Progressive Cholestatic Liver Disease Research Articles

Immunobiology of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory progressive cholestatic liver disease. Genetic risk factors, presence of autoantibodies, the strong clinical link with inflammatory bowel disease (IBD), and associations with other autoimmune disorders all suggest a pivotal role for the immune system in PSC pathogenesis. In this review, we provide a comprehensive overview of recent immunobiology insights in PSC. A particular emphasis is given to immunological concepts such as tissue-residency and knowledge gained from novel technologies including single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST). This review of the immunobiological landscape of PSC covers major immune cell types known to be enriched in PSC-diseased livers as well as recently described cell types whose biliary localization and contribution to PSC immunopathogenesis remain incompletely described. Finally, we emphasize the importance of time and space in relation to PSC heterogeneity as a key consideration for future studies interrogating the role of the immune system in PSC.

Network proximity analysis as a theoretical model for identifying potential novel therapies in primary sclerosing cholangitis

Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have identified genes that correlate significantly with PSC, and these were identified by systematic review. Here we use novel Network Proximity Analysis (NPA) methods to identify already licensed candidate drugs that may have an effect on the genetically coded aspects of PSC pathophysiology.Over 2000 agents were identified as significantly linked to genes implicated in PSC by this method. The most significant results include previously researched agents such as metronidazole, as well as biological agents such as basiliximab, abatacept and belatacept. This in silico analysis could potentially serve as a basis for developing novel clinical trials in this rare disease.

Odevixibat as an adjunctive treatment for refractory pruritus in rare variants of cholestatic liver disease.

Odevixibat, a reversible ileal bile acid transport inhibitor, has been shown to reduce serum bile acids (sBA) and pruritus mostly in children with progressive familial intrahepatic cholestasis (PFIC) 1 and 2 in clinical trials and case reports. There are currently no published case reports or series describing its use in rare variants of cholestatic liver disease. We describe three children with progressive cholestatic liver disease who developed refractory pruritus, who had a genotypic diagnosis of AKR1D1, ABCB4 variant, and PKHD1 and PKHD2 variants; all being variants of unknown significance as per the American College of Medical Genetics and Genomics guidelines. On Odevixibat there was a significant improvement in sBA (absolute change from baseline: -196 and -393 μmol/L) and pruritus in two children with heterozygous AKR1D1 and ABCB4 mutations. The child with ABCB4 variants was found to have features of sclerosing cholangitis along with a diagnosis of Crohn's disease, which represents the first reported usage of Odevixibat in such a case with good response. There was some reported improvement in the third child with PKHD1 and PKHD2 variants; however, we hypothesize that no sustained improvement could be due to severe and progressive nature of the disease. There were no side effects reported and it was well tolerated in all. We suggest that Odevixibat may be used as an adjunctive drug in refractory pruritus and could be started early in the course of disease if clinically and phenotypically indicated.

P621 Safety and effectiveness of vedolizumab and ustekinumab in inflammatory bowel disease patients after liver transplantation for primary sclerosing cholangitis: results from an ECCO-confer case series

Abstract Background Primary sclerosing cholangitis (PSC) is a chronic progressive cholestatic liver disease often necessitating liver transplantation (LTX). Approximately 70% of PSC patients have a concomitant diagnosis of inflammatory bowel disease (IBD) and could need treatment with biological therapy on top of the immunosuppression to prevent transplant rejection. Vedolizumab (VDZ) and ustekinumab (UST), both agents with a favorable safety profile, are often used in this population despite lack of data concerning safety and effectiveness in the post-LTX setting. Methods A retrospective multicenter case series was performed as a part of the European Crohn's and Colitis Organisation [ECCO] Collaborative Network of Exceptionally Rare case reports [CONFER] project. Primary endpoints were clinical and endoscopic remission at week 52, occurrence of infectious complications, occurrence of malignancy, hospitalizations, and death after liver transplantation. Results In this retrospective study, 58 patients (male n= 34 (59%), median age 42 (interquartile range (IQR) 32-52) were included across 16 participating centers of which 24 (38%) were treated with UST and 40 (63%) with VDZ. Twelve patients (20%) were diagnosed with Crohn’s disease (CD), 44 (76%) with ulcerative colitis (UC), 2 (3%)- with unclassified IBD (IBD-U) and in 12 (20%) patients had an ileal pouch anal anastomosis (IPAA). Median disease duration was 16 years (IQR 13-26) and 33 (56%) had received biological therapy prior to LTX (33% anti-TNF, 11% VDZ, 5% UST). Median disease duration for PSC was 15.5 years (IQR 11-25) and median time since LTX was 6 years (IQR 4-10). Clinical remission, assessed according to physician global assessment, at week 52 was achieved in 44% of VDZ compared to 38% of UST treated patients (p=0.17), while endoscopic remission was seen in 17% of patients in the VDZ group versus 33% in the UST treated patients (p=0.87). Clinical effectiveness was similar across CD (respectively 33% and 20%), UC (33% and 37%) and IPAA patients (36% vs 60%). Infectious complications occurred in 21 patients (29%; 27% VDZ vs 33% UST) post LTX on biological therapy (p=0.66), malignancy occurred in 10 patients (14.1%, 12.8% VDZ vs 16.7% UST, p=0.66), hospitalizations in 32 (45%; 51% VDZ vs 34% UST, p=0.15), and death in 2 patients (3.4%; 2.1% VDZ vs 4.2% UST, p=0.66) (see table). Conclusion In IBD-PSC patients who underwent LTX both UST and VDZ show similar effectiveness with clinical remission rates of respectively 44% and 38% after 1 year. Safety profiles are similar although infectious complications and occurrence of malignancy remains an important concern in this patient group.

Primary Sclerosing Cholangitis in Very Early Age: Two Case Reports

Primary Sclerosing Cholangitis (PSC) is a rare, chronic, progressive cholestatic liver disease which affects intrahepatic and extrahepatic bile ducts. That eventually progresses to end stage liver disease that requires liver transplantation. It mostly occurs in adolescent males and boys. Pediatric disease appears milder in contrast to adult-onset PSC. The diagnosis is made by Magnatic Resonance Cholangiopancreatography (MRCP). Though there is no practical guideline available in pediatric patients for treating PSC UDCA is prescribed chronically in over 80% of patients. There is close association of PSC with inflammatory bowel disease and autoimmune hepatitis in children. So the treatment is complex in case of children. We reported here two cases of PSC, because of rarity of this disease in such a young age.
 BANGLADESH J CHILD HEALTH 2022; VOL 46 (1) : 30-34

Myosteatosis independently predicts transplant-free survival in patients with primary sclerosing cholangitis

BackgroundPrimary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with liver transplantation (LT) as the only curative therapy. Some regions use body-weight-loss as standard-exception criteria for organ allocation but data on the impact of body composition on survival of patients with PSC is scarce. MethodsAbdominal MRI of PSC patients were quantitatively analyzed for intramuscular fat fraction (IMFF) as surrogate of myosteatosis. Clinical and laboratory data were retrieved from patient records. Primary outcome was transplant-free survival (TFS). Results116 PSC patients were included. Median age was 38 (18–71) years with 74 (64%) male patients. 15 (13%) patients had significant weigh loss. IMFF was significantly associated with survival. Multivariate regression analysis showed IMFF ≥ 15% as independent predictor for TFS (p = 0.032, HR 3.215 CI 1.104–9.366), but not significant weight loss (p = 0.618). ConclusionIMFF is independently associated with TFS in patients with PSC and may identify patients with more urgent need for LT. NCT03584204.

Management of Cholestatic Pruritus in Primary Biliary Cholangitis: Ileal Bile Acid Transporter Inhibition and Holistic Care

Symptoms of the progressive cholestatic liver disease primary biliary cholangitis (PBC) include pruritus and fatigue. Pruritus can persist chronically in at least one-third of people with PBC and can range from mild to severe, with fluctuations over time, including on a daily basis. Proposed causative factors for PBC-associated pruritus include bile acids, lysophosphatidic acid (LPA), and endogenous opioids, with proposed symptom mechanisms linked to increases of these substances, or associated pathways. All offer potential routes for drug treatment to help alleviate pruritus in some patients. PBC-associated pruritus can have a significantly detrimental effect on a person’s quality of life (QoL) due to a sometimes constant feeling of ‘bugs crawling’ on their skin, and the need to ‘tear my skin off’. Pruritus may lead to secondary skin lesions, embarrassment, and social isolation. Pruritus is associated with sleep deprivation and subsequent daytime tiredness and fatigue, as well as depression, and sometimes in the worst cases, leading to suicide. Treatments for PBC-associated pruritus include bile acid sequestrants, rifampicin, opioid antagonists, sertraline, and gabapentin, as well as topical moisturisers, behavioural changes, and ultraviolet light therapy. Though not currently approved for such, ileal bile acid transporter (IBAT) inhibitors are undergoing clinical trials, as success in alleviating pruritus is shown in similar conditions. In patients where PBC-associated pruritus is very severe, liver transplantation is a consideration. At the 2023 European Association for the Study of the Liver (EASL) Congress, leading experts in the field of PBC, including clinician-researchers, a nurse specialist, and a representative from the PBC Foundation, highlighted the importance of discussing, assessing, and treating pruritus in people with PBC, using a holistic approach to understanding and caring for this QoL-affecting symptom.

Serum miRNA profiles are altered in patients with primary sclerosing cholangitis receiving high-dose ursodeoxycholic acid

Background & AimsPrimary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease that can lead to end-stage liver disease and cholangiocarcinoma. High-dose ursodeoxycholic acid (hd-UDCA, 28–30 mg/kg/day) was evaluated in a previous multicentre, randomised placebo-controlled trial; however, the study was discontinued early because of increased liver-related serious adverse events (SAEs), despite improvement in serum liver biochemical tests. We investigated longitudinal changes in serum miRNA and cytokine profiles over time among patients treated with either hd-UDCA or placebo in this trial as potential biomarkers for PSC and response to hd-UDCA, as well as to understand the toxicity associated with hd-UDCA treatment. MethodsThirty-eight patients with PSC were enrolled in a multicentred, randomised, double-blinded trial of hd-UDCA vs. placebo. ResultsSignificant alterations in serum miRNA profiles were found over time in both patients treated with hd-UDCA or placebo. Additionally, there were striking differences between miRNA profiles in patients treated with hd-UDCA compared with placebo. In patients treated with placebo, the changes in concentration of serum miRNAs miR-26a, miR-199b-5p, miR-373, and miR-663 suggest alterations of inflammatory and cell proliferative processes consistent with disease progression. However, patients treated with hd-UDCA exhibited a more pronounced differential expression of serum miRNAs, suggesting that hd-UDCA induces significant cellular miRNA changes and tissue injury. Pathway enrichment analysis for UDCA-associated miRNAs suggested unique dysregulation of cell cycle and inflammatory response pathways. ConclusionsPatients with PSC have distinct miRNAs in the serum and bile, although the implications of these unique patterns have not been studied longitudinally or in relation to adverse events related to hd-UDCA. Our study demonstrates marked changes in miRNA serum profiles with hd-UDCA treatment and suggests mechanisms for the increased liver toxicity with therapy. Impact and implicationsUsing serum samples from patients with PSC enrolled in a clinical trial comparing hd-UDCA with placebo, our study found distinct miRNA changes in patients with PSC who are treated with hd-UDCA over a period of time. Our study also noted distinct miRNA patterns in patients who developed SAEs during the study period.

A large-scale plasma proteome Mendelian randomization study identifies novel causal plasma proteins related to primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a progressive chronic autoimmune cholestatic liver disease characterized by the destruction of small intrahepatic bile ducts leading to biliary cirrhosis. Liver biopsy is required in the diagnosis of Antimitochondrial antibody-negative patients. Therefore, novel biomarkers are needed for the non-invasive diagnosis of PBC. To identify novel biomarkers for PBC, we conducted large-scale plasma proteome Mendelian randomization (MR). A total of 21,593 protein quantitative trait loci (pQTLs) for 2297 circulating proteins were used and classified into four different groups. MR analyses were conducted in the four groups separately. Furthermore, the results were discovered and replicated in two different cohorts of PBC. Colocalization analysis and enrichment analysis were also conducted. Three plasma proteins (ficolin-1, CD40 and protein FAM177A1) were identified and replicated as being associated with PBC. All of them showed significant protective effects against PBC. An increase in ficolin-1 (OR=0.890 [0.843-0.941], p=3.50×10-5), CD40 (OR=0.814 [0.741-0.895], p=1.96×10-5) and protein FAM177A1 (OR=0.822 [0.754-0.897], p=9.75×10-6) reduced the incidence of PBC. Ficolin-1 (PP4 = 0.994) and protein FAM177A1 (PP4 = 0.995) colocalized with the expression of the genes FCN1 and FAM177A1 in whole blood, respectively. Furthermore, CD40 (PP4 = 0.977) and protein FAM177A1 (PP4 = 0.897) strongly colocalized with PBC. We expand the current biomarkers for PBC. In total, three (ficolin-1, CD40, and protein FAM177A1) plasma proteins were identified and replicated as being associated with PBC in MR analysis. All of them showed significant protective effects against PBC. These proteins can be potential biomarkers or drug targets for PBC.

The Genetics of Primary Biliary Cholangitis: A GWAS and Post-GWAS Update.

Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which the small intrahepatic bile ducts are destroyed by autoimmune reactions. Among autoimmune diseases, which are polygenic complex traits caused by the combined contribution of genetic and environmental factors, PBC exhibits the strongest involvement of genetic heritability in disease development. As at December 2022, genome-wide association studies (GWASs) and associated meta-analyses identified approximately 70 PBC susceptibility gene loci in various populations, including those of European and East Asian descent. However, the molecular mechanisms through which these susceptibility loci affect the pathogenesis of PBC are not fully understood. This study provides an overview of current data regarding the genetic factors of PBC as well as post-GWAS approaches to identifying primary functional variants and effector genes in disease-susceptibility loci. Possible mechanisms of these genetic factors in the development of PBC are also discussed, focusing on four major disease pathways identified by in silico gene set analyses, namely, (1) antigen presentation by human leukocyte antigens, (2) interleukin-12-related pathways, (3) cellular responses to tumor necrosis factor, and (4) B cell activation, maturation, and differentiation pathways.

Successful Treatment of Patient With Ewing Sarcoma in the Setting of Inherited Cholestatic Liver Disease.

Progressive familial intrahepatic cholestasis type 1 (PFIC1) is an inherited, progressive cholestatic liver disease. Here, we present an approach to the treatment of Ewing sarcoma in a patient with PFIC1. The diagnosis of PFIC1 presents a unique challenge in the treatment of Ewing sarcoma, as the standard-of-care vincristine, doxorubicin, cyclophosphamide/ifosfamide and etoposide chemotherapy backbone for Ewing sarcoma therapy treatment relies heavily on intact hepatic metabolism. In addition, we report prolonged lymphopenia and severe infectious complications in this patient, both of which may be attributed to more severe immunosuppression in setting of poor hepatic metabolism of chemotherapeutic agents.

Primary biliary cholangitis: diagnosis and management

Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a progressive autoimmune cholestatic liver disease that results in end-stage liver disease and the need for liver transplantation if left untreated​[1]​. A UK study involving 770 individuals with definite or probable PBC demonstrated a prevalence of 35 cases per 100,000 and an annual incidence […]

Primary Biliary Cholangitis: A Review

Primary biliary cholangitis (PBC), which is formally known as primary biliary cirrhosis, is a progressive chronic cholestatic liver disease. Previous epidemiologic studies have demonstrated female predominance. Furthermore, the pathophysiology of PBC is multifactorial, and involves loss of immune tolerance to biliary epithelial cells, with interdependent biliary injury, cholestasis, and progressive liver fibrosis. Moreover, its progression to liver fibrosis highly varies among individuals, but most cases are indolent and slowly progressive. Over the past decade, research has provided great insight into personalized care for patients with PBC. Individualized care and early utilization of second- and third-line therapies have improved the outcomes, and decreased the progression of this disease. The present mini-review focused in providing an overview of PBC, including its pathophysiology, clinical presentation, treatment, treatment goals, recommended follow-up, and future research.

ZO-2/Tjp2 suppresses Yap and Wwtr1/Taz-mediated hepatocyte to cholangiocyte transdifferentiation in the mouse liver

TJP2/ZO-2-inactivating mutations in humans cause progressive cholestatic liver disease. Liver-specific deletion of Tjp2 in the mouse (Tjp2 cKO mice) leads to mild progressive cholestasis without an overt degradation of the bile-blood barrier (BBB). These mice are more susceptible to cholic acid (CA) induced liver injury. Interestingly, while initially also more susceptible, Tjp2 cKO mice develop tolerance to a DDC-supplemented diet. The DDC diet induces an exacerbated ductular reaction in Tjp2 cKO mice, which arises from the transdifferentiation of hepatocytes to cholangiocytes. Consequently, this transdifferentiation is only observed if Tjp2 is inactivated in hepatocytes, but not if deleted in cholangiocytes. The DDC-diet-induced hepatocyte transdifferentiation in Tjp2 cKO mice requires Yap and Wwtr1/Taz, whose protein expression is upregulated in hepatocytes lacking Tjp2, but is independent of Notch2. Although inactivating Tjp2 is sufficient for the upregulation of Yap and Wwtr1/Taz protein, efficient transdifferentiation requires the DDC-diet insult. Thus, Tjp2 negatively regulates Yap/Taz-mediated transdifferentiation of hepatocytes to cholangiocytes in response to DDC-diet-induced liver injury. Furthermore, transdifferentiation is regulated at multiple levels and the type of injury inflicted on the Tjp2 deficient liver plays an important role in the resulting pathophysiology.

Leveraging a New ICD-10 Diagnosis Code to Characterize Hospitalized Patients With Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease characterized by inflammation and destruction of the biliary tree, often leading to cirrhosis requiring liver transplantation.1,2 PSC is rare, affecting ∼1–16 per 100,000 in the United States,1 and is typically considered a disease of young White males.1,3 However, with changing demographics of US population in terms of age, gender, and race/ethnicity, it is unknown whether demographics of patients with PSC has also shifted.

50 Years Ago in TheJournalofPediatrics: Understanding Progressive Cholestatic Liver Disease

50 Years Ago in TheJournalofPediatrics: Understanding Progressive Cholestatic Liver Disease

Novel histological scoring for predicting disease outcome in primary sclerosing cholangitis.

BackgroundPrimary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease that may lead to liver cirrhosis or cholangiocarcinoma. Liver histology and fibrosis stage are predictive markers of disease progression, and histological cirrhosis is defined as a significant endpoint. PSC‐specific histological scoring methods are lacking at present. We aimed to develop a tailored classification system for PSC, the PSC histoscore, based on histological features associated with disease progression.MethodsIn total, 300 PSC patients diagnosed between 1988 and 2018 were enrolled; their data were collected from the PSC registry (Helsinki University Hospital), and liver specimens were obtained from the Biobank of Helsinki. Five histological features included in the adapted Nakanuma scoring system and three additional parameters typical for PSC histology were evaluated and compared with the clinical and laboratory data. A compound endpoint consisting of liver transplantation, development of cholangiocarcinoma, or death was used as outcome measurement.ResultsStage (fibrosis, bile duct loss, ductular reaction, and chronic cholestasis) and grade (portal inflammation, portal edema, hepatitis activity, and cholangitis activity) parameters were found to be independent predictive risk factors for the compound endpoint (P < 0.001). High disease grade (2–6) and stage (2–4) better correlated with clinical endpoints when evaluated with the PSC histoscore system compared to the adapted Nakanuma classification. The risk for disease progression in sequential endoscopic retrograde cholangiography (ERC) examinations was increased with elevated total PSC histoscores.ConclusionThe PSC histoscore is a novel histological classification system for PSC. Our findings support the applicability of liver histology as a marker for disease progression.

Efficacy of ursodeoxycholic acid for primary biliary cholangitis: Experience from a tertiary care centre in Saudi Arabia.

Primary biliary cholangitis (PBC) is a progressive autoimmune cholestatic liver disease that primarily affects females more than males and may lead to end-stage liver disease. We studied baseline characteristics, and the biochemical and clinical response to ursodeoxycholic acid (UDCA), a first-line treatment option for patients with PBC, in a cohort of patients diagnosed with PBC from Saudi Arabia. A total of 30 patients meeting the diagnostic criteria of PBC who were being followed in the King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia, between January 1, 2008, and December 31, 2017, were enrolled in the study. The patients with autoimmune hepatitis, primary sclerosing cholangitis, and overlap syndromes were excluded. The baseline characteristics of the patients were recorded. The response to UDCA treatment was assessed according to the Barcelona, Paris I, Paris II, and Toronto criteria, and clinical outcomes, and biochemical changes were ascertained. The mean age was 46 years ± 11.7 with a female gender predominance of 93% (n = 28). Pruritus was the predominant symptom reported by 90% (n = 27) of the patients. A total of 23 (77.7%) patients underwent liver biopsy and all of them showed histological features suggestive of PBC. Cirrhosis was documented in 30% (n = 9) of the patients at baseline. Overall, 86.7% (n = 26) of the patients were positive for antimitochondrial antibodies. The biochemical response rates to UDCA based on Paris I, Paris II, Barcelona, and Toronto criteria were 73.3, 40, 56.7, and 53.3%, respectively. Over 10 years, 30 patients with PBC were diagnosed at a large referral center in Saudi Arabia. The response to UDCA treatment was inadequate.

Cyr61 Alleviates Cholangitis by Inhibiting Cytotoxic Effects of CD8+ T Cells on Biliary Epithelial Cells.

Primary biliary cholangitis (PBC) is a chronic progressive cholestatic liver disease. In recent years, researchers have found that cysteine-rich angiogenic inducer 61 (Cyr61, also known as CCN1) has a potential role in reducing portal inflammation in patients with PBC. This study aimed to explore the relationship between Cyr61 and PBC to provide new ideas and an experimental basis for the clinical treatment of PBC. After induction of the overexpression of Cyr61 in a mouse model of PBC using recombinant adenovirus, hematoxylin and eosin staining and pathological scores were used to indicate intrahepatic inflammation and bile duct damage. Real-time PCR was used to detect changes in inflammation-related cytokines in the liver. To further study the mechanism, we assessed whether Cyr61 protects bile duct epithelial cells from cytotoxic effects. Serum and hepatic Cyr61 levels were increased in the murine model of PBC. Overexpression of Cyr61 alleviated hepatic inflammation and bile duct injury in vivo. Cyr61 inhibited the cytotoxic effects of CD8+ T cells by acting on biliary epithelial cells (BECs) in vitro. Our results provide novel insight into the pathogenesis of PBC and suggest that Cyr61 plays a dominant role in the cytotoxic effects on BECs in PBC. Consequently, therapeutic strategies targeting Cyr61 could be a potent therapy for PBC.

Congenital Myotonic Dystrophy with Combined Heterozygous ATP8B1/ABCB4 Mutation Leading to Progressive Cholestasis and Liver Failure

Myotonic dystrophy (MyoD) is an inherited genetic disorder caused by the expansion of a CTG trinucleotide repeat in the dystrophia myotonica protein kinase gene. It manifests as a multisystem disease affecting not only skeletal muscles, but also heart, lung, eye, gastrointestinal tract, central nervous system, and endocrine system. However, MyoD is rarely associated with a progressive liver disorder. We report a case of congenital MyoD with combined heterozygous ATP8B1/ABCB4 mutation who developed chronic, progressive low gamma-glutamyltransferase cholestatic liver disease at early infancy, and eventually underwent successful liver transplantation.