Monoconjugated bilirubin is a major component of hemolysis-induced gallstones in mice

Trotman, Bruce W.; Nair, C. R.; Bernstein, Seldon E.

doi:10.1002/hep.1840080436

Cited by 17 publications

(6 citation statements)

References 35 publications

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“…This study also confirms that the (TA) 7 /(TA) 7 UGT1‐A1 genotype co‐inherited with thalassemia defects is one of the main determinants of cholelithiasis, as already shown by other studies in hemolytic disorders (spherocytosis and sickle cell anemia) (5–7). Hemolysis and Gilbert’s syndrome determine high levels of monoconjugate bilirubin that interacts with bile salts, calcium, or other biliary components, initiating pigment, and cholesterol gallstone development (14–17). However, the high prevalence of cholelithiasis even in thalassemia patients without Gilbert’s genotype, also at a young age, underlines that gallstone formation is a complex mechanism involving local factors such as impaired gallbladder motility, and general factors such as fluctuation of bilirubin values over time and diet.…”

Section: Discussionmentioning

confidence: 99%

Cholelithiasis in thalassemia major

Origa

Galanello

Perseu

et al. 2008

European J of Haematology

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Objectives: Aim of this study was to evaluate prevalence and characteristics of cholelithiasis in a large population of patients with thalassemia major (TM). Methods: Data from 858 consecutive patients with transfusion-dependent thalassemia at five major Italian centers were analyzed. In these centers, a complete abdomen ultrasonography is performed yearly after the beginning of the transfusion regimen. The role of co-inheriting Gilbert's syndrome genotype was investigated studying the promoter region of the UGT1-A1 gene by automated sequencing. Results: Thirty percent of TM patients had gallstones. The Gilbert's genotype [homozygosity for (TA) 7 motif at UGT1A promoter gene], influenced both the prevalence of cholelithiasis and the age at which it developed. Conclusions: Cholelithiasis has a remarkable frequency and precocity in patients with TM and especially in those with (TA) 7/(TA) 7 UGT1-A1 genotype. An early biliary ultrasonography is recommended from childhood and a closer follow-up in patients with thalassemia and associated Gilbert's syndrome may be indicated

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Section: Discussionmentioning

confidence: 99%

Cholelithiasis in thalassemia major

Origa

Galanello

Perseu

et al. 2008

European J of Haematology

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“…Like humans with HS, the nb/nb mice have increased unconjugated and total bilirubin in hepatic bile and are disposed to gallstone formation 105. Of the 115 nb/nb mice examined by infrared spectroscopy, 57% had calcium bilirubinate pigment gallstones 106 primarily of unconjugated and monoconjugated origin 107. The incidence is higher in females than in males and is age‐related.…”

Section: Clinical Manifestations Secondary To Red Cell Membrane Skelementioning

confidence: 99%

Highly Accurate CCSD(T) and DFT–SAPT Stabilization Energies of H‐Bonded and Stacked Structures of the Uracil Dimer

et al. 2008

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The CCSD(T) interaction energies for the H-bonded and stacked structures of the uracil dimer are determined at the aug-cc-pVDZ and aug-cc-pVTZ levels. On the basis of these calculations we can construct the CCSD(T) interaction energies at the complete basis set (CBS) limit. The most accurate energies, based either on direct extrapolation of the CCSD(T) correlation energies obtained with the aug-cc-pVDZ and aug-cc-pVTZ basis sets or on the sum of extrapolated MP2 interaction energies (from aug-cc-pVTZ and aug-cc-pVQZ basis sets) and extrapolated DeltaCCSD(T) correction terms [difference between CCSD(T) and MP2 interaction energies] differ only slightly, which demonstrates the reliability and robustness of both techniques. The latter values, which represent new standards for the H-bonding and stacking structures of the uracil dimer, differ from the previously published data for the S22 set by a small amount. This suggests that interaction energies of the S22 set are generated with chemical accuracy. The most accurate CCSD(T)/CBS interaction energies are compared with interaction energies obtained from various computational procedures, namely the SCS-MP2 (SCS: spin-component-scaled), SCS(MI)-MP2 (MI: molecular interaction), MP3, dispersion-augmented DFT (DFT-D), M06-2X, and DFT-SAPT (SAPT: symmetry-adapted perturbation theory) methods. Among these techniques, the best results are obtained with the SCS(MI)-MP2 method. Remarkably good binding energies are also obtained with the DFT-SAPT method. Both DFT techniques tested yield similarly good interaction energies. The large magnitude of the stacking energy for the uracil dimer, compared to that of the benzene dimer, is explained by attractive electrostatic interactions present in the stacked uracil dimer. These interactions force both subsystems to approach each other and the dispersion energy benefits from a shorter intersystem separation.

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“…The finding of bilirubin monoglucuronide in these stones has led to the suggestion that the pigment might also be important in the formation of the central and presumably first pigmented nidus present in many cholesterol stones. 21 In the analysis of bile pigment composition, the handling of the bile samples is important. The pigments undergo photocomposition on exposure to ambient light and they will also, especially in acid medium, undergo schism into their underlying dipyrroles with random recombination, to form the IIIa and XIIIa as well as the recombined IXa isomers of bilirubin and its conjugates, with changes in the conjugate species corresponding to the schism and recombination.…”

Section: Discussionmentioning

confidence: 99%

Bilirubin conjugate changes in the bile of gallbladders containing gallstones

et al. 1995

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Gallbladder bile was obtained at laparoscopic cholecystectomy from 31 patients with gallstones, and duodenal aspirates from 18 normal controls. Bile pigments (9 conjugates and unconjugated bilirubin) were analyzed by high-performance liquid chromatography. The average proportional composition of the bile pigments from the patients with gallstones was characteristically different from the controls. Whereas the average values for the principal conjugates in the controls were bilirubin diglucuronide 83.4%, bilirubin monoglucuronide 10.1%, bilirubin monoglucuronide monoglucoside 4.5%, and bilirubin monoglucuronide monoxyloside 1.0%, the corresponding values in the biles from the patients with gallstones were 66.3%, 20.6%, 6.5%, and 2.8%, respectively. Values from the more minor conjugates and unconjugated bilirubin were less than 2% in either data set. In samples obtained in 9 of the gallstone patients early and late in the procedure, no significant change was found. Over the spectrum of findings in the gallstone patients, as the proportion of bilirubin diglucuronide became smaller, that of bilirubin monoglucuronide increased substantially, whereas those of bilirubin monoglucuronide monoglucoside and bilirubin monoglucuronide monoxyloside increased to a small extent. The findings suggest that bilirubin diglucuronide hydrolysis occurs in the gallbladder bile of gallstone patients, with the production of bilirubin monoglucuronide, and that if further hydrolysis of bilirubin monoglucuronide occurs with the formation of unconjugated bilirubin, the latter does not ordinarily increase because it is being absorbed. Stasis with increased gallbladder residence time was likely present in some of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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Monoconjugated bilirubin is a major component of hemolysis-induced gallstones in mice

Cited by 17 publications

References 35 publications

Cholelithiasis in thalassemia major

Cholelithiasis in thalassemia major

Highly Accurate CCSD(T) and DFT–SAPT Stabilization Energies of H‐Bonded and Stacked Structures of the Uracil Dimer

Bilirubin conjugate changes in the bile of gallbladders containing gallstones

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