Hepatobiliary Disease Research Articles

Analysis of biofilm-forming ability and drug resistance for Hypervirulent Klebsiella pneumoniae

Investigate the biofilm-forming ability and drug resistance of Hypervirulent Klebsiella pneumoniae (HvKP) to provide scientific basis for the treatment of HvKP-infection. A total of 96 Klebsiella pneumoniae strains isolated from clinical infection specimens in Changsha Central Hospital from January to December in 2021 were retrospectively collected, and the clinical data of patients were collected. The string test preliminarily distinguished between HvKP and classic Klebsiella pneumoniae (CKP). The biofilm-forming ability of clinical strains of Klebsiella pneumoniae (KP) was determined by microplate method. The Vitek 2 Compact automatic microbial identification/drug sensitivity analysis system was used for bacterial identification and drug sensitivity test. The clinical data of patients, biofilm forming ability and drug resistance in the HvKP group and those in the CKP group were compared and analyzed. The results showed that a total of 20 strains of HvKP were isolated from 96 non-repetitive KP, and the detection rate was 20.8%. HvKP mainly come from respiratory specimens, up to 75.0%.The prevalence of hepatobiliary diseases and the infection rate of multiple sites in patients with HvKP infection were higher than those in patients with CKP infection, and the difference was statistically significant(χ2=5.184,7.488;P=0.023,0.006).There was no significant difference between the two groups in terms of gender, age, ICU admission, hypertension, diabetes, coronary heart disease, lung disease, urinary system disease, central nervous system disease and laboratory test indexes (all P>0.05).17 (85.0%) strains of HvKP can form biofilm, including 2 strains with weak biofilm-forming ability (10.0%), 10 strains with moderate biofilm-forming ability (50.0%) and 5 strains with strong biofilm-forming ability (25.0%). Among the 76 CKP, 71 (93.4%) could form biofilm, including 13 (17.1%) with weak biofilm-forming ability, 30(39.5%) with moderate biofilm-forming ability and 28 (36.8%) with strong biofilm-forming ability. There was no significant difference in biofilm-forming ability between HvKP and CKP (χ2=1.470,P=0.225).The overall resistance rate of HvKP was not high, but a multi-resistant HvKP resistant to carbapenems was found. The detection rate of multi-resistant HvKP (5.0%) was lower than that of multi-resistant CKP (28.9%), and the difference was statistically significant (χ2=4.984, P=0.026).The resistance rate of HvKP to piperacillin/tazobactam, aztreonam, ciprofloxacin, levofloxacin, ceftazidime, cefepime, tobramycin, minocycline, doxycycline, and compound sulfamethoxazole was lower than that of CKP, and the difference was statistically significant (all P<0.05). In conclusion, most of hypervirulent Klebsiella pneumoniae can form biofilm in this study, but the difference of biofilm-forming ability is not obvious compared with classic Klebsiella pneumoniae. HvKP maintains high sensitivity to commonly used antibacterial drugs, but the drug resistance monitoring of the bacteria cannot be ignored.

Detection of Non-Alcoholic Fatty Liver Disease with Non-invasive Tools in Turkish People Living with HIV and with Apparently Normal Liver Function.

Non-alcoholic fatty liver disease (NAFLD) has become a significant cause of mortality and morbidity in people living with HIV. We aimed to investigate NAFLD presence by magnetic resonance imaging (MRI) methods, including MRI-derived proton density fat fraction (MRI-PDFF) and MRE, and ultrasound elastography among Turkish people living with HIV (PLWH), and identify factors correlated with fatty liver. We included 57 PLWH attending outpatient clinics on antiretroviral therapy (ART) for more than six months, without HBV/HCV co-infection, significant alcohol consumption, active opportunistic infection, previously diagnosed hepatobiliary disease, T2DM, and hyperlipidemia. We performed MRI, MRE, and US elastography on all participants. The mean age of the participants (M/F, 47/10) was 41.7± 12 years. The median duration of HIV infection was 3 (0.5-19 years) years. The mean MRI-PDFF was 4.4 ± 3.8 %, and 11 had fatty liver. The mean MRE value was 2.27 ± 0.6 kPa, inflammation was present in 16, and 4 participants had values consistent with fibrosis. The mean US elastography of the study population was 4.1±2.4 kPa. The mean right and left CCA intima-media of the study population was 0.65± 0.23 mm and 0.66± 0.25 mm; 16 had increased intima-media thickness. In patients with fatty liver, a significant positive correlation was present between MRE and CCA intima-media thickness (rs=0.82, p:0.006 for MRE-left CCA; r=0.68, p=0.042 for MRE-right CCA). We demonstrated that even a significant proportion of PLWH individuals with normal transaminase levels have fatty liver. Future prospective trials are warranted to understand and mitigate the risk factors, course of NAFLD, and accurate non-invasive tests, predicting fibrosis in people living with HIV.

Role of Red Cell Distribution Width and Platelet Count Ratio to Predict the Severity and Outcome in Acute Pancreatitis

Clinical course of acute pancreatitis (AP) varies widely, its clinical features exhibit very low sensitivity for the prediction of severity of disease which is associated with high morbidity and mortality. Several single or multi parameter scoring systems have been described to evaluate the severity of AP. But sometimes, it is not clinically practicable to use these scoring systems for evaluation. This study aimed to find out the Role of Red Cell Distribution Width and Platelet Count Ratio (RPR) to predict the Severity and Outcome in AP. This prospective longitudinal study was carried out from July 2019 to July 2020, at the in-patient department of Gastrointestinal, Hepatobiliary and Pancreatic Disorders, BIRDEM General Hospital, Dhaka. Total 100 patients with AP were included for this study according to selection criteria. An informed written consent was taken from all the participants. Detail history was taken and thorough physical examination was done along with relevant laboratory investigations. Ranson's score, Modified Glasgow score, Bedside index of severity in acute pancreatitis (BISAP), red cell distribution width and platelet count ratio (RPR) were calculated. All data were recorded and analyzed by Statistical package for social sciences (SPSS) 23. In this study 44% patients were more than 60 years with a mean age of 51.34 (±15.45) year. More than two thirds patients were (67%) male. In mild acute pancreatitis mean value of Ranson's score, BISAP score and modified Glasgow score was 0.79 (±0.14), 0.90 (±0.1) and 0.80 (±0.14) and 3.29 (±1.16), 1.77 (±0.46) ,2.74 (±0.69) in moderate to severe pancreatitis respectively with statistically difference were found in both severities (p&lt;.05). The patients with mild pancreatitis and the patients with moderate to severe pancreatitis had significant difference (p&lt;.05) between mean RDW (14.68±1.59% versus 15.51±3.27%), mean RPR (0.043±0.06 versus .062±.002) and platelet count (340.9±841.6 cells/mm3 Versus 236.4±825.4 cells/mm3). The ROC analysis of RPR in predicting severity of pancreatitis showed a cut-off value of ≥ 0.056 and diagnostic accuracy test showed sensitivity, specificity, PPV, NPV and accuracy as 63.6%, 82.2%, 81.4%, 64.9% and 72% respectively. Mean Ranson's score, BISAP score and Modified Glasgow score was 2.09 (±1.45), 1.34 (±0.39) and 1.83 (±1.08) in survived patients and 5.50 (±0.70), 4 and 3.50 (±0.70) in dead patients with significant difference between both groups (p&lt;.05). Mean RDW (15.08±2.67% Vs 17.85±0.21%), mean platelet count (284.43±143×109/L Vs 236.4± 825.4×109/L) and mean RPR (0.053±0.02 Vs 0.094± 0.005) was also significant between survived and dead patients (p&lt;.05). The ROC analysis of RPR in predicting outcome showed cut-off value of ≥ 0.06 and diagnostic accuracy test showed sensitivity, specificity, PPV, NPV and accuracy as 100%, 63.27%, 5.26%, 100% and 64% respectively. Red cell distribution width and platelet count ratio (RPR) can be used as a novel biomarker to predict the severity and mortality of acute pancreatitis in very early stage. Bangladesh Med J. 2021 Sept; 51(1): 18-24

Variations of bile bacterial community alongside gallstone disease progression and key taxa involved in poor outcomes after endoscopic surgery

Gallstone disease is a prevalent biliary disease worldwide, and bacteria play vital roles in the disease development and progression, as well as the prognosis after endoscopic surgery. However, there have been limited studies to explore the key taxa involved. In this study, bile samples from healthy controls (HCs, liver donors without hepatobiliary disease) and three diseased groups, namely patients with gallbladder stones (GBS), patients with common bile duct stones (CBDS), and patients with stricture in the common bile duct (SCBD), were collected and analyzed. Bacterial community characterization based on 16S rRNA amplicon sequencing showed that bacterial diversities did not change significantly alongside gallstone disease development and progression. The predominant phyla in each group were Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota, representing over 80% in abundance of the biliary bacteria community. Specifically, the abundance of Proteobacteria decreased greatly while that of Firmicutes and Bacteroidota increased greatly in the diseased groups when compared to that in HCs. Moreover, linear discriminant analysis identified several genera highly represented in the diseased groups. Among them, Klebsiella, Prevotella, Pseudomonas and Veillonella are persistent in both the HCs group and the diseased groups, indicating an enrichment of local bile bacteria in the diseased bile; while Lachnoanerobaculum, Atopobium, Oribacterium, and Stomatobaculum, those aligned to oral cavity taxa, are persistent in the diseased groups but are transient in the HCs group, and their abundances sequentially increased with the disease development and progression (HCs→GBS→CBDS→SCBD), implying a translocation and colonization of the oral cavity bacteria in the diseased bile. Moreover, co-occurrence network analysis revealed that bacterial infection (e.g., Photobacterium and Plesiomonas) from the intestine was developed during endoscopic surgery with reduced bile bacteria diversity. The results of this study revealed that the bile bacterial community is relatively stable and dominated by a few persistent taxa. Moreover, we hypothesized that translocation and colonization of specific bacteria from the oral cavity happens alongside gallstone disease development and progression, and bacterial infection from the intestinal tract results in poor outcomes after endoscopic surgery.

Assessing risks of hepatobiliary disorders in children under combined exposure to persisting herpes and technogenic chemicals

Chronic persistent viral infection leads to developing immune deficiency and may induce lesions in many organs, the hepatobiliary system included. This, in its turn, may facilitate the onset of diseases of the digestive system under exposure to technogenic chemicals, especially those able to produce hepatotoxic effects. In this study, our aim was to examine risks of developing hepatobiliary disorders in children under combined exposure to persisting herpes infection and technogenic chemicals. We conducted a clinical examination of 324 children aged between 6 and 17 years living either in a large industrial city or on a territory where the sanitary-hygienic situation was favorable. The examination included a clinical checkup, laboratory diagnostic tests identifying herpes markers, chemical analyses aimed at establishing levels of technogenic chemicals in blood, and ultrasound scanning of hepatobiliary organs. We established that exposure to airborne technogenic chemicals created elevated levels of aromatic hydrocarbons and formaldehyde in 64.9–97.6 % of the exposed children; elevated manganese and chromium levels, in 20.8–34.6 % of them. Markers of cytomegalovirus (CMV) and Epstein Barr virus (EBV) were detected in 75 % of the exposed children; each second child had HSV-1 or HSV-2; each third child had human herpesvirus 6. Hepatobiliary disorders occurring under combined exposure to persistent herpes and echnogenic chemicals were represented by structural liver changes in 30.8 % of the examined children; abnormally shaped gallbladder or reactive changes in its walls and dyscholia, in 15.7–48.8 %. These disorders entail elevated levels of direct bilirubin and greater ALT against imbalance of oxidant and antioxidant systems and manifest themselves as biliary pathology in 69.5 % of cases. Exposed children with persistent herpes infection have 1.2–2.3 times higher likelihood of developing structural changes in the liver and gallbladder pathology and up to 4.3 times higher risks of biliary dysfunction and chronic gastroduodenitis.

Chuanxiong Rhizoma extracts prevent cholestatic liver injury by targeting H3K9ac-mediated and cholangiocyte-derived secretory protein PAI-1 and FN.

Chuanxiong Rhizoma (CX, the dried rhizome of Ligusticum wallichii Franch.), a well-known traditional Chinese medicine, is clinically used for treating cardiovascular, cerebrovascular and hepatobiliary diseases. Cholestatic liver damage is one of the chronic liver diseases with limited effective therapeutic strategies. Currently, little is known about the mechanism links between CX-induced anti-cholestatic action and intercellular communication between cholangiocytes and hepatic stellate cells (HSCs). The study aimed to evaluate the hepatoprotective activity of different CX extracts including the aqueous, alkaloid, phenolic acid and phthalide extracts of CX (CXAE, CXAL, CXPA and CXPHL) and investigate the intercellular communication-related mechanisms by which the most effective extracts work on cholestatic liver injury. The active compounds of different CX extracts were identified by UPLC-MS/MS. A cholestatic liver injury mouse model induced by bile duct ligation (BDL), and transforming growth factor-β (TGF-β)-treated human intrahepatic biliary epithelial cholangiocytes (HIBECs) and HSC cell line (LX-2 cells) were used for in vivo and in vitro studies. Histological and other biological techniques were also applied. The results indicated that CXAE, CXAL and CXPHL significantly reduced ductular reaction (DR) and improved liver fibrosis in the BDL mice. Meanwhile, both CXAE and CXPHL suppressed DR in injured HIBECs and reduced collagen contraction force and the expression of fibrosis biomarkers in LX-2 cells treated with TGF-β. CXPHL suppressed the transcription and transfer of plasminogen activator inhibitor-1 (PAI-1) and fibronectin (FN) from the 'DR-like' cholangiocytes to activated HSCs. Mechanistically, the inhibition of PAI-1 and FN by CXPHL was attributed to the untight combination of the acetyltransferase KAT2A and SMAD3, followdd by the suppression of histone 3 lysine 9 acetylation (H3K9ac)-mediated transcription in cholangiocytes. In conclusion, CXPHL exerts stronger anti-cholestatic activity in vivo and in vitro than other CX extracts, and its protective effect on the intracellular communication between cholangiocytes and HSCs is achieved by reducing KAT2A/H3K9ac-mediated transcription and release of PAI-1 and FN.

Update on Cystic Fibrosis in Pediatric Patients.

Cystic fibrosis is an inherited, multisystem disease that affects the gastrointestinal system in numerous ways. This article reviews the nutritional, gastrointestinal, and hepatobiliary manifestations of cystic fibrosis with an emphasis on the effects of CFTR modulator therapy. The life expectancy of individuals with cystic fibrosis has increased substantially in recent years. CFTR modulator therapy improves pulmonary function and results in weight gain. An individualized approach to nutrition is encouraged. Pancreatic exocrine function may improve with intervention early in life. The use of non-invasive methods to screen for hepatobiliary involvement is recommended. Highly effective CFTR modulators lead to increased survival and improved quality of life for many individuals. Their effects on gastrointestinal symptoms and hepatobiliary disease are not fully understood. Patient-reported outcome measures and biomarkers are important clinical endpoints for studying the effects of modulators.

Microbiome analysis of bile samples in patients with choledocholithiasis and hepatobiliary disorders.

The involvement of bacteria in the pathogenesis of biliary tract disease is largely unknown. In this study, we investigated the microbiota of the biliary tissue among adult patients with choledocholithiasis during endoscopic retrograde cholangiography (ERCP). 16S rDNA sequencing of bile samples, culture, and data of the medication history, underlying diseases, and liver function tests were used for the interpretation of differences in the composition of detected bacterial taxa. The four most common phyla in the bile samples included Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Infection with anaerobic and microaerophilic bacteria showed host specificity, where Fusobacterium, Prevotella, Veillonella, Propionibacterium, Gemella, and Helicobacter coexist in the same patients. Clostridium and Peptoclostridium spp. were detected in 80% and 86% of the patients, where the highest relative abundance rates were detected in patients with elevated alkaline phosphatase (ALP) levels and leukocytosis, respectively. Higher diversity in the bacterial population was detected in patients with common bile duct (CBD) stone, in which the richness of an unclassified member of Alphaproteobacteria plus Helicobacter, Enterobacter/Cronobacter spp., Sphingomonas, Prevotella, Fusobacterium and Aeromonas were detected. Our findings suggested correlations between the presence and relative abundance of several bacterial taxa and CBD stone formation and the effect of medication and underlying diseases on the bile microbial communities. A study on a higher number of bile samples from patients compared with the control group could reveal the role of these bacteria in the pathogenesis of biliary tract disease.

Epidemiology of cholangiocarcinoma

Cholangiocarcinoma (CCA) represents a heterogenous set of malignancies arising from the biliary tract. Classification of CCA subdivides tumours into intrahepatic (iCCA) and extrahepatic (eCCA), with eCCA further categorised as perihilar (pCCA) and distal (dCCA) lesions. Tumour subtypes show distinct epidemiological, genetic and clinical characteristics. Global incidence and mortality are rising, with the highest rates seen in Asian populations compared to the West. There has been a divergence in recent mortality trends observed between CCA subtypes, with rising rates of iCCA seen compared with eCCA. There are several drivers for these differing trends, including specific risk factors, misclassification of CCA subtypes and variation in diagnosis and surveillance. Risk factors for CCA can be divided into hepatobiliary, extra-hepatic and environmental, with hepatobiliary diseases conferring the largest risk. Surgery represents the only curative treatment for CCA, but can only be offered to early-stage candidates who are otherwise fit; the majority of patients are therefore treated with chemotherapy and, recently, immunotherapy. Due to late-stage presentation of disease, prognosis is poor, with 5-year survival <20%.

Treatment of Cholestasis in Infants and Young Children.

Cholestasis is characterized by a conjugated hyperbilirubinemia secondary to impaired bile synthesis, transport, or excretion from the liver. It is always pathologic and can be indicative of an underlying hepatobiliary, genetic, or metabolic disorder, several of which require timely diagnosis to ensure proper management and optimal outcomes. This review provides an overview of the evaluation of cholestasis with a focus on current and emerging treatment strategies. Increased accessibility of next generation sequencing (NGS) allows for utilization of genetic testing early in the diagnostic process. This may alter the clinical algorithm for diagnosis of cholestatic disorders. An enhanced understanding of the underlying pathophysiology may help guide future development of targeted therapies, such as ileal bile acid transporter (IBAT) inhibitors. These were recently approved for treatment of cholestatic pruritus in patients with Alagille syndrome and Progressive Familial Intrahepatic Cholestasis. Current management of cholestasis is aimed at the biochemical consequences of impaired bile flow, including malnutrition, pruritus, and progressive fibrosis. NGS has led to an enhanced understanding of biliary pathology and may guide development of future treatment modalities based on specific gene mutations. Rapid discernment of the underlying etiology is essential as new treatment modalities emerge.

Unravelling the mystery of porta hepatis for surgical benefit.

Hepatobilliary surgery is nowadays growing with increasing popularity throughout the world with advent of newer liver imaging modalities. Anticipating a wide range of morphological variations of porta hepatis (PH), a precise understanding is pertinent to preoperative diagnosis, operative procedure and post-operative outcome of hepatobiliary disease. Considering recent interest, present study was undertaken. One-hundred and ten isolated adult cadaveric livers of unknown age and sex were dissected to explore detail morphology and morphometry of PH. Classical picture of PH was observed in 20% liver. The standard representation of structures was highest in hepatic artery (59.1%) followed by portal vein (55.5%) and hepatic duct (51.8%). On the basis of structural distribution PH was described as 16 types. Maximum variable number was found in hepatic artery followed by portal vein and hepatic duct. In morphometric analysis, transverse diameter of PH was more than antero-posterior diameter, indicated that PH was slightly oval in transverse plane. Position of PH was more towards posterior and slightly right in inferior surface of liver. Variations of portal anatomy regarding circulatory and biliary dynamics is worth knowing in successful planning of hepatobiliary surgeries with least complications.

Second-line immunosuppressant administration for steroid-refractory immune-related adverse events in patients with lung cancer.

Evidence for use of second-line immunosuppressants for immune-related adverse events (irAEs) is inadequate. Therefore, a multicenter analysis should assess the efficacy of second-line immunosuppressants for severe irAEs associated with different malignant diseases. This descriptive study aims to investigate the effects of second-line immunosuppressants on corticosteroid-refractory irAEs in patients with lung cancer. We analyzed the effects of second-line immunosuppressants on underlying lung cancer and associated adverse effects. Our study included 4589 patients who had received immune checkpoint inhibitor treatment, with 73 patients (1.6%) developing irAEs requiring second-line immunosuppressants. The most commonly observed irAE was pneumonitis (26 patients), followed by hepatobiliary disorders (15 patients) and enteritis (14 patients). We found a confirmed response rate of 42.3% for pneumonitis, which was lower than the response rates of 86.7% for hepatobiliary disorders and 92.9% for enteritis. The time from the start of corticosteroid therapy to the addition of a second-line immunosuppressant correlated significantly with the resolution of irAE to Grade 1 (correlation coefficients of r = 0.701, p < 0.005). The median progression-free survival and duration of response of underlying lung cancer from second-line immunosuppressant administration were 2.1 and 3.0months, respectively. Of the patients with irAE, 27.4% developed infections and 5.5% might die due to infection. Second-line immunosuppressant response was confirmed in 72.2% of irAEs in patients with lung cancer, with lower response rates observed in irAE pneumonitis compared to other irAEs.

Role of MRCP in Patients with Jaundice When Biliary Tree Is Normal on Previous Imaging

Background Obstructive jaundice is one of the most frequent and grave form of hepatobiliary disease. It is important for treatment planning to detect level and cause of obstruction. Aim of the Work To assess the role of MRCP in patients presented with jaundice, right hypochondrial pain with the absence of dilated biliary system by ultrasound. Patients and Methods This was cross sectional study that included 38 patients who presented with obstructive jaundice or right hypochondrial pain with normal biliary system by ultrasound referred to the Radio diagnosis Department for MRCP. Results MRCP has high sensitivity reaching 100% and high specificity reaching 93.33% in gall bladder pathology and high specificity 100% in biliary and pancreatic pathology in comparison to ultrasound. Conclusion if there is high clinical suspicion of ductal pathology when patient presented by jaundice or right hypochondrial pain with abnormal liver function tests despite normal biliary tree by ultrasound, an MRCP examination should be strongly considered as next imaging modality of choice

Predictive Factors for Two-Year Survival in Dogs with Hepatobiliary Diseases: Importance of Clinical and Laboratory Monitoring.

Long-term outcomes and survival predictors for different clinicopathologies (idiopathic chronic hepatitis, liver fibrosis, vacuolar hepatopathy) in dogs with hepatobiliary diseases are poorly described. In this study, ninety dogs were followed up for up to five years to investigate clinical factors that predict two-year survival in canine patients after liver biopsy. Univariate and multivariate analyses were performed based on clinical and laboratory data to determine the association between clinical and laboratory data and mortality rates. Overall, the one-, two-, and five-year mortality rates were 28.9%, 45.6%, and 78.9%, respectively. Univariate analysis indicated that male gender, ascites, elevated serum gamma-glutamyl transpeptidase (GGT), hypercholesterolemia, hypoalbuminemia, prolonged activated partial thromboplastin clotting time (aPTT), and prolonged thrombin clotting time (TT) were associated with an increased two-year mortality rate. Results from multivariate analysis demonstrated a significant association between male gender (p = 0.022), elevated serum GGT (p < 0.001), hypoalbuminemia (p < 0.001), and prolonged aPTT (p < 0.001) and an increased two-year mortality rate, regardless of the specific type of liver pathology. Elevated GGT was associated with the highest risk for increased two-year mortality (95% CI: hazard ratio 6.02-41.21). In conclusion, various clinical factors in dogs with liver diseases are useful for prognosis prediction.

Metabolic Encephalopathy After Surgery Hepatobiliary and Pancreatic Diseases

Metabolic Encephalopathy (ME) is a group of diseases with central nervous system dysfunction caused by a variety of etiologies. According to the etiology, it can be divided into Wernicker's encephalopathy (WE) caused by thiamine deficiency, hepatic encephalopathy (HE) caused by liver dysfunction and eventual ammonia poisoning in patients with cirrhosis, hyponatremic encephalopathy caused by plasma hypotonic due to low serum sodium, uremic encephalopathy (UE) caused by toxin accumulation after renal dysfunction, and dysglycemic encephalopathy caused by excessive blood glucose fluctuation. The pathophysiological mechanism of ME is not the same, but for the clinical symptoms, it all show different degrees of neuro-mental symptoms. The mild manifestations are indifference, irritability, time-space sensory disorders, thinking retardation, mental decline etc., and the serious manifestations are delirium, lethargy, coma. In patients with existing metabolic encephalopathy, treating the disease is not an easy task for every clinician, but prevention of metabolic encephalopathy may be much simpler and the return greater than treatment.

Pkhd1cyli/cyli mice have altered renal Pkhd1 mRNA processing and hormonally sensitive liver disease.

Autosomal-recessive polycystic kidney disease (ARPKD; MIM #263200) is a severe, hereditary, hepato-renal fibrocystic disorder that causes early childhood morbidity and mortality. Mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, which encodes the protein fibrocystin/polyductin complex (FPC), cause all typical forms of ARPKD. Several mouse lines carrying diverse, genetically engineered disruptions in the orthologous Pkhd1 gene have been generated, but none expresses the classic ARPKD renal phenotype. In the current study, we characterized a spontaneous mouse Pkhd1 mutation that is transmitted as a recessive trait and causescysticliver (cyli), similar to the hepato-biliary disease in ARPKD, but which is exacerbated by age, sex, and parity. We mapped the mutation to Chromosome 1 and determined that an insertion/deletion mutation causes a frameshift within Pkhd1 exon 48, which is predicted to result in a premature termination codon (UGA). Pkhd1cyli/cyli (cyli) mice exhibit a severe liver pathology but lack renal disease. Further analysis revealed that several alternatively spliced Pkhd1 mRNA, all containing exon 48, were expressed in cyli kidneys, but in lower abundance than in wild-type kidneys, suggesting that these transcripts escaped from nonsense-mediated decay (NMD). We identified an AAAAAT motif in exon 48 upstream of the cyli mutation which could enable ribosomal frameshifting, thus potentially allowing production of sufficient amounts of FPC for renoprotection. This mechanism, expressed in a species-specific fashion, may help explain the disparities in the renal phenotype observed between Pkhd1 mutant mice and patients with PKHD1-related disease. KEY MESSAGES: The Pkhd1cyli/cylimouse expresses cystic liver disease, but no kidney phenotype. Pkhd1 mRNA expression is decreased in cyli liver and kidneys compared to wild-type. Ribosomal frameshifting may be responsible for Pkhd1 mRNA escape from NMD. Pkhd1 mRNA escape from NMD could contribute to the absent kidney phenotype.

Serum-Based Detection of Liver Pathology Using a Fluorogenic Alkaline Phosphatase Probe.

Development of "ultrahigh contrast" fluorogenic probes for trapping alkaline phosphatase (ALP) activities in human serum is highly desirable for clinical auxiliary diagnosis for hepatobiliary diseases. However, the intrinsic dilemma of incomplete ionization of intramolecular charge transfer (ICT)-based ALP fluorophores and autofluorescence interference of serum result in low sensitivity and accuracy. Given that unique halogen effects could lead to a drastic decrease in the pKa value and a significant enhancement in the fluorescence quantum yield, herein we report an enzyme-activatable near-infrared probe based on a difluoro-substituted dicyanomethylene-4H-chromenep for achieving fluorescent quantification of human serum ALP. Rational design strategy is demonstrated by altering the substituted halogen groups to well regulate the pKa for meeting the physiological precondition. Owing to the complete ionization at pH 7.4 with tremendous fluorescence enhancement, the difluoro-substituted DCM-2F-HP manifests a linear relationship between the emission intensity and ALP concentration in both solution and serum samples. Along with measuring 77 human serum samples, the DCM-2F-HP based fluorescence method not only exhibits significant correlations with clinical colorimetry, but also distinguishes ALP patients from healthy volunteers, as well as assessing the progress of liver disease, thus providing a potential toolbox for quantitatively detecting ALP and warning the stage of hepatopathy.

The Association Between Common Bile Duct Diameter and the Severity of Coronary Artery Atherosclerosis, Based on Calcium Score

Objective: The aim was to assess the relationship between the coronary calcium score and the common bile duct (CBD) diameter, to determine whether the increase in CBD diameter in patients without hepatobiliary disease could represent cardiovascular disease, or the extent of atherosclerosis in coronary arteries. Materials and Methods: The study cohort consisted of 103 patients referred for computed tomographic angiography (CTA) for coronary artery assessment. None of the patients had a gallbladder, biliary, or pancreatic disease or surgery history. The Agatston score determined the rates of arterial calcification. The diameter of the CBD was measured for a sonogram. Results: There was a statistically significant relatively strong correlation between calcium score and CBD diameter ( r = 0.44, P = .001), independent of baseline variables, such as demographics and cardiovascular risk profiles. In the multivariable regression model, advanced age (beta = 0.825, P = .005), history of hypertension (beta = 0.591, P = .034), and history of coronary stenting (beta = 1.339, P = .001) were shown to be the main determinants of CBD dilatation. Conclusion: A statistically significant correlation existed between the CBD diameter and calcium score, within the coronary arteries and this could represent a shared pathophysiology between CBD dilatation and the severity of coronary atherosclerosis.

Study on synthesis of ursodeoxycholic acid by reduction of 7-ketolithocholic acid in double aprotic solvents and molecular simulations

Ursodeoxycholic acid (UDCA) is not only safer than chenodeoxycholic acid in the treatment of hepatobiliary diseases, but also has a wide range of applications in Acute Kidney Injury and Parkinson’s Disease. The purpose of this experiment is to improve the conversion rate of 7-ketocholic acid (7K-LCA) and the yield of ursodeoxycholic acid in aprotic solvents during electrochemical reduction process. Three aprotic solvents were investigated as electrolytes. 1,3-Dimethyl-2-imidazolidinone (DMI) has a stable five-membered ring structure, and 7K-LCA has undergone two nucleophilic reactions and “Walden” inversion, the 7K-LCK was stereoselectively reduced to UDCA. Hexamethylphosphoramide (HMPA) and 1,3-methyl-3,4,5,6-Tetrahydro-2(1H)-pyrimidinone (DMPU) can be attacked by chloride ions to produce by-products. Molecular orbital theory-based simulations were conducted to study the reducibility of three aprotic solvents [hexamethylphosphoramide (HMPA), 1,3-methyl-3,4,5,6-Tetrahydro-2(1H)-pyrimidinone (DMPU), and 1,3-Dimethyl-2-imidazolidinone (DMI)] in combination with experiments. Choose the best solvent based on the simulation results, the electrolysis reaction can be carried out by applying current and voltage when lithium chloride is used as electrolytes. Calculations using Materials Studio showed that Cu, Pb, Hg–Cu, and Ni exhibited the highest binding energies to the substrate in this system. Using Cu as the electrode when the solvent is a 1:1 mix of DMI and HMPA, the conversion rate of 7-ketocholic acid (could reach 98%, the yield of ursodeoxycholic acid was up to 80%. Under the same conditions, linear voltammetry was performed on the electrochemical workstation to study the electrolysis behavior, and the obtained results were consistent with the experiment.Graphical

Three-dimensional visualization and evaluation of hilar cholangiocarcinoma resectability and proposal of a new classification

BackgroundAs digital medicine has exerted profound influences upon diagnosis and treatment of hepatobiliary diseases, our study aims to investigate the accuracy of three-dimensional visualization and evaluation (3DVE) system in assessing the resectability of hilar cholangiocarcinoma (hCCA), and explores its potential clinical value.Materials and methodsThe discovery cohort, containing 111 patients from April 2013 to December 2019, was retrospectively included to determine resectability according to revised criteria for unresectability of hCCA. 3D visualization models were reconstructed to evaluate resectability parameters including biliary infiltration, vascular involvement, hepatic atrophy and metastasis. Evaluation accuracy were compared between contrast-enhanced CT and 3DVE. Logistic analysis was performed to identify independent risk factors of R0 resection. A new comprehensive 3DVE classification of hCCA based on factors influencing resectability was proposed to investigate its role in predicting R0 resection and prognosis. The main outcomes were also analyzed in cohort validation, including 34 patients from January 2020 to August 2022.Results3DVE showed an accuracy rate of 91% (95%CI 83.6–95.4%) in preoperatively evaluating hCCA resectability, significantly higher than 81% (95%CI 72.8–87.7%) of that of CT (p = 0.03). By multivariable analysis, hepatic artery involvement in 3DVE was identified an independent risk factor for R1 or R2 resection (OR = 3.5, 95%CI 1.4,8.8, P < 0.01). New 3DVE hCCA classification was valuable in predicting patients’ R0 resection rate (p < 0.001) and prognosis (p < 0.0001). The main outcomes were internally validated.Conclusions3DVE exhibited a better efficacy in evaluating hCCA resectability, compared with contrast-enhanced CT. Preoperative 3DVE demonstrated hepatic artery involvement was an independent risk factor for the absence of R0 margin. 3DVE classification of hCCA was valuable in clinical practice.