Insight into the distinctive paradigm of Human Cytomegalovirus associated intrahepatic and extrahepatic cholestasis in neonates.

Human Cytomegalovirus has been implicated as a probable cause for the development of hepatic cholestasis among neonates. Our study tried to ascertain the exact demographic, biochemical and immunological markers to differentially diagnose patients with HCMV associated intrahepatic and extrahepatic cholestasis and also decipher the phylogenetic variability among the viral strains infecting the two groups. A total of 110 neonates collected over a span of 2 years were selected for the study classified into four different groups based on the presence of hepatic cholestasis and active HCMV infection. Our analysis predicted that total Cholesterol, GGT, ALP and TNFα were the only significant biological markers with exact cut-off scores, capable of distinguishing between HCMV associated intrahepatic and extrahepatic cholestasis. We confirmed that in patients belonging to both of these groups, the inflammasome is activated and the extent of this activation is more or less same except for the initial activators NLRP3 and AIM2 respectively. When we performed two separate phylogenetic analyses with HCMV gM and gN gene sequences, we found that in both cases the sequences from the IHC and EHC groups formed almost separate phylogenetic clusters. Our study has shown that the HCMV clinical strains infecting at intrahepatic and extrahepatic sites are phylogenetically segregated as distinct clusters. These two separate groups show different physiological as well as immunological modulations while infecting a similar host.

Maternal hepatitis B infection status and adverse pregnancy outcomes: a retrospective cohort analysis.

PURPOSE: To investigate the association between maternal HBsAg-positive status and pregnancy outcomes. METHODS: The study enrolled women with singleton pregnancies who delivered during January-December 2018. Data of maternal demographics and main adverse pregnancy outcomes were collected from the institutional medical records and analyzed by univariate and multivariate logistic regression models to determine the association between maternal HBV markers (HBsAg/HBeAg/HBV-DNA loads status) and adverse pregnancy outcomes. RESULTS: Total 1146 HBsAg-positive and 18,354 HBsAg-negative pregnant women were included. After adjusting for potential confounding variables, maternal HBsAg-positive status was associated with a high risk of gestational diabetes mellitus (GDM) [adjusted odds ratio (aOR) = 1.24; 95% confidence interval (CI) 1.07-1.43], intrahepatic cholestasis of pregnancy (ICP) (aOR = 3.83; 95% CI 3.14-4.68), preterm birth (aOR = 1.42; 95% CI 1.17-1.72), and neonatal asphyxia (aOR = 2.20; 95% CI 1.34-3.63). Further, higher risks of ICP and neonatal asphyxia remained with either HBeAg-positive status (aOR = 1.64; 95% CI 1.10-2.44; aOR = 3.08; 95% CI 1.17-8.00) or high HBV-DNA load during the second trimester (aOR = 1.52; 95% CI 1.06-2.35; aOR = 4.20; 95% CI 4.20-15.83) among HBsAg-positive pregnant women. CONCLUSION: Women with maternal HBsAg-positive status may have increased risks of GDM, ICP, preterm birth, and neonatal asphyxia; furthermore, the risks of ICP and neonatal asphyxia were higher in women with HBeAg-positive status and a high HBV-DNA load during the second trimester among the HBsAg-positive pregnant women, implying that careful surveillance for chronic HBV infection during pregnancy is warranted.

Manifestaciones cutáneas en contexto del brote actual de enfermedad por coronavirus 2019 / Cutaneous manifestations in the current pandemic of coronavirus infection disease (COVID 2019)

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Maternal hepatitis B virus carrier status and pregnancy outcomes: a prospective cohort study.

BACKGROUND: Infection with hepatitis B virus (HBV) in pregnant women may be a threat for both mothers and fetuses. This study was performed to explore the impact of maternal HBV carrier status on pregnancy outcomes. METHODS: We conducted a prospective cohort study at the Obstetrics & Gynecology Hospital of Nantong University between January 1, 2012 and September 30, 2015. A consecutive sample of 21,004 pregnant women, 513 asymptomatic HBV carriers and 20,491 non-HBV controls, was included in this study. The main outcomes of interest were selected pregnancy outcomes including miscarriage, stillbirth, preterm birth (PTB), gestational diabetes (GDM), intrahepatic cholestasis of pregnancy (ICP), preterm premature rupture of the membrane (PPROM), low birth weight (LBW), small for gestational age (SGA) and Apgar scores. The incidence of adverse pregnancy outcomes between asymptomatic HBV carriers and non-HBV controls were compared using the chi-square test and logistic regression. P values were two sided, and P <0.05 was considered to indicate statistical significance. RESULTS: The incidences of stillbirth, PTB, GDM, ICP, PPROM, LBW, and SGA were similar between the HBV carrier and non-HBV groups. The proportion of miscarriage was significantly higher among the HBV carriers than the controls (9.36% vs 5.70%; P <0.001). After using multivariate modelling to adjust for possible socio-demographical variables and obstetric complications, women with HBV carrier status were still more likely to have miscarriage (adjusted OR 1.71, 95% CI 1.23-2.38). In addition, the incidences of other maternal and neonatal outcomes were similar between the two groups. CONCLUSION: Maternal HBV carrier status may be an independent risk factor for miscarriage and careful surveillance is warranted.

Successful treatment with telaprevir of post-transplant fibrosing cholestatic hepatitis C in an HIV co-infected patient.

Hepatitis C recurrence is the main cause of graft loss in liver transplant patients co-infected with human immunodeficiency virus (HII). These patients have higher risk of fibrosing cholestatic hepatitis, which is the most severe type of hepatitis C recurrence. Until direct antiviral agents were released, only a minority of patients could be satisfactorily treated. We describe the successful treatment with pegylated-interferon, ribavirin and telaprevir of an hepatitis C virus (HCV)/HIV co-infected patient who developed fibrosing cholestatic hepatitis after liver transplantation. A 40-year- old male (HCV genotype 1a; IL-28 CC) underwent liver transplantation for decompensated cirrhosis. On post-transplant day 60, he rapidly developed progressive jaundice, worsening of liver function tests and ascites. A transjugular liver biopsy confirmed the diagnosis of fibrosing cholestatic hepatitis. Treatment with peglated-interferon, ribavirin and telaprevir was indicated for 48 weeks, achieving sustained virological response at 12 weeks of follow-up. The rapid negativization of the viral load observed during the first 4 weeks of treatment was associated with regression of ascites andjaundice. Red blood cell transfusions, erythropoietin and filgrastim were required for the management of anemia and neutropenia. Triple therapy with telaprevir might be indicated for the treatment of severe HCV recurrence in selected HCV/HIV co-infected patients, especially in countries with limited access to pegylated-interferon-free regimens.

Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease.

BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

Case report of successful treatment of fibrosing cholestatic hepatitis C with sofosbuvir and ribavirin after liver transplantation.

Fibrosing cholestatic hepatitis is an unusual complication of hepatitis C virus (HCV) recurrence after liver transplant. Fibrosing cholestatic hepatitis is marked by aggressive progression of cholestasis and fibrosis, leading to accelerated graft loss and/or death. Sofosbuvir (GS-7977) is an oral nucleotide analogue inhibitor of HCV polymerase activity. It is a second-generation, direct-acting, antiviral for the treatment of HCV infection. This case illustrates a patient with recurrent HCV with fibrosing cholestatic hepatitis, who was successfully treated with a combination of sofosbuvir and ribavirin with normalization of liver enzyme activities and resolution of HCV-related symptoms. The favorable side effect profile and the lack of drug-drug interaction with immunosuppressive medications make the combination of sofosbuvir and ribavirin a promising regimen for severe HCV recurrence.

Fibrosing cholestatic hepatitis after successful interferon and ribavirin therapy for recurrent hepatitis C post living related liver transplantation: a case report.

A 33-year-old Japanese man who had suffered from liver cirrhosis due to hepatitis C virus (HCV) underwent living related liver transplantation (LRLT). The allograft was given by his brother, who was healthy with no history of hepatitis or hepatic virus infection. After LRLT, the patient's hepatitis C recurred. Liver biopsy revealed chronic viral hepatitis and no allograft rejection such as shown by portal lymphocytic infiltration or mild bridging fibrosis. Interferon and ribavirin were administered, and sustained viral response (SVR) was obtained. Although serum hepatitis B virus (HBV)-DNA/HCV-RNA polymerase chain reaction found no presence of hepatic virus, the serum examination demonstrated liver dysfunction seven months after SVR. Liver biopsies histopathologically showed portal fibrosis invading to the sinusoids, cholestasis, mild hyperplasia of the cholangioles, and no features of allograft rejection. Fibrosing cholestatic hepatitis (FCH) was diagnosed. The FCH was resistant to treatment and advanced, and the patient died 17 months post-LRLT. Several serum examinations failed to demonstrate the existence of HBV/HCV during the patient's course. FCH is a type of viral hepatitis that is characterized by recurrent viral hepatitis after allograft transplantation. Because SVR obtained by anti-viral therapy commonly resolves FCH, we believe that this patient represented a rare case of FCH. The present case suggests that not only direct viral cytotoxicity, but other factors as well, promote the development of fibrosis and cholestasis. FCH sometimes progresses irreversibly despite the absence of serum viral load. The present case informed us that immediate anti-viral therapy should be initiated when recurrent allograft viral hepatitis is diagnosed.

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.

The Hepatitis Aggressiveness Score (HAS): a novel classification system for post-liver transplantation recurrent hepatitis C.

Several histopathologic features have been described in cases of fibrosing cholestatic hepatitis C (FCH-C). We investigated whether FCH-associated features can be utilized as the basis of a novel grading system for the entire population of post-liver transplantation (LT) recurrent hepatitis C virus (HCV) infection. Liver biopsies obtained at a median (interquartile range) of 12.3 (10.4-13.8) months post-LT from 170 patients with recurrent HCV were included. Biopsies were assessed for the following FCH features: (1) ductular reaction, (2) cholestasis, (3) hepatocyte ballooning, and (4) periportal sinusoidal fibrosis. A Hepatitis Aggressiveness Score (HAS) was assigned on the basis of the number of FCH features as follows: 0 features=HAS 1; 1 to 2 features=HAS 2; and 3 to 4 features=HAS 3. We analyzed the performance of this novel system in predicting clinicopathologic outcomes compared with conventional grading systems after a median (interquartile range) follow-up of 24 (13-45.5) months. The HAS classification was highly predictive of fibrosis progression (P<0.001) and was the best predictor of graft loss in a multivariable analysis model, which included all conventional hepatitis grading systems (adjusted hazard ratio=5.5, confidence interval 2.9-10.7, P<0.001 for HAS 3 vs. HAS 1 and 2, compared with adjusted hazard ratio=1.0, confidence interval 0.5-1.9, P=0.94 for the presence of moderate to severe necroinflammation by at least 1 conventional grading system). Presence of at least 3 of 4 FCH features (HAS 3 group) characterized a subset of patients with distinctly worse prognosis and severe cholestatic disease (ie, FCH-C). We propose a novel approach to the histologic grading of post-LT recurrent HCV based exclusively on FCH features. This system allows accurate identification of FCH-C cases and stratification of all recurrent HCV patients into distinct prognostic categories.

Prolonged cholestasis due to hepatitis A virus infection.

We present a 12-year old boy with jaundice for 2 weeks. The child was deeply icteric and had hepatomegaly. IgM antibodies for hepatitis A virus were positive. However this child had prolonged cholestasis and cholestyramine was started. The child responded only after prednisolone was started.

Cytomegalovirus frequency in neonatal intrahepatic cholestasis determined by serology, histology, immunohistochemistry and PCR.

AIM: To determine cytomegalovirus (CMV) frequency in neonatal intrahepatic cholestasis by serology, histological revision (searching for cytomegalic cells), immunohistochemistry, and polymerase chain reaction (PCR), and to verify the relationships among these methods. METHODS: The study comprised 101 non-consecutive infants submitted for hepatic biopsy between March 1982 and December 2005. Serological results were obtained from the patient's files and the other methods were performed on paraffin-embedded liver samples from hepatic biopsies. The following statistical measures were calculated: frequency, sensibility, specific positive predictive value, negative predictive value, and accuracy. RESULTS: The frequencies of positive results were as follows: serology, 7/64 (11%); histological revision, 0/84; immunohistochemistry, 1/44 (2%), and PCR, 6/77 (8%). Only one patient had positive immunohistochemical findings and a positive PCR. The following statistical measures were calculated between PCR and serology: sensitivity, 33.3%; specificity, 88.89%; positive predictive value, 28.57%; negative predictive value, 90.91%; and accuracy, 82.35%. CONCLUSION: The frequency of positive CMV varied among the tests. Serology presented the highest positive frequency. When compared to PCR, the sensitivity and positive predictive value of serology were low.

Post-transplant recurrent hepatitis C: immunohistochemical detection of hepatitis C virus core antigen and possible pathogenic implications.

INTRODUCTION: The mechanisms by which severe cholestatic hepatitis develops after liver transplantation are not fully understood. Reports on immunohistochemical distribution of hepatitis C virus (HCV) antigens are still scarce, but recently, HCV immunostaining was suggested for early diagnosis of cholestatic forms of recurrent hepatitis C in liver grafts. After purification, Rb246 pab anticore (aa1-68) yielded specific, granular cytoplasmic staining in hepatocytes. Signal amplification through the Envision-Alkaline Phosphatase System avoided endogenous biotin and peroxidase. AIMS/METHODS: Rb246 was applied to liver samples of explants of 12 transplant recipients, six with the most severe form of post-transplantation recurrence, severe cholestatic hepatitis (group 1) and six with mild recurrence (group 2). We also assessed immuno-reactivity at two time-points post-transplantation (median 4 and 22 months) in both groups. HCV-core Ag was semiquantified from 0 to 3+ in each time point. Serum HCV-RNA was also measured on the different time points by branched DNA. RESULTS: In the early post-transplant time point, one patient had a mild staining (1+), two patients had a moderate staining (2+) and the other three had no staining in group 1, compared with five patients with no staining (0) and one patient with mild staining (1+) in group 2. Late post-transplant liver samples were available in nine patients, and two out of four samples in group 1 showed a mild staining, compared with no staining patients in five patients in group 2. Strikingly, on the explant samples, HCV immunostaining was strongly positive in group 1, and mildly positive in group 2. Two out of five samples showed 3+ staining, and three samples showed 2+ staining in group 1; two out of five samples showed no staining, two samples showed 1+ staining and one sample showed 2+ staining in group 2. Serum HCV-RNA was significantly higher in group 1, on both time-points post-transplantation. HCV-core Ag was not directly associated with serum HCV-RNA on the different time points. CONCLUSION: These preliminary results suggest that strong HCV immunostaining in the explant is predictive of more severe disease recurrence.

Intravenous interferon during the anhepatic phase of liver retransplantation and prevention of recurrence of cholestatic hepatitis C virus.

Cholestatic hepatitis C virus (HCV) infection post orthotopic liver transplantation is associated with a poor prognosis. We describe 2 patients who received interferon and ribavirin for cholestatic HCV infection with clearance of HCV RNA from the serum. Both developed signs of graft failure necessitating repeat orthotopic liver transplantation, and at surgery, interferon was administered during the anhepatic phase to prevent graft reinfection. Both patients are doing well with no evidence of recurrent viremia at 36 and 24 months of follow-up after repeat transplantation, respectively. Our results suggest that in those with cholestatic HCV infection, repeat transplantation after viral clearance is feasible and can occur without reinfection of the graft, challenging the current practice of denying retransplantation for patients with cholestatic HCV. The role of anhepatic administration of interferon deserves further examination, and this combination may provide a solution in a subset of patients with an otherwise poor prognosis.

Vitamin K-deficient intracranial hemorrhage as the first symptom of cytomegalovirus hepatitis with cholestasis.

Since vitamin K2 (VitK2) syrup prophylaxis has become a routine measure for neonates and young infants, the incidence of vitamin K deficiency (VitK-D) in infancy has markedly decreased. However, we recently experienced 2 infantile cases of VitK deficiency, in whom intracranial hemorrhage (ICH) was the first clinical sign of CMV hepatitis. Case 1 is a breast-fed boy who received VitK2 syrup orally at birth and at the age of 1 month. He did not suckle well and developed a generalized tonic convulsion twice at the age of 8 weeks. Case 2 is a mixed-fed boy who also received VitK2 syrup twice but developed vomiting and drowsiness at the age of 4 months. In both cases, laboratory tests showed anemia, leukocytosis, liver dysfunction with cholestasis, and coagulopathy, consistent with VitK-D abnormality. Their serological analyses showed that cytomegalovirus (CMV) IgG and IgM were both positive. In case 1, CMV DNA was positive, as judged by the PCR method. In case 2, CMV antigenemia was positive. Hence we diagnosed these two patients as having VitK-D ICH caused by CMV hepatitis with cholestasis. CMV hepatitis is a risk factor of VitK-D ICH.

Antiviral therapy in neonatal cholestatic cytomegalovirus hepatitis.

BACKGROUND: Neonatal hepatitis refers to a heterogeneous group of disorders, caused by many factors including cytomegalovirus infection, revealing similar morphologic changes in the liver of an infant less than 3 months of age. Approximately 40% of cholestasis in infants is due to neonatal hepatitis. It may cause latent or acute cholestatic or chronic hepatitis, including cirrhosis in immunocompetant infant. METHODS: Twelve infants diagnosed with neonatal cytomegalovirus hepatitis in the last one year were included in the study. Group 1 consisted of seven babies treated with ganciclovir for 21 days. Group 2 included five cases who did not receive antiviral treatment. Physical examination, biochemical, serologic and virologic tests were done for both groups at the time of diagnosis and in the third month. RESULTS: Initial levels of total bilirubin, aminotransferases, gamma glutamyl transpeptidase, and alkaline phosphatase revealed a significant decrease after the treatment in Group 1 (p < 0.05) when compared with Group 2. This study revealed that ganciclovir treatment is a safe and effective in cases with cholestatic hepatitis. Similarly, all the patients in the treatment group had evidence of improvement serologically and virologically, while the comparison group did not reveal any significant change(p < 0.01). CONCLUSION: The clinical spectrum of perinatal infection varies from an asymptomatic infection or a mild disease to a severe systemic involvement, including central nervous system. The treatment in the early period of infection improved serologic markers and cholestatic parameters significantly. Further studies will lead us to clarify the efficacy of ganciclovir treatment in the early period of cytomegalovirus hepatitis, and the preventive role of anti-viral therapy on progressive liver disease due to cholestasis and hepatitis in neonatal cytomegalovirus infection.

[A case of cholestatic hepatitis induced by epstein-barr virus infection].

Acute viral hepatitis in human can be caused by a large number of viruses with a wide range of clinical manifestations and laboratory findings. EBV is a rare causative agent of an acute hepatitis, during the course of infectious mononucleosis. Hepatic manifestations of EBV are usually mild and resolve without serious complications. EBV is rather uncommonly confirmed as an etiologic agent in acute viral hepatitis of adults and it rarely causes cholestatic hepatitis. We report a case of EBV hepatitis with cholestatic feature that was verified through serum viral marker and liver biopsy.

Immunohistochemical assessment of hepatitis C virus antigen in cholestatic hepatitis after liver transplantation.

BACKGROUND: Patients with common variable immunodeficiency may exhibit rapidly progressive hepatitis when infected with hepatitis C virus (HCV), leading to cirrhosis and liver failure. Liver transplantation in these patients may result in a cholestatic form of HCV reinfection with exceptionally high virus loads. AIMS: To report an immunohistochemical investigation of the pretransplant and post-transplant liver of one such patient. METHODS/RESULTS: On immunohistochemical staining of frozen sections with anti-HCV core monoclonal antibody or fluorescein labelled human polyclonal anti-HCV IgG, no HCV antigens were demonstrated in the native cirrhotic liver removed at transplant, despite a viral load of 10(6.4) genomes/g. The transplanted liver, collected six weeks post-transplant, exhibited cholestatic recurrent hepatitis, had an HCV virus load of 10(10) genomes/g of liver, and revealed HCV antigen in the cytoplasm of most hepatocytes, with a pronounced periportal distribution. No virus antigen was demonstrable in other cell types. The core antigen was also detected in paraffin wax embedded, formaldehyde fixed tissue of this liver after high temperature antigen retrieval, but not in the native cirrhotic liver or a selection of HCV positive livers collected pretransplant from immunocompetent patients. Attempts to delineate the distribution of E1, NS3, and NS4 antigens were unsuccessful because monoclonal antibodies to these antigens produced "false positive" staining of foci of hepatocytes in the post-transplant livers of HCV seronegative patients with cholestasis. CONCLUSION: This case provided an opportunity to study the natural development of HCV during acute infection in the absence of an immune response, and may help to elucidate the pathogenesis of HCV recurrence in liver allografts.

Hepatitis C virus-related fibrosing cholestatic hepatitis in a renal transplant recipient.

Fibrosing cholestatic hepatitis (FCH) is a severe and progressive form of liver dysfunction seen in organ transplant recipients and immunosuppressed patients; it is usually associated with hepatitis B virus infection. We report 36-year-old man, a renal transplant recipient, also developed FCH with hepatitis C virus infection and succumbed to it.