Hepatitis-Associated Aplastic Anemia: Etiology, Clinical Characteristics and Outcome.

Hepatitis-associated aplastic anemia (HAA) is a form of acquired aplastic anemia (AA) in which bone marrow failure develops after an acute attack of hepatitis. Bone marrow failure leading to AA is generally severe in cases of HAA and fatal if left untreated. This retrospective multicenter study investigated clinical and laboratory characteristics, possible causes, treatment, and outcome of HAA in children. Twenty patients from 8 centers were included in the study. Aspartate aminotransferase and alanine aminotransferase were <3 to 5×upper limit of normal (ULN) in 2 patients, <5 to 10×ULN in 2 patients, and >10×ULN in 16 patients. Acute liver failure developed in 5 (29%) patients. Pancytopenia was simultaneously present in 6 of 20 (30%) patients. Eleven of the 20 patients (55%) were alive, in remission and transfusion free. Those who were alive either had undergone hematopoietic stem cell transplantation and/or immunosuppressive treatment, except 1 patient who had received no treatment. Patients with the diagnosis of acute hepatitis should be evaluated and followed up carefully for presence of cytopenia, so that definitive treatment of AA can be initiated in a timely and appropriate manner when needed.

Ubiquitously specific protease 4 inhibitor-Vialinin A attenuates inflammation and fibrosis in S100-induced hepatitis mice through Rheb/mTOR signalling.

Inflammation and fibrosis are major consequences of autoimmune hepatitis, however, the therapeutic mechanism remains to be investigated. USP4 is a deubiquitinating enzyme and plays an important role in tissue fibrosis and immune disease. Vialinin A is an extract from mushroom and is a specific USP4 inhibitor. However, there is lack of evidences that Vialinin A plays a role in autoimmune hepatitis. By employing S100-induced autoimmune hepatitis in mice and AML12 cell line, therapeutic mechanism of Vialinin A was examined. Inflammation was documented by liver histological staining and inflammatory cytokines. Fibrosis was demonstrated by Masson, Sirius red staining and fibrotic cytokines with western blot and real-time RT-PCR. In experimental animal, there were increases in inflammation and fibrosis as well as USP4, and which were reduced after treatment of Vialinin A. Vialinin A also reduced Rheb and phosphorylated mTOR. Moreover, in LPS-treated AML12 cells, LPS-induced USP4, inflammatory and fibrotic cytokines, phosphorylated mTOR and Rheb. Specific inhibitory siRNA of USP4 reduced USP4 level and the parameters mentioned above. In conclusion, USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver. The mechanism may be related to regulation of Rheb/mTOR signalling.

Acute human parvovirus B19 infection triggers immune-mediated transient bone marrow failure syndrome, extreme direct hyperbilirubinaemia and acute hepatitis in patients with hereditary haemolytic anaemias: multicentre prospective pathophysiological study.

A total of 244 patients with hereditary haemolytic anaemias (HHA) were screened for acute symptomatic human parvovirus B19 infection (HPV-B19) in a prospective study. To assess the risks associated with HPV-B19 infection, patients were classified into Group I and Group II according to presence or absence (symptoms, signs and specific serology) of acute HPV-B19 infection respectively. In all, 131 (53·7%) patients had ß-thalassaemia, 75 (30·7%) hereditary spherocytosis (HS), 27 (11·1%) sickle cell anaemia (SCA) and 11 (4·5%) glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of 33 (13·5%) patients who presented with symptomatic HPV-B19 infection, 19 (57·5%) had HS, nine (27·3%) had ß-thalassaemia and five (15·2%) had SCA. In Group I, there were significant differences in the mean white blood cell, red blood cell and platelet counts, haemoglobin concentration, total bilirubin (TB), alanine aminotransferase, aspartate aminotransferase and serum creatinine (all P < 0·001) compared to Group II. In all, 27 (81·8%) patients had arthropathy and bone marrow failure (BMF); 13 (39·4%) had acute kidney injury (AKI), more in SCA (80%); and 12 (36·4%) patients had hepatitis, more in HS (66·8%). Five (15·2%) patients with HS had BMF, AKI, nervous system involvement and extreme hyperbilirubinaemia (TB range 26·3-84·7 mg/dl). Five (15·2%) patients had haemophagocytic syndrome. Two patients with HS combined with Type-I autoimmune hepatitis presented with transient BMF. Complete recovery or stabilisation was noted at 12 months in every patient except for one patient with SCA who died during the infection. HPV-B19 must be suspected and screened in patients with HHA with typical and atypical presentations with careful follow-up.

Lupus hepatitis, more than just elevated liver enzymes.

Systemic lupus erythematosus (SLE), a multisystem autoimmune inflammatory disease, may involve any organs, including the liver. Liver involvement in SLE is not part of the American College of Rheumatology criteria and is relatively rare. Liver disease is usually mild, manifesting as subtle elevation of liver enzymes. Jaundice and hepatomegaly can be seen in some patients; advanced liver disease with cirrhosis is extremely rare. Precise pathology remains obscure. SLE may cause non-specific changes, including hepatocellular, cholestatic, or vascular changes. Alcohol, drugs, viral infections, metabolic disorders, autoimmune hepatitis, and other common causes of liver dysfunction should be excluded. Corticosteroids may expedite the recovery process, but may lead to non-alcoholic fatty liver disease and liver damage. Several large-scale multicentre studies have shown that liver involvement is not the major cause of morbidity and mortality in SLE patients. In this review, we discuss the pathogenesis, diagnosis, differential diagnosis, clinical manifestations, management, complications, and prognosis of lupus hepatitis.

Biochemical and histopathological changes in Wistar rats after consumption of boiled and un-boiled water from high and low disease prevalent areas for chronic kidney disease of unknown etiology (CKDu) in north Central Province (NCP) and its comparison with low disease prevalent Colombo, Sri Lanka.

BACKGROUND: Chronic Kidney Disease of unknown etiology (CKDu) is prevalent in North Central Province (NCP) of Sri Lanka. Consumption of un-boiled dug well water has been identified as one of the causative factors. This in-vivo study was performed to investigate some of the suspected factors associated with the pathogenesis of CKDu mediated via ground water. METHOD: Rats were given water, collected from high and low disease prevalent areas from the NCP of Sri Lanka and the results compared with those obtained from previously identified low disease prevalent area; Colombo. Blood Urea Nitrogen, creatinine, urinary microalbumin:creatinine ratio together with ALT and AST levels were analyzed and results were compared using one-way ANOVA and paired t-Test. Histopathology was analyzed using non-parametric method. RESULTS: Rats that ingested water from New Town Medirigiriya (NTM) from high disease prevalent NCP reported significantly elevated microalbumin:creatinine ratios compared to other water sources after 8 months, whilst boiled water from NTM had been able to significantly reduce it. Histopathological findings after the 14 months experimental period revealed significantly high tubular lesion index in rats that ingested water from NCP compared to Colombo. Rats that ingested water from high disease prevalent Divuldamana (DD) from NCP showed the highest kidney lesion index though the fluoride content was relatively low in this area compared to other water sources from high disease prevalent NCP. Rats that ingested boiled and un-boiled water from NTM also developed severe lesions whilst the group from Colombo reported the lowest. Low disease prevalent area from NCP, Huruluwewa (HW) also reported elevated liver enzymes and altered renal histopathology. Association of Na+:Ca2+ ratio in the disease progression was not reflected by the current study. Compared to Colombo, high fluoride, calcium and sodium contents were observed in water from high disease prevalent areas. All the water samples were negative for heavy metals. CONCLUSIONS: Though Fluoride is a known kidney toxic agent it cannot be the sole reason for CKDu in NCP, Sri Lanka. Various toxic elements present in NCP water may contribute to different grade of kidney and liver lesions in Wistar rats.

Clinical role of combining alpha-fetoprotein and lens culinaris agglutinin-reactive fraction of alpha-fetoprotein for hepatocellular carcinoma: Evidence from literature and an original study.

BACKGROUND: To evaluate the clinical diagnostic efficacy of the combination of alpha-fetoprotein (AFP) and lens culinaris agglutinin-reactive fraction of AFP/total AFP (AFP-L3%) for detecting hepatocellular carcinoma (HCC). METHODS: A comprehensive and systemic literature search was executed in Web of Science, PubMed, and the Cochrane Library websites. Then, the related articles were reviewed and the quality of included studies was evaluated with the QUADAS tool. Further, serum samples were collected from 49 HCC patients, 52 cirrhosis patients, 47 hepatitis patients, and 48 healthy controls and these samples were tested for AFP and AFP-L3% levels. RESULTS: A total of 16 eligible articles were included in our meta-analysis. The overall sensitivity (SEN) of AFP + AFP-L3% was higher than that of AFP or AFP-L3 alone; the overall specificity (SPE) of AFP + AFP-L3% was lower than that of AFP or AFP-L3 alone. In the original study, the related statistics were, respectively, SEN = 0.592 and SPE = 0.918 for AFP; SEN = 0.367 and SPE = 1.000 for AFP-L3%; and SEN = 0.592 and SPE = 0.918 for the combination. CONCLUSION: The results of meta-analysis indicate there is a beneficial effect of using the unity of AFP and AFP-L3% for HCC diagnosing. However, in the original study, just for the results of sensitivity and specificity, there is no significant difference between AFP alone and AFP + AFP-L3%.

Serum Alanine Transaminase as a Predictor of Type 2 Diabetes Incidence: The Yuport Prospective Cohort Study.

Prior studies have shown an association between the incidence of diabetes with liver enzymes, such as alanine transaminase (ALT). Liver fibrosis scores, such as the Fibrosis-4 index which indicates chronic liver damage, were also associated with diabetes development. However, no literature compared predictive accuracy between ALT and Fibrosis-4 index. Thus, we aimed to determine it, and to assess its association using inverse probability of treatment weighting. This was a non-concurrent prospective cohort study of 9,748 subjects without diabetes receiving Yuport Health Checkup in Japan between 1998 and 2006. ALT was categorized into three groups: the highest ALT group (men ≥ 30 U/L and women ≥ 20 U/L), the middle (men ≥ 20 and < 30 U/L, and women ≥ 14 and < 20 U/L), and the lowest (men < 20 U/L and women < 14 U/L). The primary outcome was the new onset of diabetes. The area under the receiver operating characteristic curves (AUC) of ALT for predicting the diabetes development was higher than that of any other markers of liver damage. The AUC for ALT was 0.71, while that for the Fibrosis-4 index was 0.51 (p < 0.001 for the difference between the AUCs). The highest and middle ALT groups had a significantly higher incidence of diabetes than the lowest group: adjusted relative risk 1.79 [95% confidence interval (CI): 1.29, 2.58], and 1.64 [95% CI: 1.17, 2.38] respectively. Of the various indicators of liver function, ALT is likely to be the most accurate and associated predictor of diabetes development.

Association between serum liver enzymes and all-cause mortality: The Japan Public Health Center-based Prospective Study.

BACKGROUND & AIMS: The association of serum liver enzyme levels with all-cause mortality in individuals without hepatitis B virus or hepatitis C virus infection is inconsistent. We aimed to investigate all-cause and non-liver disease mortality according to levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) stratified by hepatitis virus infection status in a Japanese cohort. METHODS: Participants were 7243 men and 13 513 women aged 40-69 years at the baseline survey in 1993-1994. Multivariate-adjusted hazard ratios of death from the baseline health check-up to December 2012 were calculated with a Cox proportional hazards model controlling for potential confounding factors. RESULTS: During follow-up, 2235 deaths in men and 1901 deaths in women were identified. All serum liver enzymes were associated with all-cause mortality in each sex and hepatitis virus infection status. In participants without infection, those with more than twice the upper level of normal (ULN), which was defined as 30 IU/L for AST and ALT and 50 IU/L for GGT, had a higher risk of non-liver disease mortality compared to those below the ULN (HR 1.69; 95% confidence interval 1.13-2.53, 1.49; 1.02-2.18, 1.39; 1.11-1.73, 1.72; 1.08-2.74 and 1.72; 1.10-2.69 for AST, ALT, and GGT in men and AST and GGT in women, respectively), except for ALT in women. CONCLUSIONS: In participants without hepatitis virus infection, serum liver enzyme levels were positively associated with all-cause mortality. Similar associations were also found for non-liver disease mortality.

5-ALA/SFC Attenuated Binge Alcohol-Induced Gut Leakiness and Inflammatory Liver Disease in HIV Transgenic Rats.

BACKGROUND: This study aimed to investigate the protective effect of 5-aminolevulinic acid (5-ALA) and sodium ferrous citrate (SFC) against binge alcohol-induced gut leakiness and inflammatory liver disease in HIV transgenic (TG) rats. METHODS: TG rats were treated with 3 consecutive doses of binge ethanol (EtOH) with or without 5-ALA/SFC. Blood and liver tissue samples were collected at 6 hours following the last dose of EtOH. RESULTS: Compared with the wild-type (WT) rats, the TG rats showed increased sensitivity to alcohol-mediated inflammation, as evidenced by the significantly elevated levels of serum endotoxin, AST, ALT, ED1, and ED2 staining in liver. In contrast, 5-ALA/SFC improved the above biochemical and histochemical profiles. 5-ALA/SFC also attenuated the up-regulated mRNA expression of leptin and CCL2. Furthermore, down-regulated intestinal ZO-1 protein expression was also inhibited by 5-ALA/SFC. Moreover, the expressions of HO-1, HO-2, Sirt1, and related signal transduction molecules in liver were increased by 5-ALA/SFC. These results demonstrated that 5-ALA/SFC treatment ameliorated binge alcohol exposure liver injury in a rat model of HIV-infected patients by reducing macrophage activation and expression of inflammatory cytokines/chemokines, and by inducing HO-1, HO-2, and Sirt1 expression. CONCLUSIONS: Taken together, these findings suggested that treatment with 5-ALA/SFC has a potential therapeutic effect for binge alcohol exposure liver injury in HIV-infected patients.

Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum.

Tissue-resident macrophages and bone marrow (BM)-derived monocytes play a crucial role in the maintenance of tissue homeostasis; however, their contribution to recovery from acute tissue injury is not fully understood. To address this issue, we generated an acute murine liver injury model using hepatocyte-specific Cflar-deficient (CflarHep-low ) mice. Cellular FLICE-inhibitory protein expression was down-regulated in Cflar-deficient hepatocytes, which thereby increased susceptibility of hepatocytes to death receptor-induced apoptosis. CflarHep-low mice developed acute hepatitis and recovered with clearance of apoptotic hepatocytes at 24 hours after injection of low doses of tumor necrosis factor α (TNFα), which could not induce hepatitis in wild-type (WT) mice. Depletion of Kupffer cells (KCs) by clodronate liposomes did not impair clearance of dying hepatocytes or exacerbate hepatitis in CflarHep-low mice. To elucidate the roles of BM-derived monocytes and neutrophils in clearance of apoptotic hepatocytes, we examined the effect of depletion of these cells on TNFα-induced hepatitis in CflarHep-low mice. We reconstituted CflarHep-low mice with BM cells from transgenic mice in which human diphtheria toxin receptor (DTR) was expressed under control of the lysozyme M (LysM) promoter. TNFα-induced infiltration of myeloid cells, including monocytes and neutrophils, was completely ablated in LysM-DTR BM-reconstituted CflarHep-low mice pretreated with diphtheria toxin, whereas KCs remained present in the livers. Under these experimental conditions, LysM-DTR BM-reconstituted CflarHep-low mice rapidly developed severe hepatitis and succumbed within several hours of TNFα injection. We found that serum interleukin-6 (IL-6), TNFα, and histone H3 were aberrantly increased in LysM-DTR BM-reconstituted, but not in WT BM-reconstituted, CflarHep-low mice following TNFα injection. CONCLUSION: These findings indicate an unexpected role of myeloid cells in decreasing serum IL-6, TNFα, and histone H3 levels via the suppression of TNFα-induced hepatocyte apoptosis. (Hepatology 2017;65:237-252).

Serum Monocyte Chemoattractant Protein-1 Predicts Liver Inflammation of Patients with Chronic Hepatitis B.

BACKGROUND: The usefulness of serum markers for predicting liver necroinflammation is limited in chronic hepatitis B (CHB) patients with normal or slightly elevated alanine aminotransferase (ALT). Monocyte chemoattractant protein-1 (MCP-1) is an important inflammatory mediator in liver disease. Our study was to investigate the expression of MCP-1 and its diagnostic value in patients with HBV-related liver necroinflammation. METHODS: One hundred and six patients with hepatitis B virus (HBV) infection were recruited. All were positive for hepatitis B e antigen (HBeAg) and underwent liver biopsy. Significant inflammation was defined as inflammatory grade ≥ 2 according to Scheuer's classification scoring system. Enzyme-linked immunosorbent assay (ELISA) was used to detect expression of MCP-1 in the peripheral blood of all patients, and receiver operating characteristics (ROC) analysis was used to evaluate diagnostic accuracy of MCP-1 and liver inflammation. RESULTS: MCP-1 level in patients with HBV infection was higher than in healthy controls (p < 0.05). Moreover, MCP-1 level in the ALT ≥ two times of upper limits of normal (2 ULN) group was higher than that of the ALT < 2 ULN group (p < 0.05). In the ALT < 2 ULN group, the MCP-1 level in patients whose inflammatory activity was grade ≥ 2 was higher than in patients with grade < 2 (p < 0.05). ROC curve analysis showed that the area under the curve of MCP-1 in diagnosis of liver inflammation was 0.842. CONCLUSIONS: MCP-1 could be used as a serological marker for non-invasive evaluation of liver inflammation in CHB patients with normal or slightly elevated ALT.

Prevalence and Prognostic Value of Abnormal Liver Test Results in Critically Ill Children and the Impact of Delaying Parenteral Nutrition.

OBJECTIVES: In the Early versus Late Parenteral Nutrition in the Pediatric ICU randomized controlled trial, delaying parenteral nutrition to beyond day 7 (late parenteral nutrition) was clinically superior to supplemental parenteral nutrition initiated within 24 hours (early parenteral nutrition), but resulted in a higher rise in bilirubin. We aimed to document prevalence and prognostic value of abnormal liver tests in the PICU and the impact hereon of withholding early parenteral nutrition. DESIGN: Preplanned secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric ICU randomized controlled trial. Total bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase plasma concentrations were measured systematically in PICU. Liver test analyses were adjusted for baseline characteristics including severity of illness. SETTING: Three PICUs in Belgium, the Netherlands, and Canada. PATIENTS: As neonatal jaundice was considered a confounder, only the 1,231 of the 1,440 Early versus Late Parenteral Nutrition in the Pediatric ICU-patients 28 days to 17 years old were included. INTERVENTIONS: Late parenteral nutrition as compared with early parenteral nutrition. MEASUREMENTS AND MAIN RESULTS: During the first seven PICU days, the prevalence of cholestasis (> 2 mg/dL [34.2 µmol/L] bilirubin) ranged between 3.8% and 4.9% and of hypoxic hepatitis (≥ 20-fold upper limit of normality for alanine aminotransferase and aspartate aminotransferase) between 0.8% and 2.2%, both unaffected by the use of parenteral nutrition. Throughout the first week in PICU plasma bilirubin concentrations were higher in late parenteral nutrition patients (p < 0.05), but became comparable to early parenteral nutrition patients as soon as parenteral nutrition was started on day 8. Plasma concentrations of gamma-glutamyl transpeptidase, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase were unaffected by parenteral nutrition. High day 1 plasma concentrations of gamma-glutamyl transpeptidase, alanine aminotransferase, and aspartate aminotransferase (p ≤ 0.01), but not alkaline phosphatase, were independent risk factors for PICU mortality. Day 1 plasma bilirubin concentrations displayed a U-shaped association with PICU mortality, with higher mortality associated with bilirubin less than 0.20 mg/dL and greater than 0.76 mg/dL (< 3.42 µmol/L and > 13 µmol/L) (p ≤ 0.01). CONCLUSIONS: Overt cholestasis and hypoxic hepatitis were rare and unrelated to the nutritional strategy. However, withholding parenteral nutrition up to 1 week in PICU increased plasma bilirubin. A mild elevation of bilirubin on the first PICU day was associated with lower risk of death and may reflect a stress response, rather than true cholestasis.

Plasma biomarkers to study mechanisms of liver injury in patients with hypoxic hepatitis.

BACKGROUND & AIMS: Hypoxic hepatitis is a clinical condition precipitated by prolonged periods of oxygen deprivation to the liver. It can have several underlying causes. Despite its prevalence in critically ill patients, which can reach upwards of 10%, very little is known about the mechanisms of injury. Thus, we set out to measure previously identified circulating biomarkers in an attempt to describe mechanisms of injury following hypoxic hepatitis. METHODS: Plasma from patients diagnosed with hypoxic hepatitis was collected for this study. Biomarkers of hepatocellular injury, mitochondrial damage and cell death were measured. These results were compared against results obtained from well-characterized acetaminophen overdose patients. RESULTS: At peak injury, ALT measured 4082±606 U/L and gradually decreased over 5 days, corresponding to the clinically observed pattern of hypoxic hepatitis. Levels of GDH showed a similar pattern, but neither ALT nor GDH were significantly higher in these patients than in acetaminophen patients. Plasma levels of DNA fragments mimicked hepatocellular injury as measured by ALT and miRNA-122. Interestingly, we found a significant increase in caspase-cleaved cytokeratin-18; however, the full-length form greatly exceeded the cleaved form at the time of maximum injury (45837±12085 vs 2528±1074 U/L). We also found an increase in acHMGB1 at later time points indicating a possible role of inflammation, but cytokine levels at these times were actually decreased relative to early time points. CONCLUSIONS: The mechanism of injury following hypoxic hepatitis involves mitochondrial damage and DNA fragmentation. Importantly, necrosis, rather than apoptosis, is the main mode of cell death.

Features of Hepatitis in Hepatitis-associated Aplastic Anemia: Clinical and Histopathologic Study.

OBJECTIVES: Hepatitis-associated aplastic anemia (HAA) is a rare variant of aplastic anemia in which patients present with severe pancytopenia after an episode of acute hepatitis. The marrow failure is often rapid, severe, and usually fatal if untreated. The preceding hepatitis is largely under-studied. METHODS: Retrospective study of the clinical and histopathologic features of hepatitis in pediatric patients who subsequently developed aplastic anemia and comparison with consecutive cases of acute liver failure and random cases of autoimmune hepatitis during the same time frame. RESULTS: All 7 patients of HAA had significant elevations in aminotransferases and conjugated hyperbilirubinemia at initial presentation. Echoing liver function indices, cholestatic hepatitis with sinusoidal obstruction-type endothelial injury was seen histomorphologically. Autoimmune hepatitis serology such as anti-F-actin, anti-liver/kidney microsome, and hypergammaglobulinemia was negative in all patients. Five of 7 patients (71.4%) had, however, elevated antinuclear antibody, all with a speckled pattern. Hepatitis virus serology was negative in all patients. By immunohistochemical staining, the lobular CD8/CD4 lymphocyte ratio was markedly elevated in all of the initial samples with significant reduction in this ratio (P = 0.03) in 3 patients post treatment (ursodiol, antibiotics, and/or immunosuppressive therapy). CONCLUSIONS: Hepatitis preceding HAA is characterized by marked elevation of aminotransferases, conjugated hyperbilirubinemia, elevated antinuclear antibody with a speckled pattern, cholestatic hepatitis with sinusoidal obstruction morphology, and CD8 dominant lobular infiltrates. The present study suggests HAA may result from cytotoxic T-cell-mediated sinusoidal endothelial and hepatocytic injury.

Hepatoprotective role of vardenafil against experimentally induced hepatitis in mice.

Vardenafil is a selective phosphodiesterase-5 inhibitor used for erectile dysfunction treatment. The hepatoprotective role of vardenafil against acute hepatitis is not reported yet. Hence, this study aims to explore the protective role of vardenafil against concanavalin A (Con A) induced acute liver injury. Mice were pretreated with vardenafil (0.17 mg/kg/day) for seven consecutive days, and then subjected to a single IV injection of Con A. The results demonstrated that the vardenafil pretreatment significantly reduced the elevated serum levels of transaminases and alkaline phosphatase. Histopathological examination showed marked necrosis and inflammation in Con A-treated mice which was significantly ameliorated in vardenafil pretreated animals. Vardenafil pretreatment significantly alleviated the expression of nuclear factor kappa-B and inducible nitric oxide synthase in the hepatic tissue. Additionally, serum levels of nitric oxide and tumor necrosis factor-alpha were decreased in vardenafil pretreated animals compared to the Con A group. Therefore, our results demonstrate that vardenafil has hepatoprotective effect and this could be linked to decrease inflammatory mediators.

Increased Red Cell Distribution Width is Strong Inflammatory Marker of Liver Diseases in a Guangxi Population.

BACKGROUND: Red cell distribution width (RDW), part of a routine complete blood count in a clinical laboratory, has been widely and routinely used in the diagnosis of various diseases. The aim of the present study was to investigate the relationship between increased RDW and liver diseases and whether RDW is a new inflammatory marker for liver diseases in a Guangxi population. METHODS: A total of 735 patients were enrolled in our study, including 113 patients with chronic hepatitis B (CHB), 133 liver cirrhosis (LC) patients, 105 patients with hepatocellular carcinoma (HCC), 55 alcoholic hepatitis (AH) patients, 44 chronic hepatitis C (CHC) patients, and 285 healthy persons. The hematological and hepatic function parameters, other tumor biomarkers, and MELD grades of subjects were tested, and, then, comparisons were made between the tested indexes of the various groups using SPSS 17 software. Statistical significance was set at a p-value of less than 0.05. RESULTS: Of the five groups, the RDW values of the liver diseases groups were higher than those in the healthy group (p < 0.05), and the MELD grades of liver diseases patients were positive with RDW (p < 0.05). In addition, in the various liver disease groups, the RDW values were positive with HGB and positive or negative with different biomarkers in different groups (p < 0.05). Besides, except CHC, the area under the ROC curve and Youden index of the RDW liver diseases groups were significant (p < 0.001), and area under the ROC curve of AST, r-GT ALP, and GLB were of worth for predicting liver diseases (p < 0.05). CONCLUSIONS: In cases of liver disease, RDW values were increased and were related with various biomarkers and MELD grades. RDW could be used as an inflammatory marker for predicting CHB, LC, HCC, and AH but not including CHC when combined with HGB, AST, r-GT ALP, and GLB.

Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis.

We have identified, by quantitative real-time PCR, hundreds of miRNAs that are dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients. Most of these circulating microRNAs decrease toward normal levels during treatment with N-acetyl cysteine (NAC). We identified a set of 11 miRNAs whose profiles and dynamics in the circulation during NAC treatment can discriminate APAP hepatotoxicity from ischemic hepatitis. The elevation of certain miRNAs can precede the dramatic rise in the standard biomarker, alanine aminotransferase (ALT), and these miRNAs also respond more rapidly than ALT to successful treatment. Our results suggest that miRNAs can serve as sensitive diagnostic and prognostic clinical tools for severe liver injury and could be useful for monitoring drug-induced liver injury during drug discovery.

Hypersplenism is correlated with increased risk of hepatocellular carcinoma in patients with post-hepatitis cirrhosis.

Several risk factors exist for hepatocellular carcinoma in patients with post-hepatitis cirrhosis (PHC), including hypersplenism. Splenectomy is a common but controversial procedure in the management of hypersplenism, but its impact on hepatocellular carcinoma (HCC) remains uncertain. We conducted a hospital-based study of PHC patients to identify potential risk factors, including a history of splenectomy, which has been associated with progression from PHC to HCC. From 2002 to 2012, 2678 patients developed hypersplenism secondary to PHC. Of these patients, 828 developed HCC and 1850 did not. Potential risk factors of HCC were determined by univariate and multivariate analyses to exclude confounding variables. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were determined for each factor. Many factors, such as liver function, platelet (PLT) counts, Child-Pugh class, and history of hepatitis, were associated with progression to HCC. PHC patients with hypersplenism who displayed elevated levels of alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (GGT), ALK, phosphatase, and prolonged prothrombin time (PT) had a significantly increased risk of HCC. However, the patients who had splenectomy showed better liver function test results and less progression to HCC. In patients with PHC and hypersplenism, abnormal levels of ALT, AST, ALP, and GGT and prolonged PT are risk factors of HCC. Splenectomy, as the intervention method of hypersplenism, is performed less frequently in patients who developed HCC than in patients who did not develop HCC. Therefore, splenectomy may act as an independent factor that is significantly associated with HCC development.

Disrupted lymphocyte homeostasis in hepatitis-associated acquired aplastic anemia is associated with short telomeres.

Hepatitis-associated aplastic anemia (HAA) is a variant of acquired aplastic anemia (AA) in which immune-mediated bone marrow failure (BMF) develops following an acute episode of seronegative hepatitis. Dyskeratosis congenita (DC) is an inherited BMF syndrome characterized by the presence of short telomeres, mucocutaneous abnormalities, and cancer predisposition. While both conditions may cause BMF and hepatic impairment, therapeutic approaches are distinct, making it imperative to establish the correct diagnosis. In clinical practice, lymphocyte telomere lengths (TL) are used as a first-line screen to rule out inherited telomeropathies before initiating treatment for AA. To evaluate the reliability of TL in the HAA population, we performed a retrospective analysis of TL in 10 consecutively enrolled HAA patients compared to 19 patients with idiopathic AA (IAA). HAA patients had significantly shorter telomeres than IAA patients (P = 0.009), including four patients with TL at or below the 1st percentile for age-matched controls. HAA patients had no clinical features of DC and did not carry disease-causing mutations in known genes associated with inherited telomere disorders. Instead, short TLs were significantly correlated with severe lymphopenia and skewed lymphocyte subsets, features characteristic of HAA. Our results indicate the importance of caution in the interpretation of TL measurements in HAA, because, in this patient population, short telomeres have limited specificity.

Trillin Reduces Liver Chronic Inflammation and Fibrosis in Carbon Tetrachloride (CCl4) Induced Liver Injury in Mice.

UNLABELLED: Trillin is an active ingredient isolated from Dioscorea nipponica Makino. This study investigated the anti-inflammatory and anti-fibrosis effects of trillin on CCl4-induced hepatotoxicity in C57BL/6 mice. Chronic inflammation and fibrosis were induced by intraperitoneal administration of CCl4 0.5 µL/g of body weight twice a week for 6 weeks. Trillin (50 mg/kg, 100 mg/kg) was administered by gavage for 12 days before finishing the CCl4 induction. Aspartate amino-transferase (AST) and glutamic-pyruvic transaminase (ALT) in serum were determined by AST and ALT kits. Superoxidase dismutase (SOD) activity and malondialdehyde (MDA) levels in serum were assayed by SOD and MDA kits. Meanwhile, the levels of inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) in serum were detected by enzyme-linked immunosorbent assay (ELISA) method. Pathological changes were observed by hematoxylin-eosin (HE) staining. The proteins of the NF-κB pathway and the TGF-ß/Smad pathway were measured by western blot. The trillin-treated group exhibited reduced AST, ALT, MDA, IL-6, TNF-α, and IL-1ß, and increased SOD. Histological analyses of the trillin-treated group exhibited reduced inflammatory process and prevented liver fibrosis. Western blot analyses of the trillin-treated group showed reduced NF-κB pathway and TGF-ß/Smad pathway. SIGNIFICANCE: Based on the results of the present study, trillin can be used as a potential anti-inflammatory drug for chronic hepatic inflammation.