Post-COVID-19 Cholangiopathy: A Novel Entity.

INTRODUCTION: Liver chemistry abnormalities are a frequent manifestation of coronavirus disease 2019 (COVID-19) but are usually transient and resolve with disease resolution. METHODS: We describe the clinical course and histologic features of 3 adults who developed prolonged and severe cholestasis during recovery from critical cardiopulmonary COVID-19. RESULTS: 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. DISCUSSION: We believe that these cases constitute a novel severe post-COVID-19 cholangiopathy with potential for long-term hepatic morbidity.

High serum resistin associates with intrahepatic inflammation and necrosis: an index of disease severity for patients with chronic HBV infection.

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-ß1 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-ß1, but not IL-23. Interestingly, serum levels of resistin was significantly positively correlated with serum levels of TGF-ß1 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.

The SRL peptide of rhesus rotavirus VP4 protein governs cholangiocyte infection and the murine model of biliary atresia.

Biliary atresia (BA) is a neonatal obstructive cholangiopathy that progresses to end-stage liver disease, often requiring transplantation. The murine model of BA, employing rhesus rotavirus (RRV), parallels human disease and has been used to elucidate mechanistic aspects of a virus induced biliary cholangiopathy. We previously reported that the RRV VP4 gene plays an integral role in activating the immune system and induction of BA. Using rotavirus binding and blocking assays, this study elucidated how RRV VP4 protein governs cholangiocyte susceptibility to infection both in vitro and in vivo in the murine model of BA. We identified the amino acid sequence on VP4 and its cholangiocyte binding protein, finding that the sequence is specific to those rotavirus strains that cause obstructive cholangiopathy. Pretreatment of murine and human cholangiocytes with this VP4-derived peptide (TRTRVSRLY) significantly reduced the ability of RRV to bind and infect cells. However, the peptide did not block cholangiocyte binding of TUCH and Ro1845, strains that do not induce murine BA. The SRL sequence within TRTRVSRLY is required for cholangiocyte binding and viral replication. The cholangiocyte membrane protein bound by SRL was found to be Hsc70. Inhibition of Hsc70 by small interfering RNAs reduced RRV's ability to infect cholangiocytes. This virus-cholangiocyte interaction is also seen in vivo in the murine model of BA, where inoculation of mice with TRTRVSRLY peptide significantly reduced symptoms and mortality in RRV-injected mice. CONCLUSION: The tripeptide SRL on RRV VP4 binds to the cholangiocyte membrane protein Hsc70, defining a novel binding site governing VP4 attachment. Investigations are underway to determine the cellular response to this interaction to understand how it contributes to the pathogenesis of BA. (Hepatology 2017;65:1278-1292).

First detection and complete genome sequence of a phylogenetically distinct human polyomavirus 6 highly prevalent in human bile samples.

Oncovirus-associated malignancies are potentially preventable diseases with major public health significance. Human polyomaviruses (HPyVs) may be associated with oncogenesis or symptomatic illnesses in immunocompromised patients, but the site of viral shedding of most recently discovered HPyVs remains obscure. Using real-time PCR assay using specific primers targeting the HPyV6 large tumor antigen gene, we detected a phylogenetically distinct HPyV6 which was highly prevalent in the bile samples of patients with malignant biliary obstruction (18.8%) and acute gallstone cholangitis (5.5%). The prevalence rate and mean viral load of this HPyV6 were highest in the cholangiocarcinoma subgroup (27.6% and 2.41 × 104copies/ml). These findings were confirmed with another real-time PCR assay using specific primers targeting the HPyV6 viral capsid protein 2 gene. These bile HPyV6 strains may represent a novel clade of HPyV6 as they formed a distinct cluster from the other HPyV6s and exhibited >2% differences in amino acid sequences in their major proteins. While HPyV6 was unlikely the cause of the patients' acute symptoms and liver dysfunction, the virus may be related to immunosuppression in patients with malignancy and/or important in the oncogenesis of cholangiocarcinoma in patients without coinfection with other oncogenic microbes. Further studies to ascertain a causative role of HPyV6 in cholangiocarcinoma should be conducted.

Parasitic and infectious diseases of the biliary tract in migrants and international travelers.

INTRODUCTION: In recent years, global and regional crises have led to extraordinary worldwide migration, accompanied by an increase in long-distance travel from Western countries. Both are linked to a rising incidence of rare parasitic and infectious diseases in first world countries, including in the biliary tract. Areas covered: A selective literature research in PubMed was performed to review the most important parasitic and infectious biliary diseases, which are caused by a wide variety of pathogens and may be latent over long periods, with chronic courses leading to cholangitis, hepatic failure or development of cholangiocarcinoma. Parasites such as Ascaris, Fasciola and Clonorchis/Opisthorchis are particularly important and may trigger biliary diseases or predisposition for bacterial superinfections. Viral or protozoal cholangitis is mainly a problem of impaired immunity. Expert commentary: Currently, these entities are still rare in migrants and long-distance travelers. However, a significant increase in Western countries has to be expected. Incidences are most likely underestimated because of protracted clinical latency. Diagnosis depends on the relevant pathogens, the host's immune status and the extent or distribution of biliary obstruction. Modern tomographic methods, ERCP and specific microbiological/parasitological/virological tests are of crucial diagnostic importance. Antimicrobial/antiparasitic/antiviral therapy along with ERCP and interventional sonography/radiology provide effective treatment options.

Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease.

BACKGROUND & AIMS: The NOD.c3c4 mouse model develops autoimmune biliary disease characterized by spontaneous granulomatous cholangitis, antimitochondrial antibodies and liver failure. This model for primary biliary cirrhosis (PBC) has evidence of biliary infection with mouse mammary tumour virus (MMTV), suggesting that the virus may have a role in cholangitis development and progression of liver disease in this mouse model. We tested the hypothesis that MMTV infection is associated with cholangitis in the NOD.c3c4 mouse model by investigating whether antiretroviral therapy impacts on viral levels and liver disease. METHODS: NOD.c3c4 mice were treated with combination antiretroviral therapy. Response to treatment was studied by measuring MMTV RNA in the liver, liver enzyme levels in serum and liver histology using a modified Ishak score. RESULTS: Combination therapy with the reverse transcriptase inhibitors, tenofovir and emtricitabine, resulted in a significant reduction in serum liver enzyme levels, attenuation of cholangitis and decreased MMTV levels in the livers of NOD.c3c4 mice. Furthermore, treatment with the retroviral protease inhibitors, lopinavir and ritonavir, in addition to the reverse transcriptase inhibitors, resulted in further decrease in MMTV levels and attenuation of liver disease in this model. CONCLUSIONS: The attenuation of cholangitis with regimens containing the reverse transcriptase inhibitors, tenofovir and emtricitabine, and the protease inhibitors, lopinavir and ritonavir, suggests that retroviral infection may play a role in the development of cholangitis in this model.

Reovirus type-2-triggered autoimmune cholangitis in extrahepatic bile ducts of weanling DBA/1J mice.

BACKGROUND: Reovirus is a proposed cause of infantile biliary atresia. However, mechanistic insight regarding Reo-2 as a potential cholangiotropic virus is lacking. Furthermore, it is unknown whether Reo-2 infection can induce autoimmune-mediated bile duct injury. METHODS: Lesions of bile ducts in newborn DBA/1J mice infected with Reo-2 were analyzed immunopathologically. RESULTS: Damage to biliary epithelia occurs after Reo-2 infection. In addition, nonsuppurative cholangitis with fibrosis in extrahepatic (especially septal) bile ducts developed following complete viral clearance from the liver. At the inflamed ducts, major histocompatibility complex class I expressing((+)) and FAS(+) cholangiocytes were associated with FAS ligand(+) lymphocytes and tumor necrosis factor-α(+) mononuclear cells (macrophages and lymphocytes). These cholangiocytes were apoptotic and necrotic. Moreover, affected ducts were infiltrated by CD3(+), CD4(+), CD8(+), IFN-γ(+), and FAS(+) lymphocytes. Analysis of blood from Reo-2-infected mice revealed that they developed anticholangiocyte cytoplasm antibodies and had high serum IFN-γ concentration. Notably, there was no increase in Foxp3(+) lymphocytes at inflamed ducts, lymph nodes, and thymi. CONCLUSION: Reo-2 infection induced T-helper cell type 1-dependent injury to bile ducts in weanling mice. The lesions observed in mice may be analogous to those associated with human infantile biliary atresia, which are caused by an autoimmune-mediated process.

Occult cytomegalovirus cholangitis as a potential cause of cholestatic complications after orthotopic liver transplantation? A study of cytomegalovirus DNA in bile.

Cholestatic complications, important causes of morbidity and mortality after orthotopic liver transplantation (OLT), often have an unclear etiology. Human cytomegalovirus (CMV) infections occur in immunosuppressed patients and can be detected in blood samples. However, CMV analyses of body fluids and biopsies are more sensitive. Here we evaluated whether a CMV analysis of bile could reveal occult CMV cholangitis. We evaluated OLT patients undergoing endoscopic retrograde cholangiography (ERC) for suspected biliary complications after OLT at a tertiary care center. Biliary CMV DNA levels were measured with real-time polymerase chain reaction. A nonanastomotic biliary lesion (NABL) group consisted of patients with nonanastomotic strictures (NASs) at the time of ERC (n = 59) and patients with normal ERC findings but microscopic biliary lesions in biopsy samples (n = 12). The anastomotic stricture (AS) group comprised patients with ASs only (n = 53). In all, 124 OLT patients underwent 240 ERC procedures. Biliary CMV DNA was detected in 14 of the 124 patients and was more frequently found in the NABL group (12/71 for the NABL group versus 2/53 for the AS group, P = 0.02). Concurrent sampling of CMV DNA in blood yielded negative results. Biliary CMV was more frequently detected in patients with a positive recipient status (13/73 or 17.8% versus 1/44 or 2.3%, P < 0.05). There was no significant difference in the incidence of biliary CMV between patients with a high-risk CMV status and patients with a low-risk CMV status. The median interval between OLT and biliary CMV detection was 8.4 months (range = 0.4-212.8 months). In conclusion, biliary CMV was detected in a substantial number of patients after OLT and was significantly associated with NASs or microscopic biliary lesions. A potential occult CMV infection could, therefore, be considered as a contributory etiological factor in the development of biliary complications.

Cytomegalovirus infection of the major duodenal papilla in a renal allograft recipient with severe biliary obstruction and acalculous cholecystitis.

Cytomegalovirus (CMV) can cause severe infections with serious consequences in renal transplant recipients. Disseminated CMV infections can affect almost every organ, but obstructive cholestasis and cholangitis, as a consequence of a CMV-induced papillitis, is extremely rare. We are reporting a rare case of obstructive cholestasis and cholecystitis due to CMV-related inflammation of the major duodenal papilla in a 60-year-old woman 3 months after renal transplantation. In addition, the patient suffered from a disseminated CMV infection with ulcerative esophagitis and gastritis. Because of the severe CMV infection, failure of the renal graft occurred. Obstructive cholestasis was resolved through internal stenting, and the progressive cholecystitis necessitated an emergency cholecystectomy. Following antiviral therapy with ganciclovir, the gastrointestinal ulcerations regressed and renal function was restored. Diagnosis of the CMV-related disease was established only in tissue samples, whereas standard serologic tests had failed.

[Hepatitis E virus: A new entity]. / Les hépatites virales E : une maladie émergente en France.

Hepatitis E virus (HEV) is a RNA enterically transmitted virus that causes large waterborne epidemics of acute hepatitis E in endemic regions (Asia and Africa). Sporadic hepatitis E is an emerging disease in developed countries such as France. The majority of acute hepatitis E in France is indigenous (non travel-associated) and is due to infection with HEV genotype 3. Diagnosis is made on the presence of specific serum antibodies and on viral RNA detection in serum or stools. Characteristic pathological signs of acute hepatitis E are severe intralobular necrosis, polymorph inflammation and acute cholangitis in portal tract with numerous neutrophils. Severe forms of hepatitis are associated with underlying chronic liver disease such alcoholic disease. In immunocompetent patients, HEV causes acute resolutive hepatitis and there is no chronic evolution. Conversely, chronic hepatitis E is frequent in immunocompromised patients with a risk of rapid evolution to cirrhosis. Histologic lesions of chronic hepatitis E are similar to those observed in patients chronically infected with hepatitis C virus with dense lymphocytic portal infiltrate, constant peacemeal necrosis and fibrosis.

Unusual presentation of cytomegalovirus infection in patients after organ transplant.

OBJECTIVES: Cytomegalovirus (CMV) infection has an enormous impact in solid-organ transplant patients. In immunocompromised patients, CMV is associated with well-known direct effects. We herein describe 3 unusual patterns occurring in the setting of tissue-invasive CMV associated with high viral load. MATERIALS AND METHODS: Of our 3 cases, the first patient after kidney transplant presented with cholestasis related to radiological cholangitis; the second patient after heart transplant presented with erythema nodosum with CMV infection as the sole cause; and the third patient after kidney transplant presented with acute renal failure related to mild interstitial nephritis with acute tubular necrosis and tubulitis. RESULTS: The first patient's cholestasis resolved with antiviral therapy, as did the erythema nodosum and CMV infection of the heart transplant patient. The third patient's acute renal failure resolved by increased steroid dosage, plasma exchanges, and ganciclovir therapy. CONCLUSIONS: These 3 unusual presentations of tissue invasive CMV had favorable outcomes with antiviral therapy.

Relationship between prognosis of biliary atresia and infection of cytomegalovirus.

BACKGROUND: The etiology of biliary atresia is still unknown. It is generally accepted that virus infection may be one of the important causes that lead to biliary atresia. This study aimed to illustrate the relationship between infection of cytomegalovirus and prognosis of biliary atresia. METHODS: From January 2002 to March 2004, 27 patients who had undergone Kasai's procedure because of biliary atresia were investigated for cytomegalovirus -IgG, IgM and pp65, and their mothers were also examined for confirmation of cytomegalovirus infection. The patients were divided into three groups: infection free group, cytomegalovirus positive group and cytomegalovirus infection group. The rate of jaundice disappearance and the incidence of reflux cholangitis were analyzed statistically. The histopathological changes of the liver were also analyzed. RESULTS: The positive expression of cytomegalovirus -IgM and cytomegalovirus-pp65 in the patients was higher than that in their mothers (48% versus 14.81% and 37% versus 3.78%, respectively). Compared with the other two groups (80% in the infection free group, and 82% in the cytomegalovirus positive group), the rate of jaundice disappearance after operation in the cytomegalovirus infection group (36%) was significantly lower (P<0.05), and the incidence of reflux cholangitis was higher (P<0.05). Histopathological examination also showed that the degree of liver fibrosis and inflammation was more serious (P<0.05). CONCLUSIONS: There is a strong correlation between cytomegalovirus infection and a lower rate of jaundice disappearance, also a higher post-operational reflux cholangitis. Liver fibrosis seems to be more severe in biliary atresia patients with cytomegalovirus infection.

[Primary infection with Epstein-Barr virus in a 77-year-old patient with B symptoms and hepatitis -- a case report]. / 77-jähriger Patient mit Epstein-Barr-Virus-Erstinfektion mit B-Symptomatik und Hepatitis -- ein Fallbericht.

Epstein-Barr virus (EBV) infection has a prevalence of 90 % and is - depending on the immune status of the host - associated with a broad spectrum of clinical manifestations. By presenting a case report we would like to demonstrate an unusual clinical course of a primary infection with EBV in an elderly patient. A 77-year-old patient was admitted to hospital in reduced health condition because of a persisting bronchopulmonary infection with B symptoms. The patient had already been treated with antibiotics. Because of elevated liver enzymes, a liver biopsy was performed. Histopathology revealed moderate acute hepatitis with cholangitis und endothelialitis, pointing to an EBV-induced hepatitis. Serological examinations confirmed the diagnosis, revealing a primary infection with positive EBV VCA IgM and IgG. EBV PCR of the liver tissue was positive, viral genome could be demonstrated within lymphocytes. A short period later the patient was discharged to reconvalescence. This case report demonstrates an unusual primary infection with EBV at the age of 77 with atypical clinical symptoms and hepatitis. The relevance of EBV in the differential diagnosis of atypical infectious diseases with hepatitis of unknown aetiology is strengthened on taking data reports from the literature into consideration.

Cytomegalovirus cholangitis and pancreatitis in an immunocompetent patient.

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.

Acute hepatitis E: a cause of lymphocytic destructive cholangitis.

Lymphocytic destructive cholangitis is a histological pattern associating bile duct intraepithelial lymphocytic infiltration and bile duct epithelial damage. Lymphocytic destructive cholangitis is an important diagnostic feature of primary biliary cirrhosis, but it can also be seen in primary sclerosing cholangitis, autoimmune hepatitis, the so-called overlap syndrome, acute or chronic viral hepatitis C, drug-induced hepatitis, and acute rejection or graft-versus-host disease in liver or bone marrow transplantation. In the present paper we report a case of acute hepatitis with lymphocytic destructive cholangitis on liver biopsy. Clinical and biological examinations showed that the patient had hepatitis E with no other cause of liver disease. Therefore, hepatitis E should be considered as a diagnostic possibility when liver biopsy shows acute hepatitis and lymphocytic destructive cholangitis. The mechanism of bile duct damage in hepatitis E remains unknown.

Pathogenicity by parenteral injection of fowl adenovirus isolated from gizzard erosion and resistance to reinfection in adenoviral gizzard erosion in chickens.

The pathogenicity of a serotype-1 fowl adenovirus (FAV-99ZH), which causes adenoviral gizzard erosion by oral inoculation in chickens, was investigated in specific pathogen-free white leghorn chickens. In trial 1, 14 chickens were inoculated intravenously with the virus at 21 days of age and euthanatized for necropsy within 1-14 days of inoculation. Gizzard erosion was grossly observed from day 7 postinoculation (PI), and histologically, FAV-99ZH antigen-positive, basophilic intranuclear inclusion bodies were seen in the gizzard lesions from day 7 to 11 PI. Necrotizing pancreatitis, and cholecystitis and cholangitis associated with the inclusions were observed from day 3 to 14 PI (pancreatitis) and from day 5 to 9 PI (cholecystitis and cholangitis), respectively. The inclusions were also observed in the epithelial cells of the cecal tonsils from day 3 to 5 PI. The virus was recovered from samples of the lesions. It was revealed that FAV-99ZH causes not only gizzard erosion but also pancreatitis, cholecystitis, and cholangitis by intravenous inoculation in chickens. In trial 2, 10 chickens were inoculated orally with the virus twice, at 13 and 36 days of age, and euthanatized for necropsy within 4-17 days after reinfection. Macroscopically, focal gizzard lesions were observed; however, neither necrosis nor inclusions were observed by microscopy. Moreover, FAV was not recovered from the gizzard or rectum of any of the chickens at necropsy. This suggests that the gizzard lesions occurred as a result of the primary infection, and that the chickens were able to resist reinfection.