Extrahepatic Infection Research Articles

'Curved tunnel' sign on MRI: a typical radiological feature in hepatic trichinellosis.

To summarize the clinical and radiological features of hepatic trichinellosis. Patients diagnosed with trichinellosis and liver involvement in our institution since 2011 were included retrospectively. Then, qualified patients were divided into a seropositive group and a clinically diagnosed group. Preoperative liver CT and/or MRI images were evaluated independently by two radiologists. The correlations between the radiological and pathological features were evaluated by a radiologist and a pathologist. Independent t-tests were carried out to assess clinical data between groups and those reported in the previous literature. Values of P less than 0.05 were considered statistically significant. Eventually, ten patients were enrolled, five in each group. All patients recovered successfully after surgical (n = 8) or conservative treatment (n = 2). The clinical, radiological, and pathological features were highly consistent between the two groups. All patients were under 60years of age (48.0 ± 7.9years in the seropositive group, 48.6 ± 10.1years in the clinically diagnosed group), and they were older than those previously reported in the literature (30.5 ± 17years, n = 31; P = 0.032 and 0.028). Eosinophilia was found in four patients, and all were mildly increased (˂ 1.5 × 109/L). Lesions in all patients were in the right lobe of the liver, and nine of them showed a characteristic 'curved tunnel' sign on DCE-MRI images. None of the patients had signs or evidence of extrahepatic infection. The 'curved tunnel' sign on MRI is a typical radiological feature in hepatic trichinellosis.

Glucose Homeostasis Is Dysregulated in Ducks Infected with Duck Hepatitis B Virus

Introduction: The association between hepatitis B virus (HBV) infection and the development of diabetes remains controversial. This study examined the effect of HBV infection on glucose homeostasis using a duck HBV (DHBV) model. Methods: Plasma DHBV DNA was detected by quantitative polymerase chain reaction (PCR). Tissue infection of DHBV was determined by detecting DHBV covalently closed circular DNA (cccDNA) with a method of rolling circle amplification combined with cross-gap PCR, and verified by fluorescence in situ hybridization assay. An intravenous injection glucose tolerance test (GTT) was used to analyze the effect of DHBV infection on glucose tolerance. Results: Of the finally included 97 domestic ducks, 53 (54.6%) were congenitally infected by DHBV. The positive rate of DHBV cccDNA in the liver, kidney, pancreas, and skeletal muscle of the infected ducks was 100, 75.5, 67.9, and 47.2%, respectively. The DHBV-infected ducks had higher blood glucose levels at 15 and 30 min post-load glucose (p < 0.01 and p < 0.001, respectively) in the GTT, much more individuals with greater glucose area under curve (p < 0.01), and a 57% impaired glucose tolerance (IGT) rate, as compared with noninfected controls. In addition, the subgroups of the infected ducks with DHBV cccDNA positive in skeletal muscle maintained the higher blood glucose level up to 2 h post-load glucose during the GTT and had a 76% IGT rate. Conclusion: These results suggest that DHBV intrahepatic and extrahepatic infection impairs glucose tolerance, and thus evidence the association of DHBV infection with the dysregulation of glucose metabolism.

Hepatitis B virus lymphotropism: emerging details and challenges

The hepatitis B virus (HBV) is predominantly a hepatotropic virus but also infects cells of the lymphatic system. HBV genomes (DNA, messenger (m)RNA, covalently closed circular (ccc) DNA) and proteins have been found in extrahepatic sites such as peripheral blood mononuclear cells (PBMC), lymph nodes, spleen, bone marrow and cerebrospinal fluid. HBV entry into hepatocytes occurs by binding of the HBV preS1 surface protein to its specific receptor, the bile acid transporter, sodium taurocholate co-transporting polypeptide (NTCP). Although the mechanism of HBV entry into lymphatic cells is unknown, the pre S1 encoded surface protein is thought to be involved. Extrahepatic HBV infection has been studied in both chronic HBV (CHB) and in occult HBV infection (OBI). Studies have shown that HBV genomes are present in different PBMC subsets from chronically infected carriers. Unique HBV variants have been found in PBMC compared to plasma or liver in both nucleos(t)ide analogue (NA) treated and untreated CHB carriers, suggesting replication and compartment specific evolution of HBV. In HBV coinfection, HBV genomes were found in PBMC from hepatitis C virus (HCV), human immunodeficiency virus (HIV) and hepatitis delta virus (HDV) co-infected individuals. Moreover, during pregnancy, the trans placental passage of HBV infected PBMC from highly viremic mothers to infants is one of the postulated means of vertical transmission of HBV. Taken together, HBV infection in extrahepatic sites (i.e., PBMC) is implicated in multiple facets of HBV pathogenesis such as persistence, viral evolution and vertical transmission.

Prospects for the treatment of patients with chronic viral hepatitis with cirrhosis

We performed a retrospective cohort study at S. P. Botkin Clinical Infectious Diseases Hospital, St. Petersburg, Russia from January to December 2014. The purpose of this study was to evaluate indications and contraindications for liver transplant in cirrhotic patients with chronic hepatitis. We analyzed 310 medical record of patients with established diagnosis “Chronic viral hepatitis, cirrhosis”. According to the EASL 2015, 59.4 % (184) of patients with liver cirrhosis had one or multiple indications for liver transplantation. 64.1 % (118) patients were of working age. Chronic hepatitis C virus infection was detected in 56.3 % (71). The most significant contraindication was active alcohol or drug addiction: 76 % (44). Extrahepatic malignant neoplasms detected in 19 % (11) and active extrahepatic infection in 5 % (3). Risk factors of mortality during the current hospitalization were significantly associated with the MELD score, the presence of hepatocellular carcinoma, active alcoholism, active extrahepatic infection and extrahepatic malignant neoplasms. Among patients hospitalized with the diagnosis “Chronic viral hepatitis, cirrhosis”, 40 % (126) had indications and had no contraindications for liver transplantation. Under the conditions of an insufficient number of liver transplantations, high mortality, especially in working-age patients with no contraindications for this operation, it is necessary to find early treatment with effective influence on the pathological mechanisms to prevent the need for liver transplantation.

Extra-hepatic infection of hepatitis C virus in the colon tissue and its relationship with hepatitis C virus pathogenesis.

Extra-hepatic compartments might contribute to hepatitis C virus (HCV) persistence and extra-hepatic manifestations. Therefore, we investigated HCV infection in colonic tissue in patients with chronic hepatitis C (CHC) and its relationship with HCV pathogenesis. Colonic biopsies were collected from three groups with CHC infection: treatment naïve (TN; n=12), non-responders (NR; n=10) to anti-HCV therapy (pegylated interferon-α and ribavirin) and sustained virologic response (SVR; n=10) and from a fourth healthy control group (n=10). Liver biopsies were examined to assess inflammation and fibrosis. HCV infection and colonic T regulatory (Treg) frequency were detected by immunohistochemistry. HCV core and NS3 proteins were detected in B cells and macrophage/monocytes of 42 % and 25 % of TN and 50 % and 30 % of NR, respectively, but not in SVR or control group. The numbers of cells expressing HCV proteins were positively correlated with both HCV viral load and colonic Treg frequency. A significant negative correlation between HCV-expressing cells with both liver inflammation and fibrosis was identified. Our study provides evidence that HCV can infect B cells and macrophages of the colon. The correlations between HCV infection in colonic tissue and HCV viral load and liver pathology underline the significance of this extra-hepatic infection in HCV pathogenesis and response to therapy.

The Pitfalls of Febrile Jaundice. A Case Report.

Jaundice in sepsis is usually caused by cholestasis, and its onset can precede other manifestations of the infection. Inflammation-induced cholestasis is a common complication in patients with an extrahepatic infection or those with inflammatory processes. We describe the case of a 47 years old female who presented with low back pain and paravertebral muscular contracture. She subsequently developed a cholestatic syndrome with clinical manifestations such as jaundice, followed by fever and sepsis with multiple organ dysfunction. Initially labeled as biliary sepsis, the diagnosis was crucially reoriented as the blood cultures were positive for Streptococcus pyogenes and the magnetic resonance imaging (MRI) findings suggested spondylodiscitis as well as a paravertebral abscess.

A Case of Ventriculitis Associated with Renal Abscess Caused by Serotype K1 Klebsiella pneumoniae.

Recently, serotype K1 Klebsiella pneumoniae has been a major agent of an invasive syndrome characterized by liver abscess and its metastatic infection. Extrahepatic infection and its characteristics in patients with renal abscess caused by K. pneumoniae are poorly understood, and few cases of central nervous system infection have been reported. This is a report of 80-year-old woman with uncontrolled type 2 diabetes mellitus with renal abscess caused by serotype K1 K. pneumoniae, complicated with ventriculitis despite of appropriate use of antibiotics. Physicians need to be aware of possibility of metastatic infection in patients with serotype K1 K. pneumoniae infection, if they develop neurologic symptom and focus of infection is still present.

Liver Transplantation in a Monolung Patient: A Strategy of Sequential Treatments of Multiple Lung Tuberculosis Ca-vitations and Hepatocellular Carcinoma on Hepatitis B Related Virus Cirrhosis

The presence of extrahepatic infection is a contraindication for liver transplantation, even more if supported by an advanced pulmonary tuberculosis with persistent cavitation not curable with medical treatment. We report a case of a young patient with hepatocellular carcinoma on hepatitis B virus related liver cirrhosis and multiple lung tuberculosis cavitations. The patient was referred to our centre for liver transplantation. We adopted a strategy with sequential treatments. First a left extra-pericardial pneumonectomy was performed without opening the infected cavern, followed by a therapy with rifampicin, isoniazid and ethambutol for a period of nine months. After the cure of tuberculosis, the monolung patient eventually was listed for liver transplantation. An accurate planning of a multistep therapeutical strategy, an appropriate anesthetic management and a meticulous surgical technique allowed to successfully transplant a young patient suffering from three life-threatening diseases: cavitary tuberculosis, hepatitis B virus cirrhosis and hepatocellular carcinoma. Thirty months after liver transplantation the patient is in good health, with normal liver function, forced expiratory volume in one second of 42% (1.53 liters) and without any tuberculosis disease reactivation.

Active hepatitis C virus infection in bone marrow and peripheral blood mononuclear cells from patients with mixed cryoglobulinaemia.

The presence of hepatitis C virus (HCV) genomic sequences was checked in plasma, liver, peripheral blood mononuclear cells (PBMC) and bone marrow cells from 11 patients with mixed cryoglobulinaemia positive for anti-HCV antibodies, and from 11 patients with chronic HCV hepatitis without serological evidence of cryoglobulinaemia. HCV RNA sequences were demonstrated by reverse transcription polymerase chain reaction in seven plasma samples, in six PBMC samples, and in seven bone marrow cell samples from the 11 cryoglobulinaemic subjects; otherwise, viral specific nucleic acids were detected in 10 plasma samples, in one PBMC sample, and in two bone marrow cell samples from the 11 patients with chronic hepatitis. The HCV replicative intermediate was evidenced in four of the six PBMC and in five of the seven bone marrow aspirate HCV RNA-positive samples. Analysis of subpopulations isolated from bone marrow and peripheral blood samples showed HCV RNA sequences in mononuclear cells belonging either the CD2+ subset or to the CD19+ subpopulation or to the adherent cells. Finally, we compared the nucleotide sequences of a large portion (-270 to -59) of the HCV 5'-untranslated region from five patients with mixed cryoglobulinaemia and from seven patients with chronic hepatitis without cryoglobulinaemia; the degree of heterogeneity, compared with the prototype HCV sequence, was similar in both groups. These findings from two groups of HCV-infected patients indicate that transient or permanent active HCV infection of bone marrow and PBMC is frequent in anti-HCV-positive patients with mixed cryoglobulinaemia, and suggest that extra-hepatic infection may play a major role in influencing the pathophysiology of this infection as well as the viral persistence.

Influence of extrahepatic viral infection on the natural history of hepatitis C: Original Article

HCV is primarily hepatotropic, but there is mounting evidence pointing to infection and replication of extrahepatic sites. Here we evaluated the occurrence of HCV infection of peripheral blood mononuclear cells (PBMC) and explored the possible association between viral extrahepatic infection and the natural history of the disease. Forty seven Chilean, HCV infected, treatment naïve patients were included in the study. HCV RNA was isolated from plasma and PBMC and subsequently reverse transcribed, amplified and sequenced. Most patients harbored HCV 1b genotype and the most common route of infection showed to be blood transfusion. HCV RNA was readily detected in PBMCs of 34 out of the 47 patients (72%). We report that HCV sequences found in PBMC differ from those in plasma of the same subjects strongly suggesting HCV compartmentalization. In addition, we found that patients with detectable HCV RNA in PBMC had a tendency for being more likely cirrhotic [OR 3.8 (95% CI: 0.98 to 14)]. In conclusion, this study provides further arguments for the existence of HCV infection of extrahepatic sites and suggests that extrahepatic infection could be a factor influencing the natural history of the disease.

Early Intrahepatic Accumulation of CD8+ T Cells Provides a Source of Effectors for Nonhepatic Immune Responses

Interactions between the liver and CD8+ T cells can lead to tolerance, due in part to CD8+ T cell death. To test whether this was the case in an extrahepatic infection, we investigated the fate and effector capacity of intrahepatic CD8+ T cells during lung-restricted influenza infection in mice. Virus-specific T cells accumulated in livers without detectable intrahepatic presentation of viral Ags, and this accumulation was not restricted to the contraction phase, but was apparent as early as day 5. Intrahepatic influenza-specific cells were functionally similar to those recovered from the bronchioalveolar lavage, based on ex vivo cytokine production and specific target lysis. Both adoptive transfer of liver lymphocytes and orthotopic liver transplant of organs containing accumulated effector T cells revealed that activated CD8s from the liver were viable, expanded during reinfection, and generated a memory population that trafficked to lymphoid organs. Thus, intrahepatic CD8+ T cells re-enter circulation and generate functional memory, indicating that the liver does not uniformly incapacitate activated CD8+ T cells. Instead, it constitutes a substantial reservoir of usable Ag-specific effector CD8+ T cells involved in both acute and recall immune responses.

Detection of replicative form of hepatitis C virus RNA in peripheral blood mononuclear cells.

Paired samples of plasma and peripheral blood mononuclear cells (PBMC) from 7 patients with posttransfusion hepatitis C were collected and studied for the presence of replicative forms of hepatitis C virus (HCV). RNA was extracted and tested for both positive and negative strands of HCV RNA by polymerase chain reaction. Positive-strand RNA of HCV was found in both plasma and PBMC of all 7 patients. However, negative-strand RNA was found in PBMC of 3 patients while none was found in the plasma. Levels of negative-strand RNA were about 10-100 times less than those of positive-strand RNA by semiquantification with serial dilution of viral cDNA. The results suggest that active infection and replication of HCV in PBMC is present in patients with posttransfusion hepatitis C and implicate the extrahepatic infection of HCV.

Hepatitis B virus and hepatitis delta virus.

Hepatitis B virus (HBV) may cause acute and chronic infection of the liver. Acute hepatitis B infection may cause serious icteric hepatitis or even fulminant hepatitis, though the infection may be anicteric and asymptomatic in a high proportion of cases. Chronic hepatitis B is defined by the presence of hepatitis B surface antigen (HBsAg) in serum for longer than six months. Several hundred million people worldwide are thus infected. The expression of the disease is complex: varying levels of viral replication occur and there is a spectrum of disease ranging from benign to severe forms of chronic hepatitis. Serum aminotransferases mayor may not be elevated, and morphologic reactions in the liver range from minimal inflammatory change to destruction of hepatocytes and widespread inflammatory infiltration, cirrhosis or even hepatocellular carcinoma (HCC) (Beasley, 1988). The disease may remain clinically silent for decades but nonetheless progresses to cirrhosis and to HCC. Superinfection with hepatitis D may affect the expression of the disease. Variants of HBV infection with atypical serological markers add to the complexity of the infection. Although HBV is predominantly hepatotrophic, extrahepatic infection and complications can occur.

Hepatitis B virus. New and evolving issues.

Recent developments in molecular biology have advanced our understanding of the pathogenesis of HBV-induced disease. New data derived from the molecular analysis of clinical material have begun to bridge the gap between bench research and the clinical arena. In this review, we consider topics that have relevance to clinical management and that have not been summarized in the recent literature. The recent advances that have been made in the areas of HBV variants, in vitro cell culture systems, and extrahepatic infection are discussed in greater detail.

Portal hypertension caused by biliary cirrhosis

Twelve patients with portal hypertension caused by biliary cirrhosis were treated from January, 1983- June. 1990. There were 6 women and 6 men. Age ranged from 20 to 50 years with an average of 35.5 years. In all patients, a significant feature of this series was the long period of biliary obstruction caused by bile duct stones (N = 7), congenital atresia of biliary tract (N = 1), Caroli disease (N = 1), sclerosing cholangitis (N = 1), sclerosing carcinoma of biliary tract (N = 1), and benign postoperative stricture of biliary tract (N = 1). The incidence was 6.6% in portal hypertension; 2.2% in biliary tract disease and 18% in intrahepatic cholelithiasis. Esophagogastric varices were demonstrated in 6 cases. In 5 cases with or without esophageal varices, varices around the extrahepatic bile duct were detected before or during operation. Some complications including poor liver function, dilated collaterals around extrahepatic bile duct and biliary infection with underlying biliary stones existed simultaneously, therefore the management of these cases was very difficult. There was no single approach to patients with portal hypertension caused by biliary cirrhosis and it should be treated as an individual basis.

Transient hyperphosphatasaemia in association with acute infection in adults

The causes of raised serum alkaline phosphatase were determined prospectively in a consecutive series of 2884 acute medical admissions. Diagnoses were established by pre-defined clinico-pathological criteria. Two hundred and four patients had hyperphosphatasaemia. Liver and bone disease accounted for only 98 (48%) of the established diagnoses. The diagnosis was not established in 31 (15%). Transient hyperphosphatasaemia occurred in 66 (32.4%) cases. In 25 of these patients (12% of the total) an acute infection was the sole illness identified. In this infected group, the isoenzyme type was predominantly hepatic, although jaundice occurred in only 3 patients. Discriminant analysis revealed that this group was characterized by haematological and biochemical features of an acute phase response. Transient hyperphosphatasaemia is commonly found in acutely ill medical inpatients and is frequently associated with acute extrahepatic infection.

Hepatologie Neuere Forschungsergebnisse in ihrer Bedeutung f�r das Verst�ndnis von Leberkrankheiten

By two exemplary clinical situations--acute viral hepatitis, acute-phase reaction of the liver--the significance of basic research for the understanding of clinical phenomena and for the development of new diagnostic and therapeutic procedures is demonstrated. The very different phenomena following infection with the hepatitis-B-virus can be explained by the variation in the interactions of virus and liver cell, by the immune reaction of the host, and by mutants of the virus. The reaction of the liver to an extrahepatic infection is mediated by interleukin-6, and characterized by an alteration in protein metabolism. The synthesis of acute-phase proteins is increased. The proteins confine the local injury and establish the homeostasis of the organism.

Duck hepatitis B virus infection of non‐hepatocytes

One hundred and seventeen ducklings, 42 inoculated with duck hepatitis B virus (DHBV) 2 days after hatching and 55 connatally infected, were studied over a 6-month period in parallel with 20 ducklings without DHBV infection. Using immunohistochemical, in situ and blot hybridization analyses, the natural course of hepatic and extrahepatic infection was examined. DHBV infection started in the liver 2-4 days post-inoculation. There, DHBV was found not only in hepatocytes, but also in bile duct epithelial cells. Further, DHBV infection occurred in exocrine and endocrine pancreas (beginning 6-10 days and 20 days post-inoculation, respectively) and in germinal centers of the spleen (beginning 8 weeks post-inoculation). Occasionally viral DNA was also found in kidney glomeruli. Using strand-specific RNA probes, viral DNA in pancreas and spleen was clearly demonstrated to be replicating intermediates. Hepatic and extrahepatic infection with DHBV was not associated with histologic inflammation or pathologic changes in these tissues or the liver. These data indicate that DHBV can infect cells other than hepatocytes. The biological significance of non-hepatocyte infection for the life-cycle of the virus and its potential significance for viral persistence remain to be determined.

Extrahepatic Hepatitis B Virus Dna Sequences in Patients With Acute Hepatitis B Infection

Recent studies have demonstrated the presence of hepadnavirus-related nucleic acids in extrahepatic tissues in various animal models. The prevalence and biological significance of extrahepatic infection in humans remains undetermined. To characterize the tissue distribution and physical state of extrahepatic hepatitis B virus nucleic acids in acute hepatitis infection, we examined serum, liver and multiple extrahepatic tissues obtained at autopsy from two patients with fulminant hepatitis and one patient with resolving hepatitis who died of an unrelated cause. Southern-blot hybridization analysis was used to analyze the physical state of hepatitis B virus-related DNA. Hepatitis B virus-related RNA sequences were examined by slot-blotting total RNA extracted from corresponding tissues. Hepatitis B virus nucleic acids were demonstrated in lymph nodes, spleen, gonads, thyroid gland, kidneys, pancreas and adrenal glands. The most intense signal of hybridization was obtained with DNA extracted from lymph nodes. In general, the levels of hepatitis B virus RNA correlated with the amount of viral DNA. Fast-migrating DNA sequences resembling replicative intermediates and ranging in size from 1 to 3.2 kb were detected in EcoRI digests. Faint high-molecular-weight smears suggesting random integration also were observed. Remarkably, little or no hepatitis B virus nucleic acid was detected in the serum or liver. In control specimens obtained from hepatitis B virus carriers, most hybridizable hepatitis B virus nucleic acid was present in liver, but hepatitis B virus DNA was also detected in extrahepatic tissues. Finally, no specific histological changes were observed in extrahepatic tissues harboring hepatitis B virus.(ABSTRACT TRUNCATED AT 250 WORDS)

Preserved cytosolic and synthetic liver function in jaundice of severe extrahepatic infection

We investigated prospectively 9 adult patients with the syndrome of jaundice complicating severe extrahepatic infection both clinically and by quantitative liver function tests. Five patients having severe extrahepatic infection without jaundice were used for comparison. Intraperitoneal infection was found to be a major risk factor for development of jaundice. Jaundice was mainly associated with gram-negative infection, but did not influence survival. Duration of jaundice was dependent on control of the underlying infection. Liver function tests showed a severely deranged organic anion transport, whereas synthetic, cytosolic, and microsomal functions remained preserved. Our study shows that (a) the syndrome of jaundice associated with extrahepatic infection is a functional disorder that is reversible upon control of infection, and that (b) cytosolic, synthetic, and microsomal function is preserved. This may have consequences for both assessing prognosis and clinical management.