Cholesterol Gallstone Prevalence Research Articles

Chemical Composition Analysis of Human Gallstones in Beni Mellal-Khenifra, Morocco

This analysis examines the link between patient characteristics and gallstone composition in Beni Mellal, Morocco. A total of 226 patients with gallstones (198 women, 28 men) from the Beni Mellal Regional Hospital Center participated in 2018. Techniques such as scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) were utilized to analyze the gallstone samples. Additionally, participants completed questionnaires regarding their demographic data and dietary habits. Among the cohort, 20 gallstones were selected for detailed analysis based on distinct morphological characteristics, such as color, size, and shape. These samples underwent thorough characterization. To represent the different composition profiles observed among the analyzed samples, six representative spectra were selected for detailed presentation in the manuscript, aiming to avoid redundancies, as several samples exhibited similar spectral characteristics. Mixed-composition gallstones were identified in 95% of patients, reflecting findings consistent with other regions. Fourier-transform infrared spectroscopy was favored for composition analysis due to its accuracy, sensitivity, and minimal sample preparation requirements. A significant association was observed between patient characteristics (age, gender, geographic origin) and the main components of the stones. Positive correlations emerged between the presence of cholesterol stones, calcium bilirubinate, calcium carbonate, and calcium phosphate, and a high consumption of protein- and calcium-rich foods (such as meat and dairy products) commonly found in the diet of Beni Mellal. The frequent consumption of cholesterol-rich products suggests a potential link with the prevalence of cholesterol gallstones in this region.

Cholesterol Gallstone among Patients with Cholelithiasis Admitted to the Department of Surgery of a Tertiary Care Center.

Gallstone is one of the most common pathological conditions found mostly in females. The incidence of cholesterol gallstones is developing higher nowadays which is increasing the burden of cost in society. This study aimed to find out the prevalence of cholesterol gallstones among patients with cholelithiasis admitted to the Department of Surgery of a tertiary care centre. A descriptive cross-sectional study was conducted among patients with cholelithiasis who presented in the Department of Surgery of tertiary care centre for cholecystectomy (laparoscopic or open) from 23 December 2022 to 22 September 2023 after obtaining ethical approval from the Institutional Review Committee. Patients who were diagnosed by use of abdominal ultrasound or CT scan were included. Those patients with gallbladder polyps, cholangitis, and gallbladder tumours were excluded from the study. A convenience sampling method was used. The point estimate was calculated at a 95% Confidence Interval. Among 190 patients, the prevalence of cholesterol gallstones was seen in 85 (44.74%) (37.67-51.81, 95% Confidence Interval). The female to male ratio was 6.72:1. The prevalence of cholesterol gallstones was found to be higher as compared to other studies done in similar settings. cholesterol; gallbladder; gallstone; prevalence.

Hepatobiliary Thyroid Hormone Deficiency Impacts Bile Acid Hydrophilicity and Aquaporins in Cholestatic C57BL/6J Mice.

Women are more prone to develop either hypothyroidism or cholesterol gallstones than men. However, a male predominance in cholesterol gallstones under hypothyroidism was reported. Recently, a novel pathogenic link between thyroid hormone (TH) deficiency and cholesterol gallstones has been described in male mice. Here, we investigate if TH deficiency impacts cholesterol gallstone formation in females by the same mechanism. Three-month-old C57BL/6J mice were randomly divided into a control, a TH deficient, a lithogenic, and a lithogenic + TH deficient group and diet-treated for two, four, and six weeks. Gallstone prevalence, liver function tests, bile composition, hepatic gene expression, and gallbladder aquaporin expression and localization were investigated. Cholesterol gallstones were observed in lithogenic + TH deficient but not lithogenic only female mice. Diminished hydrophilicity of primary bile acids due to decreased gene expression of hepatic detoxification phase II enzymes was observed. A sex-specific expression and localization of hepatobiliary aquaporins involved in transcellular water and glycerol permeability was observed under TH deficient and lithogenic conditions. TH deficiency promotes cholesterol gallstone formation in female C57BL/6J mice by the same mechanism as observed in males. However, cholesterol gallstone prevalence was lower in female than male C57BL/6J mice. Interestingly, the sex-specific expression and localization of hepatobiliary aquaporins could protect female C57BL/6J mice to cholestasis and could reduce biliary water transport in male C57BL/6J mice possibly contributing to the sex-dependent cholesterol gallstone prevalence under TH deficiency.

Hypothyroidism Increases Cholesterol Gallstone Prevalence in Mice by Elevated Hydrophobicity of Primary Bile Acids.

Background: Thyroid hormone (TH) deficiency has been associated with increased cholesterol gallstone prevalence. Hypothyroidism impacts hepatic lipid homeostasis, biliary secretion, gallbladder motility, and gallstone (LITH) gene expression, all potential factors contributing to cholesterol gallstone disease (CGD). However, how TH deficiency may lead to gallstone formation is still poorly understood. Therefore, we performed molecular studies in a CGD mouse model under lithogenic conditions and modulation of TH status. Methods: Male, three-month-old C57BL/6 mice were randomly divided into a control (euthyroid) group, a hypothyroid (hypo) group, a gallstone (litho) group, and a gallstone+hypothyroid (litho+hypo) group and were treated for 2, 4, and 6 weeks (n = 8/treatment period). Gallstone prevalence, biliary composition and cholesterol crystals, hepatic expression of genes participating in cholesterol, bile acid (BA), and phosphatidylcholine synthesis (Hmgcr, Cyp7a1, Pcyt1a), and canalicular transport (Abcg5, Bsep, Abcb4) were investigated. Results: Increased cholesterol gallstone prevalence was observed in hypothyroid mice under lithogenic diet after 4 and 6 weeks of treatment (4 weeks: 25% vs. 0%; 6 weeks: 75% vs. 37.5%). Interestingly, neither the composition of the three main biliary components, cholesterol, BAs, and phosphatidylcholine, nor the hepatic expression of genes involved in synthesis and transport could explain the differences in cholesterol gallstone formation in the mice. However, TH deficiency resulted in significantly increased hydrophobicity of primary BAs in bile. Furthermore, downregulation of hepatic sulfonation enzymes Papss2 and Sult2a8 as well as diminished biliary BA sulfate concentrations in mice were observed under hypothyroid conditions all contributing to a lithogenic biliary milieu as evidenced by microscopic cholesterol crystals and macroscopic gallstone formation. Conclusions: We describe a novel pathogenic link between TH deficiency and CGD and suggest that the increased hydrophobic character of biliary BAs due to the diminished expression of hepatic detoxification enzymes promotes cholesterol crystal precipitation and enhances cholesterol gallstone formation in the bile of hypothyroid mice.

Recent advances in understanding and managing cholesterol gallstones.

The high prevalence of cholesterol gallstones, the availability of new information about pathogenesis, and the relevant health costs due to the management of cholelithiasis in both children and adults contribute to a growing interest in this disease. From an epidemiologic point of view, the risk of gallstones has been associated with higher risk of incident ischemic heart disease, total mortality, and disease-specific mortality (including cancer) independently from the presence of traditional risk factors such as body weight, lifestyle, diabetes, and dyslipidemia. This evidence points to the existence of complex pathogenic pathways linking the occurrence of gallstones to altered systemic homeostasis involving multiple organs and dynamics. In fact, the formation of gallstones is secondary to local factors strictly dependent on the gallbladder (that is, impaired smooth muscle function, wall inflammation, and intraluminal mucin accumulation) and bile (that is, supersaturation in cholesterol and precipitation of solid crystals) but also to “extra-gallbladder” features such as gene polymorphism, epigenetic factors, expression and activity of nuclear receptors, hormonal factors (in particular, insulin resistance), multi-level alterations in cholesterol metabolism, altered intestinal motility, and variations in gut microbiota. Of note, the majority of these factors are potentially manageable. Thus, cholelithiasis appears as the expression of systemic unbalances that, besides the classic therapeutic approaches to patients with clinical evidence of symptomatic disease or complications (surgery and, in a small subgroup of subjects, oral litholysis with bile acids), could be managed with tools oriented to primary prevention (changes in diet and lifestyle and pharmacologic prevention in subgroups at high risk), and there could be relevant implications in reducing both prevalence and health costs.

Association between diet and gallstones of cholesterol and pigment among patients with cholecystectomy: a case-control study in Korea

BackgroundThe prevalence of cholesterol gallstones is high in Western populations, while pigment gallstones are common in Asian populations. Dietary factors are suggested to be associated with gallstone risk, but their relationship with gallstone type has not been evaluated. This study investigated the association between diet and risk of cholesterol gallstone or pigment gallstone in a Korean population whose dietary pattern and type of gallstone were changed during the last 30 years.MethodsPatients with cholesterol (n = 40) and pigment (n = 59) gallstones were recruited after laparoscopic cholecystectomy and were compared with those of age- and sex-matched controls without gallstones (n = 99). Dietary intakes were assessed by trained dietitians using a semi-quantitative food frequency questionnaire. Multinomial logistic regression analysis was performed to calculate odds ratios and 95% confidence intervals to examine the associations between diet and risk for type of gallstones adjusted by potential confounders.ResultsPatients with cholesterol gallstone consumed more lipid, animal lipid, beef, pork, and fried food than those with pigment gallstones and control, while patients with pigment gallstone consumed more carbohydrate and noodles than patients with cholesterol gallstone and control. In multinomial logistic regression analysis using control as reference group, dietary pattern with high consumption of beef, pork, and fried food was associated with risk of cholesterol gallstones, while there was no association between the risk of pigment gallstone and dietary pattern. In addition, control consumed more alcohol than patients with cholesterol and pigment gallstones.ConclusionsThe present study suggested consumption of fat from meat and fried foods increased the risk of cholesterol gallstone, and intake of carbohydrate from noodles increased the risk of pigment gallstone.

Cholesterol gallstones and bile host diverse bacterial communities with potential to promote the formation of gallstones

The prevalence of cholesterol gallstones has increased in recent years. Bacterial infection correlates with the formation of gallstones. We studied the composition and function of bacterial communities in cholesterol gallstones and bile from 22 cholesterol gallstone patients using culture-dependent and culture-independent methods. Altogether fourteen and eight bacterial genera were detected in cholesterol gallstones and bile, respectively. Pseudomonas spp. were the dominant bacteria in both cholesterol gallstones and bile. As judged by diversity indices, hierarchical clustering and principal component analysis, the bacterial communities in gallstones were different from those in bile. The gallstone microbiome was considered more stable than that of bile. The different microbial communities may be partially explained by differences in their habitats. We found that 30% of the culturable strains from cholesterol gallstones secreted β-glucuronidase and phospholipase A2. Pseudomonas aeruginosa strains showed the highest β-glucuronidase activity and produced the highest concentration of phospholipase A2, indicating that Ps. aeruginosa may be a major agent in the formation of cholesterol gallstones.

Has the prevalence of cholesterol gallstones increased in Korea? A preliminary single-center experience

We aimed to determine the prevalence of cholesterol gallstones, the compositional changes of gallstones and its predisposing factors in Korea with this single-center study. Data of 365 patients who underwent cholecystectomy for cholecystolithiasis from July 2008 to September 2011 were reviewed. Based on the compositional analysis of the gallstones, patients were assigned to either cholesterol gallstone group or pigment gallstone group. The characteristics of the patients and the gallstones were summarized and compared. After eight patients with mixed gallstones were excluded, 357 patients were enrolled in the study, including cholesterol gallstones in 175 (49.0%) and pigment gallstones in 182 (51.0%). The number of patients with cholecystolithiasis increased but the prevalence of cholesterol gallstone decreased with age. Compared with the pigment gallstone group, the cholesterol gallstone group was associated with young age (<50 years), female gender, obesity (body mass index ≥ 25 kg/m²) and the absence of chronic liver diseases. The relative prevalence of cholesterol gallstones in Korea has been stationary so far, but may change in the future since cholesterol gallstones are increasingly prevalent in the young generation.

An analysis of the role of the indigenous microbiota in cholesterol gallstone pathogenesis.

Background and AimsCholesterol gallstone disease is a complex process involving both genetic and environmental variables. No information exists regarding what role if any the indigenous gastrointestinal microbiota may play in cholesterol gallstone pathogenesis and whether variations in the microbiota can alter cholesterol gallstone prevalence rates.MethodsGenetically related substrains (BALB/cJ and BALB/cJBomTac) and (BALB/AnNTac and BALB/cByJ) of mice obtained from different vendors were compared for cholesterol gallstone prevalence after being fed a lithogenic diet for 8 weeks. The indigenous microbiome was altered in these substrains by oral gavage of fecal slurries as adults, by cross-fostering to mice with divergent flora at <1day of age or by rederiving into a germ-free state.ResultsAlterations in the indigenous microbiome altered significantly the accumulation of mucin gel and normalized gallbladder weight but did not alter cholesterol gallstone susceptibility in conventionally housed SPF mice. Germ-free rederivation rendered mice more susceptible to cholesterol gallstone formation. This susceptibility appeared to be largely due to alterations in gallbladder size and gallbladder wall inflammation. Colonization of germ-free mice with members of altered Schaedler flora normalized the gallstone phenotype to a level similar to conventionally housed mice.ConclusionsThese data demonstrate that alterations in the gastrointestinal microbiome may alter aspects of cholesterol gallstone pathogenesis and that in the appropriate circumstances these changes may impact cholesterol cholelithogenesis.

486 Lack of Endogenous Cholecystokinin (CCK) Promotes Cholelithogenesis in Mice: A Model Relevant to Celiac Disease

formation (25%). No significant alterations in cholesterol, bile salts or phospholipids were noted demonstrating that this protective effect occurs independently of gallbladder bile lipid concentration. Conclusion: These data demonstrate that IL10 deficiency appreciably and chronically reduces the prevalence of cholesterol gallstones. This protection, at least at the time-point analyzed, appears to be independent of lipid concentration. Because IL10 -/mice displayed significantly reduced gallbladder volumes and mucin gel accumulation, a potential mechanism for this protection is repression of mucin glycoprotein production as well as maintenance of gallbladder wall contractility. These data contrast starkly with other models of chronic gastrointestinal inflammation (i.e., colitis) in which IL10 deficiency promotes disease.

Sex hormones and bile acids in intrahepatic cholestasis of pregnancy

Sex hormones and bile acids in intrahepatic cholestasis of pregnancy

T-Cell Function Is Critical for Murine Cholesterol Gallstone Formation

The formation of cholesterol gallstones is a complex process involving contributions from genes and environmental factors. Although gallbladder inflammation is believed to be common during cholelithogenesis, the role of immunologic factors is unknown. The role of adaptive immunity in cholesterol cholelithogenesis was analyzed utilizing immunocompetent Helicobacter spp.-infected and -uninfected BALB/c and congenic immunodeficient Rag2(-/-) (Rag) mice. Lymphocyte transfer studies were performed to determine which cellular subset was responsible for cholesterol gallstone formation. Also, gallbladder inflammation was quantified to determine the nature of the inflammatory response associated with cholelilithogenesis. When fed a lithogenic diet for 8 weeks, wild-type mice developed significantly more cholesterol gallstones (27%-80% prevalence) than Rag mice ( approximately 5%, P < .05). Helicobacter spp.-infected BALB/cJ mice displayed statistically significant increases in cholesterol gallstone prevalence compared with uninfected mice (81% vs. 39%; P < .05). Transfer of splenocytes or T lymphocytes to Rag2(-/-) mice increased stone prevalence markedly (26% and 40% respectively; P < .05), whereas transfer of B cells was not appreciably cholelithogenic (13%). The adaptive immune response increased the expression of gallbladder Muc genes and accumulation of mucin gel. In addition, T cells and cholesterol monohydrate crystals induced proinflammatory gene expression in the gallbladder, which likely contributes to gallbladder dysfunction. These studies indicate that T cells are critical in murine cholesterol cholelithogenesis. Furthermore, cholesterol monohydrate crystals induce expression of proinflammatory cytokines in a T-cell-dependent fashion. Acquired immunity and inflammation are likely to be crucial factors in cholesterol gallstone pathogenesis, rather then merely the result of cholelithogenesis.

Identification of cholelithogenic enterohepatic Helicobacter species and their role in murine cholesterol gallstone formation

Helicobacter spp are common inhabitants of the hepatobiliary and gastrointestinal tracts of humans and animals and cause a variety of well-described diseases. Recent epidemiologic results suggest a possible association between enterohepatic Helicobacter spp and cholesterol cholelithiasis, chronic cholecystitis, and gallbladder cancer. To test this, we prospectively investigated the effects of Helicobacter spp infection in cholesterol gallstone pathogenesis in the highly susceptible C57L/J mouse model. Helicobacter spp-free adult male C57L mice were infected with several different enterohepatic Helicobacter spp or left uninfected and fed either a lithogenic diet or standard mouse chow for 8 and 18 weeks. At the conclusion of the study, bile was examined microscopically and diagnostic culture and polymerase chain reaction were performed. Mice infected with Helicobacter bilis or coinfected with Helicobacter hepaticus and Helicobacter rodentium and fed a lithogenic diet developed cholesterol gallstones at 80% prevalence by 8 weeks compared with approximately 10% in uninfected controls. Monoinfections with H hepaticus , Helicobacter cinaedi , and H rodentium gave a cholesterol gallstone prevalence of 40%, 30%, and 20%, respectively; the latter 2 groups did not differ significantly from uninfected animals. Neither infected nor uninfected mice fed a chow diet developed cholesterol gallstones. These findings, along with prior epidemiologic studies, suggest that Helicobacter spp play a major role in the pathophysiology of cholesterol gallstone formation in mice and perhaps humans.

The effect of cholestyramlne on gallbladder motillity and liver biochemistry in patients with primary sclerosing cholangitis (PSC)

Background: The prevalence of cholesterol gallstones has substantially increased in the last century, especially in affluent countries. Genetic and environmental factors have been implicated in the pathogenesis of gallstones. Yet, the role of many specific environmental factors remains unclear or controversial. Aim: To study the role of diet and lifestyle habits in asymptomatic gallstone disease. Methods: Subjects with asymptomatic, gallbladder stones detected by ultrasonography (US) were enrolled. A total of 103 newly diagnosed patients (75 females, 28 males) were matched by age, sex and ethnic origin to 103 gallstone-free subjects. All subjects underwent abdominal US and were extensively interviewed on their dietary habits using a Food Frequency Questionnaire, and on their lifestyle habits. Major food items were analyzed for their phospholipid content and included in the food composition tables. Results: The paired analysis revealed the following dietary risk factors for the development of gallstones: Total fat intake (p = 0.038), especially fat of animal origin (p = 0.001), total protein (p<O.OOl), protein of animal origin (p<O,OOl), chicken (p<O.O01) and phosphatidylsedne (p=0.016). The following factors were found to be protective: Dietary fiber (p = 0.009), starch (p = 0.03), zinc (p = 0.028) and alcohol (p = 0.039). In addition, high BMI (p<O.O01), serum cholesterol (p=O.042) and triglyceddes (p=O.OO8), marital status (p=O.OOf) and a family history of gallstones (p<O.O05) were found to correlate with the presence of gallstones. Conclusions: The results of the study indicate that nutritional factors are strongly associated with gallstone disease, as risk factors as well as protective factors. The significant association with fat and protein of animal origin, suggests that foods, of this origin should be avoided by subjects with any additional risk of gallstone development.

Gallstones in obesity and weight loss.

The prevalence of cholesterol gallstones is increased in obese persons. The risk is especially high in those with the highest body mass index (relative risk 5-6). Weight loss further increases the risk of gallstones: the prevalence of new gallstones reaches 10-12% after 8-16 weeks of low-calorie diet and more than 30% within 12-18 months after gastric by-pass surgery. About one-third of the stones are symptomatic. The increased prevalence of stones is mostly due to supersaturation of bile with cholesterol, because of an increased synthesis by the liver and secretion into bile. Saturation is further increased during weight loss. It returns toward normal after weight stabilization at a lower level, allowing spontaneous stone dissolution in some cases. Identified risk factors for gallstones during weight loss are a relative loss of weight greater than 24% of initial body weight, a rate of weight loss greater than 1.5 kg per week, a very low calorie diet with no fat, a long overnight fast period and a high serum triglyceride level. Ursodeoxycholic acid decreases cholesterol saturation of bile and gallstone incidence during weight loss. Other preventive measures include a control of weight loss rate, a reduction of the length of overnight fast, and maintenance of a small amount of fat in the diet.

High-resolution maps of the murine Chromosome 2 region containing the cholesterol gallstone locus, Lith1.

The Lith1 region on Chromosome (Chr) 2 contains a gene that markedly affects the prevalence of cholesterol gallstones in inbred mice. We report the high-resolution genetic and radiation hybrid maps of the chromosomal region surrounding Lith1, using three resources: a DNA panel from 188 progeny from two reciprocal backcrosses between C57BL/6 and Mus spretus inbred strains; 423 progeny of an N4 generation from backcrossing the susceptible C57L/J alleles at Lith1 into the resistant AKR/J strain; and the newly developed hamster-mouse T31 radiation hybrid panel. We mapped 17 microsatellite markers in the D2Mit182 to D2Mit14 region and two candidate genes for Lith1, the canalicular bile salt export pump (Bsep) also known as sister of P-glycoprotein (Spgp) and the low-density-lipoprotein-receptor-related gene megalin (Gp330). Both genetic maps were in agreement and ordered the microsatellite markers into a 10.4 +/- 1.5 cM region. The high-resolution physical map revealed ordering of microsatellite markers and relative distances between markers in almost complete agreement with the genetic maps. Mapping of Bsep revealed its location on Chr 2, homologous to the human chromosomal position (Nature Genet 20, 233-238, 1998). The radiation hybrid results also provided the highest resolution of the area containing the two candidate genes, which both mapped in the Lith1 region with close linkage, being separated by a distance of only 15 cR(3000). The total radiation hybrid map length of the region between D2Mit182 and D2Mit14 was 326 cR(3000), suggesting that 31 cR(3000) is equivalent to 1 cM in this region of Chr 2.

Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: pathophysiology of biliary lipid secretion

The inbred C57L strain but not the AKR strain of mice carry Lith genes that determine cholesterol gallstone susceptibility. When C57L mice are fed a lithogenic diet containing 15% fat, 1% cholesterol, and 0.5% cholic acid, gallbladder bile displays rapid cholesterol supersaturation, mucin gel accumulation, increases in hydrophobic bile salts, and rapid phase separation of solid and liquid crystals, all of which contribute to the high cholesterol gallstone prevalence rates (D. Q-H. Wang, B. Paigen, and M. C. Carey. J. Lipid Res. 1997. 38: 1395;-1411). We have now determined the hepatic secretion rates of biliary lipids in fasting male and female C57L and AKR mice and the intercross (C57L x AKR)F(1) before and at frequent intervals during feeding the lithogenic diet for 56 days. Bile flow and biliary lipid secretion rates were measured in the first hour of an acute bile fistula and circulating bile salt pool sizes were determined by the "washout" technique after cholecystectomy. Compared with AKR mice, we found that i) C57L and F(1) mice on chow displayed significantly higher secretion rates of all biliary lipids, and larger bile salt pool sizes, as well as higher bile salt-dependent and bile salt-independent flow rates; ii) the lithogenic diet further increased biliary cholesterol and lecithin outputs, but bile salt outputs remained constant. Biliary coupling of cholesterol to lecithin increased approximately 30%, setting the biophysical conditions necessary for cholesterol phase separation in the gallbladder; and iii) no gender differences in lipid secretion rates were noted but male mice exhibited significantly more hydrophobic bile salt pools than females. We conclude that in gallstone-susceptible mice, Lith genes determine increased outputs of all biliary lipids but promote cholesterol hypersecretion disproportionately to lecithin and bile salt outputs thereby inducing lithogenic bile formation.

Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical-chemistry of gallbladder bile

Lith genes control susceptibility to cholesterol gallstone formation in inbred strains of mice on a lithogenic diet containing high fat, high cholesterol and 0.5% cholic acid. Our study defines the physical-chemical phenotypes of C57L, AKR, and (C57L x AKR) F1 mouse gallbladder biles during 56 days on the lithogenic diet. We found enhanced cholesterol supersaturation, accumulation of mucin gel, and larger gallbladders in all C57L and F1 mice, as well as more frequent gallstone formation in male C57L and F1 mice (80%) compared to females (40%) or AKR mice (15%). In male C57L and F1 mice, mucin gel accumulated at 3 days, followed by cholesterol supersaturation and phase separation of liquid crystals, solid monohydrate crystals, and, in 43% of mice, anhydrous cholesterol crystals; whereas, in females, phase separations were delayed 2 to 9 days, and anhydrous crystals did not form. In AKR mice, cholesterol supersaturation and phase separations were infrequent and delayed, and gender did not influence the phenotype. Taurocholate invariably replaced endogenous bile salts, especially tauro-beta-muricholate, with crystallization sequences matching taurocholate-containing model bile systems. We conclude: i) Lith genes determine biliary cholesterol supersaturation, mucin gel accumulation, gallbladder size, phase-separation, and prevalence of cholesterol gallstones. ii) Identical phenotypes in C57L and F1 mice indicate susceptibility to cholesterol gallstones is genetically dominant, favoring males 2:1. iii) Mucin gel accumulation, crystallization, and stone formation are rare in AKR mice. This definition of the physical chemistry of lithogenesis should aid in further elucidation of the Lith genes and the proteins they encode.

Genetics of responsiveness to high-fat and high-cholesterol diets in the mouse

The natural variation among inbred strains of mice was used to elucidate the genetic factors underlying the responsiveness to high-fat and high-cholesterol diets. The nine strains examined are the progenitors of recombinant inbred strain sets: C57BL/6J, C57L/J, SWR/J, SJL/J, SM/J, A/J, AKR/J, C3H/HeJ, and DBA/2J. Plasma lipids, liver lipids, the prevalence of cholesterol gallstones, and the size of aortic fatty streak lesions were examined after 18 wk of consumption of the diet containing 15% fat and 1% cholesterol. The variation in aortic lesions found among inbred strains provided the basis for several additional studies that demonstrated the existence of eight genes affecting atherosclerosis. These genes, named Ath1 to Ath8, are briefly described. The genetic analysis of variation in gallstone formation demonstrated that more than one gene affects this phenotype.

The Chemistry of the American Indian's Burden

Gallstones consisting principally of cholesterol are common in Western industrialized and "developed" nations. On the other hand, cholesterol stones have been uncommon to rare in many Asian and African peoples1 (who do, however, have calcium bilirubinate and parasite-related biliary-tract concretions). In Japan, since that nation has increasingly adopted Western ways and food, the prevalence of cholesterol gallstones is reported as on the increase.2 It is therefore not surprising that those who enthusiastically advocate high-fiber foods, and with equal fervor denounce the consumption of "refined sugar" products, list cholesterol gallstones among our diseases of civilization.3 How is it then that American . . .