Chronic Cholestasis Research Articles

Prevalence of Primary Biliary Cholangitis in a Cohort of Primary Sjögren's Syndrome Patients.

ObjectiveTo analyze the prevalence and clinical progression of primary biliary cholangitis (PBC) in patients with primary Sjögren's syndrome (pSS) and possible associations between biochemical and immunological features and the development of PBC.MethodsWe retrospectively reviewed a cohort of 115 pSS patients followed up in an outpatient clinic from 1987 to 2020, without a history of liver disease, and looked for the presence of PBC through analysis of several biochemical, immunological, and histologic characteristics.ResultsTwenty patients (17.4%) had chronic cholestatic liver biochemistry. After exclusion of extrahepatic liver disease by abdominal ultrasound, 13 of them were tested for antimitochondrial autoantibodies (AMA) detected by indirect immunofluorescence (IF), of which five tested positive, fulfilling the diagnostic criteria for PBC. Three of the five PBC patients and three of the eight chronic cholestasis AMA-negative patients were further investigated with liver biopsy, which showed features of PBC in all three PBC patients and in one of the chronic cholestasis AMA-negative patients, allowing for the diagnosis of AMA-negative PBC in the latter. The remaining two AMA-negative patients had liver histology compatible with autoimmune hepatitis and unspecific findings, respectively. Overall, six (5.2%) patients with pSS had AMA-positive PBC (n=5) or AMA-negative PBC (n=1). Comparing immunological characteristics between PBC and non-PBC patients, we found that PBC patients had a higher mean maximum erythrocyte sedimentation rate (ESR) during follow-up than patients without PBC. All PBC patients were treated with ursodeoxycholic acid (UDCA) and after treatment with UDCA, only one patient showed biochemical and clinical progression of PBC, with increasing alkaline phosphatase and total bilirubin levels, eventually progressing to cirrhosis.ConclusionsAmong patients with pSS, PBC had an overall prevalence of six of 115 (5.2%). Higher ESR was a feature associated with PBC patients. In our cohort, after initiation of UDCA treatment, PBC showed predominantly slow progress, with only one patient progressing to cirrhosis during follow-up.

Serum metabolomics of Tibetan medicine Ershiwuwei Songshi Pills against chronic cholestasis in mice

A chronic cholestasis model was induced in mice by feeding a diet containing 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine(DDC). The effects of Ershiwuwei Songshi Pills(ESP) on endogenous metabolites in mice with chronic cholestasis were investigated by metabolomics analysis based on liquid chromatography-mass spectrometry(LC-MS). The results showed that ESP was effective in improving pathological injury and reducing serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), alkaline phosphatase(ALP), and total bile acid in the model mice. Meanwhile, 13 common differential metabolites were revealed in metabolomic screening between the model/control group and the model/ESP group, including uric acid, glycolaldehyde, kynurenine, flavin adenine dinucleotide, L-3-phenyllactic acid, I-urobilin, leukotriene D4(LTD4), taurocholic acid, trioxilin A3, D-inositol-1,4-diphosphate, PC [16:0/20:2(11Z,14Z)], PC[14:0/22:2(13Z,16Z)], and PC[20:4(5Z,8Z,11Z,14Z)/20:4(5Z,8Z,11Z,14Z)]. After ESP intervention, the levels of all 13 differential metabolites were significantly retraced, and pathway analysis showed that ESP achieved its therapeutic effect mainly by affecting arachidonic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism, and primary bile acid biosynthesis. This study elucidated the mechanism of action of ESP against chronic cholestasis based on metabolites.

Combination therapy of ursodeoxycholic acid and glucocorticoid and (or) immunosuppressant in patients with primary biliary cholangitis: A meta-analysis.

Background/objectives:Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune cholestasis liver disease. There were many studies comparing a combination of glucocorticoids and/or immunosuppressants to a single UDCA therapy in PBC patients, while the literature demonstrated divergent finds. To evaluate the effectiveness of ursodeoxycholic acid (UDCA) combined with glucocorticoids and (or) immunosuppressants on biochemistry, immunology, histology, clinical symptoms, and adverse reactions of PBC from the perspective of evidence-based medicine.Materials and methods:PubMed, web of science, the Cochrane Library, EMBASE databases were searched to collect clinical randomized trials and self-control studies of UDCA combined with glucocorticoids and (or) immunosuppressants and UDCA monotherapy in the treatment of PBC. The retrieval time is from the establishment of the database to August 2020. Two reviewers independently screened literature, extracted data and evaluated the bias of included studies. Revman 5.3 software was used for meta-analysis.Results:Six studies including 201 patients were included. The meta-analysis found that the combination therapy can improve some biochemical indexes, immunological indexes, and clinical symptoms of patients with PBC. However, combination therapy has no significant improvement in other biochemical indicators which respond to liver and bile duct damage, such as ALT, GGT, and ALB. Besides, the improvement of liver histology is limited, and the incidence of adverse events is higher.Conclusion:Overall, the combination therapy showed no improvement in key biochemical parameters and limited improvement in liver pathology. Besides, the side effects were more serious. Therefore, in the current treatment regimen, it is not recommended for PBC patients.

Uremic Pruritis in Patients of End Stage Renal Disease on Thrice-Weekly Hemodialysis

Objective: To determine the frequency of uremic pruritus in ESRD patients on thrice-weekly maintenance hemodialysis. Study Design: Cross-sectional analytical study Place and Duration of Study: Department of Nephrology, Sir Ganga Ram Hospital, Lahore from 1st Mar 2018 to 15th February 2019. Methodology: Sixty five adult patients on hemodialysis for >3 months duration were included whereas patients on hemodialysis for acute kidney injury duration <3 months and exhibiting clinical or laboratory features of other conditions as chronic skin disease, cholestasis, and malignancies were excluded from the study. Results: The mean age was 48±13.29 years, 46 (70.8%) were males and 19 (29.2%) were females. The mean BMI of patients was 23.73 kg/m2. Thirty one (47.1%) was diabetics and 34(52.9%) was nondiabetics. Hypertension was found in 61(93.9%) while 4(6.2%) were normotensive, 3 (4.6%) were on HD from 6 months to 1 year, while 19(29.4%), 43(66.0%) were on HD for 1 to 3 years and >3 years respectively. Conclusion: The frequency of uremic pruritis in patients on thrice-weekly MHD is 23.1% in our population. Key words: Uremic pruritis, Hemodialusis, End stage renal disease

Human menstrual blood-derived stem cell transplantation suppresses liver injury in DDC-induced chronic cholestasis

BackgroundCholestatic liver injury can lead to serious symptoms and prognoses in the clinic. Currently, an effective medical treatment is not available for cholestatic liver injury. Human menstrual blood-derived stem cells (MenSCs) are considered as an emerging treatment in various diseases. This study aimed to explore the treatment effect of MenSCs in cholestatic liver injury.MethodsThe treatment effect of MenSCs on chronic cholestatic liver injury was verified in 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC)-induced C57/BL6 mice. Pathological, fibrosis area in the liver tissue and serum liver enzymes were tested. Proteomics and western blot were used to explore the related targets and molecular mechanisms. Adeno-associated virus (AAV) 9-infected mice were applied for verification.ResultsMenSCs markedly improved the survival rate of the DDC-treated mice (60% vs. 100%), and decreased the mouse serum aspartate aminotransferase (AST) (169.4 vs. 108.0 U/L, p < 0.001), alanine aminotransferase (ALT) (279.0 vs. 228.9 U/L, p < 0.01), alkaline phosphatase (ALP) (45.6 vs. 10.6 U/L, p < 0.0001), direct bilirubin (DBIL) (108.3 vs. 14.0 μmol/L, p < 0.0001) and total bilirubin (TBIL) (179.2 vs. 43.3 μmol/L, p < 0.0001) levels as well as intrahepatic cholestasis, bile duct dilation and fibrotic areas (16.12 vs. 6.57%, p < 0.05). The results further indicated that MenSCs repaired the DDC-induced liver tight junction (TJ) pathway and bile transporter (OATP2, BSEP and NTCP1) injury, thereby inhibiting COL1A1, α-SMA and TGF-β1 activation by upregulating liver β-catenin expression.ConclusionsMenSC transplantation could be an effective treatment method for cholestatic liver injury in mice. MenSCs may exhibit therapeutic effects by regulating β-catenin expression.

PRIMARY BILIARY CHOLANGITIS COMPLICATED WITH ULCERATIVE COLITIS: A CASE REPORT

Liver involvement is not unusual in patients with inflammatory bowel disease (IBD), where one third of patients have abnormal liver biochemical tests, becoming a diagnostic challenge. Primary biliary cholangitis (CPB) is an autoimmune liver disease that presents with chronic cholestasis, the presence of specific antibodies and histological findings of destructive non-suppurative cholangitis. Genetic, immunological, and environmental factors that contribute to the pathogenesis of IBD may also contribute to associated hepatobiliary disorders. Objective: Present the case of a 67-year-old woman who consulted for cholestatic symptoms. Medical record of smoking for 25 years was suspended 15 years ago with a smoking index of 5. She reported a history of weakness, asthenia, self-limited palmar and plantar pruritus of 2 years of evolution, associated with abnormal liver function tests (total bilirubin 1.8 mg / dl, INR 1.40, albumin 3.2 g / dL). The initial physical examination revealed jaundice in the sclera, palmar erythema, evidence of telangiectasia in the abdomen, collateral circulation with medusa caput, positive ascitic wave, and splenomegaly. R factor is cholestatic, with alkaline phosphatase of 416 U / L, gamma glutamyl transpeptidase 660 U / L, alanine transferase 59 U / L, for which possible viral and autoimmune causes are addressed as the first possibility, reflecting antimitochondrial antibodies with high titers (278 U / L), associated with immunoglobulin G of 2490 mg / dl and immunoglobulin M of 734 mg / dl. During her one-year follow-up, she reported the onset of diarrheal stools Bristol 6, 2 to 3 episodes per day, with occasional urgency and with inflammatory characteristics, due to the presence of mucus and blood. Infectious causes are ruled out, elevated acute phase reactants are reported, followed up with a colonoscopy and biopsy samples, reporting the presence of nonspecific proctitis, chronic colitis with focal ulceration, lymphoid aggregates, focal atrophy, and glandular distortion compatible with ulcerative colitis (UC). (Panel A) Due to the unusual association between UC and PBC, magnetic resonance cholangiography was requested, ruling out the overlap syndrome between primary biliary cholangitis and primary sclerosing cholangitis. (Panel B) A diverse heterogeneous group of hepatobiliary manifestations is reported in both UC and CD, and approximately 5% of adults with IBD have developed chronic liver disease. PBC is not usually associated with IBD, and concomitant reported cases are anecdotal. The presentations are different than the typical CBP without UC. PBC usually affects middle-aged women. The sex ratio is 10: 1 (female to male) and the mean age at diagnosis is 57.5 years. While the disease tends to affect men more often, with a female / male sex ratio of 2: 1 when associated with IBD. The distribution of ulcerative colitis in PBC patients is usually mild with limited bowel involvement. In a review by Tasa et al., eleven of 15 patients described left side colitis and proctitis. The association between PBC and UC remains rare, as there are still few reported cases regarding the combined presentation of these diseases. Although PSC is the most specific hepatobiliary manifestation among UC patients with cholestasis, PBC should be considered in those with unexplained intrahepatic cholestasis. The use of a reliable test such as AMAs is of utmost importance to avoid misdiagnosis and/or under diagnosis. The authors declare that there is no conflict of interest.

CONNECTIVE TISSUE GROWTH FACTOR (CTGF) AS A PROMOTER IN THE DEVELOPMENT OF FIBROSIS IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS

Primary biliary cholangitis (PBC), an immune-mediated disease, is characterized by destroying the intrahepatic bile ducts, leading to progressive damage to the biliary tree, cholestasis, and development of progressive fibrosis leading to cirrhosis with all its complications. The development of fibrosis is multifactorial and includes connective tissue growth factor (CTGF). in a mouse model of cholestasis by bile duct ligation, the hepatic and serum increase in CTGF associated with the progression of fibrosis was demonstrated. Our goal was to determine the relationship between CTGF levels and their association with the development of fibrosis in patients with PBC. Prospective, cross-sectional, and analytical study, including patients with PBC. The degree of fibrosis was determined by transient elastography (Fibroscan). Serum concentrations of FCTC-8pg/ml were quantified, for statistical analysis, the SPSS version 25.0 software was used; the medians (Q3, Q1) of CTGF, alkaline phosphatase, gamma-glutamyl-transpeptidase, and degree of fibrosis were compared with the Mann-Whitney U test with significantly less than 0.05. We included 30 patients, 29 women (96.6%) and 1 man (3.4%), with a mean age of 55.5±12.4 years. Overexpression of CTGF protein was shown in 28 subjects (93.3%). Regarding the degree of fibrosis, all patients were categorized into one of two stages: Significant fibrosis (F2) and cirrhosis (F4). The F2 group had 11 patients with a median and standard deviation for CTGF of 915.9 and 522.9, respectively; The F4 group had 19 patients who showed a median: 945.7 (1313.85-738.32); p :0.025 . In relation to the differences between fibrosis levels and markers of alkaline phosphatase cholestasis, the median and interquartile ranges F2: 79 (180.60) F4: 169(266-5.84) p : 0.066 ; GGT: F2: 1.51(7.7-1,04); F4: 1.2(2-1.92) p:0.746 In (Figure 1) The difference in medians of patients with different degrees of fibrosis and different concentration of CTGF is shown, confirming the association between peptide and the development and progression of fibrosis. According to the results obtained in patients with CBP and chronic cholestasis, the increase in CTGF showed significant differences between the degree of fibrosis and its levels; this could perhaps be interpreted as if it were an important factor for the development and progression of liver fibrosis, taking into account the antecedent of the initial study in mice with bile duct ligation and secondary cholestasis, where this factor was overexpressed at the hepatic and serum level in subjects with advanced fibrosis. It will be important to add more samples to this work and compare it with healthy controls to have better evidence. Connective tissue growth factor (CTGF) probably participates directly in the processes of synthesis of extracellular matrix and therefore in the progression of fibrosis in subjects with primary biliary cholangitis, which makes it a possibility of a therapeutic target to develop in future studies. The authors declare that there is no conflict of interest.

Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- Mice.

Background & AimsThe endocannabinoid system is involved in the modulation of inflammatory, fibrotic, metabolic, and carcinogenesis-associated signaling pathways via cannabinoid receptor (CB)1 and CB2. We hypothesized that the pharmacologic antagonization of CB1 receptor improves cholestasis in Abcb4-/- mice.MethodsAfter weaning, male Abcb4-/- mice were treated orally with rimonabant (a specific antagonist of CB1) or ACEA (an agonist of CB1) until up to 16 weeks of age. Liver tissue and serum were isolated and examined by means of serum analysis, quantitative real time polymerase chain reaction, Western blot, immunohistochemistry, and enzyme function. Untreated Abcb4-/- and Bagg Albino Mouse/c wild-type mice served as controls.ResultsCholestasis-induced symptoms such as liver damage, bile duct proliferation, and enhanced circulating bile acids were improved by CB1 antagonization. Rimonabant treatment also improved Phosphoenolpyruvat-Carboxykinase expression and reduced inflammation and the acute-phase response. The carcinogenesis-associated cellular-Jun N-terminal kinase/cellular-JUN and signal transducer and activator of transcription 3 signaling pathways activated in Abcb4-/- mice were reduced to wild-type level by CB1 antagonization.ConclusionsWe showed a protective effect of oral CB1 antagonization in chronic cholestasis using the established Abcb4-/- model. Our results suggest that pharmacologic antagonization of the CB1 receptor could have a therapeutic benefit in cholestasis-associated metabolic changes, liver damage, inflammation, and carcinogenesis.

Liver histology in short telomere syndrome: A case report and review of the literature

Abstract Introduction/Objective Short telomere syndrome (STS) is a genetically inherited syndrome resulting in premature telomere shortening. STS encompasses a spectrum of clinical manifestations, including dyskeratosis congenita, premature hair graying, bone marrow failure, immunodeficiency, pulmonary fibrosis and liver disease. Liver histopathologic features in STS patients have not been well characterized. Methods/Case Report A 46-year-old man presented for dyspnea and cryptogenic cirrhosis. He had a complicated medical history significant for immune thrombocytopenic purpura and splenectomy, recurrent respiratory tract infections, pneumonia, sepsis, primary immunodeficiency, pulmonary mucosa-associated lymphoid tissue lymphoma, and severe hepatopulmonary syndrome. He and his brother had gray hair in their late 20s. He also had a long history of intermittently elevated liver enzymes starting at age 33. A liver biopsy performed 12 years before showed chronic portal inflammation with hepatocellular damage without significant fibrosis. These clinical manifestations prompted an evaluation for a possible telomere biology disorder, which revealed the telomere length was critically short and fell at or below the first percentile for age, supportive of the diagnosis. The most recent liver biopsy showed marked portal lymphocytic inflammation with interface hepatitis, bile ductular reaction and frequent foci of lobular inflammation with focal hepatocyte dropout. Some hepatocytes around the portal tracts were swollen with feathery degeneration and occasional Mallory-Denk bodies. A Rhodanine stain highlighted copper granules in the periportal hepatocytes, suggesting chronic cholestasis. Trichrome and reticulin stains demonstrated portal/periportal/pericellular/perisinusoidal fibrosis and focal bridging fibrosis. Results (if a Case Study enter NA) NA Conclusion Partly due to the rarity of STS and the risk of bleeding associated with biopsies, liver histology was described in only few limited studies with small samples of STS patients, including inflammation, nodular regenerative hyperplasia, steatohepatitis, hemosiderosis, cholestasis, cirrhosis, and large cell change of hepatocytes. Our case and others suggest liver disease associated with STS demonstrates a spectrum of histopathology. Being aware of these histomorphologic features in STS is important for establishing the correct diagnosis.

S1655 COVID-19-Induced Persistent Jaundice With Secondary Sclerosing Cholangitis

Introduction: The ongoing COVID-19 infection has demonstrated potential devastating organ damage including direct liver injury;however the long-term complications are limited. We demonstrate a case of post COVID-19 cholangiopathy with prolonged hyperbilirubinemia partially responsive to ursodiol. Case Description/Methods: Patient is a 59-year-old male presented with weakness and COVID-19 infection. His clinical course continued to deteriorate with multi-organ failure. After a prolonged ICU course, patient's respiratory failure improved, but had a persistent hyperbilirubinemia. Patient underwent ERCP showing a normal-appearing common bile duct with no evidence of any filling defects. He underwent autoimmune workup with positive ASMA with a titer 1:20, but negative ANA and AMA. HIDA scan showed poor clearance and no activity within the biliary tree, suggestive of underlying intrinsic hepatic abnormality. MRCP showed innumerable cystic dilation and areas of narrowing. Liver biopsy showed extensive cholestatic changes, perisinusoidal and bridging fibrosis, and iron deposition primarily within Kupffer cells. Repeat ERCP showed diffuse intrahepatic cholangiopathy in a pattern most consistent with PSC. Patient was started on ursodiol 250 mg three times a day with a mild improvement of bilirubin levels of about 25%. After a 6-month hospital course, patient was discharged to an acute care facility. Upon discharge, patient remained jaundice with persistent liver enzymes and a bilirubin of 21 mg/dL. Discussion: We described a case of an individual who recovered from severe sepsis secondary to COVID-19 developing significant post COVID-19 cholangiopathy. Despite recovery, patient continued to have chronic cholestasis and liver injury. Liver biopsy demonstrated predominant cholangiocyte injury with bridging fibrosis consistent with progression of secondary sclerosing cholangitis (SCC). Based on histopathological changes, it is postulated that damage occurs secondary to direct bile duct ischemia. While no standard therapies exist and only 1 case report showing post COVID-19 liver transplantion, many therapeutic options are limited. However, in our case, ursodiol demonstrated a significant improvement with a plateau of about 25% of the total bilirubin level. SCC carries a poor outcome in the general population without a liver transplantation. Early identification and treatment will be vital with the ongoing pandemic as SCC is associated with considerable morbidity and mortality left untreated.

Apical sodium-dependent bile acid transporter inhibition in children with Alagille syndrome

In The Lancet, Emmanuel Gonzales and colleagues 1 Gonzales E Hardikar W Stormon M et al. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study. Lancet. 2021; 398: 1581-1592 Google Scholar present the findings of the phase 2 placebo-controlled, randomised withdrawal period, open-label, extension ICONIC study of the apical sodium-dependent bile acid transporter (ASBT) inhibitor, maralixibat, in paediatric patients with Alagille syndrome. Alagille syndrome is a cholestatic liver disease that leads to pruritus, xanthomas, and impaired quality of life. Surgical interventions to interrupt the enterohepatic bile acid circulation or liver transplantation are often pursued 2 Wang KS Tiao G Bass LM et al. Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis. Hepatology. 2017; 65: 1645-1654 Google Scholar , 3 Kamath BM Ye W Goodrich NP et al. Outcomes of childhood cholestasis in Alagille syndrome: results of a multicenter observational study. Hepatol Commun. 2020; 4: 387-398 Google Scholar because there are no approved medical therapies. ASBT has a key role in the enterohepatic circulation of bile acids because it absorbs approximately 95% of bile acids from the terminal ileum. Because intrahepatic bile acids are thought to be the main driver behind hepatocellular injury in cholestatic diseases, pharmacological inhibition of ASBT has the potential to not only improve pruritus, but also disease trajectory. Studies in mouse models of cholestasis have shown that ASBT inhibition can decrease intrahepatic bile acid concentrations and improve fibrosis and disease progression. 4 Miethke AG Zhang W Simmons J et al. Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice. Hepatology. 2016; 63: 512-523 Google Scholar , 5 Baghdasaryan A Fuchs CD Osterreicher CH et al. Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis. J Hepatol. 2016; 64: 674-681 Google Scholar Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 studyIn children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. Full-Text PDF

The Possible Protective Effect of Selenium on Liver Dysfunction in a Rat Model of Extrahepatic Cholestasis

Abstract Background Oxidative stress and inflammation are primarily implicated in the development and progression of liver injury during cholestasis. Selenium, a known essential antioxidant trace element, was found to provide a remarkable antioxidant and anti-inflammatory effects on various diseases. Aim This study was planned to evaluate the possible protective effect of selenium supplementation in a rat model of chronic cholestasis. Design Experimental study. Methods This study was carried out on adult male rats allocated randomly into sham, bile duct ligated (BDL), and BDL-selenium treated (BDL-Se) groups. Sodium selenite was given by gavage daily, in a dose of 100 µg/kg for 6 weeks, starting 2 weeks before the BDL. Results BDL group presented a significant increase in serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and liver levels of malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), and transforming growth factor beta 1(TGF-β1), associated with a significant decrease in serum levels of total proteins (TP) compared to sham group . Selenium supplementation significantly lowered serum levels of AST, ALT, ALP, and liver levels of MDA, TNF-α, and TGF-β1 along with a significant increase in serum TP in BDL-Se group versus BDL rats. Histological analysis of liver showed a significant attenuation of the inflammatory score and a significant decrease in the percentage area of collagen deposition in BDL-Se group versus BDL rats. Conclusion Selenium supplementation reduces liver injury and improves liver functions in experimental cholestasis probably by its antioxidant and anti-inflammatory activities, which further alleviate the liver fibrosis. Abbreviations BDL: bile duct ligated group, BDL-Se: bile duct ligated-selenium group, MDA: malondialdehyde, TNF-α: tumour necrosis factor-alpha, TGF-β1: transforming growth factor- beta1, ROS: reactive oxygen species, mRNA: messenger RNA, IL-6: interleukin-6, BW: body weight, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, TP: total proteins, CCl4: carbon tetrachloride, GPx: glutathione peroxidase enzyme, SOD: superoxide dismutase, IL-1: interleukin-1.

Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study

Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome. ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment. Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 μmol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 μmol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity. In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. Mirum Pharmaceuticals.

Malnutrition in Pediatric Chronic Cholestatic Disease: An Up-to-Date Overview

Despite recent advances, the causes of and effective therapies for pediatric chronic cholestatic diseases remain elusive, and many patients progress to liver failure and need liver transplantation. Malnutrition is a common complication in these patients and is a well-recognized, tremendous challenge for the clinician. We undertook a narrative review of both recent and relevant older literature, published during the last 20 years, for studies linking nutrition to pediatric chronic cholestasis. The collected data confirm that malnutrition and failure to thrive are associated with increased risks of morbidity and mortality, and they also affect the outcomes of liver transplantation, including long-term survival. Malnutrition in children with chronic liver disease is multifactorial and with multiple potential nutritional deficiencies. To improve life expectancy and the quality of life, patients require careful assessments and appropriate management of their nutritional statuses by multidisciplinary teams, which can identify and/or prevent specific deficiencies and initiate appropriate interventions. Solutions available for the clinical management of these children in general, as well as those directed to specific etiologies, are summarized. We particularly focus on fat-soluble vitamin deficiency and malnutrition due to fat malabsorption. Supplemental feeding, including medium-chain triglycerides, essential fatty acids, branched-chain amino acids, and the extra calories needed to overcome the consequences of anorexia and high energy requirements, is reviewed. Future studies should address the need for further improving commercially available and nutritionally complete infant milk formulae for the dietary management of this fragile category of patients. The aid of a specialist dietitian, educational training regarding nutritional guidelines for stakeholders, and improving family nutritional health literacy appear essential.

Inhibition of autotaxin by bile salts and bile salt-like molecules increases its expression by feedback regulation

BackgroundAutotaxin is an enzyme that converts lysophospholipid into lysophosphatidic acid (LPA), a highly potent signaling molecule through a range of LPA receptors. It is therefore important to investigate which factors play a role in regulating ATX expression. Since we have reported that ATX levels increase dramatically in patients with various forms of cholestasis, we embarked on a study to reveal factors that influence the enzyme activity ATX as well as its expression level in vitro and in vivo. MethodsBile from cholestatic patients was fractionated by HPLC and analyzed for modulation of ATX activity. ATX expression was measured in fibroblasts upon stimulation or inhibition of LPA signaling. ResultsSurprisingly, ATX activity was stimulated by most forms of its product LPA, but it was inhibited by bile salts and bile salt-like molecules, particularly by 3-OH sulfated bile salts and sulfated progesterone metabolites that are known to accumulate during chronic cholestasis and cholestasis of pregnancy, respectively. Activation of fibroblasts by LPA decreased ATX expression by 72%. Conversely, inhibition of LPA signaling increased ATX expression 3-fold, indicating strong feedback regulation by LPA signaling. In fibroblasts, we could verify that inhibition of ATX activity by bile salts induces its expression. Furthermore, induction of cholestasis in mice causes increased plasma ATX activity. ConclusionsMultiple biliary compounds that accumulate in the systemic circulation during cholestasis inhibit ATX activity and thereby increase ATX expression through feedback regulation. This mechanism may contribute to increased serum ATX activity in patients with cholestasis.

Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process

Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process

Modern imaging of cholangitis.

Cholangitis refers to inflammation of the bile ducts with or without accompanying infection. When intermittent or persistent inflammation lasts 6 months or more, the condition is classified as chronic cholangitis. Otherwise, it is considered an acute cholangitis. Cholangitis can also be classified according to the inciting agent, e.g. complete mechanical obstruction, which is the leading cause of acute cholangitis, longstanding partial mechanical blockage, or immune-mediated bile duct damage that results in chronic cholangitis.The work-up for cholangitis is based upon medical history, clinical presentation, and initial laboratory tests. Whereas ultrasound is the first-line imaging modality used to identify bile duct dilatation in patients with colicky abdominal pain, cross-sectional imaging is preferable when symptoms cannot be primarily localised to the hepatobiliary system. CT is very useful in oncologic, trauma, or postoperative patients. Otherwise, magnetic resonance cholangiopancreatography is the method of choice to diagnose acute and chronic biliary disorders, providing an excellent anatomic overview and, if gadoxetic acid is injected, simultaneously delivering morphological and functional information about the hepatobiliary system. If brush cytology, biopsy, assessment of the prepapillary common bile duct, stricture dilatation, or stenting is necessary, then endoscopic ultrasound and/or retrograde cholangiography are performed. Finally, when the pathologic duct is inaccessible from the duodenum or stomach, percutaneous transhepatic cholangiography is an option. The pace of the work-up depends upon the severity of cholestasis on presentation. Whereas sepsis, hypotension, and/or Charcot’s triad warrant immediate investigation and management, chronic cholestasis can be electively evaluated.This overview article will cover the common cholangitides, emphasising our clinical experience with the chronic cholestatic liver diseases.

Common ABCB4 and ABCB11 Genotypes Are Associated with Idiopathic Chronic Cholestasis in Adults

Introduction: Pathogenic mutations in genes encoding the hepatocanalicular transporters ATP8B1, ABCB11 and ABCB4 are causative for progressive cholestatic liver disease in children. In adults, less severe variants such as the common ABCB4 c.711A>T polymorphism have been associated with intrahepatic cholestasis in pregnancy and elevated liver enzymes. Hence, our aim was to study the role of common polymorphisms in adult patients with chronic unexplained cholestasis. Methods: Screening of outpatients of two university hospitals identified a cohort of 94 patients with chronic cholestasis of unknown origin after thorough exclusion of other causes. Genotyping was performed using TaqMan assays, and frequencies for the ABCB4 rs2109505 (c.711A>T), rs1202283 (c.504T>C), ABCB11 rs2287622 (p.A444V) and rs497692 (c.3084A>G) variants of the study cohort were compared to a cohort of 254 healthy controls. Results: The dominating symptoms of the patients were pruritus and jaundice, though the majority of them did not report symptoms at inclusion. Advanced fibrosis or cirrhosis was present in 11 patients (11.7%) only. Genotyping revealed the presence of the ABCB4 c.711A>T risk variant in 79 patients (84%), a frequency that is significantly (p = 0.037) higher than that in controls (71%). The ABCB11 p.A444V variant was also more frequent in cholestatic patients (p = 0.042). Conclusion: The common ABCB4 c.711A>T and ABCB11 p.A444V polymorphisms are more prevalent in adult patients with idiopathic cholestasis than in healthy controls and may therefore represent risk factors for the development of chronic cholestatic liver disease.

Immune pathogenesis of primary biliary cholangitis

Primary biliary cholangitis (PBC) is an autoimmune liver disease, mainly characterized by chronic progressive cholestasis. The root cause of PBC is the loss of immune tolerance to autoantigen E2 subunit of pyruvate dehydrogenase (PDC-E2). The unique immunobiological characteristics of intrahepatic bile duct epithelial cells make it an active participant in the pathogenesis of PBC. In recent years, the detection rate of PBC has been increasing year by year, but the clinical situation of ursodeoxycholic acid monotherapy has not changed. Therefore, an in-depth understanding of the immune pathogenesis of PBC will help clinicians better prevent and treat diseases.

Drug-Induced Vanishing Bile Duct Syndrome: From Pathogenesis to Diagnosis and Therapeutics.

The most concerned issue in the context of drug/herb-induced chronic cholestasis is vanishing bile duct syndrome. The progressive destruction of intrahepatic bile ducts leading to ductopenia is usually not dose dependent, and has a delayed onset that should be suspected when abnormal serum cholestasis enzyme levels persist despite drug withdrawal. Immune-mediated cholangiocyte injury, direct cholangiocyte damage by drugs or their metabolites once in bile, and sustained exposure to toxic bile salts when biliary epithelium protective defenses are impaired are the main mechanisms of cholangiolar damage. Current therapeutic alternatives are scarce and have not shown consistent beneficial effects so far. This review will summarize the current literature on the main diagnostic tools of ductopenia and its histological features, and the differential diagnostic with other ductopenic diseases. In addition, pathomechanisms will be addressed, as well as the connection between them and the supportive and curative strategies for ductopenia management.