COVID-19 related biliary injury: A review of recent literature.

Since its emergence in 2019, it has become apparent that coronavirus 2019 (COVID-19) infection can result in multi systemic involvement. In addition to pulmonary symptoms, hepatobiliary involvement has been widely reported. Extent of hepatic involvement ranges from minor elevation in liver function tests (LFTs) to significant hepatocellular or cholestatic injury. In majority of cases, resolution of hepatic injury or improvement in LFTs is noted as patients recover from COVID-19 infection. However, severe biliary tract injury progressing to liver failure has been reported in patients requiring prolonged intensive care unit stay or mechanical ventilation. Due to the timing of its presentation, this form of progressive cholestatic injury has been referred to as COVID-19 cholangiopathy or post-COVID-19 cholangiopathy, and can result in devastating consequences for patients. COVID-19 cholangiopathy is recognized by dramatic elevation in serum alkaline phosphatase and bilirubin and radiologic evidence of bile duct injury. Cholangiopathy in COVID-19 occurs weeks to months after the initial infection and during the recovery phase. Imaging findings and pathology often resemble bile duct injury associated with primary or secondary sclerosing cholangitis. Etiology of COVID-19 cholangiopathy is unclear. Several mechanisms have been proposed, including direct cholangiocyte injury, vascular compromise, and cytokine release syndromes. This review summarizes existing data on COVID-19 cholangiopathy, including reported cases in the literature, proposed pathophysiology, diagnostic testing, and long-term implications.

[Clinical and genetic analysis of cases of progressive familial intrahepatic cholestasis type 3].

Objective: To conduct clinical and genetic analysis in two cases of cholestatic liver disease to determine the specific etiology of cholestasis. Methods: Clinical data and the medical histories in family members of two cases were collected. The gene variation was detected by whole-exome sequencing technology. Sanger sequencing validation and bioinformatics analysis were performed on patients and their parents with suspected pathogenic mutations. Results: Whole-exome sequencing showed that the ABCB4 gene of case 1 (a male, 16 years old) had compound heterozygous mutations of c.646C > T from the father and c.927T > A from the mother, while the ABCB4 gene of case 2 (a female, 17 years old) had a compound heterozygous mutation of c.2784-1G > A from the father and c.646C > T from the mother. New mutation sites that had not been previously reported were c.646C > T, c.927T > A, and c.2784-1G > A. Conclusion: In this study, both cases had progressive familial intrahepatic cholestasis type 3 (PFIC-3) caused by ABCB4 gene mutations, and it also enriched the ABCB4 pathogenic variant spectrum. Whole-exome sequencing technology provides a reliable diagnostic tool for etiological analysis.

A Case of Progressive Cholestatic Drug-Induced Liver Injury Due to Terbinafine.

INTRODUCTION: Terbinafine is commonly prescribed for onychomycosis. It rarely leads to severe, prolonged cholestatic drug-induced liver injury. Clinicians should remain vigilant for this complication. CASE PRESENTATION: A 62-year-old woman was started on terbinafine and developed mixed hepatocellular and cholestatic drug-induced liver injury, confirmed on liver biopsy. The injury became predominantly cholestatic. Unfortunately, she developed coagulopathy with elevated international normalized ratio and progressive drug-induced liver injury with severely elevated alkaline phosphatase and total bilirubin, requiring repeat liver biopsy. Fortunately, she did not develop acute liver failure. DISCUSSION: Prior case reports and series have documented severe cholestatic drug-induced liver injury (although with lesser degree of bilirubin elevation) due to terbinafine, which has very rarely been associated with acute liver failure, need for liver transplantation, and/or death. CONCLUSIONS: Non-acetaminophen drug-induced liver injury is idiosyncratic. Complications including acute liver failure and vanishing bile duct syndrome can be slow to develop, so monitoring for them is important over longitudinal follow-up.

Interleukin-1ß Attenuates Expression of Augmenter of Liver Regeneration (ALR) by Regulating HNF4α Independent of c-Jun.

Inflammasomes and innate immune cells have been shown to contribute to liver injury, thereby activating Kupffer cells, which release several cytokines, including IL-6, IL-1ß, and TNFα. Augmenter of liver regeneration (ALR) is a hepatotropic co-mitogen that was found to have anti-oxidative and anti-apoptotic properties and to attenuate experimental non-alcoholic fatty liver disease (NAFLD) and cholestasis. Additionally, hepatic ALR expression is diminished in patients with NAFLD or cholestasis, but less is known about the mechanisms of its regulation under these conditions. Therefore, we aimed to investigate the role of IL-1ß in ALR expression and to elucidate the molecular mechanism of this regulation in vitro. We found that ALR promoter activity and mRNA and protein expression were reduced upon treatment with IL-1ß. Early growth response protein-1 (Egr-1), an ALR inducer, was induced by IL-1ß but could not activate ALR expression, which may be attributed to reduced Egr-1 binding to the ALR promoter. The expression and nuclear localization of hepatocyte nuclear factor 4 α (HNF4α), another ALR-inducing transcription factor, was reduced by IL-1ß. Interestingly, c-Jun, a potential regulator of ALR and HNF4α, showed increased nuclear phosphorylation levels upon IL-1ß treatment but did not change the expression of ALR or HNF4α. In conclusion, this study offers evidence regarding the regulation of anti-apoptotic and anti-oxidative ALR by IL-1ß through reduced Egr-1 promoter binding and diminished HNF4α expression independent of c-Jun activation. Low ALR tissue levels in NAFLD and cholestatic liver injury may be caused by IL-1ß and contribute to disease progression.

Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom.

This study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people. Five genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency < 5%. Variants were filtered, and annotated to perform rare variant burden analysis, protein structure, and modelling analysis in-silico. Out of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were mostly heterozygous unless specified. 90 were novel and of those variants, 22 were considered likely pathogenic and 9 pathogenic. We identified variants in volunteers with gallstone disease (n = 31), intrahepatic cholestasis of pregnancy (ICP, n = 16), cholangiocarcinoma and cirrhosis (n = 2). Fourteen novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. The rare variant burden was significantly increased in ABCB11. Protein modelling demonstrated variants that appeared to likely cause significant structural alterations. This study highlights the significant genetic burden contributing to cholestatic liver disease. Novel likely pathogenic and pathogenic variants were identified addressing the underrepresentation of diverse ancestry groups in genomic research.

Feasibility of in vivo swine models using guide wire-assisted intraductal radiofrequency ablation for benign biliary stricture.

Several in vivo swine models of benign biliary stenosis (BBS) have been recently reported for preclinical studies of novel endoscopic techniques and devices. The aim of this study was to evaluate the efficacy and feasibility of large animal models of BBS by using intraductal radiofrequency ablation (RFA) assisted by guide wire. Six in vivo swine models were made by using an intraductal RFA for cauterization at 10 W, 80 °C, 90 s in the common bile duct (CBD). Endoscopic retrograde cholangiopancreatography (ERCP) was performed with cholangiography and histologic evaluation was done for the common bile duct. Blood tests were examined before, after, and at the final follow-up. Guide wire assisted RFA electrode produced BBS in all (6/6, 100%) animal models without severe complications. Fluoroscopy findings at 2 weeks after intraductal RFA in every model revealed BBS in the common bile duct. In histologic evaluations, fibrosis and chronic inflammatory changes were noted. After the procedure, ALP, GGT, and CRP were elevated and decreased after an appropriate drain. A swine model of BBS is developed by inducing intraductal thermal injury using intraductal RFA assisted by guide wire. This novel technique for inducing BBS in swine is effective and feasible.

Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study.

BACKGROUND: Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC. METHODS: This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed. RESULTS: Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline. CONCLUSIONS: Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540.

Clinical and cost effectiveness of endoscopic bipolar radiofrequency ablation for the treatment of malignant biliary obstruction: a systematic review.

Background: Early evidence suggests that using radiofrequency ablation as an adjunct to standard care (i.e. endoscopic retrograde cholangiopancreatography with stenting) may improve outcomes in patients with malignant biliary obstruction. Objectives: To assess the clinical effectiveness, cost-effectiveness and potential risks of endoscopic bipolar radiofrequency ablation for malignant biliary obstruction, and the value of future research. Data sources: Seven bibliographic databases, three websites and seven trials registers were searched from 2008 until 21 January 2021. Review methods: The study inclusion criteria were as follows: patients with biliary obstruction caused by any form of unresectable malignancy; the intervention was reported as an endoscopic biliary radiofrequency ablation to ablate malignant tissue that obstructs the bile or pancreatic ducts, either to fit a stent (primary radiofrequency ablation) or to clear an obstructed stent (secondary radiofrequency ablation); the primary outcomes were survival, quality of life or procedure-related adverse events; and the study design was a controlled study, an observational study or a case report. Risk of bias was assessed using Cochrane tools. The primary analysis was meta-analysis of the hazard ratio of mortality. Subgroup analyses were planned according to the type of probe, the type of stent (i.e. metal or plastic) and cancer type. A de novo Markov model was developed to model cost and quality-of-life outcomes associated with radiofrequency ablation in patients with primary advanced bile duct cancer. Insufficient data were available for pancreatic cancer and secondary bile duct cancer. An NHS and Personal Social Services perspective was adopted for the analysis. A probabilistic analysis was conducted to estimate the incremental cost-effectiveness ratio for radiofrequency ablation and the probability that radiofrequency ablation was cost-effective at different thresholds. The population expected value of perfect information was estimated in total and for the effectiveness parameters. Results: Sixty-eight studies (1742 patients) were included in the systematic review. Four studies (336 participants) were combined in a meta-analysis, which showed that the pooled hazard ratio for mortality following primary radiofrequency ablation compared with a stent-only control was 0.34 (95% confidence interval 0.21 to 0.55). Little evidence relating to the impact on quality of life was found. There was no evidence to suggest an increased risk of cholangitis or pancreatitis, but radiofrequency ablation may be associated with an increase in cholecystitis. The results of the cost-effectiveness analysis were that the costs of radiofrequency ablation was £2659 and radiofrequency ablation produced 0.18 quality-adjusted life-years, which was more than no radiofrequency ablation on average. With an incremental cost-effectiveness ratio of £14,392 per quality-adjusted life-year, radiofrequency ablation was likely to be cost-effective at a threshold of £20,000 per quality-adjusted life-year across most scenario analyses, with moderate uncertainty. The source of the vast majority of decision uncertainty lay in the effect of radiofrequency ablation on stent patency. Limitations: Only 6 of 18 comparative studies contributed to the survival meta-analysis, and few data were found concerning secondary radiofrequency ablation. The economic model and cost-effectiveness meta-analysis required simplification because of data limitations. Inconsistencies in standard reporting and study design were noted. Conclusions: Primary radiofrequency ablation increases survival and is likely to be cost-effective. The evidence for the impact of secondary radiofrequency ablation on survival and of quality of life is limited. There was a lack of robust clinical effectiveness data and, therefore, more information is needed for this indication. Future work: Future work investigating radiofrequency ablation must collect quality-of-life data. High-quality randomised controlled trials in secondary radiofrequency ablation are needed, with appropriate outcomes recorded. Study registration: This study is registered as PROSPERO CRD42020170233. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 7. See the NIHR Journals Library website for further project information.

The bile and pancreatic ducts transport fluids to the intestines to help people digest their food properly. Some types of cancer can cause these ducts to become totally or partially blocked. We wanted to know if endoscopic radiofrequency ablation is safe and works well to treat people who have one of these blockages that cannot be removed by surgery. Radiofrequency ablation burns away a blockage by hitting it with radio waves. Endoscopic means that the radio waves are directed to the blockage using a thin, tube-like wire with a camera at the end. During radiofrequency ablation, a person might have a small tube called a stent put into their bile or pancreatic duct to keep it open or to replace an already blocked stent.

We searched for research studies that looked at (1) whether or not radiofrequency ablation was able to remove blockages from the ducts, (2) if radiofrequency ablation allowed people to live longer, (3) if patients had a better quality of life after radiofrequency ablation, (4) if radiofrequency ablation caused any side effects and (5) how much it costs to treat people with radiofrequency ablation.

We found that treatment with radiofrequency ablation before giving a person a stent helped them to live a little longer with their cancer. We did not find any evidence that radiofrequency ablation increased pain or swelling in the bile duct or pancreatic duct. Radiofrequency ablation might cause more swelling in the gall bladder than having a stent without radiofrequency ablation, but there was not enough research available for us to be certain of this.

Radiofrequency ablation before inserting a stent could be a safe option to add to treatment of bile and pancreatic duct blockages caused by cancer. There is limited research evidence and so we are unable to recommend radiofrequency ablation as a treatment for standard clinical practice.

Pharmacologic inhibition of HNF4α prevents parenteral nutrition associated cholestasis in mice.

Prolonged parenteral nutrition (PN) can lead to PN associated cholestasis (PNAC). Intestinally derived lipopolysaccharides and infused PN phytosterols lead to activation of NFκB, a key factor in PNAC. Our objective was to determine if inhibition of HNF4α could interfere with NFκB to alleviate murine PNAC. We showed that HNF4α antagonist BI6015 (20 mg/kg/day) in DSS-PN (oral DSS x4d followed by Total PN x14d) mice prevented the increased AST, ALT, bilirubin and bile acids and reversed mRNA suppression of hepatocyte Abcg5/8, Abcb11, FXR, SHP and MRP2 that were present during PNAC. Further, NFκB phosphorylation in hepatocytes and its binding to LRH-1 and BSEP promoters in liver, which are upregulated in DSS-PN mice, were inhibited by BI6015 treatment. BI6015 also prevented the upregulation in liver macrophages of Adgre1 (F4/80) and Itgam (CD11B) that occurs in DSS-PN mice, with concomitant induction of anti-inflammatory genes (Klf2, Klf4, Clec7a1, Retnla). In conclusion, HNF4α antagonism attenuates PNAC by suppressing NFκB activation and signaling while inducing hepatocyte FXR and LRH-1 and their downstream bile and sterol transporters. These data identify HNF4α antagonism as a potential therapeutic target for prevention and treatment of PNAC.

Farnesoid X receptor regulators from natural products and their biological function.

Metabolic syndrome (MetS) has been a growing public health concern worldwide without specific medicine. Through summarizing the chemical structure type and effect mechanisms of natural products targeted on farnesoid X receptor (FXR), to provide the research basis for exploring the treatment of MetS. The following databases were searched for natural products which targeting FXR: PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure Database, Wanfang Database, China Science and Technology Journal Database, and Chinese Biomedical Literature Database. Totally 120 natural products were summarized, including terpenoids (51 compounds), steroidal saponins (27 compounds), phenylpropanolds (19 compounds), flavonoids (13 compounds), alkaloids (3 compounds) and others (7 compounds), most researches focus on terpenoids and part of synthetic FXR regulators were based on the structure of terpenoids. FXR regulators could improve cholestasis and liver injury, hyperlipidemia, diabetes and atherosclerosis. FXR is a potential target of treating MetS. Natural products are characteristics with unique novel structures and special biological activity, and they are important sources of bioactive precursor compounds and drug discovery. Exploring the effects and mechanism of natural products and its derivative on MetS by targeting FXR may be a new way to develop the new drugs of treating MetS.

Analysis of risk factors for parenteral nutrition-associated cholestasis in preterm infants: a multicenter observational study.

BACKGROUND: It is proposed that the development of parenteral nutrition-associated cholestasis (PNAC) was significantly associated with preterm birth, low birth weight, infection, etc.; however, the etiology and pathogenesis of PNAC are not fully understood. Most of the studies examining PNAC-associated risk factors were single-center studies with relatively small sample sizes. OBJECTIVE: To analyze the risk factors associated with PNAC in preterm infants in China. METHODS: This is a retrospective multicenter observational study. Clinical data on the effect of multiple oil-fat emulsions (soybean oil-medium chain triglycerides-olive oil-fish oil, SMOF) in preterm infants were collected from a prospective multicenter randomized controlled study. A secondary analysis was performed in which preterm infants were divided into the PNAC group and the non-PNAC group based on the PNAC status. RESULTS: A total of 465 cases very preterm infants or very low birth weight infants were included in the study in which 81 cases were assigned to the PNAC group and 384 cases were assigned to the non-PNAC group. The PNAC group had a lower mean gestational age, lower mean birth weight, longer duration of invasive and non-invasive mechanical ventilation, a longer duration oxygen support, and longer hospital stay (P < 0.001 for all). The PNAC group had higher respiratory distress syndrome, hemodynamically significant patent ductus arteriosus, necrotizing enterocolitis (NEC) with stage II or higher, surgically treated NEC, late-onset sepsis, metabolic bone disease, and extrauterine growth retardation (EUGR) compared to the non-PNAC group (P < 0.05 for all). In contrast with the non-PNAC group, the PNAC group received a higher maximum dose of amino acids and fat emulsion, more medium/long-chain fatty emulsion, less SMOF, had a longer duration of parenteral nutrition, lower rates of breastfeeding, higher incidence of feeding intolerance (FI), more accumulated days to achieve total enteral nutrition, less accumulated days of total calories up to standard 110 kcal/kg/day and slower velocity of weight growth (P < 0.05 for all). Logistic regression analysis indicated that the maximum dose of amino acids (OR, 5.352; 95% CI, 2.355 to 12.161), EUGR (OR, 2.396; 95% CI, 1.255 to 4.572), FI (OR, 2.581; 95% CI, 1.395 to 4.775), surgically treated NEC (OR, 11.300; 95% CI, 2.127 ~ 60.035), and longer total hospital stay (OR, 1.030; 95% CI, 1.014 to 1.046) were independent risk factors for the development of PNAC. SMOF (OR, 0.358; 95% CI, 0.193 to 0.663) and breastfeeding (OR, 0.297; 95% CI, 0.157 to 0.559) were protective factors for PNAC. CONCLUSIONS: PNAC can be reduced by optimizing the management of enteral and parenteral nutrition and reducing gastrointestinal comorbidities in preterm infants.

Loss of toll-like receptor 5 potentiates spontaneous hepatocarcinogenesis in farnesoid X receptor-deficient mice.

BACKGROUND: HCC is the most common primary liver cancer and a leading cause of cancer-related mortality. Gut microbiota is a large collection of microbes, predominately bacteria, that harbor the gastrointestinal tract. Changes in gut microbiota that deviate from the native composition, that is, "dysbiosis," is proposed as a probable diagnostic biomarker and a risk factor for HCC. However, whether gut microbiota dysbiosis is a cause or a consequence of HCC is unknown. METHODS: To better understand the role of gut microbiota in HCC, mice deficient of toll-like receptor 5 (TLR5, a receptor for bacterial flagellin) as a model of spontaneous gut microbiota dysbiosis were crossed with farnesoid X receptor knockout mice (FxrKO), a genetic model for spontaneous HCC. Male FxrKO/Tlr5KO double knockout (DKO), FxrKO, Tlr5KO, and wild-type (WT) mice were aged to the 16-month HCC time point. RESULTS: Compared with FxrKO mice, DKO mice had more severe hepatooncogenesis at the gross, histological, and transcript levels and this was associated with pronounced cholestatic liver injury. The bile acid dysmetabolism in FxrKO mice became more aberrant in the absence of TLR5 due in part to suppression of bile acid secretion and enhanced cholestasis. Out of the 14 enriched taxon signatures seen in the DKO gut microbiota, 50% were dominated by the Proteobacteria phylum with expansion of the gut pathobiont γ-Proteobacteria that is implicated in HCC. CONCLUSIONS: Collectively, introducing gut microbiota dysbiosis by TLR5 deletion exacerbated hepatocarcinogenesis in the FxrKO mouse model.

Circulating cell-free messenger RNA secretome characterization of primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease characterized by multifocal bile duct strictures. To date, underlying molecular mechanisms of PSC remain unclear, and therapeutic options are limited. METHODS: We performed cell-free messenger RNA (cf-mRNA) sequencing to characterize the circulating transcriptome of PSC and noninvasively investigate potentially bioactive signals that are associated with PSC. Serum cf-mRNA profiles were compared among 50 individuals with PSC, 20 healthy controls, and 235 individuals with NAFLD. Tissue and cell type-of-origin genes that are dysregulated in subjects with PSC were evaluated. Subsequently, diagnostic classifiers were developed using PSC dysregulated cf-mRNA genes. RESULTS: Differential expression analysis of the cf-mRNA transcriptomes of PSC and healthy controls resulted in identification of 1407 dysregulated genes. Furthermore, differentially expressed genes between PSC and healthy controls or NAFLD shared common genes known to be involved in liver pathophysiology. In particular, genes from liver- and specific cell type-origin, including hepatocyte, HSCs, and KCs, were highly abundant in cf-mRNA of subjects with PSC. Gene cluster analysis revealed that liver-specific genes dysregulated in PSC form a distinct cluster, which corresponded to a subset of the PSC subject population. Finally, we developed a cf-mRNA diagnostic classifier using liver-specific genes that discriminated PSC from healthy control subjects using gene transcripts of liver origin. CONCLUSIONS: Blood-based whole-transcriptome cf-mRNA profiling revealed high abundance of liver-specific genes in sera of subjects with PSC, which may be used to diagnose patients with PSC. We identified several unique cf-mRNA profiles of subjects with PSC. These findings may also have utility for noninvasive molecular stratification of subjects with PSC for pharmacotherapy safety and response studies.

Effect of radiofrequency ablation in addition to biliary stent on overall survival and stent patency in malignant biliary obstruction: an updated systematic review and meta-analysis.

OBJECTIVES: Radiofrequency ablation (RFA) is used in addition to stent placement to manage extrahepatic malignant biliary obstruction. We aimed to study the effect of RFA on overall survival (OS) and stent patency in malignant biliary obstruction. METHODS: A comprehensive literature search was performed from inception to May 2022 for all studies measuring the effect of RFA plus stents compared to stents placement only on OS and stent patency in patients with malignant biliary obstruction. We measured differences in OS, stent patency, and odds of adverse events. A random effect model was used to pool data for stent patency, OS, and adverse event. RESULTS: A total of 17 studies (14 observational and 3 RCT) containing 1766 patients were included in the analysis. The weighted pooled mean survival difference was 58.5 days [95% confidence interval (CI): 32.6-84.4, I2 = 71%] in favor of the RFA treatment group. The weighted mean difference in stent patency was better in the RFA plus stent group by 45.3 days (95% CI: 30.1-60.5, I2 = 16.4%) compared to stent only group. The pooled odds of adverse events were the same in both groups [odds ratio (OR) 1.52, 95% CI: 0.96-2.43, I2 = 59%], and no serious adverse event was seen in either group, or no death reported secondary to RFA procedure. No difference in stent patency based on procedure type, including percutaneous transhepatic cholangiography versus endoscopic retrograde cholangiopancreatography (P = 0.06), and an underline cause of bile duct obstruction was found (P = 0.261). CONCLUSION: RFA treatment, in addition to stent placement in malignant biliary obstruction, potentially improves OS and stent patency duration.

Citrin Deficiency: Clinical and Nutritional Features.

SLC25A13 gene mutations are responsible for diseases related to citrin deficiency (CD), such as neonatal intrahepatic cholestasis caused by citrin deficiency and adult-onset type II citrullinemia (CTLN2). From childhood to adulthood, CD patients are apparently healthy due to metabolic compensation with peculiar dietary habits-disliking high-carbohydrate foods and liking fat and protein-rich foods. Carbohydrate overload and alcohol consumption may trigger the sudden onset of CTLN2, inducing hyperammonemia and consciousness disturbance. Well-compensated asymptomatic CD patients are sometimes diagnosed as having non-obese (lean) non-alcoholic fatty liver disease and steatohepatitis, which have the risk of developing into liver cirrhosis and hepatocellular carcinoma. CD-induced fatty liver demonstrates significant suppression of peroxisome proliferator-activated receptor α and its downstream enzymes/proteins involved in fatty acid transport and oxidation and triglyceride secretion as a very low-density lipoprotein. Nutritional therapy is an essential and important treatment of CD, and medium-chain triglycerides oil and sodium pyruvate are useful for preventing hyperammonemia. We need to avoid the use of glycerol for treating brain edema by hyperammonemia. This review summarizes the clinical and nutritional features of CD-associated fatty liver disease and promising nutritional interventions.

Crosstalk between Gut Microbiota and Bile Acids in Cholestatic Liver Disease.

Emerging evidence suggests the complex interactions between gut microbiota and bile acids, which are crucial end products of cholesterol metabolism. Cholestatic liver disease is characterized by dysfunction of bile production, secretion, and excretion, as well as excessive accumulation of potentially toxic bile acids. Given the importance of bile acid homeostasis, the complex mechanism of the bile acid-microbial network in cholestatic liver disease requires a thorough understanding. It is urgent to summarize the recent research progress in this field. In this review, we highlight how gut microbiota regulates bile acid metabolism, how bile acid pool shapes the bacterial community, and how their interactions contribute to the pathogenesis of cholestatic liver disease. These advances might provide a novel perspective for the development of potential therapeutic strategies that target the bile acid pathway.

Arthrogryposis, renal dysfunction, cholestasis syndrome in a neonate: an uncommon association of common problems.

A male infant born out of non-consanguineous marriage to a primigravida presented to us as his third hospitalisation with ichthyotic lesions all over the body, cholestatic jaundice, multiple joint contractures and a history of recurrent sepsis. Blood and urine investigations revealed Fanconi syndrome, hypothyroidism and direct hyperbilirubinaemia with elevated liver enzymes and normal gamma glutamyl transpeptidase levels. The combination of arthrogryposis, renal dysfunction and cholestasis led to the suspicion of arthrogryposis, renal tubular dysfunction, cholestasis (ARC) syndrome, which was then proved by genetic testing. The baby was managed conservatively with respiratory support, antibiotics, multivitamins, levothyroxine and other supportive measures but succumbed to the illness on day 15 of hospitalisation. Genetic analysis using next-generation sequencing was confirmatory of a homozygous mutation in VIPAS39 gene leading to ARC syndrome type 2 in the present case. Genetic counselling was provided and prenatal testing was advised to the parents for future pregnancies.

Yinchen decoction protects against cholic acid diet-induced cholestatic liver injury in mice through liver and ileal FXR signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Cholestasis is a pathophysiological syndrome characterized by the accumulation of bile acids (BAs) that leads to severe liver disease. Artemisia capillaris is documented in Chinese Pharmacopoeia as the authentic resources for Yinchen. Although Yinchen (Artemisia capillaris Thunb.) decoction (YCD) has been used in China for thousands of years to treat jaundice, the underlying mechanisms to ameliorate cholestatic liver injury have not been elucidated. AIM OF THE STUDY: To investigate the molecular mechanism of how YCD protects against 1% cholic acid (CA) diet-induced intrahepatic cholestasis through FXR signaling. MATERIALS AND METHODS: Wild-type and Fxr-deficient mice were fed a diet containing 1% CA to establish the intrahepatic cholestasis model. The mice received low-, medium-, or high-dose YCD for 10 days. Plasma biochemical markers were analyzed, liver injury was identified by histopathology, and hepatic and plasma BA content was analyzed. Western blot was used to determine the expression levels of transporters and enzymes involved in BA homeostasis in the liver and intestine. RESULTS: In wild-type mice, YCD significantly improved plasma transaminase levels, multifocal hepatocellular necrosis, and hepatic and plasma BA contents, upregulated the expression of hepatic FXR and downstream target enzymes and transporters. Meanwhile, YCD significantly induced the expressions of intestinal FXR and FGF15 and hepatic FGFR4. In contrast, the hepatic protective effect of YCD on cholestasis was abolished in Fxr-deficient mice. CONCLUSION: YCD protects against cholestatic liver injury induced by a CA diet by restoring the homeostasis of BAs via activation of the liver FXR/SHP and ileal FXR/FGF15 signaling pathways. Furthermore, chlorogenic acid and caffeic acid may be the pharmacological agents in YCD responsible for protecting against cholestatic liver injury.