Apoptotic and anti-apoptotic seromarkers for assessment of disease severity of non-alcoholic steatohepatitis

This study aimed to find out non-invasive markers for the assessment of severity of non-alcoholic steatohepatitis [NASH] in an attempt to decrease the need for liver biopsy. It also aimed to evaluate the key role of apoptosis in the pathogenesis of the disease and the suggested role of anti-apoptotic factors in therapeutic modalities and disease prognosis. The serum levels of soluble Fas [s. Fas], s. Fas ligand, cytokeratin 18 [CK-18] fragment and Bcl-2 were measured in 80 patients and 15 non-hepatic subjects as control. The patients were divided based on histological examination of liver biopsy into three groups. Group I included 40 patients with NASH, group II had 40 patients with non-alcoholic fatty liver disease [NAFLD] non-NASH and group III had 15 non-hepatic subjects as control. Apoptosis of hepatocytes was assessed by morphological examination using a light microscope and expressed as number per square millimeter. There was a significant increase in the serum levels of s. Fas, s. Fas ligand and CK-18 fragments in the NASH group. The anti-apoptotic protein Bcl-2 showed significantly low levels in NASH patients. Apoptosis of hepatocytes was significantly higher in the NASH group. The degree of apoptosis was inversely correlated with the level of Bcl-2. A significant correlation between both s. Fas and CK-18 fragment with liver histology with regard to lobular inflammation and ballooning was found. Increased serum levels of s. Fas and CK-18 fragment in the NASH group and its correlation with the severity of disease suggested the key role of apoptosis in NASH pathogenesis which can be used for the assessment of the severity of NASH. A high level of anti-apoptotic Bcl-2 in NAFLD suggests its protective role in disease progress

Effect of a disintegrin and metalloprotease 33 [ADAMSS] gene polymorphisms and smoking in COPD

COPD is characterized by air flow limitation that is not fully reversed and associated with an influx of neutrophils, macrophages and CD8 T lymphocytes in the airways. The disease is characterized by airflow limitation and is associated with an abnormal inflammatory response of the lungs in response to noxious particles or gases and associated with systemic manifestation. Sixty consecutive patients with COPD and 40 normal healthy individuals were included. All cases and controls were subjected to detection of 2 polymorphic loci [S1 AND Q1] of ADAM33 by PCR-RFLP technique. The percentage of S1 and Q1 AA genotype and A allele were significantly increased in control than in COPD patients while there was significant increase in S1 and Q1 GG genotype and G allele in COPD patients than in control [p < 0.001]. No significant difference was found between smoker and non-smoker among the two studied groups in genotype and alleles distribution of ADAM33 SNPs S1 and Q1 p > 0.05, whereas there was significant increase in ADAM33 S1 G allele and Q1 G allele in smoker and non-smoker in COPD patients as compared to their corresponding fellows in control group [p < 0.05]. As regard to Pulmonary function test there was significant decrease in% of FEV1 in COPD patients as compared to control group for both smokers and non-smokers [p < 0.001]. Within both control and COPD groups smokers had significant decrease in FEV1% as compared to non-smokers [p < 0.001]. There was a significant decrease in FEV1% among all genotypes in smoker as compared to non-smoker COPD patients [p < 0.001], the most prominent decrease was found in smoker GG genotype for both ADAM33 S1 and Q1 in COPD patients. In conclusion, we found that polymorphisms in the SNPs [Q1 and S1] of ADAM33 gene are associated with COPD in the general population. In addition, smoker patients with GG genotype in [S1 and Q1] ADAM33 will have more pronounced decline in the pulmonary function test [FEV1]

Circulating MCP-1 level and tilde 2518 gene polymorphism as a marker of nephropathy development in Egyptian patients

Monocyte chemoattractant protein-1 [MCP-1] is a member of CC chemokine that plays an important role in the recruitment of monocytes/macrophages into renal tubulointerstitium. A biallelic A/G polymorphism at position tilde 2518 in the MCP-1 gene was found to regulate MCP-1 expression. MCP-1 and its A/G gene polymorphism have been implicated in the pathogenesis of some renal diseases. The aim of this study was to evaluate the role of circulating MCP-1 level and the relevance of functional genetic variations of MCP-1 as early predictors of the development of glomerulonephropathy [GN] in Egyptian patients. This is a case control study that was conducted in 50 GN patients, 20 non-GN cases and 20 ethnically matched healthy controls. MCP-1 serum level was detected by ELISA technique, while genotyping of polymorphisms in the MCP-1 genes was performed using a polymerase chain reaction [PCR] followed by restriction fragment length polymorphism [RFLP] detection High MCP-1 circulating levels and subsequently MCP-1tilde 2518G polymorphism are associated with the developing of nephropathy irrespective to the underlying etiology. MCP-1 serum level was significantly high when compared with healthy controls [P = 0.0007] and non-GN cases [P = 0.01]. There was predominance of A allele at tilde 2518 of MCP-1 gene in healthy controls [87.5%] and non-GN cases [77.5%]. The frequency of the tilde 2518G MCP-1 polymorphism was significantly higher in GN patients than in healthy controls [P <0.0001; OR= 15.6] and non-GN cases [P < 0.0001; OR = 7.7]. Interestingly, homozygosity for G allele plays the main role in such association. A/G polymorphism in MCP-1 gene and subsequently high circulating MCP-1 level confer a relevant role in the susceptibility to the development of nephropathy in the Egyptian population denoting that MCP-1 system could be an early predictor of such renal complication

Altered BANKL/OPG system in hepatic osteodystrophy

The coexistence of liver disease and metabolic bone disease has been recognized for many years and is now the subject of increasing attention. Hepatic Osteodystrophy was established in patients with cholestatic liver disease, but new research suggests that it is prevalent in patients with other chronic liver diseases. Its etiology is complex and multifactorial. Receptor activator of nuclear factor Kb ligand [RANKL] plays a role in the differentiation and activation of bone resorbing osteoclasts by binding to its high affinity receptor [RANK] located on the surface of osteoclasts. This effect is counterbalanced by osteoprotegren [OPG], which acts as a decoy receptor competing with RANKL for RANK. To evaluate bone mineral density [BMD] and OPG/RANKL system in cirrhotic patients with backache. This study included 50 subjects suffering from backache, divided into 4 groups as follows: Group I: 10 subjects with normal BMD, Group II: 10 patients with pathological BMD but otherwise healthy considered as control, Group III: 15 patients with cirrhosis and normal BMD, Group IV: 15 patients with cirrhosis and pathological BMD. All patients underwent clinical examination, routine liver function tests, alkaline phosphatase, total calcium, serum OPG, serum RANKL, added to BMD. The lowest BMD values are estimated at the lumber spine, femoral neck, and lastly lower end of radius. There was a significant decrease in OPG in osteopenic/ osteoporotic non cirrhotic patients compared to control group, while it is significantly higher than control in both osteopenic/osteoporotic and patients with normal BMD of cirrhotic groups. RANKL, was significantly higher in non cirrhotic patients with pathological BMD compared to control group, but lower than control in cirrhotic groups both with normal and pathological BMD, with significant difference in cirrhotic with pathological BMD and non significant in those with normal BMD compared to controls. Serum OPG was negatively correlated to serum calcium, albumin, and International Normalized Ratio [INR], but positively correlated to bone alkaline phosphatase, and AST in cirrhotic patients of both groups. In cirrhotic patients, low BMD has tendency to affect axial bone early, which is similar to postmenopausal osteoporosis. On the contrary, higher OPG and lower RANKL levels are opposite to postmenopausal osteoporosis. This difference indicates that: OPG/RANKL system is activated in a different way in cirrhosis, suggesting a role for OPG/RANKL system in pathogenesis of hepatic osteodystrophy

Rankl/OPG system is altered in hepatic osteodystrophy

The coexistence of liver disease and metabolic bone disease has been recognized for many years and is now the subject of increasing attention. Hepatic Osteodystrophy has been established in patients with cholestatic liver disease, but new research suggests that it is prevalent in patients with other chronic liver diseases. Its etiology is complex and multifactorial. The Receptor activator of nuclear factor Kb ligand [RANKL] plays a role in the differentiation and activation of bone resorbing osteoclasts by binding to its high affinity receptor [RANK] located on the surface of osteoclasts. This effect is counterbalanced by osteoprotegren [OPG], which acts as a decoy receptor competing with RANKL for RANK. In this study we aim to evaluate OPG/RANKL system in cirrhotic patients with backache. This study includes 50 subjects suffering backache, divided into 4 groups as follows: Group I:10 subjects with normal bone mineral density [BMD] as control, Group II: 10 patients with pathological BMD but who are otherwise healthy, Group III: 15 patients with cirrhosis and normal BMD, Group IV: 15 patients with cirrhosis and pathological BMD. All patients underwent clinical examination, routine liver function tests, alkaline phosphatase, total calcium, serum OPG, serum RANKL, added to BMD estimation. The lowest BMD values were estimated at the lumber spine, then femoral neck, and lastly lower end of radius. There was a significant decrease in OPG in osteopenic non cirrhotic patients compared to the control group, while it was significantly higher than controls in both osteopenic and non osteopenic patients of the cirrhotic groups. SRANKL was significantly higher in non cirrhotic patients with pathological BMD compared to the control group, but lower than controls in cirrhotic groups both with normal and pathological BMD, with a significant difference in cirrhotics with pathological BMD, and a non significant difference in those with normal BMD compared to controls. Serum OPG was negatively correlated to serum calcium, albumin, and INR, but positively correlated to bone alkaline phosphatase, and AST in cirrhotic patients of both groups. OPG/RANKL system plays a role in the pathogenesis of hepatic Osteodystrophy. In cirrhotic patients, low BMD has a tendency to affect axial bone earlier, which is similar to postmenopausal osteoporosis. However in cirrhosis there are higher OPG and lower sRANKL levels which are opposite to postmenopausal osteoporosis. This difference indicates that: either OPG/RANKL system is working in a different way in cirrhosis, which might be due to an increased RANK/RANKL affinity which is not measurable, and consumes part of total RANKL leaving a smaller amount of measurable soluble RANKL to be assessed, which would explain its lower level in serum despite increased osteoporotic changes in bone, or there are other factors associated with this process to make their mechanism of action different than in postmenopausal osteoporosis