Letter: development of biliary/renal stone and sludge after Ceftriaxone intake is associated with aberrant UDP‐Glucuronosyltransferase activity (ie Gilbert’s syndrome)

Abstract

EDITORS, Ethnicity, age, gender, dietary patterns (vegetarian/eggetarian/non‐ vegetarian) and lifestyle(s) (tobacco usage/active or passive cigarette smoking/tobacco consumption; alcohol/substance abuse) are emerging as significant predictors of gastrointestinal/hepatic malignancies, mor‐ bidities and mortalities in ethnically disparate susceptible populations worldwide with substantial financial burden in patients of differential socioeconomic strata.1,2 The recently published article by Heydari et al in GastroHep provides critical research insights in cost‐effective man‐ agement of Gilbert s syndrome in ‘at‐risk’ genetically susceptible pop‐ ulation.1 This well‐designed cohort‐based study had stringent inclusion and exclusion criteria with 176 unrelated infant and children ≤12 years old receiving Ceftriaxone for ≥7 days; adherence to ethical clinical re‐ search with written informed consent of eligible participants added to overall study quality with appreciable sample size/statistical power (≥80%). Moreover, accurate biochemical, genetic analyses with sophis‐ ticated bidirectional Sanger‐based sequencing of promoter and exon1 regions of UGT1A1 gene and robust, bias‐free statistical data analyses with relevant adjustments of confounders led to meaningful, technically sound, error‐free results with definitive conclusions. The findings revealed that 80 participants (45.5%) were female and the remaining (n = 96; 54.5%) were male, with 16.5% partici‐ pants presenting with abnormal gall bladder conditions after receiv‐ ing Ceftriaxone; precise biotransformation enzymatic sequelae in gender‐based subgroup stratification should be further explored by investigating genetic variants in UDP‐Glucuronosyltransferse/iso‐ forms with subsequent immunodiagnostic imaging‐based magnetic resonance/computed tomography modalities in subsets with signif‐ icant Ceftriaxone‐related adverse effects/toxicity. In patients with TA7/7, and Gly71Arg (G/A) genotype (ie Gilbert s syndrome) preva‐ lence of biliary sludge and stone was significantly higher than controls (P = 0.008 and 0.05 respectively); however, TA7/7 genotype played significant role in increasing relative risk (3.3 time s normal population), suggesting that aberrant UDP‐Glucuronosyltransferase (ie Gilbert s syndrome) had a pivotal role in drug adverse effects. Allosteric en‐ zyme subunit(s)‐based co‐operativity pharmacokinetic/pharmcody‐ namic‐modelling coupled with biomarker‐based pharmacogenetic/ genomic research would certainly strengthen our current understand‐ ing of the pharmacological basis of Ceftriaxone in genetically heterog‐ enous patient population subsets with adverse drug‐related toxicities. Future multicentric, pharmacogenetic studies with metabolomics and cell‐based assays would provide further clinical insights in cost‐effec‐ tive management of Gilbert s syndrome globally for eventual design of clinically validated predictive biomarkers and safe, patient‐friendly Ceftriaxone drug‐dose treatment protocols/regimens with significant reduction in drug‐related adverse effects (biliary and renal stones or sludge). Moreover, genetic variants in interrelated metabolic/bio‐ chemical signalling cascades/molecular regulatory networks including Toll‐like receptors/Wnt‐Frizzled/Autophagy‐Microtubule Associated Light Chain Protein (I/II)/Ceramide/Sphingolipids/Necrosis/High Mobility Group Box‐1/ Apoptosis/Transforming Growth Factor/Smad, etc may be investigated in pooled multiethnic study cohorts in robust, multicentric epidemiological genetic association studies for precisely dissecting the intermediary lipid mediators in Gilbert s syndrome.