A comparison of Child-Pugh, APACHE II and APACHE III scoring systems in predicting hospital mortality of patients with liver cirrhosis

BACKGROUND: The aim of this study was to assess the prognostic accuracy of Child-Pugh and APACHE II and III scoring systems in predicting short-term, hospital mortality of patients with liver cirrhosis. METHODS: 200 admissions of 147 cirrhotic patients (44% viral-associated liver cirrhosis, 33% alcoholic, 18.5% cryptogenic, 4.5% both viral and alcoholic) were studied prospectively. Clinical and laboratory data conforming to the Child-Pugh, APACHE II and III scores were recorded on day 1 for all patients. Discrimination was evaluated using receiver operating characteristic (ROC) curves and area under a ROC curve (AUC). Calibration was estimated using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: Overall mortality was 11.5%. The mean Child-Pugh, APACHE II and III scores for survivors were found to be significantly lower than those of nonsurvivors. Discrimination was excellent for Child-Pugh (ROC AUC: 0.859) and APACHE III (ROC AUC: 0.816) scores, and acceptable for APACHE II score (ROC AUC: 0.759). Although the Hosmer-Lemeshow statistic revealed adequate goodness-of-fit for Child-Pugh score (P = 0.192), this was not the case for APACHE II and III scores (P = 0.004 and 0.003 respectively) CONCLUSION: Our results indicate that, of the three models, Child-Pugh score had the least statistically significant discrepancy between predicted and observed mortality across the strata of increasing predicting mortality. This supports the hypothesis that APACHE scores do not work accurately outside ICU settings

Ο ρόλος της σωματοστατίνης και άλλων νευροπεπτιδίων στο ηπατοκυτταρικό καρκίνωμα

Hepatocellular carcinoma (HCC) represents more than 5% of all cancers and the estimated annual number of cases exceeds 500,000. It is also estimated to be the seventh most common cancer in men and the ninth in women. Patients with HCC tumours that are inoperable have an unfavourable natural course despite various therapeutic modalities. Such patients should be included in prospective investigations aiming to identify therapies that ultimately may lead to a survival improvement. Recently, a randomized controlled trial of octreotide in the treatment of advanced HCC has shown a significant survival benefit in the treated patients. The results of the present thesis provide data in regard to the role of the somatostatin and opioid systems in hepatocellular carcinoma. HepG2 cells were found to express mRNA for the subtypes sst2, sst3 and sst5 of the somatostatin receptors (ssts). Immunocytochemistry verified the presence of these receptors on HepG2 cells and sst2 was found to be of the sst2A variant. Ssts were found to be located mainly intracellularly in HepG2 cells and the pattern of distribution of the three subtypes was unique and characteristic for each one of them, implying different mechanisms of regulation of each subtype. Binding assays led to the characterization of functional receptors in the membranes of HepG2 cells that belong mainly in the sst3 and sst5 subtypes while minimal sst2 binding sites were detected. Octreotide was found to bind specifically to the ssts present on HepG2 cells membranes. Furthermore octreotide was found to inhibit the proliferation of HepG2 cells in a dose dependent manner and in concentrations that can be achieved in the blood of patients receiving octeotide for the treatment of HCC. Inhibition of the Protein Tyrosine Phosphatases pathway (PTPs) blocked the antiproliferative effect of octreotide in a dosedependent manner. The mainly intracellular localization of ssts in HepG2 cells led to the suspicion that this cell line produces a somatostatinergic peptide which regulates ssts in an autocrine manner. HepG2 cells were found to express and produce cortistatin (CST) but not somatostatin (SRIF). Incubation of HepG2 cells with additional CST did not have an effect in their proliferation while extracellular binding of CST with the use of a specific antibody led to a significant inhibition of cellular proliferation. The opioids EKC, aS1-casomorphin, DADLE and DAGO were also found to inhibit the proliferation of HepG2 cells. EKC and aS1-casomorphin were the most effective opioid agonists. The antiproliferative effect of EKC could not be blocked by the general opioid inhibitor diproenorphine. HepG2 cells were found to express mRNA for the cloned receptor KOR (_1) while no DOR (!2) or MOR (μ1 and μ2) mRNA transcripts were detected. However no _1 functional binding sites were detected on HepG2 cells. Furthermore probable !1 binding sites were detected but the presence _2 and _3 binding sites cannot be excluded. The inability of diproenorphine to block the antiproliferative effect of EKC in combination with presence of only low affinity opioid receptors in HepG2 cells, led us to the study of possible interaction of EKC with ssts. EKC was found to bind specifically on the ssts present on HepG2 cells. It is therefore possible that EKC exerts its antiproliferative effect via these receptors. Inhibition of PTPs, like in the case of octreotide, blocked EKCs effect on cellular proliferation. Octreotide and opioids were found to induce the production of nitric oxide metabolites from HepG2 cells, but this induction was not related to the antiproliferative effect of these substances. In conclusion the results of the present study are in accordance with those of the in vivo trial of octreotide for the treatment of HCC. They also characterize PTPs as a key intracellular pathway for the regulation of octreotide's antiproliferative effect. CST production and its possible role in the autocrine regulation of ssts in HepG2 cells, is an interesting result that gives further insight on the role of this natural peptide on the biology of ssts. Moreover in this study we report for the first time a method for the quantification of CST production. Finally opioids were found to have antiproliferative effects on HepG2 cells and in particular EKC which was also found to act via binding to ssts and activating the PTPs pathway

Genetic cause of heterogeneous inherited myopathies in a cohort of Greek patients

Inherited muscle disorders are caused by pathogenic changes in numerous genes. Herein, we aimed to investigate the etiology of muscle disease in 24 consecutive Greek patients with myopathy suspected to be genetic in origin, based on clinical presentation and laboratory and electrophysiological findings and absence of known acquired causes of myopathy. Of these, 16 patients (8 females, median 24 years-old, range 7 to 67 years-old) were diagnosed by Whole Exome Sequencing as suffering from a specific type of inherited muscle disorder. Specifically, we have identified causative variants in 6 limb-girdle muscular dystrophy genes (6 patients; ANO5, CAPN3, DYSF, ISPD, LAMA2, SGCA), 3 metabolic myopathy genes (4 patients; CPT2, ETFDH, GAA), 1 congenital myotonia gene (1 patient; CLCN1), 1 mitochondrial myopathy gene (1 patient; MT-TE) and 3 other myopathy-associated genes (4 patients; CAV3, LMNA, MYOT). In 6 additional family members affected by myopathy, we reached genetic diagnosis following identification of a causative variant in an index patient. In our patients, genetic diagnosis ended a lengthy diagnostic process and, in the case of Multiple acyl-CoA dehydrogenase deficiency and Pompe\u27s disease, it enabled specific treatment to be initiated. These results further expand the genotypic and phenotypic spectrum of inherited myopathies