Hepatitis Injury Research Articles

Manganese Superoxide Dismutase Therapy in a Murine Hepatitis-Associated Injury

We aim to test the hypothesis that Con A-induced hepatitis and cell death can be prevented by the administration of the MnSOD mimetic MnTBAP. Male C57 mice were divided into 3 groups, 1) pretreated with MnTBAP (30 mg/kg) for 2 days and then Concanavalin A (Con A) (15 mg/kg); 2) pretreated with saline for 2 days and then Con A (15 mg/kg); 3) was the control treated with saline for 3 days. Extensive hepatic necrosis, with a significant increase in apoptosis, lipid peroxidation and decreased MnSOD enzymatic activity was found in the hepatic tissue of Con A-treated mice with significantly attenuation of all factors by pretreatment with MnTBAP. MnTBAP protected hepatocytes from Con A-induced hepatic injury with less degree of liver inflammation—ConA + MnTBAP (2.1 ± 0.4) vs. Con A (2.6 ± 0.3)—and significantly less cell death (1.2 ± 0.3 vs. 2.7 ± 0.4, p = 0.03). MnSOD supplementation attenuated the oxidative-induced stress effects of Con A-induced injury and the protective effects of MnSOD supplementation against Con A-induced hepatitis could be through its anti-oxidative properties. Further evaluation of MnSOD manipulation could have the potential to prevent ongoing hepatic injury in hepatitis.

Type 1 T Helper Cells Induce the Accumulation of Myeloid-Derived Suppressor Cells in the Inflamed Tgfb1 Knockout Mouse Liver

Immune-mediated liver injury in hepatitis is due to activated T cells producing interferon-γ (IFN-γ). It is important to identify negative feedback immune mechanisms that can regulate T cell activity. In this study, we demonstrate that liver inflammation mediated by type 1 T helper (Th1) cells can induce the accumulation of myeloid-derived suppressor cells (MDSCs), pleiomorphic cells capable of modulating T cell-mediated immunity, that heretofore have been studied almost exclusively in the context of tumor-associated inflammation. Mice deficient in the gene encoding transforming growth factor-β1 (Tgfb1(-/-) mice) acutely develop liver necroinflammation caused by IFN-γ-producing clusters of differentiation 4-positive (CD4(+)) T cells. Liver Th1 cell accumulation was accompanied by myeloid cells expressing CD11b and Gr1, phenotypic hallmarks of MDSCs. Isolated Tgfb1(-/-) liver CD11b(+)Gr1(+) cells were functional MDSCs, readily suppressing T cell proliferation in vitro. Pharmacologic inhibitors of inducible nitric oxide (NO) synthase completely eliminated suppressor function. Suppressor function and the production of NO were dependent on cell-cell contact between MDSCs and T cells, and upon IFN-γ, and were specifically associated with the "monocytic" CD11b(+)Ly6G(-) Ly6C(hi) subset of liver Tgfb1(-/-) CD11b(+) cells. The rapid accumulation of CD11b(+)Gr1(+) cells in Tgfb1(-/-) liver was abrogated when mice were either depleted of CD4(+) T cells or rendered unable to produce IFN-γ, showing that Th1 activity induces MDSC accumulation. Th1 liver inflammation mobilizes an MDSC response that, through the production of NO, can inhibit T cell proliferation. We propose that MDSCs serve an important negative feedback function in liver immune homeostasis, and that insufficient or inappropriate activity of this cell population may contribute to inflammatory liver pathology.

405 SERUM LEVELS OF CHEMERIN, VASPIN, VISFATIN AND SPECAM-1 IN PATIENTS WITH CHRONIC HEPATITIS C

injury in hepatitis C and non-alcoholic steatohepatitis patients. The safety, tolerability, and pharmacokinetics (PK) of single and multiple oral dose administration of GS-9450 in healthy volunteers were studied. Gender and food effects were also evaluated. Methods: Two Phase I, randomized, double-blind, placebo-controlled studies were conducted to evaluate the PK of GS-9450 following single and multiple dose administration. Single ascending oral doses of 0, 5, 10, 20, 40, 80 and 120mg of GS-9450 were administered to 48 healthy male volunteers. Volunteers in the 40mg cohort who received the single dose in a fasted state also received GS-9450 after a high fat breakfast. Six female volunteers received GS-9450, 40mg, to evaluate the effect of gender on GS-9450 PK. In the second study, 24 volunteers received multiple daily doses of 0, 40, 80 and 120mg of GS-9450 over 15 days. Results: GS-9450 reached peak plasma concentrations (Cmax) at 0.5−3 hours (hrs) post-dose. GS-9450 was eliminated with median elimination half-lives (T1/2) of approximately 10 to 16 hrs across all dose levels. Systemic exposure to GS-9450 increased in a dose-proportional manner over the range of single and multiple doses. Only 2−4% of the dose was excreted unchanged as GS-9450 in urine consistent with metabolism of GS-9450 in the liver. Neither food nor gender had a significant effect on the PK of GS-9450. GS-9450 was well tolerated without serious or severe adverse events (AEs). The most frequently reported AE was headache. There was no clear relationship between dose and incidence, frequency, onset or duration of treatment-related AEs, which were transient and mild in nature. One male volunteer discontinued dosing due to development of a rash of mild severity. No clinically significant changes in laboratory data, vital signs, and ECG values were observed. Conclusions: The half-life of GS-9450 supports once-daily dosing and no evidence was found for a significant gender or food effect on GS-9450 PK. GS-9450 was well tolerated by healthy male and female volunteers.

Role of CD44 in CTL-induced acute liver injury in hepatitis B virus transgenic mice

There are many uncertain points regarding leukocyte movement in the liver, especially interaction between liver sinus endothelial cells (LSECs) and cytotoxic T lymphocytes (CTLs). We examined the role of CD44 in these interactions using the hepatitis model. CTLs were administered to hepatitis B virus transgenic mice (HBVTg) mice and HBVTg x CD44 knockout (KO) mice, and alanine aminotransferase activity (ALT), number of intrahepatic leukocytes, cytokines, and chemokine mRNA level were examined. To determine the number and distribution of CTLs in the liver, 5,6-carboxyfluoroscein succinimidyl ester (CFSE)-labeled CTLs was administered to HBVTg mice with or without CD44. Serum ALT activity increased after 12 h, although it had declined to 4 h in the CD44KO x HBVTg mice after CTL injection. Similarly, the levels of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and macrophage inflammatory protein (MIP)-2 mRNAs were reduced in 4 h, although the levels were increased after 12 h in the CD44KO x HBVTg mice. The number of apoptotic hepatocytes increased intentionally at 24 h in the CD44KO x HBVTg livers, and this was thought to result from the lower activity of initial nuclear factor kappa B (NF-kappaB). Although the number of CTLs was lower at 4 h in the CD44KO x HBVTg livers, the difference of intercellular adhesion molecule (ICAM)-1 and CD86 expression on LSECs was not detected. CD44 exerts and important effect on LSECs for CTL migration into the hepatocytes. However, because the CD44-deficient state exacerbated hepatic injury, attention is necessary for hepatitis treatment as CD44 target therapy.

Alcohol abuse and chronic hepatitis C

AbstractChronic infection with hepatitis C virus (HCV) and alcohol abuse are two of the most common causes of chronic liver disease in the United States. These two entities often coexist and contribute to accelerated development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although the effect of one drink per day in the setting of chronic HCV infection is unclear, there is overwhelming evidence for the deleterious effects of heavy alcohol use on HCV liver disease. The mechanisms by which alcohol increases liver injury in hepatitis C are poorly understood. Potential pathways include impaired host immune systems and increased viral replication. Alcohol use may decrease the success of treatment. Physicians should encourage patients with chronic hepatitis C to abstain from regular alcohol use.

Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice

Hepatocyte apoptosis is an important feature of liver injury in hepatitis C virus (HCV) infection. However, the mechanism of apoptosis and consequences on disease progression in vivo have not been investigated fully in part due to the lack of adequate small animal models. In this study, transgenic (tg) mice were produced that express conditionally HCV structural proteins (core, E1, E2 and p7) in the liver following Cre-mediated DNA recombination. Using a novel Cre-estrogen receptor fusion protein (Cre-ER) induction strategy, tamoxifen was injected intraperitoneally (i.p.), which induced Cre nuclear translocation, transgene recombination and HCV protein expression in the liver. Hepatic expression of HCV core and envelope proteins resulted in increased hepatocyte apoptosis, detected by the TUNEL assay, between 7 and 33 days after induction. These results were confirmed by the presence of increased levels of apoptosis-associated cytokeratin 18 (CK-18) in the sera of the same animals. The presence of cleaved caspase-3 and elevated levels of CHOP/GADD153 in the liver suggests an endoplasmic reticulum (ER) stress-associated apoptosis mechanism. This study suggests an in vivo correlation between HCV structural protein expression, ER stress and hepatocyte apoptosis, implicating a potentially important mechanism of HCV pathogenesis.

Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells

The innate immunopathogenesis responsible for the susceptibility to hepatocyte injury in chronic hepatitis B surface antigen carriers is not well defined. In this study, hepatitis B virus (HBV) transgenic mice (named HBs-Tg) were oversensitive to liver injury after immunologic [polyinosinic:polycytidylic acid or concanavalin A (ConA)] or chemical (CCl4) triggering. It was then found that the nonhepatotoxic low dose of ConA for wild-type mice induced severe liver injury in HBs-Tg mice, which was dependent on the accumulated intraheptic natural killer (NK) cells. Expressions of NKG2D ligands (Rae-1 and Mult-1) in hepatocytes were markedly enhanced upon ConA stimulation in HBs-Tg mice, which greatly activated hepatic NK cells via NKG2D/Rae-1 or Mult-1 recognition. Interestingly, the presence of NK T cells was necessary for NK cell activation and worked as positive helper cell possibly by producing interferon-gamma and interleukin-4 in this process. Our findings for the first time suggested the critical role of NKG2D recognition of hepatocytes by NK cells in oversensitive liver injury during chronic HBV infection.

Inhibition of nuclear factor‐kappa B induces inflammatory cell migration and exacerbates severe liver injury in hepatitis B virus transgenic mice

Nuclear factor-kappa B (NF-kappaB) has a central role in co-ordinating the expression of a wide variety of genes that control the immune response and it is also recognized as an antiapoptotic transcription factor. In this study, we focused on the role of the NF-kappaB signaling pathway in liver injury induced in hepatitis B virus (HBV) transgenic mice. A fulminant hepatitis model was created in mice by the adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTLs) into HBV transgenic mice. We used an adenovirus expressing a mutant form of the IkappaB super-repressor (Ad5IkappaB), an NF-kappaB inhibitor, to inhibit the NF-kappaB signaling pathway. We observed that pretreatment with Ad5IkappaB increased the migration of inflammatory cells into the liver 6-24 h after a single intravenous injection of antigen-specific CTLs, in comparison to pretreatment with a control adenovirus. We also demonstrated that the presence of the NF-kappaB inhibitor exacerbated severe liver injury and hepatocellular apoptosis 24 h after the injection of the antigen-specific CTLs. These results suggest that the inhibition of NF-kappaB activity induces severe fulminant hepatitis in HBV transgenic mice.

Stronger Neo‐Minophagen C™, a glycyrrhizin‐containing preparation, protects liver against carbon tetrachloride‐induced oxidative stress in transgenic mice expressing the hepatitis C virus polyprotein

Stronger Neo-Minophagen C (SNMC), a glycyrrhizin-containing preparation, has been used as a treatment for chronic hepatitis for more than 30 years in Japan, and shown to be effective in preventing the development of hepatocellular carcinoma in chronic hepatitis C patients, but its underlying mechanisms remain elusive. The aim of this study was to investigate if SNMC had an anti-oxidative effect, as oxidative stress has been proposed to be one of the mechanisms of liver injury in hepatitis C virus (HCV)-associated chronic liver diseases. The protective effect of SNMC against carbon tetrachloride (CCl4)-induced liver injury was examined using transgenic mice expressing the HCV polyprotein. A small dose of CCl4 (10 microl/kg of body weight) significantly increased the serum alanine aminotransferase (ALT) level and hepatic malondialdehyde content, decreased hepatic reduced glutathione (GSH) content and induced ultrastructural alterations of hepatic mitochondria in transgenic mice, but not in nontransgenic mice. A single SNMC treatment equivalent to a clinical dose significantly restored the serum ALT level and hepatic malondialdehyde and GSH contents, attenuated the ultrastructural alterations of hepatic mitochondria, and increased mRNA expression of gamma-glutamylcysteine synthetase (gamma-GCS). Transgenic mice expressing the HCV polyprotein are abnormally vulnerable to oxidative stress. SNMC protects hepatocytes against CCl4-induced oxidative stress and mitochondrial injury in the presence of HCV proteins by restoring depleted cellular GSH.

C‐Myc partially mediates IFNγ‐induced apoptosis in the primary hepatocyte

Interferon-gamma (IFNgamma) is a central component of the complex cytokine and inflammatory response that contributes to liver cell injury in hepatitis. We report that in the primary hepatocyte IFNgamma synergizes with the mechanistically distinct apoptotic stimuli CD95, tumour necrosis factor-alpha (TNFalpha) and UV-irradiation. For the first time in primary hepatocytes, we show that IFNgamma-mediated apoptotic signalling requires the cell surface interaction of CD95 and its ligand, and we demonstrate that IFNgamma induces soluble CD95 ligand release from hepatocyte monolayers. Utilizing c-myc phosphorothioate antisense fragments, we suppresses hepatocyte apoptosis induced by IFNgamma. In summary, we identify apoptotic pathways that contribute to IFNgamma-mediated cell death. The hepatocellular response to IFNgamma signalling can be modulated by cytokines and by the interruption of CD95 interaction with its ligand. We present evidence to suggest that c-myc contributes to IFNgamma signalling.

Thymic Stromal Lymphopoietin Transgenic Mice Develop Cryoglobulinemia and Hepatitis with Similarities to Human Hepatitis C Liver Disease

Essential mixed cryoglobulinemia in humans is strongly associated with chronic hepatitis C virus infection. It remains controversial whether liver injury in hepatitis C is primarily attributable to direct viral cytopathic effect or to an immune-mediated response. We characterized the role of cryoglobulinemia in the development of liver disease in thymic stromal lymphopoietin (TSLP) transgenic mice that produce mixed cryoglobulinemia and develop hepatitis. The role of immune complexes in this animal model was evaluated using techniques of light, immunofluorescence, and electron microscopy. To assess the role of Fc receptor engagement in mediation of the disease, TSLP transgenic mice were crossbred with mice deficient for immunoglobulin-binding receptor gamma IIb (FcgammaRIIb). Livers from the TSLP transgenic animals showed mild to moderate liver injury, minimal to mild fibrosis, and deposition of immunoglobulin around the portal tracts. TSLP transgenic mice deficient in inhibitory FcgammaRIIb had more severe hepatitis and accelerated mortality. TSLP-associated hepatitis bears strong similarity to hepatitis C virus-related hepatitis as it occurs in humans, making this a valuable model system of chronic hepatitis and fibrosis to study therapies aimed at manipulating immune responses. Periportal immune complex deposition may play an important role in the pathogenesis of hepatitis occurring in the setting of systemic cryoglobulinemia.

Insulin resistance and liver injury in hepatitis C is not associated with virus-specific changes in adipocytokines

The role of tumor necrosis factor alpha, interleukin 6, leptin, and adiponectin in the pathogenesis of hepatitis C virus (HCV)-associated insulin resistance (IR) remains controversial. We tested the hypothesis that these adipocytokines contribute to chronic HCV-associated IR and liver injury by first comparing their serum levels and homeostasis model assessment of insulin resistance (HOMA-IR) in 154 untreated, non-diabetic, HCV-infected male subjects with fibrosis stage 0-2, to that in 75 healthy volunteers matched for age, body mass index (BMI), and waist-hip ratio (WHR). We next examined whether the adipocytokine levels were associated with the extent of hepatic steatosis, portal/periportal inflammation and fibrosis in our total cohort of 240 HCV-infected male subjects. Significantly higher levels of HOMA-IR (2.12 versus 1.63, P = 0.01), TNFalpha (1.28 versus 0.60 pg/ml, P < 0.001) and IL6 (2.42 versus 1.15 pg/ml, P = 0.001) were noted in the HCV cohort compared with healthy controls respectively, but there were no significant differences in leptin and adiponectin concentrations. By multiple linear regression, independent predictors of HOMA-IR included the body mass index, and the serum levels of leptin (positive correlation) and adiponectin (negative correlation), but not that of TNFalpha and IL6. Only TNFalpha levels were correlated with the extent of histological injury (portal/periportal inflammation, P = 0.02). Whereas leptin and adiponectin contribute to IR, none of the adipocytokines accounted for the elevated IR in HCV-infected subjects. The adipocytokines were not associated with histological features of chronic HCV infection except for TNFalpha which correlated with portal/periportal inflammation. HCV-associated IR is most likely an adipocytokine-independent effect of the virus to modulate insulin sensitivity.

The HBSP gene is expressed during HBV replication, and its coded BH3-containing spliced viral protein induces apoptosis in HepG2 cells

The mechanisms of liver injury in hepatitis B virus (HBV) infection are defined to be due not to the direct cytopathic effects of viruses, but to the host immune response to viral proteins expressed by infected hepatocytes. We showed here that transfection of mammalian cells with a replicative HBV genome causes extensive cytopathic effects, leading to the death of infected cells. While either necrosis or apoptosis or both may contribute to the death of infected cells, results from flow cytometry suggest that apoptosis plays a major role in HBV-induced cell death. Data mining of the four HBV protein sequences reveals the presence of a Bcl-2 homology domain 3 (BH3) in HBSP, a spliced viral protein previously shown to be able to induce apoptosis and associated with HBV pathogenesis. HBSP is expressed at early stage of our cell-based HBV replication. When transfected into HepG2 cells, HBSP causes apoptosis in a caspase dependent manner. Taken together, our results suggested a direct involvement of HBV viral proteins in cellular apoptosis, which may contribute to liver pathogenesis.

Diagnostic accuracy of a fibrosis serum panel (FIBROSpect II) compared with Knodell and Ishak liver biopsy scores in chronic hepatitis C patients

Liver biopsy is the primary method of assessing liver injury in hepatitis C patients. FIBROSpect II (FS), a diagnostic panel of three extracellular matrix remodelling markers, may be useful as a noninvasive alternative to this procedure. The purpose of this study was to correlate FS results with liver fibrosis scores to determine if this test is sufficiently accurate to be a viable alternative to liver biopsy. A total of 142 serum specimens were evaluated for fibrosis with FS and were compared with Knodell and Ishak fibrosis scores. FS reports an index score ranging from 0.1 to 1.0, which corresponds to the probability of progressive liver fibrosis. Using a FS index cut-off of 0.42, 50 of 54 patients with Ishak 3-6 were classified as having advanced fibrosis (METAVIR F2-F4) and 58 of 88 patients with Ishak 0-2 as having no/mild fibrosis (METAVIR F0-F1), resulting in a sensitivity of 93%, specificity of 66%, and an overall test accuracy of 76%. With a 38% prevalence of advanced fibrosis, the negative predictive value was 94% and positive predictive value was 63%. A biopsy length of > or = 2 cm was associated with higher concordance between FS results and liver fibrosis scores (P = 0.01). FS was clinically useful in ruling out advanced fibrosis in hepatitis C by identifying patients with mild disease in whom treatment could be deferred. The limitation of this test is its decreased sensitivity and specificity in the middle of the test's reporting range between scores of 0.42 and 0.80.

Parenchymal Expression of CD86/B7.2 Contributes to Hepatitis C Virus-Related Liver Injury

Hepatitis C virus (HCV) infection is a major global health problem. Hepatic expression of immune costimulatory signaling molecules (e.g., B7) is known to be associated with ongoing liver injury in hepatitis C patients. However, due to the general lack of viral culture systems and adequate animal models, the function of these molecules in disease pathogenesis is poorly understood. To investigate the role of CD86 in HCV-related liver injury, we developed two transgenic mouse lineages with inducible expression of HCV structural proteins and constitutive expression of the costimulatory molecule CD86/B7.2 in the liver. Using a hydrodynamic-based, nonviral delivery protocol, we induced HCV transgene expression in the livers of HCV and CD86 single- and double-transgenic mice. We found that hepatic CD86 expression resulted in increased activation of and cytokine production (e.g., interleukin-2 and gamma interferon) by CD4+ T cells and that the retention of these cells was associated with more pronounced necroinflammatory lesions in the liver. Taken together, these data suggest that augmented, parenchymal antigen presentation conferred by hepatocyte CD86 expression alters homeostasis and effector functions of CD4+ T cells and contributes to liver injury. This study provides an additional rationale for exploring immunomodulation-based therapies that could reduce disease progression in individuals with chronic HCV infection.

Essential role for neutrophil recruitment to the liver in concanavalin A-induced hepatitis.

Leukocyte infiltration into the liver is paramount to the development of liver injury in hepatitis. Hepatitis occurring after the administration of Con A in mice is felt to be a T lymphocyte-mediated disease. In this study, we report that neutrophils are the key initiators of lymphocyte recruitment and liver injury caused by Con A. The objectives of this study were to investigate the involvement of neutrophils in Con A-induced hepatitis in vivo via intravital microscopy. After Con A administration, we observed a significant increase in leukocyte rolling flux, a decrease in rolling velocity, and an increase in leukocyte adhesion to the hepatic microvasculature. Fluorescence microscopy identified that within 4 h of Con A administration only a minority of the recruited leukocytes were T lymphocytes. Furthermore, immunohistochemistry showed a significant increase in neutrophils recruited to the liver post-Con A treatment in association with liver cell damage, as reflected by elevated serum alanine aminotransferase levels. Using flow cytometry, we observed that Con A could bind directly to neutrophils, which resulted in a shedding of L-selectin, an increase in beta(2)-integrin expression, and the production of reactive oxidants. Following neutrophil depletion, a significant inhibition of Con A-induced CD4+ T lymphocyte recruitment to the liver resulted and complete reduction in hepatic injury, as assessed by serum alanine aminotransferase levels. In summary, the present data support the concept that neutrophils play an important and previously unrecognized role in governing Con A-induced CD4+ T cell recruitment to the liver and the subsequent development of hepatitis.

Interleukin-10 Therapy for Chronic HCV Infection

The pathogenesis of cellular injury in hepatitis C virus (HCV) infection is thought to be immune-mediated rather than due to a direct cytopathic effect

Significance of serum soluble Fas antigen level in chronic hepatitis C patients treated with interferon: relationship to the therapeutic response.

Fas system-mediated cytotoxicity is thought to be involved in the development of liver injury in hepatitis C virus (HCV) infection. In this study, we investigated serum soluble Fas antigen levels in chronic hepatitis C patients treated with interferon and their correlation with the therapeutic response. The subjects were 67 chronic hepatitis C patients who underwent a 24-week course of alpha-interferon therapy. Patients were categorized into three groups; sustained responders (n = 22), transient responders (n = 24), and non-responders (n = 21), according to changes in the serum alanine aminotransferase level during and after therapy. The viral genotype, viremic level and diversity in the hypervariable region were examined before therapy. Serum soluble Fas antigen levels were assayed by using serum samples taken at the beginning and the end of therapy. In the univariate analysis, serum soluble Fas antigen levels tended to be higher in non-responders (10.0 +/- 3.4 ng/mL) than in sustained responders (8.5 +/- 3.0 ng/mL) and transient responders (8.2 +/- 2.1 ng/mL; P = 0.13 and P < 0.05). The non-response to therapy was observed in eight of the 15 (53%) patients with serum soluble Fas antigen > or = 11 ng/mL, compared with 13 of the 52 (25%) patients with serum soluble Fas antigen < 11 ng/mL (P < 0.05). As for the multivariate analysis, the only significant factor contributing to the sustained response was a low HCV viremic level (P = 0.0046). Significant factors contributing to the non-response were a high serum alanine aminotransferase (P = 0.0407) and a high serum soluble Fas antigen level (P = 0.0483). High production levels of soluble Fas antigen may be associated with a poor response to interferon therapy in chronic hepatitis C patients.

A prospective clinical study of isoniazid-rifampicin-pyrazinamide-induced liver injury in an area endemic for hepatitis B.

In order to evaluate the incidence, predisposing factors and clinical course of antituberculous drug-induced liver injury in hepatitis B surface antigen (HBsAg)-positive carriers and non-carriers, in an area endemic for hepatitis B, we prospectively followed 240 patients (154 male, 86 female; mean age 40 years) who had received daily isoniazid, rifampicin, ethambutol and pyrazinamide for the treatment of pulmonary tuberculosis. Patients with heavy alcohol consumption, with pretreatment serum alanine aminotransferase (ALT) elevation and who had less than 3 months post-treatment follow-up were excluded from the study. Thirty-one (13%) patients were positive for serum HBsAg before treatment. Sixty-three (26%; 95% CI: 21-32%) patients developed antituberculous drug-induced liver injury. The incidence of drug-induced liver injury was significantly more frequent in patients > 35 years of age than in patients < or = 35 years of age (33 vs 17%; P < 0.05), but was not different between HBsAg carriers and non-carriers (29 vs 26%; P > 0.05). Using step-wise logistic regression analysis, patient age > 35 years was the only independent variable for predicting antituberculous drug-induced liver injury, while sex, acetylator phenotype, HBsAg carrier status and severity of tuberculosis were not. The peak serum ALT levels in antituberculous drug-induced liver injury were not significantly different between HBsAg carriers and non-carriers. Only one 61-year-old HBsAg carrier developed severe jaundice after 6 months antituberculous therapy; he subsequently died of hepatic failure. In conclusion, the incidence of antituberculous drug-induced liver injury was significantly higher in patients > 35 years of age than in patients < or = 35 years of age, but was not different between HBsAg carriers and non-carriers. Mortality occurred in an aged HBsAg carrier superimposed with antituberculous drug-induced liver injury.

Hepatocellular Injury in Hepatitis B and C Virus Infections

Most of the liver cell injury in hepatitis B and C infections is likely to be immune-mediated. Variation in the pathogenesis of these infections likely is contributed by a variety of host and virus factors. Host factors include the human leukocyte antigen (HLA) haplotype as well as the ability of the host to both recognize antigen on virus-infected cells and to receive the appropriate co-stimulatory signals in a timely fashion during infection. Virus factors include the genetic variation, direct cytopathic effects, and the alteration of infected hepatocytes to cytotoxic cytokines. The lack of suitable tissue culture systems and animal models limits the ability to understand the pathogenesis fully but provides challenges for their future development so that the basis for liver cell damage can be elucidated and approaches for therapeutic intervention can be achieved.