Course of disease and survival after onset of decompensation in hepatitis B virus‐related cirrhosis

Background: Data regarding the outcome of hepatitis B virus (HBV)‐related cirrhosis after the onset of decompensation is scanty. Method: From January 1998 to December 2008, a retrospective–prospective inception cohort study involving HBV‐related decompensated cirrhotics was performed. Predictors of death and clinical events after the onset of decompensation were evaluated. Patients with co‐infection with hepatitis C virus and/or human immunodeficiency virus, alcohol consumption to any degree and diabetes diagnosed before the detection of liver disease were excluded. Result and analysis: Two hundred and fifty‐three patients (231 males, 139 e‐negative), including 102 untreated patients, were analysed. The mean (±SD) age was 43.0 (±12.0) years. The mean (±SD) follow‐up period was 47 (±47) months. Decompensation was the first presentation of liver disease in 210 (83%) patients. Ascites (70%) and variceal bleed (28%) were predominant modes of decompensation. Forty‐three (17%) patients died (22 vs 14% in untreated and treated cohort, respectively; P=0.002). Type 2 hepato‐renal syndrome was the commonest cause of death (32%). Survival was independent of e‐antigen status. In the total cohorts, predictors of death were occurrence of sepsis with systemic inflammatory response (SIRS), ascites as the initial mode of decompensation, absence of antiviral therapy and events of high‐grade hepatic encephalopathy [hazards ratios (HR) of 4.4, 3.6, 2.2 and 1.7 respectively]. In the untreated cohort, initial decompensation with ascites and development of sepsis with SIRS were independent predictors of death (HR 8.5 and 2.3 respectively), while 5‐year survival was higher in patients having initial decompensation with variceal bleed vs ascites (29 vs 16%, respectively, P=0.002). Conclusion: Decompensation with ascites and sepsis with SIRS predict reduced survival. Antiviral therapy beyond 6 months improves outcome.     

Arsenic induces apoptosis in mouse liver is mitochondria dependent and is abrogated by N-acetylcysteine

Arsenicosis, caused by arsenic contamination of drinking water supplies, is a major public health problem in India and Bangladesh. Chronic liver disease, often with portal hypertension occurs in chronic arsenicosis, contributes to the morbidity and mortality. The early cellular events that initiate liver cell injury due to arsenicosis have not been studied. Our aim was to identify the possible mechanisms related to arsenic-induced liver injury in mice. Liver injury was induced in mice by arsenic treatment. The liver was used for mitochondrial oxidative stress, mitochondrial permeability transition (MPT). Evidence of apoptosis was sought by TUNEL test, caspase assay and histology. Pretreatment with N-acetyl-L-cysteine (NAC) was done to modulate hepatic GSH level. Arsenic treatment in mice caused liver injury associated with increased oxidative stress in liver mitochondria and alteration of MPT. Altered MPT facilitated cytochrome c release in the cytosol, activation of caspase 9 and caspase 3 activities and apoptotic cell death. Pretreatment of NAC to arsenic-treated mice abrogated all these alteration suggesting a glutathione (GSH)-dependent mechanism. Oxidative stress in mitochondria and inappropriate MPT are important in the pathogenesis of arsenic induced apoptotic liver cell injury. The phenomenon is GSH dependent and supplementation of NAC might have beneficial effects.     

Cytogenetics of childhood T-cell leukemia

The karyotypes of 57 cases of childhood T-cell acute lymphoblastic leukemia (ALL) were analyzed to establish the cytogenetic profile in this disease. Three questions were of particular interest. Do the chromosomal changes in T-cell ALL preferentially affect bands where genes encoding the T-cell receptor for antigen (TCR) have been mapped? Do alterations involving the TCR gene regions appear with any notable frequency in B-progenitor ALL? Do chromosomal abnormalities in this disease relate to stage of T-cell ontogeny? A relatively high proportion of cases (65%) had a pseudodiploid karyotype at presentation, the majority (58%) characterized by a translocation. The overall frequency of translocations was 44%, comparable to that among all banded cases of ALL seen in our laboratory. Hypodiploidy and hyperdiploidy were exceedingly rare (only four of 57 cases); 16 cases (28%) had apparently normal karyotypes. In half the cases with a translocation (14 of 24), the breakpoints were in regions to which the alpha and beta chain TCR genes have been mapped. Chromosomal breakpoints that were consistently observed in the vicinity of TCR gene loci were 7q32-q36 (TCR beta chain; n = 8), 14q11-q13 (TCR alpha chain; n = 6); other frequent breakpoints were 9p13-pter (n = 8) and 6q15-qter (n = 9). Chromosomal alterations occurred near TCR gene loci significantly more often in T-cell cases than in a comparison group of 335 patients with B-cell precursor ALL (26% v 1.5%, P = .0001). Stage I thymocyte development (CD7+, CD2+, CD5+, CD1-, CD3-, CD4-, CD8-) was noted in 23 cases, stage II (CD7+, CD2+, CD5+, CD1+, CD3-, CD4 +/-, CD8 +/-) in 25 cases, and stage III (CD9+, CD2+, CD1-, CD5+, CD3+, and either CD4+ or CD8+) in nine cases. The only statistically significant associations between cytogenetic findings and T-cell ontogeny were a higher frequency of normal karyotypes in cases with stage I thymocytes, and of pseudodiploidy in stage II cases. There was no apparent relationship between particular translocations and level of thymocyte maturation. Our findings indicate that most children with T-cell ALL have pseudodiploid karyotypes, although a surprisingly high percentage lack demonstrable abnormal clones. Specific chromosomal changes do not appear to be related to discrete stages of T-cell ontogeny as defined in this study, but they occur preferentially in bands containing TCR genes.