Primary Sclerosing Cholangitis Associated With Ulcerative Colitis Coexisting With Cholangiocarcinoma: A Case Report.

Primary sclerosing cholangitis (PSC) is a rare chronic inflammatory disease in which multifocal fibrosis of bile ducts causes eventually narrowing and even blocking, forming multifocal strictures alternated to dilatations. Here, we reported an extremely rare case of PSC associated with ulcerative colitis (UC) and coexisting with cholangiocarcinoma in a 33-year-old male presented with right upper quadrant pain and dark urine. Liver function tests were deranged, and ERCP found a beaded cholangiography appearance due to multifocal bile duct strictures alternating with normal and dilated segments of the common hepatic duct and the intrahepatic bile ducts. We aim to document this typical case of PSC associated with UC and coexisted with cholangiocarcinoma to add the existing data on these rare pathologies.

Total astragalus saponins attenuate primary sclerosing cholangitis in mice by upregulation of TGR5.

Total astragalus saponins (TAS) are the main active components of astragali radix, and have potent anti-hepatic fibrosis effect. However, the therapeutic efficacy of TAS and their potential mechanisms in the treatment of primary sclerosing cholangitis (PSC) remain unclear. In this study, two mouse models of PSC, including 3,5-Diethoxycarbonyl-1,4-Dihydro-2,4,6-Collidine (DDC)-induced PSC and Mdr2-/- spontaneous PSC, and the Tgr5-/- mice were used to investigate the therapeutic effect and mechanisms of TAS. Treatment with TAS, particularly with a dose of 56 mg/kg, significantly ameliorated the PSC-related liver injury, cholestasis, collagen deposition, ductular reaction (DR), and fibrosis in the DDC-induced and Mdr2-/-spontaneous PSC mice. Furthermore, treatment with TAS significantly mitigated the PSC-related inflammatory responses in vivo and HIBEpiC cells by inhibiting the expression of TNF-α, IL-6, and IL-1ß. Mechanistically, treatment with TAS rescued the PSC-decreased hepatic TGR5 expression to attenuate the NF-κB p65 phosphorylation. Notably, the therapeutic efficacy of TAS on PSC in DDC-induced mice was abrogated in Tgr5-/- mice, suggesting the anti-PSC effect of TAS may depend on enhancing TGR5 expression. In conclusion, TAS ameliorated DR, inflammation and liver fibrosis in both models of PSC mice by rescuing TGR5 expression. Our findings may aid in the design of new therapeutic strategies for the treatment of PSC.

Inflammatory bowel disease associated with primary sclerosing cholangitis is associated with an altered gut microbiome and bile acid profile.

BACKGROUND: Primary sclerosing cholangitis associated with inflammatory bowel disease (IBD-PSC) carries significant morbidity compared to IBD without PSC. Alterations in microbial composition and bile acid (BA) profiles have been shown to modulate chronic inflammation in IBD, but data in IBD-PSC is scarce. We aimed to assess the differences in gut microbiome composition as well as in the BA profile and BA-related microbial functions between IBD-PSC and IBD-only. METHODS: 54 IBD-PSC and 62 IBD-only subjects were enrolled from 2012 to 2021. Baseline samples were collected for fecal DNA shotgun metagenomic sequencing, fecal and serum BA quantitation using mass spectrometry and fecal calprotectin. Liver fibrosis measured by transient elastography (TE) was assessed in the IBD-PSC group. Data was analyzed using general linear regression models and Spearman rank correlation tests. RESULTS: Patients with IBD-PSC had reduced microbial gene richness (p=0.004) and significant compositional shifts (PERMANOVA: R2=0.01, p=0.03) compared to IBD-only. IBD-PSC was associated with altered microbial composition and function, including decreased abundance of Blautia obeum, increased abundance of Veillonella atypica, Veillonella dispar and Clostridium scindens (q<0.05 for all), and increased abundance of microbial genes involved in secondary BA metabolism. Decreased serum sulfated and increased serum conjugated secondary BA were associated with IBD-PSC and increased liver fibrosis. CONCLUSION: We identified differences in microbial species, functional capacity and serum BA profiles in IBD-PSC compared with IBD-only. Our findings provide insight into the pathophysiology of IBD associated with PSC and suggest possible targets for modulating the risk and course of IBD in subjects with PSC.

Modulation of miR-155-5p signalling via 5-ASA for the prevention of high microsatellite instability: an in vitro study using human epithelial cell lines.

5-aminosalicylic acid (5-ASA) is a first-line treatment for maintaining colitis remission. It is a highly effective, safe, and well-tolerated drug with anti-inflammatory and chemo-preventive properties. While patients with primary sclerosing cholangitis (PSC) with concomitant ulcerative colitis are treated with 5-ASA, the molecular mechanisms underlying the drug's chemo-preventive effects are not entirely understood. We previously reported that bile acids and lipopolysaccharide-induced miR-155 expression was associated with downregulating mismatch repair (MMR) proteins in CACO-2 cell lines. Therefore, in this investigation, a set of in vitro functional studies was performed to show the possible mechanisms behind the epigenetic relationship between miR-155 and 5-ASA's prevention of high microsatellite instability (MSI-H). In transient transfection with miR-155Mimic, which behaves like endogenous miRNA, we confirmed the relationships between miR-155 and its target MMR in three human intestinal epithelial cell lines: CACO-2, NCM460D and HT-29. We have shown, for the first time, that 5-ASA modulates MLH1, MSH2, MSH6 in miR-155 transfected cells. These findings underline that chemoprotective 5-ASA therapy can effectively attenuate the expression of miR-155 and potentially prevent a development of MSI-H in a subset of colorectal cancers associated with PSC.

A case report of immune checkpoint inhibitor-related myositis and cholangitis induced by pembrolizumab.

Key Clinical Message: Rare but severe, immune-related adverse events such as myositis and sclerosing cholangitis can occur with immune checkpoint inhibitors in lung cancer treatment. This case report highlights their co-occurrence after pembrolizumab treatment, indicating the need for vigilance and management strategies in immune checkpoint inhibitors therapy. Abstract: Immune checkpoint inhibitors (ICI) are used in advanced treatment of lung cancer but can lead to immune-related adverse events. ICI-related myositis and cholangitis are rare, and their combination has not been previously reported. Here, we report the first case of ICI-related myositis and sclerosing cholangitis. A patient with stage IV lung adenocarcinoma who received one cycle of pembrolizumab with cisplatin and pemetrexed developed myositis. Treatment with prednisolone improved the myositis, but the patient subsequently developed cholangitis. The patient did not respond to a regimen of prednisolone, mycophenolate mofetil, and azathioprine, and eventually died due to worsening lung cancer. An autopsy confirmed the presence of ICI-related myositis and sclerosing cholangitis.

[An analysis of related factors in thrombocytopenia combined with cirrhosis: a cross-sectional study of 2 517 cases].

Objective: To explore the related factors of thrombocytopenia (TCP) occurrence in patients with cirrhosis. Methods: A cross-sectional study was conducted. Inpatients with an initial diagnosis of cirrhosis at Peking University First Hospital from January 1, 2010 to December 31, 2020 were included. Clinical data such as demographic characteristics, etiology of cirrhosis, complications of cirrhosis, laboratory indicators, Child-Pugh grade, invasive procedures, and mortality during hospitalization were collected. A logistic regression model was used to explore the related factors of TCP occurrence in patients with cirrhosis. Categorical variables were compared by the χ(2) test. The inter-group comparison was performed using continuous variables, a t-test, one-way analysis of variance (ANOVA), or a nonparametric test. Results: There were a total of 2 592 cases of cirrhosis. 75 cases with incomplete clinical data were excluded. 2 517 cases were included for analysis. The median age was 58 (50, 67) years. Males accounted for 64%. 1 435 cases (57.0%) developed TCP, and 434 cases (17.2%) had grade 3-4 TCP. Gender, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and concomitant esophagogastric varices (EGV) were the major factors associated with TCP. Females were more prone to combine with TCP (OR=1.32, 95%CI: 1.12-1.56, P=0.001). Patients combined with EGV (OR=3.09, 95%CI: 2.63-3.65, P<0.001) were more prone to develop TCP, which was associated with the increased incidence of hypersplenism (P<0.001). Patients with PBC (OR=0.64, 95%CI: 0.50-0.82, P<0.001) and PSC (OR=0.23, 95%CI: 0.06-0.65, P=0.010) were less prone to develop TCP, which was due to the shorter prothrombin time and better coagulation function of PBC patients (P<0.001), and the lower proportion of hypersplenism in combined PSC patients (P=0.004). Patients with TCP and grade 3-4 TCP had a higher rate of hemostatic procedures (P<0.05), but a lower rate of liver biopsy (P<0.05). Patients with grade 3-4 TCP had a higher nosocomial mortality rate compared to those without (P=0.004). Conclusion: TCP is common in patients with cirrhosis. However, TCP occurrence is higher in female patients with EGV and lower in patients combined with PBC and PSC. TCP affects invasive procedures and is associated with adverse outcomes.

Causality of metabolites and metabolic pathways on cholestatic liver diseases: a Mendelian randomization study.

Background and Aims: Blood metabolite abnormalities have revealed an association with cholestatic liver diseases (CLDs), while the underlying metabolic mechanisms have remained sluggish yet. Accordingly, the present evaluation aims to investigate the causal relationship between blood metabolites and the risk of two major CLDs, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Methods: Univariable and multivariable Mendelian randomization (MR) approaches were employed to uncover potential causal associations between blood metabolites and 2 CLDs, including PBS and PSC, through extracting instrumental variables (IVs) for metabolites from genome-wide association studies (GWAS) conducted on European individuals. The GWAS summary data of PBC or PSC were sourced from two distinct datasets. The initial analysis employed inverse variance weighted (IVW) and an array of sensitivity analyses, followed by replication and meta-analysis utilizing FinnGen consortium data. Finally, a multivariable MR analysis was carried out to ascertain the independent effects of each metabolite. Furthermore, the web-based tool MetaboAnalyst 5.0 was used to perform metabolic pathway examination. Results: A genetic causality between 15 metabolites and CLDs was recognized after preliminary analysis and false discovery rate (FDR) correction. Subsequently, 9 metabolites consistently represented an association through replication and meta-analysis. Additionally, the independent causal effects of 7 metabolites were corroborated by multivariable MR analysis. Specifically, the metabolites isovalerylcarnitine (odds ratio [OR] = 3.146, 95% confidence intervals [CI]: 1.471-6.726, p = 0.003), valine (OR = 192.44, 95%CI: 4.949-7483.27, p = 0.005), and mannose (OR = 0.184, 95%CI: 0.068-0.499, p < 0.001) were found to have a causal relationship with the occurrence of PBC. Furthermore, erythrose (OR = 5.504, 95%CI: 1.801-16.821, p = 0.003), 1-stearoylglycerophosphocholine (OR = 6.753, 95%CI: 2.621-17.399, p = 7.64 × 10-5), X-11847 (OR = 0.478, 95%CI: 0.352-0.650, p = 2.28 × 10-6), and X-12405 (OR = 3.765, 95%CI: 1.771-8.005, p = 5.71 × 10-4) were independently associated with the occurrence of PSC. Furthermore, the analysis of metabolic pathways identified seven significant pathways in two CLDs. Conclusion: The findings of the present study have unveiled robust causal relationships between 7 metabolites and 2 CLDs, thereby providing novel insights into the metabolic mechanisms and therapeutic strategies for these disorders.

Primary sclerosing cholangitis with IgG4-positive plasma cells in bile duct biopsies - Frequency and characterization.

OBJECTIVES: Patients diagnosed with primary sclerosing cholangitis (PSC) but with characteristics of immunoglobulin G4 (IgG4)-associated cholangitis (IAC) have been described. IAC often presents with biliary IgG4-positive plasma cell (IgG4+ PC) infiltration and responds to corticosteroids. In PSC, the frequencies or implications of biliary IgG4+ PC are unknown. We aimed to characterize the phenomenon of biliary IgG4+ PC in patients with an established PSC diagnosis. METHODS: Bile duct biopsies from 191 surveillance or therapeutic endoscopic retrograde cholangiography of 58 PSC patients were retrospectively analyzed for IgG4+ PC infiltration. Patients with ≥10 IgG4+ PC per high-power field (HPF) were identified and characterized by clinical parameters, including serum IgG4 and cholangiographic presentations. RESULTS: Altogether 39.7% of the PSC patients showed ≥10 IgG4+ PC/HPF in bile duct biopsies. Patients with biliary IgG4+ PC infiltration were significantly younger at diagnosis of PSC (P = 0.023). There was no association between biliary IgG4+ PC infiltration and transplant-free survival (P = 0.618). Patients with IgG4+ PC infiltration in bile duct biopsies showed significantly higher baseline (P = 0.002) and maximum (P = 0.001) serum IgG4 compared to those without. Biliary IgG4+ PC infiltration was associated with high-grade bile duct strictures (P = 0.05). IgG4-positive plasma cell infiltrations were found multifocally in 72.7% of this subgroup of PSC patients. CONCLUSIONS: IgG4+ PC ≥10/HPF can be found abundantly in bile duct biopsies in PSC. Histological findings correlated with serum IgG4, age, and high-grade bile duct strictures. IgG4+ PC was located multifocally, hinting at a systemic biliary phenotype.

New target-HMGCR inhibitors for the treatment of primary sclerosing cholangitis: A drug Mendelian randomization study.

Background: No intervention definitively extends transplant-free survival in primary sclerosing cholangitis (PSC). Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), may enhance PSC prognosis, but their efficacy is debated. Methods: We analyzed HMGCR single-nucleotide polymorphisms from published genome-wide association studies using Mendelian randomization to assess the causal relationship between HMGCR and PSC risk. Effects of HMGCR were compared with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, common lipid-lowering drugs, using coronary heart disease risk as a positive control. The inverse-variance weighted (IVW) method was the primary analysis, complemented by the weighted median method. Heterogeneity analysis, examination of horizontal pleiotropy, and leave-one-out sensitivity analysis were conducted for result robustness. Results: Genetically predicted HMGCR exhibited a pronounced detrimental effect on PSC in both the IVW method (odds ratio [OR] [95%] = 2.43 [1.23-4.78], P = 0.010) and the weighted median method (OR [95%] = 2.36 [1.02-5.45], P = 0.044). However, PCSK9 did not reach statistical significance. Moreover, all analyses passed through heterogeneity analysis, horizontal pleiotropy analysis, and leave-one-out sensitivity analysis. Conclusion: This study has confirmed a causal relationship between HMGCR and PSC risk, suggesting statins targeting HMGCR could enhance PSC patient outcomes.

Clinical outcomes and reintervention after endoscopic retrograde cholangiopancreatography in primary sclerosing cholangitis in absence of cholangitis.

BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) may help detect cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC), but it may be associated with complications. This study was aimed at determining the prognostic impact of ERCP on patients with PSC without cholangitis. METHODS: Patients with PSC without cholangitis were divided into two groups: those who underwent ERCP within three years after diagnosis (ERCP-performed group) and those who did not (non-ERCP group). These groups were compared in terms of clinical outcomes (liver-related death or liver transplantation, endoscopic treatment requirement and repeated cholangitis) and the composite outcome. RESULTS: Of 99 patients with PSC with detailed medical history, 49 were included in the ERCP-performed group and 21 in the non-ERCP group. In Kaplan-Meier analysis, the non-ERCP group was less likely to achieve the three outcomes and the composite outcome, showing statistical significance (endoscopic treatment requirement; p = 0.017 and composite outcome; p = 0.014). A Cox proportional hazards model indicated that ERCP in the asymptomatic state was a significant predictor of endoscopic treatment requirement (hazard ratio [HR]: 4.37, 95% confidence interval [CI]: 1.03-18.59) and the composite outcome (HR: 4.54, 95% CI: 1.07-19.28). CONCLUSION: ERCP in patients with PSC without cholangitis is likely to require further endoscopic treatment and may be associated with poor prognosis.

Progress in the Management of Patients with Cholestatic Liver Disease: Where Are We and Where Are We Going?

Cholestatic liver disease is a group of diseases in which bile acid accumulates in the liver for various reasons, resulting in abnormal liver biochemical indicators and histological damage. Cholestasis can be divided into intrahepatic cholestasis and extrahepatic cholestasis, which will contribute to liver damage and progress to liver fibrosis and cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis are the two most typical cholestatic liver diseases. Ursodeoxycholic acid is currently the first-line treatment for PBC, while obeticholic acid, budesonide and fibrates have also shown good potential in the treatment of PBC. There are currently no official drugs approved to treat primary sclerosing cholangitis, and the use of ursodeoxycholic acid may have certain clinical benefits. At present, progress has been made in new treatment directions for cholestatic liver disease, including fibroblast growth factor 19, cholestyramine, S-adenosyl-L-methionine, steroid drugs, farnesoid X receptor agonists, and more. Considerable progress has been made in the management of cholestatic liver disease but there are still many opportunities and challenges. In this review, we summarized the recommended guidelines for the management of cholestatic disease and the progress of new drug research and development, in order to provide an important reference for the clinical practice of cholestatic liver disease.

Causality of immune cells on primary sclerosing cholangitis: a bidirectional two-sample Mendelian randomization study.

Background: Observational studies have indicated that immune dysregulation in primary sclerosing cholangitis (PSC) primarily involves intestinal-derived immune cells. However, the causal relationship between peripheral blood immune cells and PSC remains insufficiently understood. Methods: A bidirectional two-sample Mendelian randomization (MR) analysis was implemented to determine the causal effect between PBC and 731 immune cells. All datasets were extracted from a publicly available genetic database. The standard inverse variance weighted (IVW) method was selected as the main method for the causality analysis. Cochran's Q statistics and MR-Egger intercept were performed to evaluate heterogeneity and pleiotropy. Results: In forward MR analysis, the expression ratios of CD11c on CD62L+ myeloid DC (OR = 1.136, 95% CI = 1.032-1.250, p = 0.009) and CD62L-myeloid DC AC (OR = 1.267, 95% CI = 1.086-1.477, p = 0.003) were correlated with a higher risk of PSC. Each one standard deviation increase of CD28 on resting regulatory T cells (Treg) (OR = 0.724, 95% CI = 0.630-0.833, p < 0.001) and CD3 on secreting Treg (OR = 0.893, 95% CI = 0.823-0.969, p = 0.007) negatively associated with the risk of PSC. In reverse MR analysis, PSC was identified with a genetic causal effect on EM CD8+ T cell AC, CD8+ T cell AC, CD28- CD127- CD25++ CD8+ T cell AC, CD28- CD25++ CD8+ T cell AC, CD28- CD8+ T cell/CD8+ T cell, CD28- CD8+ T cell AC, and CD45 RA- CD28- CD8+ T cell AC. Conclusion: Our study indicated the evidence of causal effects between PSC and immune cells, which may provide a potential foundation for future diagnosis and treatment of PSC.

Exploring the Pathogenesis of Autoimmune Liver Diseases from the Heterogeneity of Target Cells.

The incidence of autoimmune liver diseases (ALDs) and research on their pathogenesis are increasing annually. However, except for autoimmune hepatitis, which responds well to immunosuppression, primary biliary cholangitis and primary sclerosing cholangitis are insensitive to immunosuppressive therapy. Besides the known effects of the environment, genetics, and immunity on ALDs, the heterogeneity of target cells provides new insights into their pathogenesis. This review started by exploring the heterogeneity in the development, structures, and functions of hepatocytes and epithelial cells of the small and large bile ducts. For example, cytokeratin (CK) 8 and CK18 are primarily expressed in hepatocytes, while CK7 and CK19 are primarily expressed in intrahepatic cholangiocytes. Additionally, emerging technologies of single-cell RNA sequencing and spatial transcriptomic are being applied to study ALDs. This review offered a new perspective on understanding the pathogenic mechanisms and potential treatment strategies for ALDs.

Still elusive: Developments in the accurate diagnosis of indeterminate biliary strictures.

Indeterminate biliary strictures pose a significant diagnostic dilemma for gastroenterologists. Despite advances in endoscopic techniques and instruments, it is difficult to differentiate between benign and malignant pathology. A positive histological diagnosis is always preferred prior to high risk hepatobiliary surgery, or to inform other types of therapy. Endoscopic retrograde cholangiopancreatography with brushings has low sensitivity and despite significant improvements in instruments there is still an unacceptably high false negative rate. Other methods such as endoscopic ultrasound and cholangioscopy have improved diagnostic quality. In this review we explore the techniques available to aid accurate diagnosis of indeterminate biliary strictures and obtain accurate histology to facilitate clinical management.

Immunological crossroads: The intriguing dance between hepatitis C and autoimmune hepatitis.

Delving into the immunological crossroads of liver diseases, this editorial explores the dynamic interplay between hepatitis C virus (HCV) and autoimmune hepatitis (AIH). While HCV primarily manifests as a viral infection impacting the liver, previous studies unveil a captivating connection between HCV and the emergence of AIH. The dance of the immune system in response to HCV appears to set the stage for an intriguing phenomenon-an aberrant autoimmune response leading to the onset of AIH. Evidence suggests a heightened presence of autoimmune markers in individuals with chronic HCV infection, hinting at a potential overlap between viral and autoimmune liver diseases. Navigating the intricate terrain of viral replication, immune response dynamics, and genetic predisposition, this editorial adds a layer of complexity to our understanding of the relationship between HCV and AIH. In this immunological crossroads, we aim to unearth insights into the complex interplay, using a compelling case where AIH and primary sclerosing cholangitis overlapped following HCV treatment with direct-acting antivirals as background.

Untangling biliary reconstruction in liver transplants for primary sclerosing cholangitis.

BACKGROUND: Biliary reconstruction technique during liver transplant (LT) for primary sclerosing cholangitis (PSC) remains controversial. This study aimed to evaluate the incidence of biliary complications in patients with PSC having a duct-to-duct (DD) anastomosis or Roux-en-Y hepaticojejunostomy (HJ). METHODS: A retrospective medical record review of patients with PSC undergoing LT at a single center between June 1st, 2000 and December 31st, 2022 was performed. Primary and secondary endpoints were the incidence of biliary strictures (anastomotic [BAS] and non-anastomotic strictures [NAS]) and non-stricture complications, respectively. Univariable and multivariable regression analyses were performed to identify associations with BAS formation. Patient survival was assessed using a Kaplan-Meier curve. RESULTS: From 105 transplants performed for 101 patients, 54 (51.4%) and 51 (48.5%) received DD and HJ anastomoses. Mean recipient age and follow-up was 47 ± 13 years and 98 ± 69 months. BAS was more common (48.1% vs. 27.5%, OR 2.45, 95% CI 1.09-5.54, p = 0.03) and occurred earlier (4.8 months, IQR 2.3-13.1 vs. 41.8 months, IQR 7.2-88.7, p = 0.001) in the DD than the HJ group. NAS (seen in 36.2% of transplants) had a comparable incidence (p = 0.53) in HJ (38.9%) and DD (33.3%) groups. No difference was seen between cohorts regarding time to NAS, requirement for extended biliary dilatation programs (clinically significant biliary stricture), bile leak, and graft failure. On multivariable analysis, only the anastomotic technique was associated with BAS (DD adjusted OR 3.00, 95% CI 1.19-7.56, p = 0.02). CONCLUSION: In carefully selected patients with PSC, DD anastomosis yielded similar outcomes to HJ anastomosis after liver transplantation.

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.

Hepatitis and Vasodilatory Shock due to an Unsuspected Culprit: A Rare Presentation of Multisystem Langerhans Cell Histiocytosis.

Introduction: Langerhans cell histiocytosis (LCH) is a rare hematologic condition which can affect multiple organ systems and has variable presentation. LCH is more commonly seen as a malignancy of childhood. LCH in adulthood can have poor outcomes depending on the involvement of critical organs. Case Presentation: We report a case of a 71-year-old female who presented with progressive weakness, weight loss, diarrhea, and jaundice, and had been undergoing outpatient workup for elevated liver enzymes for the last 2 years. She required admission to the intensive care unit for vasodilatory shock, requiring vasopressor and chronotropic support. Imaging showed an underlying multiorgan process involving the gastrointestinal tract, liver, spleen, and central nervous system. A repeat liver biopsy after a prior inconclusive one revealed the diagnosis of multisystem LCH presenting as secondary sclerosing cholangitis. Conclusion: The uniqueness of this multisystem LCH case lies not only in its rarity but also in the diagnostic journey that necessitated a repeat biopsy for a conclusive diagnosis. Early identification and targeted intervention can help in ensuring better patient outcomes, especially when the presentation can overlap with various other possible conditions.