Some apoptotic signals in patients with chronic HCV infection

Hepatitis C virus [HCV] infects an estimated 3% of the world population and causes an estimated 470,000 death per year caused by complications of the end stage liver disease. Mechanisms leading to liver cell injury, are not fully understood, both immune mediated reactions and more direct cytopathic effects of HCV may be involved. Agoptosis of liver cells may play a significant role in the pathogenesis of hepatitis C. The aim of this study is to evaluate the role of apoptosis in chronic HCV infection by estimating serum levels of Fas, Fas-Ligand [FasL] and hepatocyte expression of Bcl-2 of patients with chronic hepatitis C virus infection, and find out the relationship [if any] between their levels and the degree of hepatic inflammatory activity. Sixty patients having chronic HCV infection [45 males and 15 females; mean age 36h8.6 years] were randomly selected. In addition, 20 apparently healthy subjects [12 males and 8 females; mean age 33.1 +/- 10.4 years] served as a control group. They were anti-HCV and HBsAg negative. Serum soluble Fas and Fas ligand levels were measured and HCV RNA quantitation was done to patients only. Immunohistochemical detection of Bcl-2 expression in the liver tissue was done to all patients. According to the histopathological assessment of hepatic necroinflammatory activity, patients were classified into 3 groups with minimal [n=23, GI], mild [n=23, GII] and moderate and severe [n=14, GIII] activity. Significant positive correlations were found between serum Fas and FasL and the grade of hepatic inflammatory activity. Mean serum levels of Fas in group I, II, and III were [0.7 +/- 0.3, 2.5/1.1 and 5.2 +/- 0.9 nglml] respectively with p<0.01. Mean serum levels of FasL in group GI, GII, and GIII were [0.6 +/- 0.2, 1.7+-0.8and 4 +/- 1.2 nglml] respectively with p<0.01. Bcl-2 expression was more prevalent in liver tissues of patients in GIII where 35.7% of hepatocytes, 57.1% of Kupffer cells and 50% of bile duct cells stained positively. For the three types of cells, it correlated positively with the grade of inflammatory activity [p<0.01 for each]. Percentage of Bci-2 expression in portal infiltrates in GI, GI1 and GI11 were [34.8, 78.3 and 100 respectively with p<0.01]. The results of the current work provide evidence of increased apoptosis in chronic hepatitis of moderate and severe activity and in cirrhosis due to chronic HCV infection suggesting that apoptotic cell death might be involved in the pathways of hepatocellular damage in both conditions. Serum sFas and sFasL levels positively correlated with the degree of necroinflammatory process in chronic HCV patients. Accordingly, serum sFas and sFasL could serve as non-invasive serological indicators of the hepatic inflammatory activity. Furthermore, the increase of serum sFas and sFasL [apoptotic signaling] as well as the increased expression of Bcl-2 [anti-apoptosis] at the same time, suggests that Bcl-2 might play as a protective mechanism against apoptosis. However, apoptosis caused by the activation of Fas/FasL pathway seems to occur by a mechanism that might not be blocked by Bcl-2

Diagnostic differentiation between extrahepatic biliary atresia and neonatal hepatitis

Neonatal cholestasis still presents a diagnostic challenge, both from the anatomical and etiologic points of view. Distinguishing intrahepatic from extrahepatic causes of cholestasis is of paramount importance since the latter may be treated by surgery but prognosis depends on the age at which operation is performed. Many tests have been proposed to help in differentiating these two entities, among which are the abdominal ultrasonography [US], magnetic resonance cholangiography [MR cholangiography] and liver biopsy. The aim of this work is to evaluate the usefulness of these methods in the differential diagnosis of neonatal cholestasis. Fifty three patients with neonatal cholestasis were evaluated prospectively through history taking, laboratory investigations, abdominal ultrasound, MR cholangiography in 10 patients, and needle liver biopsy. The collected data were compared to that of the final diagnosis. The final diagnosis was reached through the operative findings, the histodiagnosis of the excised specimens or the clinical course of the disease. Thirty patients were found to have extrahepatic cholestasis [all with biliary atresia] and 23 patients with intrahepatic cholestasis. Sensitivity was 80% for ultrasonography and 90% for liver biopsy in diagnosing extrahepatic cholestasis. Specificity was 83% for ultrasonography and 100% for liver biopsy. Accuracy was 81% for ultrasonography and 94.3% for liver biopsy. Accuracy was 92.4% when both tests were considered together. Biliary atresia was suspected in 5/10 patients by MR cholangiography, but one of them was having sclerosing cholangitis, while another one showed atresia involving only one part of the extrahepatic bile duct [EHBD]. Based on these findings we strongly recommend ultrasonography with definite criteria as the initial investigation tool in the management of neonatal cholestasis, associated with liver biopsy. The use of MR cholangiography in diagnosis of biliary atresia has certain limitations according to its type

Mesenteric vein thrombosis: a diagnostic and therapeutic challenge

Mesenteric vein thrombosis [MVT] is a rare but a potentially lethal form of mesenteric ischemia. Thirteen patients having MVT [7 males and 6 females] were included in this study. Their ages ranged from 30 to 50 years with a mean +/- standard deviation [SD] of [46.15 +/- 5.52]. Nine of these patients [9/13; 69%] had associated hepatopancreatic diseases: 4 with hepatocellular carcinoma [HCC] on top of cirrhosis, 3 with cirrhosis and previous splenectomy, one with cirrhosis, and one with pancreatitis. The remaining four patients [4/13; 31%] had associated nonhepatopancreatic disease: 2 with deep venous thrombosis [DVT], and 2 with history of contraceptive pill intake. Severe subcontinuous abdominal pain out of proportion to the physical findings [11/13; 84%] and abdominal distention [9/13; 69%] were the major symptoms. Color duplex ultrasound [US] was performed in all patients and was diagnostic for MVT in only 10 patients [10/13; 77%]. In the remaining 3 patients, diagnosis of MVT was established by computed tomography [CT] in 2, and mesenteric angiography in one. Once the diagnosis of acute MVT was confirmed, all patients were anticoagulated with heparin.Signs of peritonitis were the main indication for immediate exploratory laparotomy in the studied cases [8/13; 61.5%]. Minimal small bowel resection with primary anastomosis was performed in 5 patients, minimal small bowel resection with diverting ileostomy in one, extended small bowel resection with primary anastomosis in one, and laparotomy without resection in one. The determination of viability in the marginally perfused bowel was done with clinical assessment. For further evaluation of bowel viability in borderline cases, Doppler US was performed in 4 patients. The 30-day operative mortality was reported in three patients [3/8; 37.5%]. All of them were having liver cirrhosis that was associated with malignancy in one and splenectomy in another. The 30-day mortality in the five non-surgically treated patients was 60% [3/5] that was mostly due to advanced liver malignancy. In conclusion; a high index of suspicion and recognition of high risk factors coupled with a history of non-specific abdominal symptoms should alert clinicians to the possibility of MVT. Early diagnosis using color duplex US or CT and prompt anticoagulation are the mainstay of therapy unless there are signs of peritonitis that necessitate surgical resection of the infarcted bowel. Although a primary anastomosis can be accomplished in most situations, a diverting ileostomy may often be the prudent approach in cases with poor liver function and bad general conditions. During operation, all nonviable bowels should be resected with intent for a second-look laparotomy after 24 hours if there is any question of ongoing ischemia. We recommend using intraoperative Doppler US for detection of the arterial signals in evaluation of the marginally viable bowel

Fas antigen in serum and liver tissue of patients with chronic hepatitis C

Fas [APO-1/CD95], a member of the tumor necrosis factor receptor Family, can mediate apoptosis when engaged by its ligand or by anti-Fas antibody. Fas is upregulated on the surface of hepatocytes in patients with a variety of liver pathologies, including hepatitis, alcoholic cirrhosis, and acute liver failure. Moreover, expression of Fas ligand is substantially upregulated, in areas of lymphocytic infiltration, in liver diseases, suggesting Fas/FasL interactions may mediate liver damage in humans. The purpose of this study was to evaluate the relationship of serum soluble Fas [sFas] levels and hepatic Fas antigen expression with the degree of hepatic inflammatory activity in patients with chronic hepatitis C infection. The effect of concomitant schistosomiasis, as an endemic liver disease in Egypt, on serum and liver Fas expression was also studied. Serum sFas levels were measured by enzyme-linked immunosorbant assay in 69 chronic hepatitis C patients; 16 of them were under 18 years and compared with those in normal volunteers, and patients with chronic HBV infection. The results of serum tests were compared with ALT levels. HCV-RNA titer, histological inflammatory activity, and Fas expression in liver biopsies. The effect of combined HCV infection and schistosomal infestation on serum sFas and tissue Fas expression was also studied. Serum sFas and tissue Fas expression were then evaluated with each components of histological inflammatory activity scoring system [modified Knodell's HAI]. Serum sFas levels in chronic hepatitis C patients were significantly higher than those in normal volunteers [p<0.001]. They showed no difference from those in patients with chronic HBV infection [p>0.05]. Hepatic schistosomiasis didn't affect serum sFas levels or tissue expression of Fas antigen in chronic hepatitis C patients. Histologically, serum sFas levels showed strong correlation with tissue Fas expression [p<0.001] and with the degree of hepatic inflammatory activity [p<0.01]. Likewise, tissue Fas expression correlated with the degree of histological inflammatory activity [p<0.05]. Moreover, positive correlation was found between serum sFas and tissue Fas expression and the degree of interface hepatitis [piecemeal necrosis] in chronic hepatitis C patients with mild [p<0.01] and moderate and severe activity [p<0.05]. However, no correlation was observed between serum sFas and serum ALT levels. Also, no correlation was observed between HCV-RNA titer and sFas levels or tissue Fas expression. Our findings suggest that serum sFas levels may reflect the expression of Fas antigen on hepatocytes and the severity of liver inflammation in chronic hepatitis C and may be used as a serological indicator of histological inflammatory activity. They also support the concept that immune-mediated apoptosis may play a crucial role in the pathogenesis of chronic hepatitis C. Hepatic schistosomiasis seems to have no impact on serum sFas levels or hepatic tissue Fas expression