Infectious Liver Diseases Research Articles

Critical Role for CD1d-Restricted Invariant NKT Cells in Stimulating Intrahepatic CD8 T-Cell Responses to Liver Antigen

V alpha14 invariant natural killer T cells (iNKT) are localized in peripheral tissues such as the liver rather than lymphoid tissues. Therefore, their role in modulating the stimulation of conventional, major histocompatibility complex (MHC)-restricted T-cell responses has remained ambiguous. We here describe a role for V alpha14 iNKT cells in modulating conventional T-cell responses to antigen expressed in liver, using transferrin-mOVA (Tf-mOVA) mice. Naïve ovalbumin-specific class I MHC-restricted T cells (OTI) were adoptively transferred into Tf-mOVA mice in the presence or absence of iNKT-cell agonist alpha-galactosylceramide, after which OTI T-cell priming, antigen-specific cytokine production, cytotoxic killing ability, and liver damage were analyzed. Transfer of OTI cells resulted in robust intrahepatic, antigen-specific proliferation of T cells. OTI T cells were activated in liver, and antigen-specific effector function was stimulated by coactivation of Valpha14 iNKT cells using alpha-galactosylceramide. This stimulation was absent in CD1d(-/-)Tf-mOVA mice, which lack V alpha14 iNKT cells, and was prevented when interferon-gamma and tumor necrosis factor-alpha production by V alpha14 iNKT cells was blocked. CD1d-restricted V alpha14 iNKT cells stimulate intrahepatic CD8 T-cell effector responses to antigen expressed in liver. Our findings elucidate a previously unknown intervention point for targeted immunotherapy to autoimmune and possibly infectious liver diseases.

Unusual Benign Focal Liver Lesions

This presentation aims to provide an overview of the manifestations of some unusual benign focal liver lesions (FLLs) on low-acoustic power contrast-enhanced sonography (CES) with a sulfur hexafluoride contrast agent. The patients were selected retrospectively from 2209 cases with FLLs who had undergone CES examinations for characterization during the past 3 years. The pathologic examinations proved that they were intrahepatic biliary cystadenoma (n = 1), angiomyolipoma (AML; n = 4), lipoma (n = 1), biliary epithelial dysplasia (n = 1), a fungal inflammatory mass (n = 1), tuberculoma (n = 2), an inflammatory pseudotumor (n = 7), sarcoidosis (n = 1), solitary necrotic nodules (n = 2), peliosis hepatis (n = 2), and focal fibrosis after surgery (n = 4). Contrast-enhanced sonography was beneficial in leading to a diagnosis of benignity for some lesions showing hyperenhancement during the arterial phase and sustained enhancement during the portal or late phase, such as liver AML and lipoma. The benign nature of other lesions showing no enhancement during all phases, such as solitary necrotic nodules and focal fibrosis, was also suggestible. On the other hand, for those lesions showing hyperenhancement, isoenhancement, or hypoenhancement during the arterial phase and hypoenhancement during the late phase, including intrahepatic biliary cystadenoma, biliary epithelial dysplasia, infected liver diseases, the inflammatory pseudotumor, sarcoidosis, and peliosis hepatis, the differential diagnosis between benignity and malignancy was difficult, and pathologic tests were mandatory. The CES features of unusual benign FLLs may enrich knowledge when performing CES examinations for characterization and may provide clues for a specific diagnosis of an individual lesion such as liver AML.

CD4-1 Increasing incidence of Type 1 diabetes in Canterbury children and adolescents and spatial-temporal clustering

Aims: The prevalence of diabetes mellitus (DM) is increasing around the world. In the Republic of Korea, the prevalence of diabetes was 7.75% (2,690,000 persons) in 2005. The increasing prevalence of diabetes is also one of the most important medical issues, as the control of chronic complications of diabetes, the main causes of morbidity and mortality of diabetes, is not easy and is required over long periods of life. In this study, we attempted to analyze all causes of mortality in Type 2 DM (T2DM) and compared our findings with previously published data. Methods: All T2DM patients older than thirty and whose death certificates were issued in Dong-A University Hospital from 2000 through 2004, were evaluated. The patients were excluded if they already had clinically significant tuberculosis, liver, thyroid, renal, connective tissue diseases and cancers when T2DM was diagnosed. We classified the cause of death into several groups using the KCD (Korean Classification of Disease)-4. The results were compared with data that was collected from 1990 through 1994. Results: A total of 102 patients were included, 66 of whom were males. 37.4% and 34.3%of the study group were aged in their 60’s or 70’s, respectively. The mean duration of diabetes was 11.8 ± 8.2 years. The most common cause of death was infectious disease (39.2%), the second was ischemic heart disease (IHD)(24.5%). Other causes were cancer (12.8%), renal disease (6.9%), liver disease (4.9%), cerebrovascular accident (CVA) (3.9%), congestive heart failure (CHF) (2.9%), DM itself (2.0%). However, in the 1990s, the most common cause of death was cardiovascular disease (IHD+CVD) with others being infectious disease, DM, liver disease, cancer and renal disease, in that order. The proportion of infectious disease was increased and that of cardiovascular disease decreased in current causes of mortality of diabetes compared with past mortality of diabetes. Conclusions: The prevalence of cardiovascular mortality in university hospital based T2DM patients decreased during the past ten years.

The Molecular Basis of Susceptibility to Infection in Liver Cirrhosis

There is much clinical evidence of a relationship between infectious disease and chronic liver disease. The consequences of this adverse association have been described and advances in the treatment and prophylaxis of infectious disease have had an important effect on the management of patients with chronic liver disease. The association between infectious disease and chronic liver disease involves altered cytokine production, cellular immunity, and vascular response. However, there is little information on the mechanisms underlying these phenomena. In this report, we review the mechanistic basis of this common association.

Incidence and causes of death in HIV‐infected persons receiving highly active antiretroviral therapy compared with estimates for the general population of similar age and from the same geographical area

Since the introduction of highly active antiretroviral therapy (HAART), the incidence of death in HIV-infected patients has dramatically decreased, and causes of death other than those related to HIV infection have increased, although it is unclear how these parameters compare with those in the age-matched general population living in the same geographical region. Consecutive HIV-infected adults who were prescribed HAART in our hospital were prospectively followed from January 1997 to December 2004 or until death, loss to follow-up or discontinuation of HAART. Estimations of the annual incidence and causes of death in the general population of similar age in Catalonia per calendar year in the study period were obtained and compared with those in the HIV-infected cohort. There were 235 deaths among the 4471 patients on HAART (5%). The incidence of mortality decreased over time in HIV-infected patients (P<0.001; chi(2) test for trend), although it has remained approximately five times higher than that for the age-matched general population. AIDS-related events were the most common cause of death (n=95; 40%), although they significantly decreased over time (P<0.001; chi(2) test for trend), whereas liver diseases (P<0.001; chi(2) test for trend) and non-AIDS-defining infections (P=0.008; chi(2) test for trend) significantly increased over time. Infections in general (33 times higher), liver diseases (11 times higher) and non-Hodgkin lymphoma (5 times higher) were overrepresented as causes of death in the HIV-infected cohort compared with the age-matched general population. Non-AIDS-defining infectious diseases, liver diseases, and non-Hodgkin lymphoma represent specific targets for efforts to further decrease mortality in HIV-infected patients receiving HAART.

Unusual cardiac features in cholestatic hepatitis A in an adolescent: Improvement with corticosteroid treatment

Hepatitis A is one of the most frequent infectious liver diseases affecting children worldwide. Extra-hepatic manifestations of acute hepatitis A virus are rare in pediatric age group. We report a case of a 16-year-old, otherwise healthy adolescent who had viral hepatitis A with cardiac manifestations. The patient is the first pediatric case of hepatitis A with a combination of hypotension, persistent bradycardia and progressive cholestasis.

Plasma Levels of High Mobility Group Box Protein in Patients with Organ Failure, Disseminated Intravascular Coagulation or Poor Outcome.

High Mobility Group Box chromosomal protein 1 (HMGB1) is a nuclear DNA-binding protein acting as a proinflammatory cytokine when released in the extracellular space from necrotic cells, activated macrophages and dendritic cells. HMGB1 acts on a specific receptor, RAGE (receptor for advanced glycation end-products), and induces prolonged inflammation, organ failure, septicaemia and death. The aim of the study was to determine the diagnostic value of plasma HMGB1 concentration and its role in the development of organ failure in patients with disseminated intravascular coagulation (DIC).Plasma HMGB-1 levels were measured in patients with suspected DIC by ELISA and their relationships with DIC, organ failure and clinical outcome were determined. The study group included 201 patients suspected of having DIC (79 females and 122 males, age; 52.1±16.5 years, mean±SD).The study group represented all such patients admitted to the Second Department of Internal Medicine and Intensive Care Unit (ICU) of Mie University Hospital between January 1, 2002 and December 31, 2003. The underlying diseases were infectious diseases (n=40), hematopoietic diseases (n=58), solid cancers (n=16), trauma (n=21), aneurysm (n=12), autoimmune diseases (n=8), liver diseases (n=7), post-operation (n=32) and other diseases (n=7).Results: Plasma HMGB1 was below the detection limit in normal subjects, but moderately elevated in patients with infectious diseases (4.54 ± 8.18 ng/ml, mean±SD), malignancies (2.15 ± 5.34 ng/ml), and traumas (6.47 ± 13.13 ng/ml). DIC was associated with significantly high plasma HMGB1 (14.05 ± 12.56 ng/ml) in these patients. The highest HMGBI levels were in patients with organ failure (8.29 ± 10.99 ng/ml) and non-survivors (16.58 ± 11.01 ng/ml). HMGB1 plasma levels correlated with the DIC score and sepsis-related organ failure assessment (SOFA) score. Plasma levels of HMGB1 were significantly higher in patients with PAI-I of >50 ng/ml (3.66 ± 6.36 ng/ml) than in those with PAI-I <50 ng/ml (1.38 ± 2.97 ng/ml) (p< 0.05) but there was no significant difference in HMGB1 levels between patients with TNF-a of >1.5 (3.04 ± 5,56 ng/ml) and those with less than 1.5 pg/ml (2.44 ± 5.36 ng/ml).Our data suggest that HMGB-1 is a potentially suitable prognostic marker of OF or DIC.

Schwere intrahepatische Cholestase bei einem 66-jährigen Patienten mit medikamentös behandeltem Vorhofflimmern

A 66-year-old male was admitted to hospital due to painless jaundice. Because of ischemic cardiomyopathy with paroxysmal atrial fibrillation as well as recurrent ventricular tachycardias and fibrillation he was treated with phenprocoumon and amiodarone (200 mg per day) for 2 years. Laboratory tests revealed significant elevation of the parameters of cholestasis and aminotransferase activity. Serological tests excluded infectious, autoimmune or metabolic liver diseases. Abdominal ultrasound and ERCP showed no mechanic cholestasis nor tumor of the pancreas. Cardiac congestive disease was also excluded. Severe intrahepatic cholestasis, consistent with drug-induced hepatotoxic damage, was diagnosed histologically. After discontinuing phenprocoumon the liver enzymes further increased. When amiodarone was stopped, however, laboratory parameters showed a continuous downward tendency. For prevention of malignant cardiac arrhythmia the patient received an atrioventricular defibrillator. Intrahepatic cholestasis is a rare presentation of amiodarone-induced hepatic toxicity. Liver damage can even occur after the drug has been taken for prolonged periods without any problems.

Discrimination against hepatitis B infected medical students could end

Students infected with hepatitis B, a highly infectious liver disease, may soon be allowed to train as doctors after a review by UK government and universities. Under the new plans, medical students would also be screened for HIV and hepatitis C for the first time. A positive result would not, however, mean that they could not become doctor. The hepatitis B virus is thought to be the leading cause of liver cancer and is about 100 times more infectious than HIV. Currently students who test positive for …

A Case of Neonatal Hemochromatosis‐Like Liver Failure with Spontaneous Remission

A Case of Neonatal Hemochromatosis‐Like Liver Failure with Spontaneous Remission

Trends in liver disease prevalence in Mexico from 2005 to 2050 through mortality data

Background and Aims. The epidemiology of liver cirrhosis differs across sex, ethnic groups, and geographic regions. In 2000, chronic liver disease was the fifth leading cause of death in Mexico. Accurate knowledge of the demographics of liver disease is essential in formulating health-care policies. Our main aim was to project the trends in liver disease prevalence in Mexico from 2005 to 2050 based on mortality data. Methods. Data on national mortality reported for the year 2002 in Mexico were analyzed. Specific-cause mortality rates were calculated for a selected age population (≥25 years old) and classified by sex and projected year (2005–2050). The following codes of the International Classification of Diseases for liver diseases were included: non-alcoholic chronic liver disease and cirrhosis, alcoholic liver disease, liver cancer, and acute and chronic hepatitis B and C infection. The projected prevalence of a chronic liver disease was estimated using the following equation: P = (ID × T) / [(ID × T) + 1], where P = prevalence, ID = incidence density (mortality rate multiplied by 2), T = median survival with the disease (= 20 years). Results: Nearly two million cases of chronic liver disease are expected. Alcohol-related liver diseases remain the most important causes of chronic liver disease, accounting for 996,255 cases in 2050. An emergent syndrome is non-alcoholic liver disease, which will be more important that infectious liver diseases (823,366 vs 46,992 expected cases, respectively). Hepatocellular carcinoma will be the third leading cause of liver disease. Conclusions: Chronic liver disease will be an important cause of morbidity and mortality in the future. Preventive strategies are necessary, particularly those related to obesity and alcohol consumption, to avoid catastrophic consequences.

Alpha-1-Antitrypsin Deficiency: A New Paradigm for Hepatocellular Carcinoma in Genetic Liver Disease *

Liver disease in alpha-1-antitrypsin (alpha1AT) deficiency is caused by a gain-of-toxic function mechanism engendered by the accumulation of a mutant glycoprotein in the endoplasmic reticulum (ER). The extraordinary degree of variation in phenotypical expression of this liver disease is believed to be determined by genetic modifiers and/or environmental factors that influence the intracellular disposal of the mutant glycoprotein or the signal transduction pathways that are activated. Recent investigations suggest that a specific repertoire of signaling pathways are involved, including the autophagic response, mitochondrial- and ER-caspase activation, and nuclear factor kappaB (NFkappaB) activation. Whether activation of these signaling pathways, presumably to protect the cell, inadvertently contributes to liver injury or perhaps protects the cell from one injury and, in so doing, predisposes it to another type of injury, such as hepatocarcinogenesis, is not yet known. Recent studies also suggest that hepatocytes with marked accumulation of alpha1ATZ, globule-containing hepatocytes, engender a cancer-prone state by surviving with intrinsic damage and by chronically stimulating in 'trans' adjacent relatively undamaged hepatocytes that have a selective proliferative advantage. Further, this paradigm may apply to other genetic and infectious liver diseases that are predisposed to hepatocellular carcinoma.

The liver as an immunological organ

Abstract The liver is an immunologically distinct organ that contains its own unique population of cells of the innate and adaptive cellular immune response. The liver is known as a site of inflammatory immune responses as well as a site of tolerance induction. This dual function is important to understand the pathogenesis of infectious liver diseases and to understand induction of tolerance upon exposure to oral and allograft antigens. This review will address the unique role of the liver in the immune system.

A Systematic Approach to the Optimization of Substrate-Based Inhibitors of the Hepatitis C Virus NS3 Protease: Discovery of Potent and Specific Tripeptide Inhibitors

The inadequate efficacy and tolerability of current therapies for the infectious liver disease caused by the hepatitis C virus have warranted significant efforts in the development of new therapeutics. We have previously reported competitive peptide inhibitors of the NS3 serine protease based on the N-terminal cleavage products of peptide substrates. A detailed study of the interactions of these substrate-based inhibitors with the different subsites of the serine protease active site led to the discovery of novel residues that increased the affinity of the inhibitors. In this paper, we report the combination of the best binding residues in a tetrapeptide series that resulted in extremely potent inhibitors that bind exquisitely well to this enzyme. A substantial increase in potency was obtained with the simultaneous introduction of a 7-methoxy-2-phenyl-4-quinolinoxy moiety at the gamma-position of the P2 proline and a tert-leucine as a P3 residue. The increase in potency allowed for the further truncation and led to the identification of tripeptide inhibitors. Structure activity relationship studies on this inhibitor series led to the identification of carbamate-containing tripeptides that are able to inhibit replication of subgenomic HCV RNA in cell culture with potencies below 1 microM. This inhibitor series has the potential of becoming antiviral agents for the treatment of HCV infections.

The infected liver: radiologic-pathologic correlation.

Recent technologic advances have significantly enhanced the role of imaging in the detection, characterization, and management of infectious diseases involving the liver. In addition, imaging-guided percutaneous drainage has greatly improved the clinical treatment of patients with focal liver abscess. Infectious liver diseases can be accurately evaluated with ultrasonography (US), computed tomography (CT), and magnetic resonance (MR) imaging. Characteristic changes in US echogenicity, CT attenuation, or MR imaging signal intensity and typical enhancement patterns can contribute to the diagnosis of specific infectious diseases, including abscesses, parasitic diseases, fungal diseases, granulomatous diseases, viral hepatitis, and other less common infections. CT is particularly helpful in revealing the presence of calcifications and gas and in detailing the enhancement pattern. The multiplanar capability of MR imaging and its sensitivity to small differences in tissue composition increase its specificity for certain hepatic infections, including hydatid cyst and candidiasis. Radiologic findings may be sufficient to obviate aspiration or histologic examination, although in most instances they are less specific. Nevertheless, imaging findings taken together with appropriate clinical information may provide the most likely diagnosis, even if biopsy is sometimes required for confirmation.

Anti-extractable Nuclear Antigens (ENA) Antibodies in Patients with Chronic Hepatitis C before and after Treatment with Interferon

A high prevalence of serological markers classically associated with autoimmune hepatitis or other autoimmune diseases has been reported in patients with chronic hepatitis C. However, the prevalence of antibodies to extractable nuclear antigens (anti-ENA) are rarely reported in such patients and the effect of treatment with interferon (IFN) on their prevalence is not known. In the present study, serum samples collected from 44 patients with chronic hepatitis C and 44 patients with non-hepatitis C virus (HCV) infected liver diseases were tested for anti-ENAs (U1 RNP, Sm, Ro/SS-A, La/SS-B and Scl-70) antibodies by enzyme-linked immunosorbent assay (ELISA). In 26 patients with chronic hepatitis C who received IFN treatment, serum samples were also collected just after completion of IFN treatment, and/or at 6–40 months after completion of the treatment, and tested for these antibodies. Sixteen (36%) of 44 sera from patients with chronic hepatitis C were positive for at least one of the above anti-ENA antibodies, whereas only 7 (16%) of 44 sera from patients with non-HCV infected liver diseases were positive for such antibodies (p=0.0290). There was no significant difference in the prevalence of each of anti-ENA antibody between men and women. Results of anti-ENA antibodies in most IFN-treated patients with chronic hepatitis C did not change after treatment. However, in some cases serum anti-U1 RNP, anti-La/SS-B and anti-Scl-70 became negative or converted to the gray zone after completion of IFN treatment regardless of HCV elimination. Our results showed that the overall prevalence of anti-ENA antibodies was significantly higher in patients with chronic hepatitis C than in those with non-HCV-infected liver diseases. However, the disappearance of anti-ENA antibodies after IFN treatment in patients with chronic hepatitis C may be due to the immunomodulating effects of IFN rather than HCV elimination.

Tissue viral load variability in chronic hepatitis C.

Liver biopsy is regarded as the gold standard for assessing disease activity in chronic hepatitis C, but sampling error is a potential limitation. Whether sampling variability applies equally to viral load assessment as it does to histology is uncertain. To examine this, we compared viral load between right- and left-lobe biopsy specimens from patients infected with hepatitis C virus (HCV). Bilobe biopsies were taken from 16 patients who were serum positive for HCV RNA by reverse transcription-polymerase chain reaction. Genotype was identified by reverse line probe hybridization. There was an absence of competing risk factors for infectious and other liver diseases in this patient group. Histology and hepatic viral load were assessed blindly. None of the patients had received antiviral therapy at the time of study. Detection of HCV in right and left lobes was concordant with serum positivity in all cases. The viral load between lobes was highly correlated (p = 0.0003, r = 0.79). In contrast, the histological activity indices of inflammation and fibrosis/cirrhosis were poorly correlated between lobes (p = 0.038, r = 0.60, and p = 0.098, r = 0.50, respectively). Hepatic viral load variability does not suffer from the same degree of heterogeneity of sampling variability as does histology.

Tissue viral load variability in chronic hepatitis C

OBJECTIVE: Liver biopsy is regarded as the gold standard for assessing disease activity in chronic hepatitis C, but sampling error is a potential limitation. Whether sampling variability applies equally to viral load assessment as it does to histology is uncertain. To examine this, we compared viral load between right- and left-lobe biopsy specimens from patients infected with hepatitis C virus (HCV). METHODS: Bilobe biopsies were taken from 16 patients who were serum positive for HCV RNA by reverse transcription-polymerase chain reaction. Genotype was identified by reverse line probe hybridization. There was an absence of competing risk factors for infectious and other liver diseases in this patient group. Histology and hepatic viral load were assessed blindly. None of the patients had received antiviral therapy at the time of study. RESULTS: Detection of HCV in right and left lobes was concordant with serum positivity in all cases. The viral load between lobes was highly correlated ( p = 0.0003, r = 0.79). In contrast, the histological activity indices of inflammation and fibrosis/cirrhosis were poorly correlated between lobes ( p = 0.038, r = 0.60, and p = 0.098, r = 0.50, respectively). CONCLUSION: Hepatic viral load variability does not suffer from the same degree of heterogeneity of sampling variability as does histology.

Cholangiopathy after short‐term administration of piperacillin and imipenem/cilastatin

We describe a patient who suffered from intestinal perforation after abdominal trauma. Perioperatively, he was treated with a single dose of piperacillin and 9 doses of imipenem/cilastatin over 3 days. The patient was discharged 5 days after surgery in good clinical condition and with normal liver values except for a marginal elevation of alanine aminotransferase. Two weeks after discharge, he developed fatigue, fever and pruritus, necessitating rehospitalization. He was jaundiced and had elevated alkaline phosphatase and transaminases. After exclusion of an intra-abdominal fluid collection, a vascular problem, and infectious or autoimmune liver disease, a liver biopsy was performed. The biopsy revealed centrizonal bilirubinostasis, a portal infiltrate rich in eosinophils and cholangitis. Lymphocyte transformation tests for piperacillin and imipenem/cilastatin were positive, suggesting an immunological mechanism for the observed hepatopathy. Cholestasis gradually decreased but was detectable for several weeks. The patient had a full clinical and biochemical recovery after 3 months. We conclude that short-term therapy with piperacillin, imipenem/cilastatin or the combination of these drugs can lead to the same type of hepatopathy as described for amoxycillin/clavulanic acid or antistaphylococcal penicillins. Liver biopsy and positive lymphocyte transformation are compatible with an immunological mechanism.

Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients

OBJECTIVES: It is currently recommend to perform a liver biopsy for patients with chronically elevated liver function tests (LFT) of unknown etiology (marker negative). The necessity and benefits of these recommendations are unknown. The aims of this study were to determine the prevalence of marker-negative LFT in patients referred for evaluation of chronically elevated LFT; to determine the prevalence of diseases that may be associated with marker-negative abnormal LFT; and to assess whether a liver biopsy alters the management of such patients. METHODS: We conducted a prospective observational study of 1124 adults referred for evaluation of chronically elevated LFT. Patients who consented to a liver biopsy were eligible. Marker-negative abnormal LFT was defined as the absence of accepted serum markers for infectious, metabolic, autoimmune, or hereditary liver disease, the absence of a history of alcohol or hepatotoxic drug use, and the absence of signs of chronic liver disease. RESULTS: Eighty-one of 1124 eligible patients were marker-negative. Liver biopsies in the 81 marker-negative patients revealed: normal histology (eight), steatosis (41), steatohepatitis (26), fibrosis (four), and cirrhosis (two). All 73 abnormal liver biopsies had some degree of steatosis. There were no significant associations between histological findings and the presence of obesity ( p = 0.13), hyperlipidemia ( p = 0.4), or diabetes ( p = 0.9). There were no significant associations when classifying patients by gender or by symptoms. CONCLUSION: In the setting of marker-negative elevated LFT, the most likely histological diagnosis is fatty metamorphosis of the liver with occasional associated fibrosis.