Chronic Cholestatic Disease Research Articles

Up-to-Date Snapshot of Current and Emerging Medical Therapies in Primary Biliary Cholangitis

Background/Objectives: Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic disease of the liver that symptomatically can present with pruritus and fatigue. Its established first- and second-line therapies are ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) although they provide limited symptom management. Liver transplantation offers a potentially curative therapeutic option in refractory cases progressing to cirrhosis. Novel research published after the current guidelines highlights the importance of providing an up-to-date analysis of treatment options available. Methods: In this study, we conducted a literature search using Pubmed, Ovid Medline, and SCOPUS to provide a narrative review of first-line, second-line, and emerging therapies in PBC. Results: UDCA has been well established as a long-term, safe therapy within the literature although it is possible that treatment dosage can be further optimised in refractory patients. It has a favourable side effect profile. Despite improving biochemical markers, histopathological profile, and overall outcomes, up to 30–40% of patients are refractory to it. Age and sex are highlighted as independent indicators of non-responsiveness. This necessitates effective second-line therapies. Future trials could aim to investigate UDCA as a co-first-line therapy. Further supporting results for OCA were found in the interim extension trial of the seminal POISE study. The long-term phase 4 COBOLT trial is still awaiting results to further assess the complications, adherence, and potential adverse effects. It is a viable option in UDCA-refractory patients. The high incidence rate of dose-related pruritis indicates that alternative second-line options are needed. Bezafibrate is an off-label antilipemic agent that shows promise as a prospective second-line therapy option. The landmark BEZURSO trial alleviated some efficacy and safety concerns, but it remains associated with elevated serum creatinine; thus, it should be considered with caution. Other prospective second-line therapies are budesonide, triple therapy, and novel agents such as seladelpar and elafibranor. Conclusions: UDCA should remain the treatment of choice for PBC, though perhaps not as monotherapy. With further investigation, BF shows promise as a new second-line therapy alongside OCA, which it may outperform.

P023 Serological markers of intestinal barrier function in patients with primary sclerosing cholangitis after liver transplantation

Abstract Background Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease associated with inflammatory bowel disease. Liver transplantation (LT) is the only curative treatment for most patients with PSC. Recurrence of PSC (rPSC) is a common long-term complication after liver transplantation in this patient group, affecting graft survival and overall patient survival. There are several lines of evidence indicating that dysregulation of the microbiome and gut barrier dysfunction are key etiologic factors in the pathogenesis of PSC. The aim of this study was to evaluate serological markers of intestinal barrier function in patients with PSC after LT and in control group, to determine potential biomarkers for rPSC. Methods This is a cross-sectional study of patients after LT for PSC at the Institute for Clinical and Experimental Medicine, Prague. The control group consists of patients who underwent liver transplantation for alcohol-related liver disease and/or hepatocellular carcinoma. The rPSC was assessed by MRCP and/or liver biopsy according to the Mayo criteria. IBD status was assessed by endoscopy, biopsy, and faecal calprotectin. We performed ELISA for Zonulin and Reg3a. The Kruskal-Wallis and Mann-Whitney test were used to evaluate the statistical differences. Results A total of 85 patients were included in the study after LT for PSC and 56 controls. rPSC was detected in 18 (21.18%) patients. IBD was diagnosed in 77 (90.5%) patients, of which 3 (3.9%) were categorised as Crohn’s disease. The remainder, 82 patients, were classified as ulcerative colitis, 41.9% with right-sided predominance and 24.3% with back-wash ileitis. The IBD treatment consisted of 5-ASA in 58 patients, azathioprine in 12 patients, vedolizumab in 5 patients, anti-TNFa in 1 patient and 9 patients were on 10 mg or more of prednisone or equivalent. MayoDAI was evaluated at the time of the visit with mean 1.74 (SD ±2.06). There was a significant difference in Reg3a levels between patients with IBD and control subjects (p<0.05, Figure 1.). No significant difference in Reg3a levels was found between rPSC patients and controls (p=0.3). Interestingly, Zonulin levels were significantly higher in the control group than in PSC patients with or without IBD (p<0.001). No significant difference in Reg3a and Zonulin was found between PSC and rPSC patients and between patients in remission and with active IBD. Conclusion Reg3a was associated with PSC-IBD in patients with PSC after LT, but its association with rPSC is unclear and should be investigated in a prospective setting. Zonulin reached higher levels in the control group.

The treatment of primary biliary cholangitis: from shadow to light.

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease characterized by the destruction of the small intrahepatic bile ducts, which can progress to liver cirrhosis. The gold standard in the treatment of PBC is ursodeoxycholic acid (UDCA), which is indicated in all patients with PBC because it improves not only biochemical parameters but also patients' survival. An important milestone in the identification of patients at risk is the assessment of biochemical response to UDCA. Patients who respond to treatment have a lower incidence of hepatic events and better prognosis than patients who do not. Several scoring systems can be used to assess the response and identify non-responders who will benefit from second-line treatment. Obeticholic acid (OCA) is currently the only approved second-line treatment for PBC, which is effective for non-responders to UDCA therapy or patients, who have not tolerated UDCA therapy. However, OCA is contraindicated in advanced liver cirrhosis and portal hypertension. Moreover, pruritus may be a limiting factor for the administration of OCA. Fibrates have shown promising data supporting their use in non-responders to UDCA because they improve the biochemical parameters and elastographic findings and have possible antipruritic effects. Therefore, the idea of a triple treatment seems interesting. Clinical research is focusing on several other groups of drugs: peroxisome proliferator-activated receptor (PPAR) δ- and α/δ agonists, non-steroidal farnesoid X receptor agonists, fibroblast growth factor 19 modulators, and inhibitors of nicotinamide adenine dinucleotide phosphate oxidase 1 and 4.

Role of biochemical markers and autoantibodies in diagnosis of early-stage primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic progressive autoimmune cholestatic disease. The main target organ of PBC is the liver, and nonsuppurative inflammation of the small intrahepatic bile ducts may eventually develop into cirrhosis or liver fibrosis. To explore the clinical characteristics of early-stage PBC, identify PBC in the early clinical stage, and promptly treat and monitor PBC. The data of 82 patients with PBC confirmed by pathology at Tianjin Second People's Hospital from January 2013 to November 2021 were collected, and the patients were divided into stage I, stage II, stage III, and stage IV according to the pathological stage. The general data, serum biochemistry, immunoglobulins, and autoimmune antibodies of patients in each stage were retrospectively analyzed. In early-stage (stages I + II) PBC patients, 50.0% of patients had normal alanine aminotransferase (ALT) levels, and 37.5% had normal aspartate aminotransferase (AST) levels. For the remaining patients, the ALT and AST levels were mildly elevated; all of these patients had levels of < 3 times the upper limit of normal values. The AST levels were significantly different among the three groups (stages I + II vs stage III vs stage IV, P < 0.05). In the early stage, 29.2% of patients had normal alkaline phosphatase (ALP) levels. The remaining patients had different degrees of ALP elevation; 6.3% had ALP levels > 5 times the upper limit of normal value. Moreover, γ-glutamyl transferase (GGT) was more robustly elevated, as 29.2% of patients had GGT levels of > 10 times the upper limit of normal value. The ALP values among the three groups were significantly different (P < 0.05). In early stage, the jaundice index did not increase significantly, but it gradually increased with disease progression. However, the above indicators were significantly different (P < 0.05) between the early-stage group and the stage IV group. With the progression of the disease, the levels of albumin and albumin/globulin ratio tended to decrease, and the difference among the three groups was statistically significant (P < 0.05). In early-stage patients, IgM and IgG levels as well as cholesterol levels were mildly elevated, but there were no significant differences among the three groups. Triglyceride levels were normal in the early-stage group, and the differences among the three groups were statistically significant (P < 0.05). The early detection rates of anti-mitochondria antibody (AMA) and AMA-M2 were 66.7% and 45.8%, respectively. The positive rate of anti-sp100 antibodies was significantly higher in patients with stage IV PBC. When AMA and AMA-M2 were negative, in the early stage, the highest autoantibody was anti-nuclear antibody (ANA) (92.3%), and in all ANA patterns, the highest was ANA centromere (38.5%). In early-stage PBC patients, ALT and AST levels are normal or mildly elevated, GGT and ALP levels are not elevated in parallel, GGT levels are more robustly elevated, and ALP levels are normal in some patients. When AMA and AMA-M2 are negative, ANA especially ANA centromere positivity suggests the possibility of early PBC. Therefore, in the clinic, significantly elevated GGT levels with or without normal ALP levels and with ANA (particularly ANA centromere) positivity (when AMA and AMA-M2 are negative) may indicate the possibility of early PBC.

Combined Inhibition of the TGF-β1/Smad Pathway by Prevotella copri and Lactobacillus murinus to Reduce Inflammation and Fibrosis in Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease characterized by inflammation and fibrosis of the bile ducts. Cholestasis may lead to hepatic inflammation and fibrosis, and amelioration of cholestasis may allow recovery from inflammatory and fibrotic pathological damage. Prevotella copri (P. copri) interventions have been reported to significantly improve cholestasis and liver fibrosis in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced PSC mouse models. Even though P. copri treatment alone cannot bring about recovery from DDC-induced inflammation, it increases the abundance of Lactobacillus murinus (L. murinus) compared with DDC treatment, which has been reported to have anti-inflammatory effects. The abundance of L. murinus still not recovering to a normal level may underlie hepatic inflammation in P. copri + DDC mice. Separate or combined interventions of P. copri and L. murinus were used to investigate the molecular mechanism underlying the improvement in PSC inflammation and fibrosis. P. copri and L. murinus significantly reduced the hepatic inflammatory cell aggregation and inflammatory factor expression as well as the hepatic collagen content and fibrin factor expression in the PSC mice. Further analysis of phosphorylation and dephosphorylation levels revealed that treating the PSC mice with the P. copri and L. murinus combined intervention inhibited the activity of the DDC-activated TGF-β1/Smad pathway, thereby reducing liver inflammation and fibrosis. The combination of P. copri and L. murinus inhibits the TGF-β1/Smad pathway and reduces inflammation and fibrosis in PSC.

EE59 Development and Validation of the Natural History Component of an Economic Model for Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic disease that can progress to cirrhosis, liver failure, and secondary cancers. Disease progression is typically non-linear, with no clearly defined milestones or disease stages. Several drugs are under investigation, but no economic model for PSC exists to evaluate the value of new treatments. The objective of this study was to develop an early economic model framework for PSC and validate through discussions with clinical and health economic experts.

Emerging Therapeutic Strategies in The Fight Against Primary Biliary Cholangitis.

The liver has a vital role in many metabolic and regulatory processes in the body. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial antigens. At this time there is no definitive cure for PBC; however, ursodeoxycholic acid (UDCA) has been shown to reduce injury when administered as the first line of treatment. Additional therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease progression. Currently, a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable pruritus. This review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.

Primary biliary cholangitis. Experience in 179 patients

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease, which can progress to cirrhosis. It mainly affects middle-aged women. Its most frequent form of presentation is asymptomatic with biochemical cholestasis and the presence of antimitochondrial antibodies (AMA). To describe the epidemiological characteristics, clinical presentation and treatment for patients with PBC at a clinical hospital. Descriptive, observational, retrospective study, carried out between January 2015 and December 2020. 179 patients (158 women) were cared in the study period. At the time of diagnosis, the median age was 54 years (range 24-76), 55% of them were asymptomatic, 45% had fatigue and 28% had pruritus. Positive AMA were present in 65% of patients, antinuclear antibodies (ANA) in 51%, and anti-smooth muscle antibodies (ASMA) in 9%. Immunoglobulin M (IgM) was elevated in 30% of the patients and 50% of patients were biopsied. Splenomegaly and esophageal varices were present in 24 and 22% of patients, respectively. PBC was associated with Sjogren's syndrome in 15%, hypothyroidism in 14%, osteoporosis in 13%, and scleroderma in 8%. The epidemiological characteristics of our patients agree with those published abroad. Laboratory cholestasis associated with the presence of AMA, currently allows diagnosis without the need for histological study. Ursodeoxycholic acid (UDCA) is the first-line treatment for patients with PBC. The use of biochemical response criteria is essential to identify patients who require other UDCA alternatives for isolated or combined treatment.

FRI460 - Copper accumulation in chronic cholestatic disease augments liver damage by impairment of mitochondrial function

FRI460 - Copper accumulation in chronic cholestatic disease augments liver damage by impairment of mitochondrial function

Practical Guide for Radiological Diagnosis of Primary and Secondary Sclerosing Cholangitis

Sclerosing cholangitis comprises a group of conditions that lead to chronic cholestatic disease of the bile ducts, characterized by inflammation, fibrosis, and segmental strictures of the intrahepatic and/or extrahepatic ducts, and can be classified as primary sclerosing cholangitis or secondary sclerosing cholangitis. In this review, we follow a logical step-by-step appraisal of the clinical and radiological findings of the main secondary sclerosing cholangitis groups, finally arriving at the exclusion diagnosis, which is primary sclerosing cholangitis. At the end, a practical guide is provided, aiming to facilitate the radiological approach to this complex group of diseases.

Secondary sclerosing cholangitis: mimics of primary sclerosing cholangitis.

Sclerosing cholangitis is a chronic cholestatic disease characterized by stricturing, beading, and obliterative fibrosis of the bile ducts. Sclerosing cholangitis is considered primary (PSC) if no underlying etiology is identified or secondary (SSC) if related to another identifiable cause. In this article, we will review the clinical features, pathogenesis, diagnosis, and imaging findings of PSC and SSC, with an emphasis on features that may aid in the distinction of these entities. We will also discuss various etiologies of SSC including recurrent pyogenic cholangitis, other infectious etiologies, ischemic damage, toxic insults, and immunologic, congenital, and miscellaneous causes, highlighting the unique imaging findings and clinical context of each diagnosis.Graphical abstract

Primary Biliary Cholangitis and its Diagnostic Challenges in a resource poor setting

Primary Biliary Cholangitis (PBC) is a chronic cholestatic disease of the liver. Due to the permanent cholestasis, fibrosis and cirrhosis eventually occur. It is said to be a rare disease in black Africans. We reported a case of Anti-Mitochondrial Antibody (AMA) negative PBC in a forty-one-yearold woman who fulfilled two out of the three diagnostic criteria. This case was reported because a diagnosis of PBC is very rare in our environment especially, AMA negative PBC which is indeed the first to be reported in our environment. Although, access to newer methods of AMA assay were not possible in the light of the resource-limited environment we practice in.

In the Absence of YAP, TAZ Contributes to Hepatocyte Adaptation in Chronic Cholestasis in Females

We previously demonstrated that loss of Yes‐associated protein 1 (YAP1) in early liver development (YAP1 KO) leads to an Alagille syndrome‐like phenotype with absence of intrahepatic bile ducts and severe cholestasis accompanied by chronic hepatocyte adaptations to reduce liver injury. We noticed that TAZ, a paralog of YAP1, was significantly upregulated in hepatocytes of YAP1 KO mice and bound to TEAD transcription factors, suggesting compensatory activity in hepatocytes.We next queried the relationship between YAP1 and TAZ by deleting both genes during early liver development using the Foxa3‐Cre promoter, similar to the YAP1 KO mice, resulting in multiple allele combinations. Interestingly, we show that YAP1/TAZ double knock‐out (DKO) mice are embryonic lethal and stillborn, the embryos surviving almost until birth with no grossly visible abnormalities. The liver morphology during development does not show gross abnormalities, suggesting an extrahepatic source of lethality. This suggests that while YAP1 loss has profound impact on biliary development, YAP1 and TAZ together play a co‐dependent critical role in foregut endoderm development yet to be determined.Next, when we examined TAZ heterozygosity in YAP1 KO mice, we found significant embryonic lethality among males, with insufficient samples to analyze a potential cause at this time. However, among females, loss of one copy of TAZ from YAP1 KO mice resulted in a similar gross phenotype to YAP1 KO, with a complete lack of intrahepatic bile ducts resulting in severe chronic cholestatic disease. While serum bilirubin levels were comparable after TAZ heterozygosity, liver transaminases were more elevated than in YAP1 KO alone, suggesting worsening hepatocyte injury. Hepatocyte proliferation levels were not affected by TAZ heterozygosity. Global gene expression patterns as detected by RNA‐sequencing were grossly similar as compared to YAP1 KO mice, although subtle alterations were identified in pathways related to apoptosis, cell division, inflammatory signaling, and metabolism, and we also show that TAZ is needed to regulate canonical YAP1 targets in YAP1 KO hepatocytes such as CTGF and CYR61. We also found significant elevation in serum cholesterol compared to YAP1 KO alone, and xanthomas were observed at later stages on these mice, suggesting worsening metabolic derangements caused by TAZ heterozygosity beyond what was observed in YAP1 KO alone. Interestingly, bile acid profiles in both liver and serum as detected by mass spectrometry showed no difference in YAP1 KO with or without TAZ heterozygosity. Ongoing work aims to further identify the role of TAZ in metabolic adaptations to chronic cholestasis with potential implications for clinical regulation of hypercholesterolemia and long‐term liver metabolic health.

Surveillance of hepatobiliary cancers in primary sclerosing cholangitis: a preliminary study on the role of PET-MRI

Introduction: Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease with a progressive course toward cirrhosis and its complication. Moreover, these patients have an increased risk of hepatobiliary (HPB) and colorectal cancer. Current guidelines recommend performing annual ultrasound for gallbladder cancer surveillance, annual colonoscopy in patients with associated inflammatory bowel disease and 6-months ultrasound surveillance in cirrhotic patients. Despite the lack of evidence, most expert centers worldwide also perform annual MRI in combination with CA19-9 for HPB cancer surveillance.

P-126 INTERPHASE HEPATITIS IN PRIMARY BILIARY CHOLANGITIS, SEVERITY FACTOR AND NO RESPONSE TO URSODEOXICOLIC ACID?

Primary biliary cholangitis (PBC) is a chronic cholestatic disease that can progress to cirrhosis. The presence of fibrosis represents a predictive factor of progression and failure of response to ursodeoxycholic acid (UDCA). Currently, liver biopsy is not required for its diagnosis, however the finding of interface hepatitis (IH) in the histology could have a prognostic role. To compare in patients with biopsied PBC the presence of fibrosis and response to UDCA (Barcelona, ​​Mayo II and Paris II criteria) according to the presence or absence of IH. Histological findings and clinical characteristics of patients with biopsied PBC were retrospectively analyzed, at the stage when it was necessary for the diagnosis or in case of subsequent diagnostic doubt, between 2013-2019. Patients meeting the Paris criteria for PBC/HAI overlap were excluded. 36 patients were identified: 94% women, mean age 53 years (32-68), ANA (+) in 77%, elevated IgG in 58%. 11/36 with HI on biopsy. IH was associated with a greater presence of fibrosis (73% vs 36%; p <0.05) and higher ANA titers > 1/640 (50% vs 17%). In 24 patients, annual response to UDCA could be evaluated: 45% of the patients with IH met at least 2 response criteria vs 69% of the group without histological IH. The presence of IH in PBC is associated with greater fibrosis and worse biochemical response. Liver biopsy may be necessary in patients who do not respond to UDCA due to suspected interface activity.

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.

Recommendations for diagnosis and treatment of primary biliary cholangitis in China (2021)

Primary biliary cholangitis is a chronic autoimmune cholestatic disease with a progressive course. This disease is not rare in China, but standardized diagnosis and treatment for primary biliary cholangitis are insufficient. Based on the evidence and guidelines from China and other countries, Rheumatology Branch of Chinese Medical Association developed the recommendations of diagnosis and treatment for primary biliary cholangitis in China. The aim is to help clinicians recognize clinical characters, therapeutic selection and prognosis judgement of primary biliary cholangitis, which will contribute to make diagnosis in time, to select treatment properly and to manage follow-up scientifically.

Meta-analysis and systematic review of liver transplantation as an ultimate treatment option for secondary sclerosing cholangitis.

IntroductionSecondary sclerosing cholangitis (SSC) is a chronic cholestatic biliary disease, characterized by inflammation, obliterative fibrosis of the bile ducts, stricture formation, and progressive destruction of the biliary tree, which leads to biliary cirrhosis. In recent years, the development of secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has increasingly been perceived as a separate disease entity.AimTo perform a systematic review and meta-analysis of secondary sclerosing cholangitis and ischaemic cholangiopathy in post organ transplant patients and intensive care unit (ICU).Material and methodsA comprehensive search strategy using the PubMed, Biosis, and EMBASE databases was designed to retrieve relevant clinical data from the published literature up to 2020. Demographic characteristics, laboratory, transplantation, mortality rate, and follow-up data undergoing liver transplantation were extracted from the inclusion studies. We used DerSimonian–Laird random-effects meta-analysis. Analysis was carried out using R statistical software version 4.02.ResultsA total of 862 patients with SSC-CIP were extracted from 16 studies. Eighteen studies were searched for the meta-analysis, out of which 16 studies were eligible for the meta-analysis and 2 were excluded. A proportion meta-analysis was performed on liver transplant patients with SSC-CIP and on mortality rate. Significant results were found (Prop = 0.30, 95% CI: 0.12–0.49, p < 0.01), with high heterogeneity among the studies (I2 = 98%, p < 0.01) and (Prop = 0.45; 95% CI: 0.35–0.56 with I2 = 80, p < 0.01), respectively. No indication of publication bias, as confirmed by the funnel plot and the risk of bias in the included studies, shows that the study reporting is adequate to judge that no major or minor sources of bias are likely to influence results.ConclusionsThe systematic review and meta-analysis show that liver transplantation is a valid option for patients with SSC-CIP, with excellent long-term outcome and improvement of quality of life.

S3525 Primary Biliary Cholangitis: A Not so Primary Suspect

INTRODUCTION: Primary biliary cholangitis (PBC) is an increasingly prevalent autoimmune (AI) chronic cholestatic disease with specific bile duct pathology. The anti-mitochondrial antibody (AMA) is found in 95% of cases and is highly specific for PBC. It is most commonly seen in females (90–95%), Caucasians, and age of diagnosis usually ranges from 30 to 65 years old. The most common symptoms include fatigue and pruritus. We present a case of an adult African male presenting with jaundice who was AMA negative and found to have PBC. CASE DESCRIPTION/METHODS: A 60-year-old African male with a past medical history of diabetes mellitus, hypertension and sickle cell trait presented with jaundice, fatigue, diffuse itching, and a 14 lb unintentional weight loss over 6 months. He had no risk factors for viral hepatitis, did not consume alcohol, and had no personal or family history of AI disorders. Physical exam was notable for scleral icterus and excoriations on extremities. Labs revealed a total bilirubin of 10.1 mg/dL, alkaline phosphatase 840 IU/L, AST/ALT 78/54 IU/L, INR 1.2 and normal iron studies. Viral hepatitis panel was negative for hepatitis A, B and C with negative AMA, ANA, and anti actin antibody. A MRCP revealed early cirrhosis vs. hepatitis, mild ascites and suboptimal visualization of the pancreatic duct but no evidence of biliary duct dilatation. EGD and colonoscopy findings were normal. EUS was done in which a prominent pancreatic head was seen; biopsies were negative. An ERCP revealing ductopenia and small intrahepatic ducts. A liver biopsy revealed pericholangitis and bridging fibrosis consistent with PBC. He was started on ursodeoxycholic acid. One month later he was seen in clinic with resolution of fatigue and pruritus. Labs revealed a total bilirubin of 5 mg/dL down from 10 mg/dL and an alkaline phosphatase of 470 IU/L down from 840 IU/L with AST/ALT 85/38 IU/L. DISCUSSION: Although PBC is commonly diagnosed in women and AMA is positive 95% of time, this case identifies an African male with negative AMA found to have PBC based on liver histology. It is important to note there have been increased cases of males diagnosed with PBC. It is unclear how many of these males are AMA negative. AMA-negative PBC has been shown to have greater bile duct damage and loss compared with AMA-positive PBC. However whether there are differences in clinical outcomes has not been determined and more studies are needed.

Determining the effects of Wnt signaling in the alleviation of cholestasis via the promotion of hepatocyte transdifferentiation

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease characterized by bile duct inflammation and fibrosis, resulting in end‐stage liver disease and reduced life expectancy. Therefore, an effective treatment for PSC is needed. Hepatocytes exhibit remarkable plasticity and are known to be capable of transdifferentiating into cholangiocytes in models of biliary injury, which could create de novo ducts, repair damaged cholangiocytes, or contribute to bile detoxification. Previous studies utilizing in vitro organoid cultures and genetic mouse models found that β‐catenin and downstream targets are upregulated in hepatic organoid cultures, and mice expressing excess β‐catenin in the liver had an increased number of hepatocytes expressing cholangiocyte markers compared to wild type (WT) when subjected to cholestatic injury. These findings led to the hypothesis that Wnt/ß‐catenin signaling drives hepatocyte‐to‐cholangiocyte transdifferentiation during biliary injury. To test this hypothesis, we utilized lineage tracing in hepatic organoid cultures and TG mice expressing a mutated non‐degradable form of β‐catenin (S45D) in liver. We show that hepatocytes transdifferentiate to cholangiocytes in organoid cultures, and the cholangiocytes present are not from native contaminating cholangiocytes. We determined that TG mice fed DDC diet, which induces bile stasis, have: 1) improved serum ALP over time, indicating less biliary injury; 2) increased bile output compared to WT mice fed DDC diet; and 3) bile ducts populated with hepatocyte‐derived cholangiocytes. Through these studies we demonstrate that Wnt/ß‐catenin signaling catalyzes hepatocyte‐to‐cholangiocyte transdifferentiation, and activation of this pathway alleviates cholestasis in mouse models of PSC.Support or Funding InformationNIH grant 1R01DK103775NIH training grant T32EB0010216NIH grant 1F31DK118802‐01