for cholecystectomy. Based upon epidemiological studies that reveal an increased overall mortality of gallstone patients in association with diabetes and cardiovascular diseases, but not cancers, this field should be shifted to handling metabolic disorders for lipids, bile acids, and other nutrients.