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- Early elevated serum gamma glutamyl transpeptidase after liver transplantation is associated with better survival. [Journal Article]
- F1000Res 2014.:85.
Gamma glutamyl transpeptidase (GGT) is a membrane bound enzyme that plays a key role in the synthesis of the antioxidant glutathione. Epidemiological studies have linked high GGT with an increased risk of morbidity and cardiovascular mortality. In contrast, GGT is usually elevated in liver transplant recipients that experience good outcomes.To study if and how GGT is correlated with mortality following liver transplantation.We analyzed the prognostic relevance of serum GGT levels during the early and late postoperative period after liver transplantation in 522 consecutive adults. We also studied alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels.Early after transplantation, the peak median (interquartile range) GGT levels were significantly higher in patients who survived more than 90 days compared to non-survivors: 293 (178-464) vs. 172 (84-239) U/l, p<0.0001. In contrast, late after transplantation, GGT levels were significantly lower in patients who survived more than 5 years than those who did not ( p<0.01). The pattern of GGT levels also differed from those of alanine aminotransferase, aspartate aminotransferase, and total bilirubin early after transplantation, while these patterns were congruent late after transplantation. Kaplan-Meier survival analysis showed that early after transplantation the higher the GGT levels, the better the 90-day survival ( p<0.001). In contrast, late after transplantation, higher GGT levels were associated with a lower 5-year survival ( p<0.001). These paradoxical findings may be explained by the time-dependent role of GGT in glutathione metabolism. Immediate postoperative elevation of GGT may indicate a physiological systemic response while chronic elevation reflects a pathological response.
- Influence of skin colour on diagnostic accuracy of the jaundice meter JM 103 in newborns. [JOURNAL ARTICLE]
- Arch Dis Child Fetal Neonatal Ed 2014 Jul 29.
To assess the diagnostic accuracy of the JM 103 as a screening tool for neonatal jaundice and explore differential effects based on skin colour.We prospectively compared the transcutaneous bilirubin (TcB) and serum bilirubin (TSB) measurements of newborns over a 3 month-period. Skin colour was assigned via reference colour swatches. Diagnostic measures of the TcB/TSB comparison were made and clinically relevant TcB cut-off values were determined for each skin colour group.451 infants (51 light, 326 medium and 74 dark skin colour) were recruited. The association between TcB and TSB was high for all skin colours (rs>0.9). The Bland-Altman analysis showed an absolute mean difference between the two measures of 13.3±26.4 µmol/L with broad limits of agreement (-39.4-66.0 µmol/L), with TcB underestimating TSB in light and medium skin colours and overestimating in dark skin colour. Diagnostic measures were also consistently high across skin colours, with no clinically significant differences observed.The JM 103 is a useful screening tool to identify infants in need of serum bilirubin, regardless of skin colour. The effect of skin colour on the accuracy of this device at high levels of serum bilirubin could not be assessed fully due to small numbers in the light and dark groups.
- Life-long correction of hyperbilirubinemia with a neonatal liver-specific AAV-mediated gene transfer in a lethal mouse model of Crigler Najjar Syndrome. [JOURNAL ARTICLE]
- Hum Gene Ther 2014 Jul 29.
Null mutations in the UGT1A1 gene result in Crigler-Najjar syndrome type I (CNSI), characterized by severe hyperbilirubinemia and constant risk of developing neurological damage. Phototherapy treatment lowers plasma bilirubin levels, but its efficacy is limited and liver transplantation is required. To find alternative therapies we applied AAV-liver specific gene therapy to a lethal mouse model of CNSI. We demonstrated that a single neonatal hUGT1A1 gene transfer was successful and the therapeutic effect lasted up to 17 months post-injection. The therapeutic effect was mediated by the presence of transcriptionally active double stranded episomes. We also compared the efficacy of two different gene therapy approaches: liver vs. skeletal muscle transgene expression. We observed that 5%-8% of normal liver expression and activity levels were sufficient to significantly reduce bilirubin levels and maintain lifelong low plasma bilirubin concentration (3.1±1.5 mg/dL). In contrast, skeletal muscle was not able to efficiently lower bilirubin (6.4±2.0 mg/dL), despite 20-30% of hUgt1a1 expression levels, compared to normal liver. We propose that this remarkable difference in gene therapy efficacy could be related to the absence of the Mrp2 and Mrp3 transporters of conjugated bilirubin in muscle. Taken together, our data support the concept that liver is the best organ for efficient and long-term CNSI gene therapy, and suggest that the use of extra-hepatic tissues should be coupled to the presence of bilirubin transporters.
- Effective Biliary Drainage and Proper Treatment Improve Outcomes of Hepatocellular Carcinoma with Obstructive Jaundice. [JOURNAL ARTICLE]
- Gut Liver 2014 Jul 25.
: We investigated the treatment outcomes and prognostic factors of hepatocellular carcinoma (HCC) with obstructive jaundice.: Among 2,861 patients newly diagnosed with HCC between 2002 and 2011, a total of 63 patients who initially presented with obstructive jaundice were analyzed. Only four patients presented with resectable tumors and underwent curative resection. In the other patients who presented with unresectable tumors, 5, 8, 9, and 18 patients received transarterial chemoembolization (TACE), chemotherapy, radiotherapy, and combined treatment, respectively. Both the clinical and the treatment factors that affect overall survival (OS) were analyzed.: The median OS was 4 months, and the 1-year OS rate was 23%. Patients who received treatment for HCC had a significantly improved OS rate compared with the patients who received supportive care only (1-year OS, 32% vs 0%; p<0.01). Responders to treatment showed a better OS than nonresponders (1-year OS, 52% vs 0%; p<0.01). TACE and radiotherapy resulted in relatively good treatment responses of 64% and 67%, respectively. In multivariate analyses, treatment of HCC (p=0.02) and the normalization of serum bilirubin by biliary drainage (p=0.02) were significantly favorable prognostic factors that affected the OS.: Unresectable HCC with obstructive jaundice has a poor prognosis. However, effective biliary drainage and treatment of HCC such as with TACE or radiotherapy improves survival.
- Rapid corticosteroid tapering: important risk factor for type 1 autoimmune hepatitis relapse in Japan. [JOURNAL ARTICLE]
- Hepatol Res 2014 Jul 29.
Patients with autoimmune hepatitis (AIH) sometimes relapse after immunosuppressive therapies are discontinued or sometimes even while they are still being administered. Furthermore, relapse often occurs in the absence of AIH relapse risk factors.This study aimed to identify the frequency of relapse and to analyze the risk factors associated with relapse in type 1 AIH patients.Clinical characteristics and therapeutic processes were assessed in 129 type 1 AIH patients.Relapse was identified in 39 (30.2%) type 1 AIH patients after alanine aminotransferase (ALT) level normalization. ALT levels significantly increased when corticosteroid treatment was initiated in relapsed patients compared with that in patients with sustained remission. The reduction dose and rate of corticosteroid taper were significantly increased in relapsed patients compared with those in sustained remission patients. Moreover, positive correlations were identified between the reduction dose/taper rate and initial corticosteroid dose, and ALT levels, total bilirubin levels, and hepatitis activity. Multivariate logistic regression analysis identified the corticosteroid reduction rate as significantly associated with AIH relapse.Corticosteroid reduction taper rate until ALT normalization is an important AIH relapse risk factor.
- Nationwide longitudinal analysis of acute liver failure in taiwan. [Journal Article]
- Medicine (Baltimore) 2014 Jun; 93(4):e35.
Acute liver failure (ALF) is uncommon but fatal. Current management is based mostly on clinical experience. We aimed to investigate the incidence, etiology, outcomes, and prognostic factors of ALF in Taiwan. Patients with the admission diagnosis of ALF between January 2005 and September 2007 were identified from the Longitudinal Health Insurance Database of Taiwan. ALF was further confirmed by disease severity based on laboratory orders, prescriptions, and duration of hospital stay, and acute onset without prior liver disease. Prognostic factors were identified using Cox regression analysis. During the study period, 218 eligible cases were identified from 28,078 potential eligible ALF patients. The incidence was 80.2 per million person-years in average and increased with age. The mean age was 57.9 ± 17.1 years and median survival was 171 days. The most common etiologies were viral (45.4%, mainly hepatitis B virus) and followed by alcohol/toxin (33.0%). Independent prognostic factors included alcohol consumption (hazard ratio, HR, 1.67 [1.01-2.77]), malignancy (HR 2.90 [1.92-4.37]), frequency of checkups per week for total bilirubin (HR 1.57 [1.40-1.76]), sepsis (HR 1.85 [1.20-2.85]), and the use of hemodialysis/hemofiltration (HR 2.12 [1.15-3.9]) and proton pump inhibitor (HR 0.94 [0.90-0.98]). Among the 130 patients who survived ≥90 days, 66 (50.8%) were complicated by liver cirrhosis. Eight (3.7%) were referred for liver transplantation evaluation, but only 1 received transplantation and survived. ALF in Taiwan is mainly due to viral infection. Patients with malignancy and alcohol exposure have worst prognosis. The use of proton pump inhibitor is associated with improved survival. Half of the ALF survivors have liver cirrhosis.
- Hepatic cytochrome P450 deficiency in mouse models for intrahepatic cholestasis predispose to bile salt-induced cholestasis. [JOURNAL ARTICLE]
- Lab Invest 2014 Jul 28.
Progressive familial intrahepatic cholestasis (PFIC) types 1 and 3 are severe cholestatic liver diseases caused by deficiency of ATB8B1 and ABCB4, respectively. Mouse models for PFIC display mild phenotypes compared with human patients, and this can be explained by the difference in bile salt pool composition. Mice, unlike humans, have the ability to detoxify hydrophobic bile salts by cytochrome P450-mediated (re)hydroxylation and thus have a less toxic bile salt pool. We have crossed mouse models for PFIC1 and PFIC3 with Hrn mice that have a reduced capacity to (re)hydroxylate bile salts. Double transgenes were obtained by backcrossing Atp8b1(G308V/G308V) and Abcb4(-/-) mice with Hrn mice that have a liver-specific disruption of the cytochrome P450 reductase gene and therefore have markedly reduced P450 activity. In these mice, a more hydrophobic bile salt pool was instilled by cholic acid supplementation of the diet, and bile formation and liver pathology was studied. As opposed to single transgenes, Atp8b1(G308V/G308V)/Hrn and Abcb4(-/-)/Hrn mice rapidly developed strong cholestasis that was evidenced by increased plasma bilirubin and bile salt levels. The bile salt pool was more toxic in both models; Atp8b1(G308V/G308V)/Hrn mice had a more hydrophobic plasma pool compared with the single transgene, whereas Abcb4(-/-)/Hrn mice had a more hydrophobic biliary pool compared with the single transgene. In line with these findings, liver damage was not aggravated in Atp8b1(G308V/G308V)/Hrn but was more severe in Abcb4(-/-)/Hrn mice. These data indicate that bile salt pool composition is a critical determinant in the initiation and progression of cholestasis and liver pathology in PFIC1 and PFIC3. Most importantly, our data suggest that the hydrophobicity of the plasma bile salt pool is an important determinant of the severity of cholestasis, whereas the hydrophobicity of the biliary bile salt pool is an important determinant of the severity of liver pathology.Laboratory Investigation advance online publication, 28 July 2014; doi:10.1038/labinvest.2014.102.
- Systems Pharmacology Modeling Predicts Delayed Presentation and Species Differences in Bile Acid-Mediated Troglitazone Hepatotoxicity. [JOURNAL ARTICLE]
- Clin Pharmacol Ther 2014 Jul 28.
Troglitazone (TGZ) caused delayed, life-threatening drug-induced liver injury (DILI) in some patients, but was not hepatotoxic in rats. This study investigated altered bile acid (BA) homeostasis as a mechanism of TGZ hepatotoxicity using a systems pharmacology model incorporating drug/metabolite disposition, BA physiology/pathophysiology, hepatocyte life cycle, and liver injury biomarkers. In the simulated human population, TGZ (400-600mg/dayx6months) resulted in delayed increases in serum ALT>3X ULN in 2.4-4.2% of the population with concomitant bilirubin elevations>2X ULN in 0.9-2.7%. In contrast, pioglitazone (15-45mg/dayx6months) did not elicit hepatotoxicity, consistent with clinical data. TGZ was not hepatotoxic in the simulated rat population. In summary, mechanistic modeling based only on BA effects accurately predicted the incidence, delayed presentation, and species differences in TGZ hepatotoxicity, and the relative liver safety of pioglitazone. Systems pharmacology models integrating physiology and experimental data can evaluate DILI mechanisms and may be useful to predict hepatotoxic potential of drug candidates.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 28 July 2014; doi:10.1038/clpt.2014.158.
- Neonatal physiological correlates of near-term brain development on MRI and DTI in very-low-birth-weight preterm infants. [Journal Article]
- Neuroimage Clin 2014.:169-77.
Structural brain abnormalities identified at near-term age have been recognized as potential predictors of neurodevelopment in children born preterm. The aim of this study was to examine the relationship between neonatal physiological risk factors and early brain structure in very-low-birth-weight (VLBW) preterm infants using structural MRI and diffusion tensor imaging (DTI) at near-term age. Structural brain MRI, diffusion-weighted scans, and neonatal physiological risk factors were analyzed in a cross-sectional sample of 102 VLBW preterm infants (BW ≤ 1500 g, gestational age (GA) ≤ 32 weeks), who were admitted to the Lucile Packard Children's Hospital, Stanford NICU and recruited to participate prior to routine near-term brain MRI conducted at 36.6 ± 1.8 weeks postmenstrual age (PMA) from 2010 to 2011; 66/102 also underwent a diffusion-weighted scan. Brain abnormalities were assessed qualitatively on structural MRI, and white matter (WM) microstructure was analyzed quantitatively on DTI in six subcortical regions defined by DiffeoMap neonatal brain atlas. Specific regions of interest included the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, the thalamus, and the globus pallidus. Regional fractional anisotropy (FA) and mean diffusivity (MD) were calculated using DTI data and examined in relation to neonatal physiological risk factors including gestational age (GA), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and sepsis, as well as serum levels of C-reactive protein (CRP), glucose, albumin, and total bilirubin. Brain abnormalities were observed on structural MRI in 38/102 infants including 35% of females and 40% of males. Infants with brain abnormalities observed on MRI had higher incidence of BPD (42% vs. 25%) and sepsis (21% vs. 6%) and higher mean and peak serum CRP levels, respectively, (0.64 vs. 0.34 mg/dL, p = .008; 1.57 vs. 0.67 mg/dL, p= .006) compared to those without. The number of signal abnormalities observed on structural MRI correlated to mean and peak CRP (rho = .316, p = .002; rho = .318, p= .002). The number of signal abnormalities observed on MRI correlated with thalamus MD (left: r= .382, p= .002; right: r= .400, p= .001), controlling for PMA-at-scan. Thalamus WM microstructure demonstrated the strongest associations with neonatal risk factors. Higher thalamus MD on the left and right, respectively, was associated with lower GA (r = -.322, p = .009; r= -.381, p= .002), lower mean albumin (r = -.276, p= .029; r= -.385, p= .002), and lower mean bilirubin (r = -.293, p= .020; r= -.337 p= .007). Results suggest that at near-term age, thalamus WM microstructure may be particularly vulnerable to certain neonatal risk factors. Interactions between albumin, bilirubin, phototherapy, and brain development warrant further investigation. Identification of physiological risk factors associated with selective vulnerability of certain brain regions at near-term age may clarify the etiology of neurodevelopmental impairment and inform neuroprotective treatment for VLBW preterm infants.
- Conjugated bilirubin triggers anemia by inducing erythrocyte death. [JOURNAL ARTICLE]
- Hepatology 2014 Jul 28.
Hepatic failure is commonly associated with anemia, which may result from gastrointestinal bleeding, vitamin deficiency and liver-damaging diseases, such as infection and alcohol intoxication. At least in theory, anemia during hepatic failure may result from accelerated clearance of circulating erythrocytes. Here we show that bile duct ligation (BDL) in mice leads to severe anemia despite increased reticulocyte numbers. Bilirubin stimulated suicidal erythrocyte death of human erythrocytes. Mechanistically, bilirubin triggered rapid Ca(2+) influx, sphingomyelinase activation, formation of ceramide and subsequent translocation of phosphatidylserine to the erythrocyte surface. Consistent with our in vitro and in vivo findings, incubation of erythrocytes in serum from patients with liver disease induced suicidal death of erythrocytes in relation to their plasma bilirubin concentration. Consistently, in patients with hepatic disease bilirubin plasma levels correlated negatively with erythrocyte count and positively with reticulocyte count. In conclusion, bilirubin triggers suicidal erythrocyte death thus contributing to anemia during liver disease. (Hepatology 2014;).