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ObjectivesThe goal of the study was to determine whether endoscopic ultrasound (EUS)-guided biliary drainage (EUS-BD) is comparable to conventional transpapillary stenting with endoscopic retrograde cholangiopancreatography (ERCP) in palliation of malignant distal biliary obstruction. Although ERCP for the palliation of malignant biliary obstruction is the standard of care, post-procedure pancreatitis and stent dysfunctions are not uncommon. While EUS-BD has garnered interest as a viable alternative when ERCP is impossible, its role as a primary palliation of malignant distal biliary obstruction is yet to be proven.MethodsWe performed random allocation to EUS-BD or ERCP in 125 patients with unresectable malignant distal biliary obstruction at four tertiary academic referral centers in South Korea.ResultsTechnical success rates were 93.8% (60/64) for EUS-BD and 90.2% (55/61) for ERCP (difference 3.6%, 95% 1-sided confidence interval lower limit −4.4%, P = 0.003 for noninferiority margin of 10%). Clinical success rates were 90.0% (54/60) in EUS-BD and 94.5% (52/55) in ERCP (P = 0.49). Lower rates of overall adverse events (6.3% vs 19.7%, P = 0.03) including post-procedure pancreatitis (0 vs 14.8%), reintervention (15.6% vs 42.6%), and higher rate of stent patency (85.1% vs 48.9%) were observed with EUS-BD. EUS-BD was also associated with more preserved quality of life (QOL) than transpapillary stenting after 12 weeks of the procedure.ConclusionsThis study demonstrated comparable technical and clinical success rates between EUS-BD and ERCP in relief of malignant distal biliary obstruction. Substantially longer duration of patency coupled with lower rates of adverse events and reintervention, and more preserved QOL were observed with EUS-BD (cris.nih.go.kr, Identifier: KCT0001396, https://cris.nih.go.kr/cris/search/search_result_st01_en.jsp?seq=9716<ype=&rtype=).

INTRODUCTION:The incidence of postendoscopic retrograde cholangiopancreatography (ERCP) infections is reported to be up to 18% in patients with biliary obstruction. Antibiotic prophylaxis may reduce the risk of infectious complications after ERCP; however, the clinical value of prophylactic antibiotics in ERCP remains controversial.METHODS:We conducted a double-blind, placebo-controlled, randomized trial to investigate whether the use of prophylactic antibiotics would reduce infectious complications after ERCP in patients with biliary obstruction. We randomly assigned patients in a 1:1 ratio to receive either a single dose of 1 g intravenous cefoxitin or normal saline as a placebo 30 minutes before undergoing ERCP. The primary outcome was the incidence of infectious complications after ERCP.RESULTS:We enrolled 378 patients, and 189 patients were assigned to each group. The risk of infectious complications after ERCP was 2.8% (5 of 176 patients) in the antibiotic prophylaxis group and 9.8% (17 of 173 patients) in the placebo group (risk ratio, 0.29; 95% confidence interval [CI], 0.11-0.74, P = 0.0073). The incidence rates of bacteremia were 2.3% (4 of 176 patients) and 6.4% (11 of 173 patients), respectively (risk ratio, 0.36; 95% CI, 0.12-1.04; P = 0.0599). The incidence rate of cholangitis was 1.7% (3 of 176 patients) in the antibiotic prophylaxis group and 6.4% (11 of 173 patients) in the placebo group (risk ratio, 0.27; 95% CI, 0.08-0.87; P = 0.0267).DISCUSSION:Antibiotic prophylaxis before ERCP in patients with biliary obstruction resulted in a significantly lower risk of infectious complications, especially cholangitis, than placebo (ClinicalTrials.gov trial number NCT02958059).

There is growing interest in, but limited data about, intestinal bile acid transport inhibitors as treatment for cholestatic liver disease. The current analyses combine two similar randomized placebo‐controlled trials with subsequent extension phases investigating the impact of maralixibat in children with severe cholestasis secondary to Alagille Syndrome (n = 57). The primary outcomes were measures of pruritus (ItchRO[Obs]) and clinician scratch scale (CSS), both increasing in severity from 0 to 4) and quality of life (QoL) (Parent PedsQL and Multidimensional Fatigue Scale module [MFS] scaled 0–100 with increased QoL) at week 48 of the extension phase relative to the baseline of the placebo‐controlled trials (week 13). Secondary assessments included other clinical and biochemical parameters assessed in participants at week 72 or end of treatment (after week 48). At week 48, statistically and clinically significant least square mean (95% CI) improvements in pruritus and QoL were observed (ItchRO[Obs] −1.59 [−1.81, −1.36], CSS −1.36 [−1.67, −1.05], PedsQL +10.17 [4.48, 15.86], and multidimension fatigue [MFS] +13.97 [7.85, 20.08]). At week 48, serum bile acids, platelet count, and cholesterol decreased, whereas alanine aminotransferase (ALT) increased and total bilirubin (TB) and albumin were stable. Changes were durable at week 72 and end of treatment. There were no deaths; 2 participants underwent liver transplantation. Study drug was discontinued in 9 participants after treatment‐emergent adverse events, 6 of which were events of increased ALT or TB. Conclusion: Maralixibat administration was associated with marked improvement in pruritus and QoL. Interpretation of these findings is complicated by the complex natural history of severe cholestasis in Alagille syndrome. Potential attribution of an impact of maralixibat or other IBATi on disease progression in pediatric cholestasis may require continued long‐term follow‐up of individuals receiving IBATi and a relevant contemporaneous natural history cohort. Future investigations of IBATi in cholestatic liver disease may need to delineate the mechanisms of action including effects on bile acid composition, the intestinal microbiome and the gut‐liver axis.

Gastrointestinal amyloidosis is a condition caused by the deposition of extracellular protein fragments. It can be associated with complex and diverse pathways and can have numerous manifestations and etiologies. Hepatic amyloid light-chain (AL) amyloidosis is a rare disorder characterized by the deposition of the insoluble amyloid protein in the liver. The clinical presentations of AL amyloidosis are frequently non-specific. In this case report, we describe a patient with amyloidosis, who initially presented with an unusual case of severe intrahepatic cholestasis, which followed a rapidly progressive clinical course that was associated with the acute hypercalcemic crisis. The diagnosis of amyloidosis was made after the liver and bone biopsies were performed. Our findings revealed that AL amyloidosis should be considered, when a patient presents with cholestatic hepatitis, renal failure, and hypercalcemia.

Patients suffering from cholestasis, the slowing or stoppage of bile flow, commonly report experiencing an intense, chronic itch. Numerous pruritogens are up-regulated in cholestatic patient sera, including bile acids (BAs). Acute injection of BAs results in itch in both mice and humans, and BA-modulating therapy is effective in controlling patient itch. Here, we present evidence that human sensory neuron-expressed Mas-related G protein-coupled receptor X4 (MRGPRX4), an orphan member of the Mrgpr family of GPCRs, is a BA receptor. Using Ca2+ imaging, we determined that pathophysiologically relevant levels of numerous BAs activated MRGPRX4. No mouse Mrgpr orthologs were activated by BAs. To assess the in vivo relevance of BA activation of MRGPRX4, we generated a humanized mouse with targeted expression of MRGPRX4 in itch-encoding sensory neurons. BAs activated MRGPRX4⁺ sensory neurons at higher levels compared with WT neurons. Compared with control animals, MRGPRX4⁺ mice scratched more upon acute injection of BAs and in a model of cholestatic itch. Overall, these data suggest that targeting MRGPRX4 is a promising strategy for alleviating cholestatic itch.

Pruritus in cholestatic liver diseases can be a major burden and dramatically impair the quality of life of those affected. Here, we provide an update on the latest insights into the molecular pathogenesis of and novel therapeutic approaches for cholestasis-associated itch. Endogenous and exogenous small-molecule pruritogen candidates bind to their receptors on unmyelinated itch C-fibres in the skin. Candidate pruritogens in cholestasis include certain lysophospholipids and sulfated progesterone metabolites, among others, whereas total bile acid or bilirubin conjugates seem unlikely to have a dominant role in the pathogenesis of cholestasis-associated pruritus. Transmission of itch signals via primary, secondary and tertiary itch neurons to the postcentral gyrus and activation of scratch responses offer various targets for therapeutic intervention. At present, evidence-based treatment options for pruritus in fibrosing cholangiopathies, such as primary biliary cholangitis and primary sclerosing cholangitis, are the peroxisome proliferator-associated receptor (PPAR) agonist bezafibrate and the pregnane X receptor (PXR) agonist rifampicin. In pruritus of intrahepatic cholestasis of pregnancy, ursodeoxycholic acid is recommended and might be supported in the third trimester by rifampicin if needed. Alternatively, non-absorbable anion exchange resins, such as cholestyramine, can be administered, albeit with poor trial evidence. Liver transplantation for intolerable refractory pruritus has become an extremely rare therapeutic strategy.Pruritus in cholestatic liver diseases is a frequent symptom that impairs quality of life. This Review describes the mechanisms underlying cholestasis-associated itch, discusses potential pruritogens, and highlights therapeutic approaches to manage pruritus in various conditions, including primary biliary cholangitis, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy.

Cholestasis describes impairment in bile formation or flow which can manifest clinically with fatigue, pruritus, and jaundice. The differential diagnosis of cholestatic liver diseases is broad, and the etiologies of cholestasis vary in the anatomical location of the defect and acuity of presentation. Cholestasis may occur in a variety of clinical scenarios. Therefore, it is important for a diverse audience with varied clinical practices to have a basic understanding of manifestations of cholestatic liver diseases.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree. The majority of PSC patients suffer from concomitant inflammatory bowel disease (IBD), which has been suggested to promote disease development and progression. However, the molecular mechanisms by which intestinal inflammation may aggravate cholestatic liver disease remain incompletely understood. Here, we employ an IBD-PSC mouse model to investigate the impact of colitis on bile acid metabolism and cholestatic liver injury. Unexpectedly, intestinal inflammation and barrier impairment improve acute cholestatic liver injury and result in reduced liver fibrosis in a chronic colitis model. This phenotype is independent of colitis-induced alterations of microbial bile acid metabolism but mediated via hepatocellular NF-κB activation by lipopolysaccharide (LPS), which suppresses bile acid metabolism in-vitro and in-vivo. This study identifies a colitis-triggered protective circuit suppressing cholestatic liver disease and encourages multi-organ treatment strategies for PSC. The association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) has been known for decades, but mechanisms of gut-liver crosstalk are incompletely understood. Here, the authors show a colitis-triggered protective circuit suppressing cholestatic liver disease which encourages multi-organ treatment strategies for PSC.

Purpose Biallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure. The occurrence of SCYL1 deficiency among patients with previously undetermined infantile cholestasis or acute liver failure has not been studied; furthermore, little is known regarding the hepatic phenotype. Methods We aimed to identify patients with SCYL1 variants within an exome-sequencing study of individuals with infantile cholestasis or acute liver failure of unknown etiology. Deep clinical and biochemical phenotyping plus analysis of liver biopsies and functional studies on fibroblasts were performed. Results Seven patients from five families with biallelic SCYL1 variants were identified. The main clinical phenotype was recurrent low γ-glutamyl-transferase (GGT) cholestasis or acute liver failure with onset in infancy and a variable neurological phenotype of later onset (CALFAN syndrome). Liver crises were triggered by febrile infections and were transient, but fibrosis developed. Functional studies emphasize that SCYL1 deficiency is linked to impaired intracellular trafficking. Conclusion SCYL1 deficiency can cause recurrent low-GGT cholestatic liver dysfunction in conjunction with a variable neurological phenotype. Like NBAS deficiency, it is a member of the emerging group of congenital disorders of intracellular trafficking causing hepatopathy.

Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucine-enkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide- and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.