Towards an Egyptian guideline from screening to treatment of hepatocellular carcinoma [part I]

These recommendations provide a data-supported and based-evidenced approach to the screening, diagnosis, staging and treatment of Egyptian patients with hepatocellular carcinoma [HCC] in which we tried to construct an Egyptian algorithm for our Egyptian HCC patients in terms of type and timing of surveillance, readily available diagnostic tools that suit our means and the proper and efficient timely treatment that suits our resources. They are based on the experience of the authors in the specified topic and the AASLD Policy on the Development and Use of Practice Guidelines. These recommendations suggest preferred approaches to screening [for early detection of cases with hepatic nodule and/or elevated AFP], diagnosis [for accurate diagnosis of HCC cases], staging [for detection of specific category of treatment according the patient's general condition] and treatment [selection of the most suitable treatment option for the patient after his proper evaluation]. In an attempt to characterize the quality of evidence supported recommendations, the Egyptian Guidelines requires a category to be assigned and reported with each recommendation [Table I]

Towards an Egyptian guideline from screening to treatment of hepatocelhilar carcinoma [part II]

These recommendations provide a data-supported and evidence based approach to the screening, diagnosis, staging and treatment of Egyptian patients with hepatocellular carcinoma [HCC] in which we tried to construct an Egyptian algorithm for our Egyptian HCC patients in terms of type and timing of surveillance, readily available diagnostic tools that suits our means and the proper and efficient timely treatment that suits our resources. They are based on the experience of the authors in the specified topic and the AASLD Policy on the Development and Use of Practice Guidelines. These recommendations suggest preferred approaches to screening [for early detection of cases with hepatic nodule and/or elevated AFP], diagnosis [for accurate diagnosis of HCC cases], staging [for detection of specific category of treatment according the patient's general condition] and treatment [selection of the most suitable treatment option for the patient after his proper evaluation]. In an attempt to characterize the quality of evidence supported recommendations, the Egyptian Guidelines requires a category to be assigned and reported with each recommendation [Table 1]

Value of PCR in the detection of occult hepatitis B virus infection in chronic end stage liver disease

Persistence of Hepatitis B virus [HBV] DNA in HBV surface antigen [HBsAg] negative individuals is termed occult HBV infection. Occult HBV infection has frequently been identified in patients with chronic HCV infection. This study aimed to evaluate the prevalence of occult HBV infection among late stage liver diseased patients and apparently healthy household contacts who may be used as potential donors for their liver transplantation. Also, prevalence of occult l-TBV infection in HCV-Ab and HBcAb seropositive subjects was evaluated. The study included 500 individuals distributed as 100 patients from National Liver Institute, 300 household contacts, and 100 apparently healthy subjects as a control group. All studied individuals were subjected to: full history taking, complete clinical examination, abdominal ultrasonography, liver biopsy if possible and laboratory investigations including: liver function tests, anti- HCV and HBV serological markers, as well as HBV- DNA detection using nested PCR. HBV-DNA was detected in 54% of patients, 18% of household contacts and 6% of control group. The prevalence of occult HBV infection in HBcAb seropositive subjects was; 75% in patients, 31.6% in household contacts, 46.2% in control group. The prevalence of occult HBV infection in HCV-Ab seropositive subjects was 55.8% in patients, 8.2% in contacts and 10% in control group. In conclusion, there is a high prevalence of occult HBV infection in patients with end stage liver disease, particularly those who are HCV-Ab and or HBcAb seropositive. The results of the current study indicate the need for a sensitive investigation for potentially infected relatives among family members of HBsAg carriers. On the other hand, apparently recovered people, are considered to be at risk for disease complications or for transmission of the infection till proved HBV-DNA negative

Histopathological changes in anti-HCV positive subjects with persistently normal aminotransferase levels

Approximately 30% of patients with chronic hepatitis C have normal serum alanine transaminase [ALT] levels; most of those patients have mild degrees of inflammation with mild or no fibrosis and the rate of disease progression is reduced compared to that in patients with elevated ALT levels. Is to study the histopathological characteristics of anti-HCV positive subjects with persistently normal aminotransferase levels in comparison with those patients having elevated aminotransferase levels. A comparative case control study was conducted on 80 patients who asked medical advice in outpatient clinics of National Liver Institute, Menoufiya University and Specialized Medical Hospital, Mansoura University. They were classified into two groups. Group I: were forty anti-HCV-positive subjects with normal enzymes. They were 28 males, 12 females. Their age ranged from 18 to 50 years with a mean age of 31 +/- 8.47 years. Group II: were forty chronic hepatitis C patients [31 males and 9 females] their age ranged between 17-53 years with a mean age 32.12 +/- 7.70 years with elevated ALT levels [one and half or more times of the upper limit of normal for at least six months], Both groups were subjected to thorough history taking and physical examination, complete blood counts [CBC], routine liver tests, abdominal ultrasound and percutaneous ultrasound guided liver biopsy to assess the severity of the necro-inflammatory process using histological activity index [HAT] of Knodell et al. and modification of Ishak et al. This research showed that the majority of anti-HCV positive patients with persistently normal ALT have histological features of minimal to mild necro-inflammation [HAT]. The severity of histological necro-inflammation is reduced in anti-HCV positive patients with persistently normal ALT compared with that of patients with elevated ALT levels. Also they have no or minimal to mild stage of fibrosis compared with that in patients with elevated ALT levels. Persistently normal ALT patients with steatosis had higher HAT grades and fibrosis stages than patients without steatosis and a significant correlation was found between steatosis and increased BMI. Moderate significant correlation was found between low platelet counts and fibrosis stage in patients with elevated ALT levels. The majority of anti-HCV positive patients with persistently normal ALT have histological-pathological changes of variant degrees of severity specially patients having steatosis. So it is recommended that patients with chronic hepatitis C should not be excluded from therapy based on ALT levels alone and the treatment must be individualized according to each patient

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

Serum and biliary cytokeratin fragment CYFRA 21-1, as a marker of resectability for extrahepatic cholangiocarcinoma

Serum levels of CEA and CA 19.9 are occasionally elevated in cases of cholangiocarcinoma [CC]. They, however, have low sensitivity and specificity, which makes the diagnosis of CC difficult, and better tumor markers are needed. CYFRA 21-1, a cytokeratin fragment, is being evaluated as a tumor marker with diagnostic potential for small cell lung carcinoma. The resectability of CC is difficult to assess accurately pre-operatively using available laboratory and imaging techniques. The aim of the present study was to assess the diagnostic value of CYFRA 21-1, CA 19.9, and CEA in serum and bile of patients with extrahepatic CC. and to evaluate whether any of these markers can be used to assess resectabilily. Fifty patients with extrahepatic obstructive jaundice were included in this study. Group 1: 30 patients with histologically proven CC had serum and bile samples measured for CYFRA 21-1, CA 19.9; and CEA. Group II: 20 patients with calcular obstructive jaundice had serum and bile samples obtained during endoscopic removal of stones to control for the effect of biliary obstruction on CYFRA 21-1, CA 19.9, and CEA. Sixteen patients in whom imaging studies showed resectability were explored and operative findings were correlated to tumor markers. CEA and CA 19.9 were measured using enzyme immnunoassay [EIA,], and CYFRA 21-1 level was measured using electrochemiluminescence immunoassay [ECLIA] in serum and bile of the CC patients and the caicular obstructive jaundice controls. Patients with CC had significantly higher serum levels of CEA [24.5 +/- 6 vs 4 +/- 1.3 ng/ml. p<0.01] CA 19.9 [118.9 +/- 25.4 vs 31.2 +/- 8.4 U/ml, p< 0.01] and CYFRA 21-1 [8.3 +/- 2.7 vs 2.1 +/- 0.5 ng/ml, p<0.01] than patients with benign calcular cholestatic disorder, and bile concentration of the 3 markers was sign higher than serum concentrations. Among the 16 patients who underwent surgery, serum and biliary levels of CYFRA 21-1 were significantly higher with irresectable tumors. CYFRA 21-1 may be a useful marker for resectabilily saving many unnecessary operations. This, however, needs further larger studies to be documented

Clinical, Biochemical, Histological and Virological Effect of·Dimthylene Dioxy Biphenyle Dicarboxylate [DOB] in Patients with Compensated Chronic Hepatitis C

Background: chronic liver disease is a major cause of mortality and morbidity in Egypt. D.D.B. was found to improve the abnormal liver function tests in those patients. Since then it has been used in the management of chronic liver disease, yet clinical improvement and changes in the biochemical and pathological examination are still considered study questions

Objectives: to evaluate the efficacy and side effects of D.D.B. compared to Silymarine in wells compensated patients with chronic HCV infection

Method: the study population included 50 patients with compensated chronic HCV infection subdivided into two groups 25 patients each. One group received D.D.B. for 48 weeks and the other received Sily-marine for the same period of time. Each patient was subjected to assessment of the liver function tests, virological studies, abdominal ultrasound, isotope liver scan, liver biopsy and rectal snip before starting the treatment. Further evaluation was performed by repeating the liver function tests every 3 months, the abdominal ultrasound every 6 months, the rest of the tests and the liver biopsy were repeated after one year i.e. at the end of treatment

Results: sustained normalization of ALT level and transient normalization of the AST level was found in the DDB group. No significant effect on the. HCV RNA, level was detected after one year of D.D.B. therapy; in none of the patients did the HCV RNA become undetectable. The liver-splenic ratio in the iso-topic studies showed significant decrease after one-year therapy with D.D.B. The grade of inflammation was unchanged in 10 cases, worse in 11 cases and better in 3 cases while fibrosis was unchanged in 22 cases and worse in 2 cases. No major side effects were observed in either group of patients

Conclusion: DDB has no antiviral effect in patients with chronic HCV infection. It does not show a histological benefit [neither in terms of degree of necroinflammation nor stage of fibrosis] after 1 year of treatment and when compared to Silymarin. On the other hand it improves some biochemical parameters [ALT] as well as the general well being of the patients. It has no major side effects

effect of stent placement on the size of common bile duct stones in cirrhotic patients: a prospective study

Background: Endoscopic retrograde cholangio-pancreato-graphy [ERCP], endoscopic sphincterotomy [ES] and basket extraction are currently used to remove bile duct stones. The technical difficulty of stone extraction increases with size of stone. Apart from surgical removal, biliary stenting is an alternative for treating difficult cases

Aim: To compare the sizes of the stones before and after stenting in cirrhotic patients with irretrievable common bile duct stones

Patients and methods: Twenty five patients with difficult common bile duct stones were treated by endoscopic stenting. They were 15 males, 10 females with mean age of 57.9+/-9.5 years, 7 of them were Child class A, 12 Child B and 6 Child C. Patients were followed-up at 3 months intervals

Results: Twenty patients [80 %] had a reduction of stone size, 3 had no change and in 2 patients it became slightly larger in size but not in number. Before stenting, the -diameter of stones ranged from 2.3 mm to 33 .mm [mean 22.9+/-3.7 mm]. After stenting, the size ranged from 1.3 to 30mm [mean 15.5+/-4.1 mm]. The difference in the stone diameter was statistically significant, P < 0.0001. Stones were successfully extracted in 22 patients [88%] after stenting, following 2. 2+/-0.4 endoscopic procedures [range 2-3]

Conclusion: Biliary stenting is a safe and effective mode of treatment of common bile duct stones in patients where stone extraction has failed after endoscopic papillotomy. These stones became smaller after stenting. As the difficulty of stone extraction increases with stone size, a period of stenting may make subsequent removal easier for patients with large stones

Effect of different dialysis membranes on endogenous antioxidant enzyme activity and lipid peroxidation in haemodialysis patients

This work aimed to clarify the most suitable type of the haemodialysis membranes in order to minimize the disequilibrium between the levels of oxidant and antioxidant factors in haemodialysis patients. This study was conducted on 79 subjects who were classified into 5 groups: The 1st group included 14 apparently healthy volunteers, the 2nd group included 13 patients with end stage renal disease [ESRD] just before the beginning of haemodialysis treatment [predialysis], the 3rd group included 18 patients with ESRD on maintenance haemodialysis using dialyzers equipped with cuprophane membrane, the 4th group included 14 patients using polysulphone membrane and the 5th group included 20 patients using hemophane membrane. All participants were subjected to thorough clinical examination and laboratory investigations [estimation of superoxide dismutase [SOD], glutathione peroxidase [GPx], catalase and lipids peroxides [MDA + 4-HNE], serum urea, creatinine, uric acid, fasting and postprandial blood sugar, haemoglobin, haematocrit, creatinine clearance and protein 24 hours urine]. The results revealed that serum lipid peroxides [MDA and 4-HNE] were significantly increased in all patients groups compared to the control group and more significantly elevated in the 3 dialyzed groups compared to the predialysis and alsosignificantly higher in the cuprophane group when compared to the other 2 membranes [polysulphone and haemophane]; while no significant change was detected between the haemophane and the polysulphone groups. There were significantly decreased levels of endogenous antioxidant enzymes [SOD, GPx and plasma catalase] in all patients when compared to the control group. SOD and catalase were significantly lower in the dialyzing groups when compared to the predialysis one; while GPx showed significant decrease only on using cuprophane membrane but not with polysulphone and haemophane. Significant negative correlation between serum lipid peroxides and each of the three antioxidant enzymes was found. Positive correlation existed between haemoglobin concentration, haematocrit and antioxidant enzyme activities. This study confirmed the presence of disequilibrium between the oxidative stress and the antioxidant protective enzymes in uraemic patients; this permanent oxidative stress could act as important mediator to the progression of renal failure and to associated complications such as anaemia and atherosclerosis. This disequilibrium is maximally enhanced by the use of incompatible membranes [cuprophane], while it is significantly reduced on using biocompatible ones [polysulphone and haemophane]. Consequently, in view of the results, the universal use of biocompatible membranes for haemodialysis in a trial to decrease the hazardous effects of haemodialysis is recommended

Elevated nitric oxide and endotoxemia in schistosonol hypertension

Nitric oxide [NO] is supposed to play a role in mediating vasodilatation and hyperdynamic circulation in liver cirrhosis and alcoholic hepatitis. It has been suggested that endotoxin might mediate increased synthesis of NO in endotoxemic patients with cirrhosis. The level of NO in schistosomal portal hypertension [SchPH] has not been studied, and whether endotoxemia plays a role in this condition is not known. To evaluate the level of NO and endotoxin in patients with schistosomal portal hypertension, and compare it to those in patients with post-necrotic cirrhosis and to normal individuals The study included 45 consenting patients; 27 with SchPH and living -schistosoma ova on rectal biopsy [11 Child A, 9 B, 7 C], and 1.8 with post-necrose cirrhosis [4 Child A, 6 B, 8 C]; and 15 healthy volunteers. Patients underwent upper GI endoscopy with grading of esophageal varices if present, ultrasonography with measurement of portal vein diameter, and liver biopsy. Patients and controls had plasma nitrite [NO[2]] measured as an indicator of NO production, and plasma endotoxin assayed by limulus amebocyte lysate test Patients with SchPH had significantly higher plasma NO[2] than controls [7.18 +/- 3 7 micro Mol/I vs 1.68 +/- 0.8 micro Mol/L p<0.005]. Endotoxin level was also significantly higher in SchPH than controls [0.46 +/- 0.09 Eu/ml vs. 0.15 +/- 0.05 Eu/ml. p < 0.05]. Non schistosomal patients had levels of NO[2] [6.3 +/- 3 micro Mol/L] and endotoxin [0.45 +/- 0.09 Eu/ml] similar to SchPH [both p > 0 05]. No difference was noted between Child classes in SchPH regarding NO[2] and endotoxin levels. NO[2] levels were positively correlated to the degree of portal hypertension assessed by portal vein diameter on ultrasound in SchPH. No correlation was found between NO[2] and endotoxin levels in SchPH [r = 0.48] SchPH is associated with increased NO production, and endotoxemia, similar to post-necrotic cirrhosis. The level of NO production increased with the severity of portal hypertension in this condition, and was not related to the level of endotoxemia