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Liver chemistry abnormalities are a frequent manifestation of coronavirus disease 2019 (COVID-19) but are usually transient and resolve with disease resolution. We describe the clinical course and histologic features of 3 adults who developed prolonged and severe cholestasis during recovery from critical cardiopulmonary COVID-19. These patients had clinical and histologic features similar to secondary sclerosing cholangitis of the critically ill patient, but with unique histologic features including severe cholangiocyte injury and intrahepatic microangiopathy suggestive of direct hepatic injury from COVID-19. We believe that these cases constitute a novel severe post-COVID-19 cholangiopathy with potential for long-term hepatic morbidity.

Background Studies have revealed that resistin plays a role as an intrahepatic cytokine with proinflammatory activities. This study investigated the association between serum resistin and fibrosis severity and the possible marker role of resistin in the inflammatory process of chronic hepatitis B. Methods In this study, 234 subjects with HBV infection were retrospectively selected, including 85 patients with chronic hepatitis B (CHB), 70 patients with HBV-related liver cirrhosis (LC-B), and 79 patients with HBV-related liver failure (LF-B). Serum levels of resistin, IL-1, IL-6, IL-17, IL-23, TNF-α, and TGF-β1 were assayed by ELISA. Demographic and clinical characteristics of patients were extracted from clinical databases of Taihe Hospital, Hubei University of Medicine, including serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), and liver stiffness (LS). Results All the selected patients with HBV infection showed significantly increased levels of serum resistin, which was rarely detectable in the healthy controls. Serum resistin levels in patients with CHB, LC-B, and LF-B were 4.119 ± 5.848 ng/mL, 6.370 ± 6.834 ng/mL, and 6.512 ± 6.076 ng/mL, respectively. Compared with the CHB group, patients with LC-B or LF-B presented with significantly higher serum levels of resistin ( p  < 0.01). On the other hand, all of the enrolled patients had high serum levels of IL-1, IL-6, IL-17, TNF-α, and TGF-β1, but not IL-23. Interestingly, serum levels of resistin was significantly positively correlated with serum levels of TGF-β1 in LC-B patients ( R  = 0.3090, p  = 0.0290), with IL-17 in LC-B ( R  = 0.4022, p  = 0.0038) and LF-B patients ( R  = 0.5466, p  < 0.0001), and with AST ( R  = 0.4501, p  = 0.0036) and LS ( R  = 0.3415, p  = 0.0310) in CHB patients. Conclusions High serum resistin associates with intrahepatic inflammation and necrosis and may be used as an index of disease severity for patients with chronic HBV infection.

Cholangitis and pancreatitis associated with cytomegalovirus (CMV) infection in an immunocompetent patient is reported. Endoscopic retrograde cholangiography performed on a 55-year-old man for evaluation of the cause of jaundice and liver dysfunction revealed a distal focal irregular narrowing of the common bile duct. Microscopic findings of the resected specimen showed chronic cholangitis and CMV pancreatitis. Immunohistochemistry disclosed that epithelial cells in the inflamed bile duct were positive for CMV antigen, which was compatible with CMV cholangitis. Inflammation of the biliary tract or pancreas by CMV has been commonly reported as a complication in immunocompromised patients. Our report appears to be a rare case, but suggests that CMV cholangitis or pancreatitis should be considered in the differential diagnoses of common bile duct stenosis or pancreatitis even in immunocompetent individuals.

This review of biliary manifestations of viral diseases includes aspects of morphologic diagnosis, therapeutic implications, prognostic effect, and natural history. The viral causes of cholangitis are reviewed, with subclassification on the basis of primary hepatic versus systemic infections and immune competence of the host. Special attention is given to the histopathologic and clinical features of viruses affecting the biliary tree. Among hepatotropic viruses, hepatitis C more frequently is associated with cholangitis than is hepatitis B. In both hepatitis B and hepatitis C, the lymphocytic cholangitis duct damage is reversible and does not adversely influence the course of disease or response to therapy. Hepatitis A and hepatitis E, despite causing clinical cholestasis, do not result in severe cholangitis. The effect of systemic viruses on the biliary tree is primarily dependent on the status of the host immune system. Infants and severely immunosuppressed patients (such as those who have undergone liver transplantation) are at risk for cytomegalovirus cholangitis, whereas patients with late-stage acquired immunodeficiency syndrome (AIDS) are at risk for cholangitis due to numerous organisms. Overall, cholangitis attributable to viral disease encompasses a wide spectrum of clinicopathologic scenarios, depending on the etiologie virus and the immune competence of the host.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 virus, is a predominantly respiratory tract infection with the capacity to affect multiple organ systems. Abnormal liver tests, mainly transaminase elevations, have been reported in hospitalized patients. We describe a syndrome of cholangiopathy in patients recovering from severe COVID-19 characterized by marked elevation in serum alkaline phosphatase (ALP) accompanied by evidence of bile duct injury on imaging. We conducted a retrospective study of COVID-19 patients admitted to our institution from March 1, 2020, to August 15, 2020, on whom the hepatology service was consulted for abnormal liver tests. Bile duct injury was identified by abnormal liver tests with serum ALP > 3x upper limit of normal and abnormal findings on magnetic resonance cholangiopacreatography. Clinical, laboratory, radiological, and histological findings were recorded in a Research Electronic Data Capture database. Twelve patients were identified, 11 men and 1 woman, with a mean age of 58 years. Mean time from COVID-19 diagnosis to diagnosis of cholangiopathy was 118 days. Peak median serum alanine aminotransferase was 661 U/L and peak median serum ALP was 1855 U/L. Marked elevations of erythrocyte sedimentation rate, C-reactive protein, and D-dimers were common. Magnetic resonance cholangiopacreatography findings included beading of intrahepatic ducts (11/12, 92%), bile duct wall thickening with enhancement (7/12, 58%), and peribiliary diffusion high signal (10/12, 83%). Liver biopsy in 4 patients showed acute and/or chronic large duct obstruction without clear bile duct loss. Progressive biliary tract damage has been demonstrated radiographically. Five patients were referred for consideration of liver transplantation after experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis. One patient underwent successful living donor liver transplantation. Cholangiopathy is a late complication of severe COVID-19 with the potential for progressive biliary injury and liver failure. Further studies are required to understand pathogenesis, natural history, and therapeutic interventions.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and its frequent complication with ulcerative colitis highlights the pathogenic role of epithelial barrier dysfunction. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC, yet its underlying mechanism remains unknown. Here, we identify Klebsiella pneumonia in the microbiota of patients with PSC and demonstrate that K.   pneumoniae disrupts the epithelial barrier to initiate bacterial translocation and liver inflammatory responses. Gnotobiotic mice inoculated with PSC-derived microbiota exhibited T helper 17 (T H 17) cell responses in the liver and increased susceptibility to hepatobiliary injuries. Bacterial culture of mesenteric lymph nodes in these mice isolated K.   pneumoniae , Proteus mirabilis and Enterococcus gallinarum , which were prevalently detected in patients with PSC. A bacterial-organoid co-culture system visualized the epithelial-damaging effect of PSC-derived K.   pneumoniae that was associated with bacterial translocation and susceptibility to T H 17-mediated hepatobiliary injuries. We also show that antibiotic treatment ameliorated the T H 17 immune response induced by PSC-derived microbiota. These results highlight the role of pathobionts in intestinal barrier dysfunction and liver inflammation, providing insights into therapeutic strategies for PSC. Klebsiella pneumoniae from the gut microbiota of patients with primary sclerosing cholangitis (PSC) can damage the intestinal epithelial barrier, resulting in bacterial translocation and T helper 17 cell responses in the liver, indicating a role in PSC pathogenesis.

Recent work has highlighted the importance of confounder control in microbiome association studies 1 , 2 . For instance, multiple pathologies previously linked to gut ecosystem dysbiosis display concomitant changes in stool consistency 3 – 6 , a major covariate of microbiome variation 2 , 7 . In those cases, observed microbiota alterations could largely reflect variation in faecal water content. Moreover, stool moisture variation has been linked to fluctuations in faecal microbial load, inducing artefacts in relative abundance profile analyses 8 , 9 . Hence, the identification of associations between the gut microbiota and specific disease manifestations in pathologies with complex aetiologies requires a deconfounded, quantitative assessment of microbiome variation. Here, we revisit a disease association microbiome data set comprising 106 patients with primary sclerosing cholangitis (PSC) and/or inflammatory bowel disease 10 . Assessing quantitative taxon abundances 9 , we study microbiome alterations beyond symptomatic stool moisture variation. We observe an increased prevalence of a low cell count Bacteroides  2 enterotype across the pathologies studied, with microbial loads correlating inversely with intestinal and systemic inflammation markers. Quantitative analyses allow us to differentiate between taxa associated with either intestinal inflammation severity ( Fusobacterium ) or cholangitis/biliary obstruction ( Enterococcus ) among previously suggested PSC marker genera. We identify and validate a near-exclusion pattern between the inflammation-associated Fusobacterium and Veillonella genera, with Fusobacterium detection being restricted to Crohn’s disease and patients with PSC–Crohn’s disease. Overall, through absolute quantification and confounder control, we single out clear-cut microbiome markers associated with pathophysiological manifestations and disease diagnosis. Here, the authors apply quantitative microbiome profiling to a metagenomics data set comprising patients with primary sclerosing cholangitis and/or inflammatory bowel disease and identify microbial taxa associated with inflammation or specific disease indicators, which were validated in an independent inflammatory bowel disease cohort.

Inflammasome is linked to many inflammatory diseases, including COVID-19 and autoimmune liver diseases. While severe COVID-19 was reported to exacerbate liver failure, we report a fatal acute-on-chronic liver failure (ACLF) in a stable primary biliary cholangitis-autoimmune hepatitis overlap syndrome patient triggered by a mild COVID-19 infection. Postmortem liver biopsy showed sparse SARS-CoV-2-infected macrophages with extensive ASC (apoptosis-associated speck-like protein containing a CARD) speck-positive hepatocytes, correlating with elevated circulating ASC specks and inflammatory cytokines, and depleted blood monocyte subsets, indicating widespread liver inflammasome activation. This first report of a fatal inflammatory cascade in an autoimmune liver disease triggered by a mild remote viral infection hopes to elucidate a less-described pathophysiology of ACLF that could prompt consideration of new diagnostic and therapeutic options.

Immune-mediated gastrointestinal (GI) diseases, including achalasia, celiac disease, and inflammatory bowel diseases, pose significant challenges in diagnosis and management due to their complex etiology and diverse clinical manifestations. While genetic predispositions and environmental factors have been extensively studied in the context of these conditions, the role of viral infections and virome dysbiosis remains a subject of growing interest. This review aims to elucidate the involvement of viral infections in the pathogenesis of immune-mediated GI diseases, focusing on achalasia and celiac disease, as well as the virome dysbiosis in IBD. Recent evidence suggests that viral pathogens, ranging from common respiratory viruses to enteroviruses and herpesviruses, may trigger or exacerbate achalasia and celiac disease by disrupting immune homeostasis in the GI tract. Furthermore, alterations in the microbiota and, specifically, in the virome composition and viral–host interactions have been implicated in perpetuating chronic intestinal inflammation in IBD. By synthesizing current knowledge on viral contributions to immune-mediated GI diseases, this review aims to provide insights into the complex interplay between viral infections, host genetics, and virome dysbiosis, shedding light on novel therapeutic strategies aimed at mitigating the burden of these debilitating conditions on patients’ health and quality of life.