Cholesterol crystallization in human gallbladder bile: Relation to gallstone number, bile composition, and apolipoprotein E4 isoform

Abstract

Patients with multiple cholesterol gallstones are at increased risk of recurrence after nonsurgical therapy, possibly because of fast biliary cholesterol crystallization. Serum apolipoprotein E4 (apo E4) is a risk factor for primary cholesterol gallstone formation as well as recurrence. We examined potential effects of stone number and apolipoprotein E genotype on crystallization and on various crystallization-influencing factors in gallbladder biles of 36 cholesterol stone patients (25 multiple stones: 10 carrying the ⑀4 allele). Biliary cholesterol saturation, bile salt composition or concentrations of total protein, immunoglobulin (Ig)A, IgG, ␣ 1 -acid glycoprotein, haptoglobin, or mucin-all crystallization promoters-did not differ between multiple and solitary stone patients, apparently not explaining different speed of crystallization (crystal observation time 3.5 ؎ 0.6 days vs. 12.7 ؎ 2.4 days, respectively; P ‫؍‬ .0003). In contrast, biliary aminopeptidase-N activities (2,607 ؎ 592 mU/mL vs. 947 ؎ 185 mU/mL; P ‫؍‬ .04) were higher and IgM levels (179 ؎ 39 vs. 65 ؎ 8 mg/L; P ‫؍‬ .09) tended to be higher in the case of multiple stones. Although patients carrying the ⑀4 allele had similar stone numbers and crystallization as patients without the ⑀4 allele, their cholesterol saturation index (CSI) was lower (1.08 ؎ 0.09 vs. 1.54 ؎ 0.13; P ‫؍‬ .01), whereas total protein and bile salt concentrations tended to be higher with preferential taurineconjugation. In conclusion, fast cholesterol crystallization is associated with multiple stones but not with apolipoprotein E4. Whereas fast crystallization may contribute to high recurrence rates after nonsurgical therapy in case of multiple gallstones, the mechanism for increased risk of gallstone formation in patients carrying the ⑀4 allele remains unknown. (HEPATOLOGY 1998;27:1508-1516.)Patients with multiple cholesterol gallstones have a higher risk of gallstone recurrence after successful nonsurgical treatment than patients with solitary stones. 1 Biliary cholesterol crystallization is much faster in the case of multiple than solitary cholesterol stones, 2,3 thus offering a potential explanation for high recurrence rates. In line with this finding, in a recent prospective study in gallstone patients treated by cholecystotomy with concomitant stone removal, fast crystallization in gallbladder bile obtained during the procedure was the only major risk factor for recurrence during follow-up. 4 Several factors may contribute to fast crystallization, such as biliary cholesterol supersaturation, increased concentration of bile in the gallbladder, 2,5 increased amounts of the hydrophobic bile salt deoxycholate, 6 a shortage of crystallizationinhibiting proteins, 7 or excessive crystallization promoting proteins. 8 The crystallization-promoting proteins have been partly isolated by means of lectin chromatography with concanavalin A-Sepharose. 8 This lectin binds glucose-and mannose-containing glycoproteins, which comprise about 10% of total biliary proteins. Increased tota...

Polymorphisms at cholesterol 7α-hydroxylase, apolipoproteins B and E and low density lipoprotein receptor genes in patients with gallbladder stone disease

“…Patients with ε4 allele had higher cholesterol content in stones, rapid cholesterol crystallization and shorter median nucleation time in the Finnish population [7] while Bertomeu [9] found significantly higher ε4 allele frequency in Spanish patients with gallstones. But other studies [9,30,31] had contradictory results. There were reports that median nucleation time [9] was similar in patients between the genotypes and that the cholesterol saturation index [30] was lower in patients with ε4 allele.…”

“…But other studies [9,30,31] had contradictory results. There were reports that median nucleation time [9] was similar in patients between the genotypes and that the cholesterol saturation index [30] was lower in patients with ε4 allele. Our study concluded that there was no significant difference in the frequency of ε4 allele between patients and controls.…”

Genetic analysis of cholesterol gallstone formation: Searching for Lith (gallstone) genes

“…Some studies have reported that certain polymorphisms of the apolipoprotein (APO) E and B genes and the cholesterol ester transfer protein, all of which are involved in carrying cholesterol in the plasma, were associated with gallstones [53][54][55][56][57][58][59]. APOE polymorphism is the most extensively studied polymorphism in gallstone patients; however, controversial results have been reported concerning the protective role of the ε 4 allele against gallstones [53][54][55][56].…”

Apolipoprotein E genotype and the risk of gallbladder disease in pregnancy

“…43 Studies are conflicting about whether bile composition, cholesterol saturation index, or nucleation time are different in patients with apoE4 compared with patients without apoE4. 11,21,44 Only further studies can help clarify this confusing situation. We did not have the statistical power to look at interactions between apoE4 and diet, age, or body mass index.…”