The association between intakes of dietary trace minerals and gallstone disease: A cross-sectional study from National Health and Nutrition Examination Survey 2017 to 2018.

The gallstone disease is becoming increasingly prevalent worldwide. Dietary trace minerals have been proven to be closely related to many metabolic diseases, and this study aims to explore the association between intakes of dietary trace minerals (copper, iron, selenium, and zinc) and gallstone disease (GSD). Using the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018, intakes of dietary trace minerals and GSD data were obtained through a 24-hour recall and diagnostic questionnaire, respectively. Weighted logistic regression models were used to identify the association between intakes of dietary trace minerals and the prevalence of GSD, and the results were presented as odds ratios (OR) and 95% confidence intervals (95% CI). A total of 4077 participants were included in the final analysis, of which 456 participants had GSD and 3621 participants serving as the control group. No significant associations between GSD and intakes of dietary trace minerals (iron, selenium, and zinc) were found. However, after adjusting for all covariates, significant association was demonstrated between dietary copper (Cu) intake and GSD (OR = 0.66, 95% CI = 0.45-0.98). After conducting a weighted quantile logistic regression, a significant negative correlation was also found between dietary Cu intake and highest GSD quartile (Q4) (OR = 0.45, 95% CI = 0.26-0.80). Following the research outlined above, no association was found between intakes of dietary trace minerals (iron, selenium, and zinc) and GSD; however, a linear negative association was identified between dietary Cu intake and GSD.

Analysis of the sonographic predictors of difficult laparoscopic cholecystectomy in symptomatic cholelithiasis.

BACKGROUND: Laparoscopic cholecystectomy (LC) is one of the most common laparoscopic procedures performed by young surgeons nowadays. Sometimes, LC could be challenging, especially for junior surgeons leading to serious complications. Therefore, this study aims to investigate the preoperative ultrasonographic features that could predict difficult LC. METHODS: In this prospective study, patients (n = 204) who underwent LC for symptomatic cholelithiasis from January 2020 to August 2022 were included. Preoperative parameters, including the ultrasonographic findings, were evaluated for their ability to predict difficult LC. RESULTS: The difficulty of LC was evaluated using two intraoperative scores. Among the ultrasonic parameters that were assessed preoperatively, thickened gallbladder (GB) wall, contracted GB, and impacted stone in the GB neck were associated with difficult LC. However, an impacted stone in the GB neck was the only independent predictor of difficult LC according to both difficulty scores in the multivariate analysis (odds ratio [OR] = 7.56, p = .001; OR = 8.42, p = .001). CONCLUSIONS: The impacted stone in the GB neck is an ultrasonographic sign of difficult LC. It should alert the surgeon for a more appropriate preoperative preparation, and the patient should be informed about the increased risk of complications, including conversion to open cholecystectomy.

Therapeutic Potential of Danyankang Capsule in High-Fat Diet-Induced Cholelithiasis and Its Impact on Liver FXR Signaling and Gut Microbiota.

Cholelithiasis, commonly known as gallstones, represents a prevalent hepatobiliary disorder. This study aimed to elucidate the therapeutic role and mechanism of Danyankang capsulein treating cholelithiasis induced by a high-fat diet in C57BL/6 mice. The therapeutical potential of Danyankang was assessed through biochemical analyses, histopathological examinations, protein detection, and 16S rDNA sequencing. A high-fat diet resulted in cholelithiasis manifestation in mice, with discernable abnormal serum biochemical indices and disrupted biliary cholesterol homeostasis. Danyankang treatment notably ameliorated liver inflammation symptoms and rectified serum and liver biochemical abnormalities. Concurrently, it addressed biliary imbalances. Elevated expressions of toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB)/pNF-κB, HMGCR, CYP7A1, and CYP8B1 observed at the inception of cholelithiasis, were notably reduced upon Danyankang administration. Furthermore, 16S rDNA analysis revealed a decline in species number and diversity of the intestinal flora in cholelithiasis-treated mice, while the decline was reversed with Danyankang treatment. Danyankang capsules reduced the abundance of Verrucomicrobiota and increased the abundance of Actinobacteriota and Proteobacteria. In conclusion, the present study demonstrates that Danyankang exerts potent therapeutic efficacy against high-fat diet-induced cholelithiasis. This beneficial outcome is potentially linked to the inhibition of the TLR4/pNF-κB and SHP/CYP7A1/CYP8B1 signaling pathways, as well as the enhancement of intestinal flora species abundance.

Independent association of general and central adiposity with risk of gallstone disease: observational and genetic analyses.

Background: General obesity is a well-established risk factor for gallstone disease (GSD), but whether central obesity contributes additional independent risk remains controversial. We aimed to comprehensively clarify the effect of body fat distribution on GSD. Methods: We first investigated the observational association of central adiposity, characterized by waist-to-hip ratio (WHR), with GSD risk using data from UK Biobank (N=472,050). We then explored the genetic relationship using summary statistics from the largest genome-wide association study of GSD (ncase=43,639, ncontrol=506,798) as well as WHR, with and without adjusting for body mass index (BMI) (WHR: n=697,734; WHRadjBMI: n=694,649). Results: Observational analysis demonstrated an increased risk of GSD with one unit increase in WHR (HR=1.18, 95%CI=1.14-1.21). A positive WHR-GSD genetic correlation (rg =0.41, P=1.42×10-52) was observed, driven by yet independent of BMI (WHRadjBMI: rg =0.19, P=6.89×10-16). Cross-trait meta-analysis identified four novel pleiotropic loci underlying WHR and GSD with biological mechanisms outside of BMI. Mendelian randomization confirmed a robust WHR-GSD causal relationship (OR=1.50, 95%CI=1.35-1.65) which attenuated yet remained significant after adjusting for BMI (OR=1.17, 95%CI=1.09-1.26). Furthermore, observational analysis confirmed a positive association between general obesity and GSD, corroborated by a shared genetic basis (rg =0.40, P=2.16×10-43), multiple novel pleiotropic loci (N=11) and a causal relationship (OR=1.67, 95%CI=1.56-1.78). Conclusion: Both observational and genetic analyses consistently provide evidence on an association of central obesity with an increased risk of GSD, independent of general obesity. Our work highlights the need of considering both general and central obesity in the clinical management of GSD.

CLINICAL AND PATHOLOGIC FINDINGS IN IGUANIDS WITH SODIUM URATE CHOLELITHIASIS.

Four green iguanas (Iguana iguana) and one blue iguana (Cyclura lewisi) from five facilities were diagnosed with sodium urate cholelithiasis. One case was diagnosed antemortem via ultrasonography, and the iguana underwent a choledochotomy for treatment. The other four cases were identified at necropsy. Pathologic hepatic and biliary changes were present in four of the five cases at necropsy. Histologically, four iguanas had hepatic fibrosis, three had bile duct hyperplasia, and one had cholangiohepatitis and pancreaticocholedochitis. Two iguanas had pathologic renal changes. This is the first report of sodium urate cholelithiasis in reptiles. This case series highlights the potential significant clinical disease caused by sodium urate cholelithiasis and the importance of biliary system evaluation. Further investigation is recommended to explore the pathogenesis of reptilian sodium urate cholelith formation.

Temporal trends of splenectomy in pediatric hospitalizations with hereditary spherocytosis from 2000 to 2019: A national survey.

BACKGROUND: Total and partial splenectomy are used in pediatric patients with hereditary spherocytosis to resolve anemia and hemolytic complications. PROCEDURE: Data from the Healthcare Cost and Utilization Project's Kid's Inpatient Database was used to profile and describe temporal trends in pediatric (≤18 years) hospital admissions in the United States from 2000 to 2019 data release years. Survey sampling methods were used to produce national estimates. RESULTS: From 2000 to 2019, the use of splenectomy declined overall, from 427 to 206 weighted procedures (difference = 222, 95% confidence interval [CI]: 124-320; p < .0001); the risk of undergoing splenectomy during admission also declined from 56.7% to 38.7% (risk difference = 17.9 percentage points [p.p.], 95% CI: 9.7-26.1; p < .0001). Total splenectomy was mostly used. Age at time of splenectomy increased 10.2 years (difference = 1.6 years, 95% CI: 0.6-2.7; p = .0018). The risk of splenectomy increased with age until 10 years, then leveled off until 18 years. The proportion of children aged ≤5 years undergoing splenectomy decreased from 27.7% to 11.2% in 2019 (risk difference: 16.5 p.p., 95% CI: 7.3-25.7; p = .0004). The strongest clinical predictors of splenectomy, adjusting for patient- and hospital-level characteristics, were a co-diagnosis of symptomatic cholelithiasis (adjusted odds ratio [aOR] = 3.18, 95% CI: 1.92-5.28; p < .0001) and splenomegaly or hypersplenism (aOR = 2.52, 95% CI: 1.74-3.65; p < .0001). Risk of splenectomy with splenomegaly or hypersplenism increased over time. CONCLUSION: Splenectomy was delayed until age greater than 10 years. Older age, co-diagnosis with splenomegaly or hypersplenism, or symptomatic cholelithiasis were strongest clinical predictors of splenectomy. Conservative management of hereditary spherocytosis appears to be more common.

Social Determinants of Health Associated With the Need for Urgent Versus Elective Cholecystectomy at an Urban, Safety-Net Hospital.

Background: Benign gallstone disease is the most frequent indication for cholecystectomy in the United States. Many patients present with complicated disease requiring urgent interventions, which increases morbidity and mortality. We investigated the association between individual and population-level social determinants of health (SDoH) with urgent versus elective cholecystectomy. Patients and Methods: All patients undergoing cholecystectomy (2014-2021) for benign gallstone disease were included. Demographic and clinical data were linked to population-level SDoH characteristics using census tracts. Data were analyzed using descriptive and inferential statistics. Results: A total of 3,197 patients met inclusion criteria; 1,913 (59.84%) underwent urgent cholecystectomy, 1,204 (37.66%) underwent emergent cholecystectomy, and 80 (2.5%) underwent interval cholecystectomy. On multinomial logistic regression, patients who were older (relative risk [RR], 1.010; p < 0.001), black (RR, 1.634; p = 0.008), and living in census tracts with a higher percent of poverty (RR, 0.017; p = 0.021) had a higher relative risk of presenting for urgent cholecystectomy. Patients who were female (RR, 0.462; p < 0.001), had a primary care provider (PCP; RR, 0.821; p = 0.018), and lived in census tracts with low supermarket access (RR, 0.764; p = 0.038) had a lower relative risk of presenting for urgent cholecystectomy. Only age (RR, 1.066; p < 0.001), female gender (RR, 0.227; p < 0.001), and having a PCP (RR, 1.984; p = 0.034) were associated with presentation for interval cholecystectomy. Conclusions: Patients who were older, black, and living in census tracts with high poverty levels had a higher relative risk of presenting for urgent cholecystectomy at our institution, whereas females and patients with PCPs were more likely to undergo elective cholecystectomy. Improved access to primary care and surgical clinics for all patients at safety-net hospitals may result in improved outcomes in the management of benign gallstone disease by increasing diagnosis and treatment in the elective setting.

Effect of various dietary fructose concentrations on the gallstone formation process in mice / Efecto de diversas concentraciones de fructosa dietética en el proceso de formación de cálculos biliares en ratones

Background: little information is availaible on the effect of fructose on bile lipids. The first stage in the formation of gallstones corresponds tobiliary cholesterol crystallization, derived from the vesicular transporters. The aim of this study was to investigate the influence of consumingdiets with different fructose concentrations on serum lipids and their implications on gallstones formation. Methods: BALB/c mice divided into a control group as well as groups were treated with different fructose concentrations (10 %, 30 %, 50 % or70 %) for different periods (1, 2 or 5 months). Blood, liver and bile samples were obtained. In bile samples, cholesterol and phospholipids levelswere analyzed, and cholesterol transporters (vesicles and micelles) were separated by gel filtration chromatography. Results: treated animals showed: 1) increases in body weight similar to the control group; 2) a significant increase in plasma triglycerides only atvery high fructose concentrations; 3) a significant increase in total serum cholesterol in the treatment for 1 month; 4) no variations in HDL-cho-lesterol; 5) a significant increase in serum glucose only at very high fructose concentrations in the second month of treatment; 6) no differencesin the plasma alanine-aminotransferase activity; 7) a significant increase in liver triglyceride levels only at very high fructose concentrations; 8)no change in biliary lipid concentrations or in micellar and vesicular phospholipids.Conclusion: changes in plasma, liver and bile lipids were only observed at very high fructose concentrations diets. We conclude that fructoseapparently does not alter the gallstone formation process in our experimental model.(AU)

Introducción: se dispone de escasa información sobre el efecto de la fructosa sobre los lípidos biliares. La primera etapa en la formación decálculos biliares corresponde a la cristalización del colesterol biliar, derivado de los transportadores vesiculares. El objetivo de este estudio fueinvestigar la influencia del consumo de dietas con diferentes concentraciones de fructosa en los lípidos séricos y sus implicaciones en el procesode formación de cálculos biliares.Métodos: ratones BALB/c fueron tratados con diferentes concentraciones de fructosa (10 %, 30 %, 50 % o 70 %) durante diferentes períodos(1, 2 o 5 meses). Se obtuvieron muestras de sangre, hígado y bilis. En muestras de bilis se analizaron los niveles de colesterol y fosfolípidos, ylos transportadores de colesterol (vesículas y micelas) se separaron mediante cromatografía de filtración en gel.Resultados: los animales tratados mostraron: 1) aumentos en el peso corporal similares al grupo de control; 2) aumento significativo en lostriglicéridos plasmáticos sólo a concentraciones muy altas de fructosa; 3) aumento significativo del colesterol sérico total en el tratamientodurante 1 mes; 4) ninguna variación en los niveles de HDL-colesterol; 5) aumento significativo en glucosa sérica solo a concentraciones muyaltas de fructosa; 6) ninguna diferencia en la actividad de la alanina-aminotransferasa plasmática; 7) aumento significativo en los niveles detriglicéridos hepáticos sólo a concentraciones muy altas de fructosa; 8) ningún cambio en las concentraciones de lípidos biliares o en los fos-folípidos micelares y vesiculares.Conclusión: se observaron cambios en los lípidos plasmáticos, hígado y bilis sólo en dietas con concentraciones muy altas de fructosa. Con-cluimos que la fructosa aparentemente no altera el proceso de formación de cálculos biliares en nuestro modelo experimental.(AU)

Acute pancreatitis presented with diffuse ST-segment elevation: A case report and literature review.

INTRODUCTION: Although electrocardiographic changes have been previously reported in patients with acute pancreatitis, diffuse ST-segment elevation without occluded coronary arteries is rarely documented. PATIENT CONCERNS: A 45-year-old man presented to our emergency department due to persistent epigastric pain for 2 hours. However, ECG in the emergency department revealed regular sinus rhythm at 67 beats per minute, peaked T waves in lead V3-5, and upsloping ST-segment elevation in leads II, III, aVF, and V2-6. DIAGNOSIS: He was diagnosed with acute pancreatitis and presented with diffuse ST-segment elevation. INTERVENTIONS: Laboratory workup and computed tomography supported the diagnosis of acute gallstone pancreatitis and endoscopic retrograde cholangiopancreatography was performed. Coronary angiography showed patent coronary arteries finally. OUTCOMES: Endoscopic retrograde cholangiopancreatography and endoscopic papillo-sphincterotomy were performed, and the stone in the common bile duct was removed smoothly without immediate complication. Due to his relatively stable condition, he was discharged on day 7 of admission. CONCLUSION: We presented an uncommon case of acute pancreatitis demonstrating similar features of AMI. This reminds cardiologists and emergency physicians to make the judgment with more caution to avoid jumping to conclusions and providing inappropriate treatment.

Cholelithiasis prevalence and risk factors in individuals with severe or profound intellectual and motor disabilities.

BACKGROUND: The prevalence and risk factors of cholelithiasis in individuals with severe or profound intellectual and motor disabilities (SPIMD) are poorly characterised. Thus, we aimed to investigate the prevalence and risk determinants of cholelithiasis in a cohort with SPIMD under medical care in a residential facility. METHODS: We categorised 84 patients in a residential hospital for persons with SPIMD into groups: those with (Group CL) and without (Group N) cholelithiasis. Gallstones were detected via computed tomography, ultrasonography or both. We evaluated gastrostomy status, nutritional and respiratory support, constipation, and bladder and kidney stones. Data were significantly analysed using univariate and multivariate logistic regression analyses. RESULTS: The prevalence rate of cholelithiasis in our SPIMD cohort was 27%. There were no significant differences in sex, age, weight, height, or Gross Motor Function Classification System between the two groups. However, more patients received enteral nutrition (39.13% vs. 6.56%; P = 0.000751) and were on ventilator support (56.52% vs. 19.67%; P = 0.00249) in Group CL than in Group N. Enteral nutrition [odds ratio (OR) 10.4, 95% confidence interval (CI) 1.98-54.7] and ventilator support (OR 20.0, 95% CI 1.99-201.0) were identified as independent risk factors for the prevalence of cholelithiasis in patients with SPIMD. CONCLUSIONS: Patients with SPIMD demonstrated an increased prevalence of cholelithiasis, with a notable association between nutritional tonic use and respiratory support. Therefore, to emphasise the need for proactive screening, it is crucial to devise diagnostic and therapeutic strategies specific to patients with SPIMD. Further investigation is essential to validate our findings and explore causative factors.

Therapeutic effect of yinchenhao decoction on cholelithiasis via mucin in the gallbladder and intestine.

Cholelithiasis is a common and frequently occurring disease worldwide that belongs to the category of jaundice in traditional Chinese medicine. Yinchenhao decoction (YD) consists of Artemisia capillaris Thunb., Gardenia jasminoides J.Ellis, and Rheum palmatum L., and is traditionally used to treat jaundice, which has a significant therapeutic effect on cholelithiasis. Our study aimed to investigate the pathological mechanism of cholelithiasis and the therapeutic mechanism of YD via mucin in the gallbladder and intestine. YD was prepared and analyzed using HPLC. The supersaturation stability experiment was designed by the solvent-shift method. The cell transport experiment was conducted by coculture monolayers. The animal experiment was performed using a cholelithiasis model with a high-cholesterol diet. The related indicators were detected by automatic biochemical analyzer, PCR, western blot, or ELISA. Statistics were analyzed using χ2-tests and t-tests. As the results, in cholelithiasis, MUC5AC highly expressed in the gallbladder shortened cholesterol supersaturation and promoted cholesterol crystallization via the inflammatory cytokine signaling pathway; MUC2 highly expressed in the small intestine prolonged cholesterol supersaturation and promoted cholesterol absorption via the inflammatory cytokine signaling pathway. YD inhibited mucin expression in the gallbladder and intestine in a concentration-dependent manner for cholelithiasis treatment by inhibiting the inflammatory cytokine signaling pathway, which was attributed to the active components, including chlorogenic acid, geniposide, and rhein.

Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium.

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m2 ); normal (18.5-22.9 kg/m2 ); overweight (23-24.9 kg/m2 ); and obese (25+ kg/m2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.

Novel insights into causal effects of serum lipids and lipid-modifying targets on cholelithiasis.

OBJECTIVE: Different serum lipids and lipid-modifying targets should affect the risk of cholelithiasis differently, however, whether such effects are causal is still controversial and we aimed to answer this question. DESIGN: We prospectively estimated the associations of four serum lipids with cholelithiasis in UK Biobank using the Cox proportional hazard model, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Furthermore, we estimated the causal associations of the genetically predicted serum lipids with cholelithiasis in Europeans using the Mendelian randomisation (MR) design. Finally, both drug-target MR and colocalisation analyses were performed to estimate the lipid-modifying targets' effects on cholelithiasis, including HMGCR, NPC1L1, PCSK9, APOB, LDLR, ACLY, ANGPTL3, MTTP, PPARA, PPARD and PPARG. RESULTS: We found that serum levels of LDL-C and HDL-C were inversely associated with cholelithiasis risk and such associations were linear. However, the serum level of TC was non-linearly associated with cholelithiasis risk where lower TC was associated with higher risk of cholelithiasis, and the serum TG should be in an inverted 'U-shaped' relationship with it. The MR analyses supported that lower TC and higher TG levels were two independent causal risk factors. The drug-target MR analysis suggested that HMGCR inhibition should reduce the risk of cholelithiasis, which was corroborated by colocalisation analysis. CONCLUSION: Lower serum TC can causally increase the risk of cholelithiasis. The cholelithiasis risk would increase with the elevation of serum TG but would decrease when exceeding 2.57 mmol/L. The use of HMGCR inhibitors should prevent its risk.

Low-pressure pneumoperitoneum with deep neuromuscular blockade versus standard pressure pneumoperitoneum in patients undergoing laparoscopic cholecystectomy for gallstone disease: a non-inferiority randomized control trial.

BACKGROUND: Low-pressure pneumoperitoneum (LPP) is an attempt at improving laparoscopic surgery. However, it has the issue of poor working space for which deep neuromuscular blockade (NMB) may be a solution. There is a lack of literature comparing LPP with deep NMB to standard pressure pneumoperitoneum (SPP) with moderate NMB. METHODOLOGY: This was a single institutional prospective non-inferiority RCT, with permuted block randomization of subjects into group A and B [Group A: LPP; 8-10 mmHg with deep NMB [ Train of Four count (TOF): 0, Post Tetanic Count (PTC): 1-2] and Group B: SPP; 12-14 mmHg with moderate NMB]. The level of NMB was monitored with neuromuscular monitor with TOF count and PTC. Cisatracurium infusion was used for continuous deep NMB in group A. Primary outcome measures were the surgeon satisfaction score and the time for completion of the procedure. Secondarily important clinical outcomes were also reported. RESULTS: Of the 222 patients screened, 181 participants were enrolled [F: 138 (76.2%); M: 43 (23.8%); Group A n = 90, Group B n = 91]. Statistically similar surgeon satisfaction scores (26.1 ± 3.7 vs 26.4 ± 3.4; p = 0.52) and time for completion (55.2 ± 23.4 vs 52.5 ± 24.9 min; p = 0.46) were noted respectively in groups A and B. On both intention-to-treat and per-protocol analysis it was found that group A was non-inferior to group B in terms of total surgeon satisfaction score, however, non-inferiority was not proven for time for completion of surgery. Mean pain scores and incidence of shoulder pain were statistically similar up-to 7 days of follow-up in both groups. 4 (4.4%) patients in group B and 2 (2.2%) in group A had bradycardia (p = 0.4). Four (4.4%) cases of group A were converted to group B. One case of group B converted to open surgery. Bile spills and gallbladder perforations were comparable. CONCLUSION: LPP with deep NMB is non-inferior to SPP with moderate NMB in terms of surgeon satisfaction score but not in terms of time required to complete the procedure. Clinical outcomes and safety profile are similar in both groups. However, it could be marginally costlier to use LPP with deep NMB.

A novel heterozygous deletion in ABCB4 gene in a Chinese family with intrahepatic cholestasis of pregnancy, neonatal hyperbilirubinemia, and cholelithiasis: Case reports and literature review.

BACKGROUND: ABCB4 gene (OMIM *171060) variant is associated with a wide clinical spectrum of hepatobiliary diseases, including familial intrahepatic cholestasis of pregnancy (ICP), progressive familial intrahepatic cholestasis type 3 (PFIC3), and neonatal hyperbilirubinemia due to impaired protection of the bile duct. The majority of reported cases, however, were missense or nonsense variants, with few deletion variant findings in the Chinese population. METHOD: We performed whole genome sequencing and confirmed it with Sanger sequencing of the proband infant and his families. Clinical courses and laboratory results were documented and collected from the proband infant and his mother. We also reviewed other published cases related to genetic variants in ABCB4 in the Chinese population. RESULTS: A 26-year-old Chinese female (II.2) who had recurrent intrahepatic cholestasis of pregnancy and her 49-day-old son (III.4) who had hyperbilirubinemia, both presented with extremely elevated total bile acid, cholestatic dominant pattern liver function abnormalities. They were able to stay relatively stable with mild pruritus on ursodeoxycholic acid treatment. After ruling out other possibilities, genetic sequencing revealed a diagnosis of heterozygous deletion variant NM_018849.3:c.1452_1454del (NP_061337.1:p.Thr485del) in ABCB4, which was not reported before, in the symptomatic mother (II.2), index patient (III.4), and the symptomatic grandmother (I.2). This variant resulted in clinical spectrums of ICP, neonatal hyperbilirubinemia, and cholelithiasis in our pedigree. CONCLUSION: We reported a novel heterozygous deletion variant of the ABCB4 gene in a Chinese family, as well as a literature review of ABCB4-related disorders. We aim to facilitate healthcare professionals to better understand genetic factors as an uncommon cause of hepatobiliary diseases, as well as improve therapeutic strategies in challenging clinical situations such as pregnancy and neonatal care.

Concurrent Cholecystectomy Does Not Increase Splenectomy Morbidity in Patients With Hemolytic Anemia: A Pediatric NSQIP Analysis.

PURPOSE: Children undergoing splenectomy for hemolytic anemia often have cholelithiasis, which may or may not be symptomatic. It is unclear whether concurrent cholecystectomy increases length of stay or morbidity after splenectomy. The purpose of this study was to compare morbidity among children undergoing laparoscopic splenectomy alone versus splenectomy with concurrent cholecystectomy in patients with hemolytic anemia. METHODS: We retrospectively evaluated children with hemolytic anemia undergoing non-traumatic laparoscopic splenectomy in the National Surgical Quality Improvement Program-Pediatric database (2012-2020). Outcomes were compared for patients undergoing splenectomy alone (n = 1010) versus splenectomy with cholecystectomy (n = 371). Pearson's Chi-square and Student's t-tests were utilized as appropriate. Propensity score-matching was completed, controlling for eight demographic and clinical variables. RESULTS: 1381 patients were identified, 73.1% undergoing splenectomy alone and 26.9% splenectomy with cholecystectomy. Splenectomy with cholecystectomy patients were older (10.9 years vs. 8.4 years, p < 0.01), more likely to have hereditary spherocytosis (56.1% vs. 40.8%, p < 0.01), less likely to have sickle cell disease (12.1% vs. 33.5%, p < 0.01), more likely ASA class 1 or 2 (49.3% vs. 42.1%, p < 0.01), and had similar preoperative hematocrit levels (29.6 vs. 29.3, p = 0.33). The splenectomy with cholecystectomy group was less likely to receive preoperative blood transfusions (13.5% vs. 25.4%, p < 0.01). There were 360 pairs selected on propensity score-matching, and splenectomy with cholecystectomy was associated with increased operative time (182 min vs. 145 min, p < 0.01) and decreased occurrences of a postoperative transfusion (4.2% vs. 8.9%, p = 0.01). Length of stay after surgery (2.5 days vs. 2.3 days, p = 0.13), composite morbidity (3.9% vs. 3.4%, p = 0.69), and 30-day readmission rates (3.3% vs. 7.4%, p = 0.08) were all similar. CONCLUSIONS: Splenectomy with cholecystectomy is associated with similar postoperative morbidity, length of stay and readmission rates compared to splenectomy alone. These data support the safety of concurrent cholecystectomy with splenectomy for children with cholelithiasis in the setting of hemolytic anemia. TYPE OF STUDY: Retrospective Cohort Study. LEVEL OF EVIDENCE: Level III.

Referral practices are associated with a delay in treatment of symptomatic cholelithiasis and cholecystitis.

BACKGROUND: The project was performed to determine if referrals to non-surgical providers after an initial presentation of symptomatic cholelithiasis are associated with a delay in surgical management. METHODS: A single institution chart review of all adult patients who underwent a cholecystectomy from 2015 to 2019 was completed. Quantitative data was analyzed using independent t-tests. RESULTS: Of 574 reviewed, 482 patients met criteria. Following initial presentation, 295 (61.2%) received a referral to surgery and 187 (38.8%) received follow up with a non-surgical provider. Those in the latter group had a significantly longer time from initial symptom presentation to surgical evaluation (65.7 days vs. 10.3 days, p â€‹< â€‹0.001) and cholecystectomy (102.0 days vs 39.1 days, p â€‹< â€‹0.001) when compared to the surgery referral group. CONCLUSIONS: This study demonstrated that cholecystectomy was significantly delayed for patients who had been referred to non-surgical providers after initial presentation, prolonging symptoms and increasing use of healthcare resources.

Obeticholic acid as a second-line treatment for low phospholipid-associated cholelithiasis syndrome.

BACKGROUND: Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare genetic cause of hepatolithiasis. A pathogenic variant of the ABCB4 gene is reported in half of all patients. Ursodeoxycholic acid (UDCA) is the only drug approved. However, in some patients, UDCA fails to prevent recurrence of symptoms and complications. Experimental evidence suggests that agonists of the farnesoid-X receptor (FXR), the main transcription factor regulating ABCB4, may be beneficial in this context. AIM: To study the efficacy of obeticholic acid (OCA) in patients with LPAC syndrome with an inadequate response or intolerance to UDCA. METHODS: This was a retrospective study of patients with LPAC syndrome treated with OCA, a selective FXR agonist. RESULTS: We reviewed the records of five OCA-treated patients (4 women; median age 29; ABCB4 variant in 4; no hepatic fibrosis). All patients received OCA at an initial dose of 5 mg daily and then 10 mg daily for a median period of 36 months in combination with UDCA (4 patients) or as a monotherapy (one patient). There were no adverse effects reported. Four patients had improvement in their symptoms - three completely and one partially. One patient had no clinical benefit. Abnormalities of blood liver tests persisted in one patient despite resolution of symptoms. Radiological signs of hepatolithiasis persisted in three of the four patients who responded clinically to OCA. CONCLUSIONS: These preliminary observations suggest that OCA may have the potential to effectively treat LPAC syndrome in patients with inadequate response or intolerance to UDCA. Larger studies are needed to confirm these data.

Clinical Significance of Frequently Down-Regulated Phosphatidylethanolamine-Binding Protein-1 in Gallbladder Cancer.

BACKGROUND: Promoter hypermethylation of tumor suppressor genes has been demonstrated to be one of the major mechanisms of their epigenetic regulation in various reports. We have studied the promoter methylation status of PEBP1 and evaluated its correlation with gallbladder carcinogenesis. AIMS: PEBP1, an endogenous inhibitor of Raf/MEK/ERK signaling pathway, is a tumor suppressor gene. We aimed to study the expression profile of PEBP1 and understand the mechanism and significance of its deregulation in gallbladder cancer. METHODS: PEBP1 expression analysis and its promoter methylation status were investigated in 77 gallbladder carcinoma (GBC) and tissue biopsies from 28 patients of gallstone disease by RT-PCR and MS-PCR, respectively. RESULTS: Our results of the mRNA expression profiling demonstrate that PEBP1 is down-regulated in 62.3% (48/77), while 31.2% (24/77) of the gallbladder cancer biopsies show no significant change and 6.5% (5/77) show up-regulated expression compared to tissue samples of gallstone diseases. In GBC, 48.1% (N = 37) GBC biopsy samples exhibited significantly heterozygous promoter hypermethylation compared to tissue samples from gallstone diseases which show promoter hypermethylation in 3 (10.7%) samples only. In gallbladder cancer, the PEBP1 methylation is significantly associated with lymph node metastasis and shorter period of survival. CONCLUSION: PEBP1 is frequently down-regulated and hypermethylated in gallbladder cancer and its promoter hypermethylation is a frequent and early inactivating mechanism in GBC.