Higher Serum Alanine Aminotransferase Levels Research Articles

Diagnostic utility of alpha-fetoprotein and des-gamma-carboxyprothrombin in nigerians with hepatocellular carcinoma.

Alpha-fetoprotein (AFP) and Des-gamma-carboxyprothrombin (DCP) have been extensively studied as biomarkers for the diagnosis of and prognostication in hepatocellular carcinoma (HCC). However there are only few reports on the clinical characteristics of hepatocellular carcinoma in relation to the combination of the two tumor markers in hepatitis B virus-related HCC. The aim of this study was to investigate the clinical characteristics of HBV-related HCC in relation to different sets of AFP and DCP values. Sixty-two patients with untreated HCC were studied. The positive value of AFP was set at 20 1U/L while DCP positive value was set at 150 mAU/ml. Patients were divided into three groups: Group 1(n=36) with AFP ≥ 20 IU/L and DCP ≥ 150 mAU/ml. Group 2(n=24) with AFP <20 1U/L and DCP ≥ 150 mAU/ml. Group 3 (n=2) with AFP < 20 1U/L and DCP < 150 mAU/ml. There were no patients in group 4 meant for those with AFP ≥ 20 1U/L and DCP < 150 mAU/ml. Clinical and laboratory variables were compared among the groups. Clinical and laboratory variables were comparable among the groups with the exception of gender and values of serum alanine aminotransferase (ALT). Males were significantly more than females among the groups (p<0.03). ALT values were significantly different among the groups (p<0.006). Paired comparisons between the groups showed the mean values of serum ALT were significantly higher in group 2 than in group 1(p<0.003). The mean serum ALT values were also higher in group 2 than in group 3 (p <0.014). There was no significant difference between group 1 and group 3 (P = 0.124). HCC patients who are sero-positive for DCP and sero-negative for AFP have significantly higher levels of serum ALT; serum ALT levels may be of diagnostic importance in AFP-negative, HBV-related HCC patients.

Aging increases the susceptibility of hepatic inflammation, liver fibrosis and aging in response to high-fat diet in mice.

We aimed to investigate whether aging increases the susceptibility of hepatic and renal inflammation or fibrosis in response to high-fat diet (HFD) and explore the underlying genetic alterations. Middle (10months old) and old (20months old) aged, male C57BL/6N mice were fed either a low-fat diet (4% fat) or HFD (60% fat) for 4months. Young (3months old) aged mice were included as control group. HFD-induced liver and kidney injuries were analyzed by serum and urine assay, histologic staining, immunohistochemistry, and reverse-transcription real-time quantitative polymerase chain reaction. Total RNA sequencing with next-generation technology was done with RNA extracted from liver tissues. With HFD feeding, aged was associated with higher serum alanine aminotransferase levels, marked infiltration of hepatic macrophages, and increased expression of inflammatory cytokines (MCP1, TNF-α, IL-1β, IL-6, IL-12, IL-17A). Importantly, aged mice showed more advanced hepatic fibrosis and increased expression of fibrogenic markers (Col-I-α1, αSMA, TGF-β1, TGF-β2, TGFβRII, PDGF, PDGFRβII, TIMP1) in response to HFD. Aged mice fed on HFD also showed increased oxidative stress and TLR4 expression. In the total RNA seq and gene ontology analysis of liver, old-aged HFD group showed significant up-regulation of genes linked to innate immune response, immune response, defense response, inflammatory response compared to middle-aged HFD group. Meanwhile, aging and HFD feeding showed significant increase in glomerular size and mesangial area, higher urine albumin/creatinine ratio, and advanced renal inflammation or fibrosis. However, the difference of HFD-induced renal injury between old-aged group and middle-aged group was not significant. The susceptibility of hepatic fibrosis as well as hepatic inflammation in response to HFD was significantly increased with aging. In addition, aging was associated with glomerular alterations and increased renal inflammation or fibrosis, while the differential effect of aging on HFD-induced renal injury was not remarkable as shown in the liver.

Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet.

Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocyte-specific Xbp1-deficient (Xbp1(-/-)) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1(-/-) mice exhibited higher serum alanine aminotransferase levels compared with Xbp1(fl/fl) controls. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1(-/-) mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFS-fed Xbp1(-/-) mice. Hepatic Col1a1 and Tgfβ1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1(-/-) compared with Xbp1(fl/fl) mice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.

Impact of Momordica charantia (karela) on serum alanine aminotransferase level in streptozotocin induced diabetic rats

The present experimental study was conducted at Department of Anatomy in BSMMU (Bangabandhu Sheikh Mujib Medical University) &amp; BIRDEM (Bangladesh Institute of Research &amp; rehabilitation in Diabetes, Endocrine &amp; metabolic Disorders) to investigate whether Momordica charantia (karela) has got any impact on serum alanine aminotransferase (ALT) level in the streptozotocin-induced diabetic rats. Sixty healthy young Long Evans rats of male sex weighing 150 to 280 gm aged between 10 to 12 weeks were used in this study. The rats were divided into 4 equal groups depending on their different sorts of dietary feedings and drug treatment. The final ALT level (on 51st day) ranged from 23 to 34 u/L (mean 30.10 u/L) in healthy rats, 56 to 80 u/L (mean 68.50 u/L) in the untreated diabetic rats, 36 o 37 u/L (mean 31.50 u/L) in the insulin-treated diabetic rats and 61 to 96 u/L (mean 81.10 u/L) in the karela-treated diabetic rats. The ALT percentage change value of diabetic rats on 51st day corresponding to the initial on 7th day was significantly higher than that healthy rats (p&lt;0.001). The value in the insulin-treated diabetic rats was significantly lower than that of the untreated diabetic rats (p&lt;0.001) &amp; the karela-treated diabetic rats (p&lt;0.001). There was no significant difference between the values of the untreated diabetic rats &amp; the karela-treated diabetic rats (p&gt;0.05). The present study did not show that karela has any significant impact of acting against higher serum ALT level in streptozotocin-induced diabetes mellitus. Further investigation is recommended for establishing karela as an agent against higher serum ALT level in diabetes mellitus. DOI: http://dx.doi.org/10.3329/mediscope.v1i1.21634 Mediscope Vol. 1, No. 1: 2014, Pages 29-32

Chronic hepatitis B virus infection in children and adolescents in Japan.

Hepatitis B e antigen (HBeAg) seroconversion is an important event in patients with chronic hepatitis B virus (HBV) infection. This study aimed to clarify the outcome of long-term follow-up of chronic HBV infection and the factors affecting HBeAg seroconversion in children in Japan. Patients who were first examined at our institution between 1980 and 2012, who were <20 years of age at the time of this initial visit, and who were positive for hepatitis B surface antigen for at least 6 months were identified retrospectively. Sex, age at diagnosis, HBV genotype, maximum serum alanine aminotransferase (ALT) level, occurrence of hepatitis flare-ups (yes/no), and transmission route were evaluated to identify the predictors of HBeAg seroconversion. A total of 205 children with chronic HBV were enrolled. Among them, 192 were positive for HBeAg upon diagnosis of chronic HBV infection. Out of this group, 95 (49%) achieved HBeAg seroconversion and 43 (21%) received treatment during the follow-up period. Only the maximum serum ALT level was significantly associated with the achievement of HBeAg seroconversion by multivariate analysis (P < 0.05). Kaplan-Meier analysis showed that the median times to HBeAg seroconversion (50% achievement of HBeAg seroconversion) of the treated and untreated children were 10.2 and 12.0 years, respectively. The cumulative proportion of HBeAg seroconversion was significantly higher in the treated children than in the untreated children (P = 0.02). A higher serum ALT level was a predictor for HBeAg seroconversion. Antiviral treatment could accelerate the achievement of HBeAg seroconversion in HBV-infected children.

Impact of JNK inhibitor XG-102 in a diet-induced rat model of non-alcoholic steatohepatitis

To observe the impact of the JNK inhibitor XG-102 in a diet-induced rat model of non-alcoholic steatohepatitis. Forty-eight Sprague-Dawley male rats were subjected to a percutaneous superior mesenteric vein retention catheter operation and fed with a standard diet for 10 days, after which the rats were randomly divided into the following three groups: normal control (NC) group; high-fat (HF) model group; XG-102 treatment group. The HF group was fed an HF diet and treated with 0.9% sodium chloride for 16 weeks. The XG-102 group was fed an HF diet for 16 weeks and simultaneously treated with XG-102 (1 mg/kg) once per day for 4 weeks. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), homeostasis model of assessment insulin resistance (HOMA-IR) and tumor necrosis factor-alpha (TNFa) were measured. Liver histological changes were observed. The protein expressions of phospho-c-Jun and cleaved caspase-3 were detected by western blotting. Compared with the NC group, the HF group showed significantly higher levels of serum ALT, AST, TC, TG, HOMA-IR and TNFa (P<0.05). Compared with the HF group, the XG-102 group showed significantly lower levels of serum ALT, AST, TC, TG, HOMA-IR and TNFa (P<0.05). The HF group also showed significantly higher protein expression of phospho-c-Jun and cleaved caspase-3 than the NC group (P<0.05) and the XG-102 group (P<0.05). The JNK inhibitor XG-102 may ameliorate lipid metabolism, reduce insulin resistance, decrease liver injury and inhibit hepatocytes apoptosis.

Therapeutic efficacy of splenectomy is attenuated by necroinflammation of the liver in patients with liver cirrhosis.

Splenectomy is a therapy for thrombocytopenia caused by hypersplenism with liver cirrhosis. However, the determinant of therapeutic outcomes for this complication has not yet been fully clarified. We studied the laboratory findings of 55 patients who underwent splenectomy for hypersplenism with liver cirrhosis. In addition, we examined the histopathological findings of hepatosplenic tissues of nine patients who underwent hepatectomy for hepatocellular carcinoma and splenectomy for hypersplenism with liver cirrhosis on one stage surgery. The locations of platelets in hepatosplenic tissues were identified by immunohistochemistry. We used monoclonal antibody against CD41. Among 55 patients, 40 patients had high serum alanine aminotransferase (ALT) level (≧38 IU/l). Blood platelet count after splenectomy of patients with high serum ALT level were significantly lower than those of patients with low serum ALT level (P = 0.02). Histopathologically, platelet area of the liver tissues was positively correlated with hepatic inflammation (P = 0.02). Platelet area of the liver tissues was negatively correlated with blood platelet count after splenectomy (P = 0.03). Hepatic inflammation contributes to the accumulation of platelets in liver; therefore, in patients with high serum ALT level, improvement of thrombocytopenia by the elimination of hypersplenism was limited.

Prevalence and predictors of anaemia in patients with HIV infection at the initiation of combined antiretroviral therapy in Xinjiang, China

We retrospectively analysed routinely collected baseline data of 2252 patients with HIV infection registered in the National Free Antiretroviral Treatment Program in Xinjiang province, China, from 2006 to 2011 to estimate the prevalence and predictors of anaemia at the initiation of combined antiretroviral therapy. Anaemia was diagnosed using the criteria set forth by the World Health Organisation, and univariate and multivariate logistic regression analyses were performed to determine its predictors. The prevalences of mild, moderate, and severe anaemia at the initiation of combined antiretroviral therapy were 19.2%, 17.1%, and 2.6%, respectively. Overall, 38.9% of the patients were anaemic at the initiation of combined antiretroviral therapy. The multivariate logistic regression analysis indicated that Uyghur ethnicity, female gender, lower CD4 count, lower body mass index value, self-reported tuberculosis infection, and oral candidiasis were associated with a higher prevalence of anaemia, whereas higher serum alanine aminotransferase level was associated with a lower prevalence of anaemia. The results suggest that the overall prevalence of anaemia at the initiation of combined antiretroviral therapy in patients with HIV infection is high in Xinjiang, China, but severe anaemia is uncommon. Patients in China should be routinely checked for anaemia prior to combined antiretroviral therapy initiation, and healthcare providers should carefully select the appropriate first-line combined antiretroviral therapy regimens for anaemic patients.

Risk stratification of HBV infection in Asia-Pacific region

Hepatitis B virus (HBV) infection is the major etiology of chronic liver disease worldwide and thus a global health problem, especially in Asia-Pacific region. The long-term outcomes of Asian HBV carriers vary widely; however, a significant proportion of them will finally develop end-stage liver disease. Over the past decade, several host and HBV factors predictive of clinical outcomes in Asian HBV carriers have been identified. The community-based REVEAL-HBV study illustrated the strong association between HBV-DNA level at study entry and risk of HCC over time, and male gender, older age, high serum alanine aminotransferase (ALT) level, positive HBeAg, higher HBV-DNA level, HBV genotype C infection and core promoter mutation are independently associated with a higher hepatocellular carcinoma (HCC) risk. Another hospital-based ERADICATE-B cohort further validated the HCC risk started to increase when HBV-DNA level was higher than 2,000 IU/mL. Of particular note, in patients with low viral load (HBV-DNA level <2,000 IU/mL), HBsAg level ≥1,000 IU/mL was a new independent risk factor for HCC. With the results from REVEAL-HBV study, a risk calculator for predicting HCC in adult non-cirrhotic patients has been developed and validated by independent international cohorts (REACH-B). With the combination of HBV-DNA, HBsAg, and ALT levels, ERADICATE-B study proposed an algorithm to predict disease progression and categorize risk levels of HCC as well as corresponding management in Asian HBV carriers. The introduction of transient elastography may further enhance the predictive power. In conclusion, HBsAg level can complement HBV-DNA level for the risk stratification of disease progression in Asian adult patients with chronic HBV infection.

Risk stratification for hepatitis B virus related hepatocellular carcinoma

Hepatitis B virus (HBV) infection is the major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide, especially in the Asia-Pacific region. Several hepatitis B viral factors predictive of clinical outcomes in HBV carriers have been identified. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV (REVEAL-HBV) study from Taiwan illustrated the strong association between HBV-DNA level at study entry and risk of HCC over time. In this community-based cohort study, male gender, older age, high serum alanine aminotransferase level, positive hepatitis B e antigen, higher HBV-DNA level, HBV genotype C infection, and core promoter mutation are independently associated with a higher risk of HCC. Another large hospital-based Elucidation of Risk Factors for Disease Control or Advancement in Taiwanese Hepatitis B Carriers cohort of Taiwanese patients further validated the findings of REVEAL-HBV. The risk of HCC started to increase when HBV-DNA level was higher than 2000 IU/mL. Both HBV-DNA and HBsAg levels were shown to be associated with HCC development. While HBV-DNA level had better predictive accuracy than HBsAg level, when investigating the overall cohort in patients with HBV-DNA level < 2000 IU/mL, HBsAg level ≥ 1000 IU/mL was identified as a new independent risk factor for HCC. With the results from REVEAL-HBV, a risk calculation for predicting HCC in non-cirrhotic patients has been developed and validated by independent cohorts (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B).Taken together, ample evidence indicates that HBsAg level can complement HBV-DNA level in predicting HCC development, especially in HBV carriers with low viral load. In conclusion, HBV treatment guidelines should include the risk stratification of HCC to individualize the management of HBV carriers with different levels of HCC risk.

Association between obesity, hypertriglyceridemia and low hepatitis B viral load

This study aimed to investigate the metabolic risk factors of high hepatitis B viral load. Large-scale, community-based cross-sectional study. A total of 3587 hepatitis B virus (HBV)-infected participants without liver cirrhosis at study entry were investigated. High HBV viral load was defined as a serum level 10(4) copies per ml for hepatitis B e antigen (HBeAg) seronegatives or 10(8) copies per ml for HBeAg seropositives. Among HBeAg seropositives (n=545), high HBV viral load was reversely associated with extreme obesity (odds ratio (OR), 0.30; 95% confidence interval (CI), 0.13-0.68; P=0.004) or central obesity (OR, 0.53; 95% CI, 0.34-0.82; P=0.004) after adjustment for gender, hypertriglyceridemia, hyperuricemia and history of hypertension. High HBV viral load remained significantly inversely associated with extreme obesity (OR, 0.17; 95% CI, 0.05-0.63; P=0.008) and central obesity (OR, 0.44; 95% CI, 0.25-0.78; P=0.005) in male HBeAg-seropositive participants in stratification analyses by gender. Among HBeAg seronegatives (n=3042), however, high HBV viral load was inversely associated with hypertriglyceridemia (OR, 0.74; 95% CI, 0.61-0.89, P=0.002) after adjustment for age, gender, high serum alanine aminotransferase level, and extreme obesity or central obesity. High HBV viral load was still inversely associated with hypertriglyceridemia in both female (OR, 0.70; 95% CI, 0.50-0.97; P=0.041) and male (OR, 0.75; 95% CI, 0.60-0.94; P=0.011) HBeAg-seronegative participants. Extreme obesity and central obesity were associated with a low prevalence of high HBV viral load in HBeAg seropositives, especially in men; while hypertriglyceridemia was associated with a low prevalence of high viral load in HBeAg seronegatives in both women and men.

Organic Anion Transporting Polypeptide 1a1 Null Mice Are Sensitive to Cholestatic Liver Injury

Organic anion transporting polypeptide 1a1 (Oatp1a1) is predominantly expressed in livers of mice and is thought to transport bile acids (BAs) from blood into liver. Because Oatp1a1 expression is markedly decreased in mice after bile duct ligation (BDL). We hypothesized that Oatp1a1-null mice would be protected against liver injury during BDL-induced cholestasis due largely to reduced hepatic uptake of BAs. To evaluate this hypothesis, BDL surgeries were performed in both male wild-type (WT) and Oatp1a1-null mice. At 24 h after BDL, Oatp1a1-null mice showed higher serum alanine aminotransferase levels and more severe liver injury than WT mice, and all Oatp1a1-null mice died within 4 days after BDL, whereas all WT mice survived. At 24 h after BDL, surprisingly Oatp1a1-null mice had higher total BA concentrations in livers than WT mice, suggesting that loss of Oatp1a1 did not prevent BA accumulation in the liver. In addition, secondary BAs dramatically increased in serum of Oatp1a1-null BDL mice but not in WT BDL mice. Oatp1a1-null BDL mice had similar basolateral BA uptake (Na(+)-taurocholate cotransporting polypeptide and Oatp1b2) and BA-efflux (multidrug resistance-associated protein [Mrp]-3, Mrp4, and organic solute transporter α/β) transporters, as well as BA-synthetic enzyme (Cyp7a1) in livers as WT BDL mice. Hepatic expression of small heterodimer partner Cyp3a11, Cyp4a14, and Nqo1, which are target genes of farnesoid X receptor, pregnane X receptor, peroxisome proliferator-activated receptor alpha, and NF-E2-related factor 2, respectively, were increased in WT BDL mice but not in Oatp1a1-null BDL mice. These results demonstrate that loss of Oatp1a1 function exacerbates cholestatic liver injury in mice and suggest that Oatp1a1 plays a unique role in liver adaptive responses to obstructive cholestasis.

The inverse relationship between alanine aminotransferase in the normal range and adverse cardiovascular and non-cardiovascular outcomes

High serum alanine aminotransferase (ALT) levels have been associated with increased risk of diabetes and with increased mortality, but associations of variations of ALT in the normal range with outcomes have been less well studied. We studied the relationship between ALT, mortality and cardiovascular events in the West of Scotland Coronary Prevention Study (WOSCOPS) and the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trials that explicitly excluded subjects with clinically significant liver damage, plus the Leiden 85-plus, a study of survivors to age 85 years. The associations between ALT and morbidity and mortality outcomes were investigated using Cox proportional hazard models adjusting for a comprehensive panel of cardiovascular risk factors. In all three study cohorts, ALT displayed an independent inverse relationship with all-cause mortality so that hazard ratios for fourth versus first quarter of ALT were all below 1.0; HRs 0.64 [95% confidence interval (CI) 0.50-0.81], 0.86 (0.73-1.01), 0.66 (0.50-0.87); WOSCOPS, PROSPER, Leiden 85-plus, respectively. In WOSCOPS and PROSPER, ALT was also inversely associated with risk of fatal plus non-fatal cardiovascular events, including coronary heart disease (CHD) events and stroke. In three independent populations, ALT in the normal range displayed an inverse relationship with total mortality, cardiovascular events and non-cardiovascular events in middle-to-older aged subjects without evidence of clinically significant liver damage, independent of traditional cardiovascular and other risk factors. These findings indicate that the relationship between ALT and clinical outcomes is more complex than generally appreciated.

Metabolic factors are associated with serum alanine aminotransferase levels in patients with chronic hepatitis C

Although serum alanine aminotransferase (ALT) activity is an important marker for the management of chronic hepatitis C (CHC), the factors associated with serum ALT levels remain to be fully understood. This study aimed to clarify the association between serum ALT levels and clinical, histological, and virological factors in patients with CHC. We retrospectively analyzed 256 patients with CHC who underwent liver biopsy, and classified them into three groups according to serum ALT levels: normal to minimal (<40 IU/L), mild (40-80 IU/L), and moderate to severe elevation (≥80 IU/L). All demographic and laboratory data were collected at the time of liver biopsy. All biopsies were evaluated for fibrosis, inflammation, and steatosis. Glucose metabolism was assessed by various indices derived from oral glucose tolerance tests, including the homeostasis model assessment for insulin resistance (HOMA-IR). In 180 patients, visceral fat area was measured at the umbilical level by abdominal computed tomography. Ordered logistic regression analysis showed that higher serum ALT levels were significantly associated with male sex, lower high-density lipoprotein cholesterol (HDL-C), higher HOMA-IR, and higher grades of histological inflammation and steatosis. HOMA-IR, HDL-C, and hepatic steatosis were associated with visceral fat accumulation. Metabolic factors, as well as sex and hepatic inflammation, are independent risk factors for serum ALT elevation in hepatitis C virus (HCV)-infected patients. Metabolic factors may offer targets to decrease serum ALT levels.

Absence of invariant natural killer T cells deteriorates liver inflammation and fibrosis in mice fed high-fat diet

Invariant natural killer T (iNKT) cells have been suggested to play critical roles in a wide range of immune responses by acting in a proinflammatory or anti-inflammatory manner. Nonalcoholic steatohepatitis (NASH) is a chronic liver disease progressing to advanced cirrhosis and hepatocellular carcinoma. Despite the abundance of iNKT cells in the liver, their role in the pathogenesis of NASH remains obscure. Here, we investigated their role in the development of diet-induced steatosis/steatohepatitis. We used BALB/c wild-type mice and Jα18-deficient (KO) mice lacking iNKT cells fed either a normal diet or a high-fat diet (HFD). The liver and blood were collected from these mice to examine liver inflammation, steatosis, and fibrosis at the indicated time points. KO mice fed the HFD, compared with control mice fed the HFD, exhibited a clearly higher serum alanine aminotransferase level and a greater number of hepatic inflammatory foci, although there was no significant difference in hepatic lipid retention between these groups of mice. The HFD enhanced hepatic messenger RNA expression of inflammatory cytokines and chemokines in KO but not in control mice. The HFD also increased the proportion of hepatic CD4 T cells and CD8 T cells that composed hepatic inflammatory foci in KO mice, but not in the controls. Prolonged feeding with the HFD augmented liver fibrosis in KO but not in control mice. These findings indicate that iNKT cells play a protective role against liver inflammation progressing to fibrosis, but not against steatosis, enhanced by dietary excess fat, suggesting a key role of these cells in NASH pathogenesis.

Atp8b1 and Abcb11 Analysis in 62 Children With Normal Gamma-Glutamyl Transferase Progressive Familial Intrahepatic Cholestasis (Pfic): Phenotypic Differences Between Pfic1 and Pfic2 and Natural History

Progressive familial intrahepatic cholestasis (PFIC) types 1 and 2 are characterized by normal serum gamma-glutamyl transferase (GGT) activity and are due to mutations in ATP8B1 (encoding FIC1) and ABCB11 (encoding bile salt export pump [BSEP]), respectively. Our goal was to evaluate the features that may distinguish PFIC1 from PFIC2 and ease their diagnosis. We retrospectively reviewed charts of 62 children with normal-GGT PFIC in whom a search for ATP8B1 and/or ABCB11 mutation, liver BSEP immunostaining, and/or bile analysis were performed. Based on genetic testing, 13 patients were PFIC1 and 39 PFIC2. The PFIC origin remained unknown in 10 cases. PFIC2 patients had a higher tendency to develop neonatal cholestasis. High serum alanine aminotransferase and alphafetoprotein levels, severe lobular lesions with giant hepatocytes, early liver failure, cholelithiasis, hepatocellular carcinoma, very low biliary bile acid concentration, and negative BSEP canalicular staining suggest PFIC2, whereas an absence of these signs and/or presence of extrahepatic manifestations suggest PFIC1. The PFIC1 and PFIC2 phenotypes were not clearly correlated with mutation types, but we found tendencies for a better prognosis and response to ursodeoxycholic acid (UDCA) or biliary diversion (BD) in a few children with missense mutations. Combination of UDCA, BD, and liver transplantation allowed 87% of normal-GGT PFIC patients to be alive at a median age of 10.5 years (1-36), half of them without liver transplantation. PFIC1 and PFIC2 differ clinically, biochemically, and histologically at presentation and/or during the disease course. A small proportion of normal-GGT PFIC is likely not due to ATP8B1 or ABCB11 mutations.

Effect of Puberty Onset on Spontaneous Hepatitis B Virus e Antigen Seroconversion in Men

Male predominance is a remarkable phenomenon in hepatitis B virus (HBV)-related liver disease. This study elucidated the effects of puberty on spontaneous hepatitis B virus e antigen (HBeAg) seroconversion in boys. One-hundred HBeAg-positive chronic HBV-infected males recruited at younger than 10 years of age who had been followed for >10 years were selected randomly from our long-term followed cohort into this study. Serum testosterone levels, androgen receptor exon-1 CAG repeat number and steroid 5alpha reductase type II (SRD5A2, valine vs leucine alleles) polymorphism were determined. Serial clinical data, HBV genotype, and spontaneous HBeAg seroconversion age were also analyzed. Seventy-two subjects had spontaneous HBeAg seroconversion during the follow-up period. Subjects with serum testosterone levels > or =2.5 ng/mL at 15 years old (earlier-onset puberty, n = 87) had earlier HBeAg seroconversion (median age, 13.2 vs 22.5 years; hazard ratio = 2.95; P = .005), higher peak alanine aminotransferase levels when HBeAg positive (305.7 +/- 372.7 vs 154.8 +/- 126.0 IU/L; P = .006), and a greater HBV viral load reduction from 10 to 20 years of age (1.6 +/- 2.4 vs 0.2 +/- 1.4 log10 copies/mL; P = .009) than those with serum testosterone levels <2.5 ng/mL (later-onset puberty, n = 13). Valine allele carrier at the SRD5A2 V89L polymorphism was also associated with earlier spontaneous HBeAg seroconversion (median age, 11.7 vs 18.7 years; hazard ratio = 1.88; P = .028). Earlier-onset puberty and increased SRD5A2 enzyme activity are associated with earlier HBeAg seroconversion, higher serum alanine aminotransferase levels, and a greater HBV viral load decrement in chronic HBV infected males.

High serum alanine aminotransferase levels for the first three successive years can predict very high incidence of hepatocellular carcinoma in patients with Child Stage A HCV-associated liver cirrhosis

Objective. To assess retrospectively whether continuously high serum alanine aminotransferase (ALAT) levels (<80 IU) in the first three successive years after the diagnosis of liver cirrhosis (LC) are predictive of a subsequent high incidence of hepatocellular carcinoma (HCC) in patients with Child Stage A hepatitis C virus (HCV)-LC. Material and methods. The study comprised 132 HCV-LC (Child Stage A) patients who had not received interferon therapy but had been treated with anti-inflammatory agents. At the end of a 3-year follow-up after the diagnosis of LC, the patients were subdivided into three groups according to their serum ALAT levels and the subsequent incidence of HCC was assessed. Results. The cumulative incidence of HCC starting from 3 years after the diagnosis of LC in the continuously high ALAT group (annual average over 3 years always ≥80 IU; n=41; Group A) was markedly higher than that in the continuously low ALAT group (always <80 IU; n=48; Group B) (p<0.005) during an observation period of 7.9±3.7 years. The incidence of HCC in Group A was 11.8%/year. The odds ratios of developing HCC in Group A and Group C (mixed high and low ALAT levels; n=43) were 5.1-fold and 1.5-fold that of Group B, respectively. A multivariate analysis revealed that the ALAT group was independently associated with HCC development. Conclusions. Continuously high ALAT levels for three successive years following the diagnosis of LC can be predictive of a very high incidence of HCC in Child A HCV-LC patients. Prospective trials using therapeutic approaches aimed at decreasing ALAT levels are necessary in order to confirm a positive impact of ALAT reduction on the incidence of HCC in patients with HCV-LC.

Association of baseline viral factors with response to lamivudine therapy in chronic hepatitis B patients with high serum alanine aminotransferase levels

With the exception of alanine aminotransferase (ALT) level, baseline factors predictive of therapeutic response to lamivudine in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) remain unknown. We thus studied the influence of pre-therapy viral factors on end-of-treatment responses to lamivudine. A total of 116 treatment-naive HBeAg-positive CHB patients who had pre-therapy ALT level >5x the upper limit of normal (ULN) and received lamivudine for 12-18 months were enrolled. HBeAg seroclearance and combined HBeAg seroclearance, ALT normalization and undetectable hepatitis B virus DNA at the end of therapy were defined as primary and secondary endpoints, respectively. Pre-therapy viral factors including viral load, genotype, precore (PC) stop codon status, basal core promoter status and pre-S deletion were determined to correlate with therapeutic endpoints. The frequency of patients with detectable PC stop codon mutation (G1896A), basal core promoter mutation (A1762T/G1764A) and pre-S deletion at baseline was 22.4%, 21.6% and 12.1%, respectively. After the end of 12-18 months of lamivudine therapy, the overall HBeAg seroclearance rate was 56.0%. Patients with HBeAg seroclearance had a higher prevalence of baseline PC stop codon mutation than those without (30.8% versus 11.8%; P=0.015). By using multivariate analyses, the odds ratio of patients with the PC stop codon mutation to develop HBeAg seroclearance was 3.33 (P=0.024). The presence of the PC stop codon mutation also correlated with the combined response. For lamivudine-treated HBeAg-positive CHB patients with pre-therapy ALT levels >5xULN, the PC stop codon mutation could predict a higher HBeAg seroclearance rate at the end of 12-18 months of therapy.

The expression of IL-2, IL-4 and interferon-gamma (IFN-gamma) mRNA using liver biopsies at different phases of acute exacerbation of chronic hepatitis B.

To investigate the hypothesis that Th1 phenotype cytokines are associated with the increasing activity of hepatitis and Th2 phenotype cytokines with decreasing activity in the liver of chronic viral hepatitis, expressions of the mRNA of the cytokines IL-2, IFN-gamma and IL-4 in the liver of 23 patients with chronic hepatitis B were investigated by reverse transcription polymerase chain reaction. Patients were divided into three groups according to the phase of acute exacerbation of hepatitis as increasing (n = 9), decreasing (n = 8), and stable phase (n = 6). Both IL-2 and IFN-gamma mRNA were preferentially expressed in increasing phase than in decreasing phase (P < 0.01, P < 0.05, respectively) and associated with the high serum alanine aminotransferase (ALT) level. On the other hand, IL-4 mRNA was detected in decreasing phase with significant frequency compared with increasing phase (P < 0.05). However, expression of IL-4 mRNA was not associated with serum ALT level. Our results suggest that Th1 phenotype cytokines up-regulate and Th2 phenotype cytokines down-regulate the liver inflammation of chronic viral hepatitis.