Nir Hilzenrat

Use of Sequence Analysis of the NS5B Region for Routine Genotyping of Hepatitis C Virus with Reference to C/E1 and 5′ Untranslated Region Sequences

ABSTRACT Nucleotide sequence analysis of the NS5B region was performed to identify genotypes of 8,479 hepatitis C virus (HCV) RNA-positive patient samples collected in the Canadian province of Quebec. Genotypes could be determined for 97.3% of patients. Genotypes 1 to 6 were found in 59.4, 9.0, 25.7, 3.6, 0.6, and 1.8% of patients, respectively. Two isolates did not classify within the six genotypes. The subtype 1 distribution was 76.7% 1a, 22.6% 1b, and 0.7% others, while the subtype 2 distribution was 31.8% 2a, 47.6% 2b, 10.9% 2c, 4.1% 2i, and 5.6% others. Subtype 3a accounted for 99.1% of genotype 3 strains, while all genotype 5 samples were of subtype 5a. The subtype 4 distribution was 39.2% 4a, 15.4% 4k, 11.6% 4d, 10.2% 4r, and 23.6% others. The subtype 6 distribution was 40.4% 6e, 20.5% 6a, and 39.1% others. The 5′ untranslated region (5′UTR) sequences of subtype 6e were indistinguishable from those of genotype 1. All samples that did not classify within the established subtypes were also sequenced in C/E1 and 5′UTR. C/E1 phylogenetic reconstructions were analogous to those of NS5B. The sequences identified in this study allowed the provisional assignments of subtypes 1j, 1k, 2m, 2r, 3i, 4q, 6q, 6r, and 6s. Sixty-four (0.8%) isolates classifying within genotypes 1 to 6 could not be assigned to one of the recognized subtypes. Our results show that genotyping of HCV by nucleotide sequence analysis of NS5B is efficient, allows the accurate discrimination of subtypes, and is an effective tool for studying the molecular epidemiology of HCV.

Preoperative alpha-fetoprotein slope is predictive of hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUNDnLiver transplantation (LT) offers a possible cure for patients with hepatocellular carcinoma (HCC) and cirrhosis. However, tumour progression while on the waiting list and tumour recurrence after LT are common. The prognostic significance of various pre- and postoperative variables were investigated in regard to tumour recurrence, with an emphasis on the slope of preoperative serum alpha-fetoprotein (AFP) levels. patients andnnnMETHODSnData from 48 patients who had HCC diagnosed preoperatively and underwent LT at the McGill University Health Centre (Montreal, Quebec) were reviewed retrospectively, and possible risk factors for tumour recurrence were examined.nnnRESULTSnUnivariate analysis revealed a positive correlation between the preoperative AFP slope and vascular invasion (P = 0.045), total tumour diameter at explant (P = 0.040), Cancer of the Liver Italian Program score (P = 0.017) and recurrence-free survival (P = 0.028). Of the preoperative variables examined, only the preoperative AFP slope was identified as an independent predictor of tumour recurrence by multivariate analysis. Receiver operating characteristic analysis showed that the best discriminant cut-off value, calculated as the value of the maximized likelihood ratio, was preoperative AFP slope greater than 50 microg/L per month. At this cut-off, sensitivity was 36%, and specificity was 97%. Patients with a preoperative AFP slope greater than 50 microg/L per month had a much worse one-year recurrence-free survival rate than those with a preoperative AFP slope 50 microg/L per month or less (40% versus 90%, P < 0.001).nnnCONCLUSIONSnThese results suggest that the preoperative AFP slope is an important predictor of HCC recurrence after LT and should be examined in future studies of patients receiving LT for HCC.

Elderly patients are at greater risk of cytopenia during antiviral therapy for hepatitis C

UNLABELLEDnThe results of antiviral therapy for hepatitis C virus (HCV) have improved recently with the use of pegylated interferon (PEG-IFN)/ribavirin (RBV) combination therapy. At this point, most patients with chronic HCV remain untreated. Thus, it is anticipated that therapy will be more appealing and prescribed more broadly than in the past, including in patients considered marginal.nnnAIMnTo examine the effects of PEG-IFN-based antiviral therapy in elderly patients with chronic HCV.nnnMETHODSnThe charts of patients treated with chronic HCV were reviewed. Patients were defined as elderly if they were 60 years of age or older. The control group consisted of patients younger than 60 years of age who were matched to the treated elderly patients based on sex, treating physician, prescribed treatment and intended prescribed treatment duration. The data recorded included end of treatment response, sustained virological response (SVR), adverse events, dose modification and withdrawal of therapy.nnnRESULTSnThirty of 147 (20.4%) elderly patients attending a hepatitis C clinic were treated. The average age of the elderly patients was 65+/-4 years. Forty-three per cent were men and 57% were women. Ten per cent received IFN monotherapy, 70% received a combination of IFN/RBV therapy and 20% received a combination of PEG-IFN/RBV therapy. The overall response rates in the elderly patients compared with the younger patients was 46.7% versus 65.8% (P=0.11) for end of treatment response and 33.3% versus 51.2% (P=0.13) for SVR. The rate of dose modification was 50% in the elderly patients compared with 29% in the control group (P=0.08). Therapy was discontinued in 53% of the elderly compared with 34% of younger patients (P=0.17). The younger patients reported more side effects than elderly patients; although, there were more laboratory abnormalities (anemia, thrombocytopenia and neutropenia) in the elderly patients during therapy than in the younger group (0.93 per patient versus 0.49 per patient, P=0.01).nnnCONCLUSIONnElderly patients with chronic HCV can be treated successfully. However, they are more at risk to develop cytopenias while on treatment. In such patients, the close monitoring of blood counts is necessary. Larger studies are needed to confirm these findings and to determine whether SVR differs in this population.

Clinical manifestations of portal hypertension.

The portal hypertension is responsible for many of the manifestations of liver cirrhosis. Some of these complications are the direct consequences of portal hypertension, such as gastrointestinal bleeding from ruptured gastroesophageal varices and from portal hypertensive gastropathy and colopathy, ascites and hepatorenal syndrome, and hypersplenism. In other complications, portal hypertension plays a key role, although it is not the only pathophysiological factor in their development. These include spontaneous bacterial peritonitis, hepatic encephalopathy, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and portopulmonary hypertension.

Colonic obstruction secondary to sarcoidosis: nonsurgical diagnosis and management.

A 57-year-old black man presented with a 2-week history of abdominal pain, weight loss, anorexia, and constipation. His history was significant for remote Hodgkins disease and systemic sarcoidosis. Physical examination showed abdominal distention and hyperactive bowel sounds, periorbital swelling, and mandibular lymphadenopathy. A barium enema examination showed two high-grade obstructive lesions in the rectum and splenic flexure. Colonoscopy confirmed the presence of the two areas of colonic obstruction. The mucosa showed diffuse fine ulcerations in the areas of obstruction as well as in the intervening region. Endoscopic biopsy specimens showed numerous mucosal noncaseating granulomas but no acid-fast bacilli or foreign bodies. The patient was treated with oral prednisone and improved symptomatically within 3 days. The ocular lesions and lymphadenopathy also responded promptly. Findings of follow-up barium enema and colonoscopy performed after 1 month of steroid treatment were essentially normal. Mucosal biopsy specimens showed only mild nonspecific chronic inflammation of the lamina propria and no granulomas. Colonic involvement is rarely reported with systemic sarcoidosis. We believe that this is the first report of colonic obstruction due to sarcoid diagnosed endoscopically and managed nonsurgically.

Does a Rapid Decline in the Hematological and Biochemical Parameters Induced by Interferon and Ribavirin Combination Therapy for the Hepatitis C Virus Predict a Sustained Viral Response

BACKGROUND AND OBJECTIVESnTo analyze whether rapid myelosuppression and a decrease in alanine aminotransferase (ALT) induced by standard interferon (IFN) and ribavirin (RBV) combination therapy predict a sustained viral response (SVR) in hepatitis C virus patients.nnnPATIENTS AND METHODSnData from 111 patients (mean age 48.1 years) with chronic hepatitis C virus were retrospectively analyzed. All patients were treated with the same initial doses of IFN and RBV combination therapy. The following laboratory values were measured at baseline, and then at weeks 2, 4, 8, 12 and 24 of treatment: hemoglobin, white blood cells (WBCs), neutrophils, platelets and ALT. A delta value was then calculated for each interval from baseline (baseline values minus two weeks, etc). The delta value of each variable was then compared between the responders and nonresponders using Wilcoxons signed rank test.nnnRESULTSnSixty patients (54%) achieved an SVR. There were no significant differences between the responder and nonresponder groups for baseline variables. The delta value of ALT was the only significant marker in the prediction of an SVR. The mean +/- SD delta values for the ALT at week 2 of treatment were 71+/-92 U/L and 44+/-85 U/L for the responders and nonresponders, respectively (P<0.0046). At week 4, the values were 101+/-96 U/L and 84+/-100 U/L for the responders and nonresponders, respectively (P<0.0154). The decline was then calculated for the ALT as a percentage decrease from baseline: at weeks 2 and 4, the decreases were 64% and 66%, respectively, for the responders, and 43% and 41%, respectively, for the nonresponders. At week 2, the delta values for WBC count were found to be significant in predicting failure to achieve an SVR, with mean +/- SD delta values of 0.85 x 10(9)/L+/-1.48 x 10(9)/L and 1.53 x 10(9)/L+/-2.16 x 10(9)/L for the responders and nonresponders, respectively (P<0.0173). The same trend emerged at two weeks for neutrophils: 0.72 x 10(9)/L+/-1.33 x 10(9)/L for the responders and 1.02 x 10(9)/L+/-1.20 x 10(9)/L for the nonresponders (P<0.0150). The delta values were insignificant for hemoglobin, lowest hemoglobin values and platelets.nnnCONCLUSIONSnThe decline rates of ALT from baseline to week 2 and 4 of IFN and RBV combination therapy are good predictors of an SVR. A significant drop in WBC and neutrophil values is a predictor of failure to achieve an SVR. The hemoglobin, platelets and lowest hemoglobin values failed to predict an SVR.

The Effect of Information Level and Coping Style on Pain and Anxiety in Needle Liver Biopsy

Biopsy of the liver is an important diagnostic procedure. The procedure is invasive and may be painful for patients. Sedative drugs are not used because the associated drop in blood pressure mimics hemorrhage, a major complication of the procedure. Cognitive and behavioural techniques have been used to decrease stress in patients undergoing other medical procedures. In the present study, it is postulated that providing procedural and sensory information may reduce patient anxiety levels. Patient coping styles were evaluated and anxiety and pain levels were assessed by using a visual analogue scale. Subjects were randomly assigned to one of two groups. The control group received basic information about the procedure. The experimental group received the same basic information followed by more detailed educational information. Subjects also filled out the Krantz Health Opinion Survey, a short questionnaire used to classify coping styles as either information-seeking or information-avoiding. Seventy-five subjects (38 control and 37 experimental) with similar demographics were included in the present study. No significant differences were found in anxiety levels or pain levels 30 min and 6 h post-biopsy. There was also no significant difference between groups once coping style was added into the analysis. The study failed to show any advantage in providing additional information to subjects before liver biopsy, regardless of coping style.

Cholestasis in Crohn's Disease: A Diagnostic Challenge

A 24-year-old male with Crohns disease who developed three independent episodes of cholestatic liver disease over an eight-year period is described. The first episode was related to an idiosyncratic drug reaction while on sulfasalazine. The second episode, at the time of an exacerbation of his colitis, was characterized by moderate portal inflammation on liver biopsy and resolved quickly while he was on corticosteroid therapy. The most recent episode, occurring when the bowel disease was quiescent, was due to granulomatous hepatitis and resolved clinically with no specific therapy. Because numerous potentially serious hepatobiliary complications have been associated with inflammatory bowel disease, prompt and aggressive investigation in these instances is recommended.

Chylous Ascites Secondary to Giant Liver Hemangioma

Chylous ascites is rare in clinical practice. It is characterized by milky-appearing peritoneal fluid with a triglycerides concentration of >1.25 mmol/l (110 mg/dl). Its pathophysiology is related to a disruption in the normal lymphatic flow. It is more common after trauma (including post surgery), neoplasia or atypical infections such as tuberculosis or filariasis. Other rare medical causes have been reported. The treatment is supportive and focused on correction of the underlying pathology. We report here the first case of chylous ascites caused by giant liver hemangioma and discuss the management of this condition.

Esophageal varices: pathophysiology, approach, and clinical dilemmas.

Portal hypertension is one of the most significant complications of both acute and chronic liver diseases. It generally develops as a result of an increase in vascular resistance at the prehepatic, intrahepatic, or postherpetic level. An increase in portal blood flow may also contribute. The dominant cause of portal hypertension relates to liver cirrhosis which increases resistance through the hepatic sinusoids. Gastroesophageal varices are the most important clinical manifestation of this syndrome and are associated with a high risk of upper gastrointestinal hemorrhage and its attendant high mortality. n nThis special issue includes nine evidence-based reviews. They discuss the pathophysiology of portal hypertension as well as its clinical manifestations and management. Selected topics and controversies related to esophageal varices are covered, including noninvasive diagnostic methods, bleeding prophylaxis in adults and children, rescue treatments, and the clinical dilemma of portal vein thrombosis. n nH. Maruyama and O. Yokosuka review the current concepts of the pathophysiology of portal hypertension and esophageal varices. Portal hypertension is initially caused by distortion of the hepatic vascular bed, which in turn leads to increased resistance to portal blood flow. This phenomenon is associated with intrahepatic endothelial dysfunction with a resultant imbalance between vasodilators such as nitric oxide and prostaglandins vasoconstrictors including endothelin. An important consequence of increased resistance to portal blood flow is splanchnic vasodilatation with consequent sodium and water retention. As a result of the plasmas expansion, and the reduction in peripheral resistance, a hyperdynamic circulation develops. Consequently, there is a significant increase in the blood flow through the portal vein which further contributes to portal hypertension. Esophageal varices appear and may bleed when the HVPG exceeds 12u2009mmHg. n nA comprehensive review of the clinical manifestations of portal hypertension is presented by S. A. Al-Busafi et al. Portal hypertension is a common clinical syndrome defined as the elevation of hepatic venous pressure gradient (HVPG) above 5u2009mmHg. Its gastrointestinal manifestations include the development of esophageal varices, gastric varices, and intestinal vasculopathy. Approximately 5–15% of cirrhotics develop esophageal varices annually. The majority of patients with cirrhosis are expected to develop this condition over their lifetime. Beyond its gastrointestinal effects, portal hypertension may also affect other vital organs resulting in extrahepatic manifestations. n nY.-I. Chen and P. Ghali present an overview of strategies to prevent and manage portal hypertension. The one-year rate of first variceal hemorrhage is 5% for small varices and 15% for large varices. Six-week mortality rate following an episode of bleeding varies between 15 and 20%. Clearly, a strategy of prophylaxis to prevent the first episode of bleeding may reduce morbidity and mortality. In this respect, nonselective beta blockers and new types of beta blockers play a major role. The overall approach and the current pharmacological therapy of acute hemorrhage and of recurrent bleeding (i.e., secondary prophylaxis) are based on understanding the pathophysiology of esophageal varices. n nEarly diagnosis of esophageal varices prior to the first episode of bleeding is essential. Studies of primary prophylaxis clearly show that the risk of first variceal haemorrhage can be reduced significantly. Upper GI endoscopy remains the gold standard for screening, but this test is not without its own limitations. K. Rye et al. review the utility of noninvasive tests to predict esophageal varices. Unfortunately, current clinical, biochemical, and radiological parameters are not accurate enough to detect varices without a screening endoscopy, but assessment of systemic hemodynamics and other serum markers may hold promise for the future. n nVariceal rupture is governed by Laplaces law. Increased wall tension is the end result of increased intravariceal pressure, increased diameter of the varices, and reduced wall thickness. The variceal wall thickness can be evaluated visually by the presence of red wale markings. These markings reflect areas where the wall is especially thin. Variceal rupture often occurs at the level of the gastroesophageal junction where the varices are very superficial and thus have thinner walls. S. A. Al-Busafi et al. discuss the role of endoscopic management of esophageal varices. They emphasized the fact that gastroscopy allows direct visualization and is an excellent tool to assess the size and the presence of high risk stigmata of bleeding. A debate exists as to whether a pharmacologic or an endoscopic approach is the best method of primary prophylaxis. It was shown that both modalities are effective in minimizing the risk of a first episode of bleeding in patients with cirrhosis and large esophageal varices, independently of the presence of red signs. However, the endoscopic approach is the treatment of choice whenever the patient is unable to tolerate beta blockers. Acute variceal bleeding in patients with cirrhosis indicates decompensation and a high risk of death. Initial treatment for these patients includes volume resuscitation and administration of vasoactive drugs and antibiotics. Emergency endoscopic variceal ligation, one of the cornerstones of management, should be performed within the first 12 hours of hospital admission. n nG. Pomier-Layrargues et al. highlight the role of transjugular intrahepatic portosystemic shunt (TIPS) in the treatment of acute esophageal varices bleeding. The clinical trials indicate that the TIPS procedure is not a first line therapy for variceal bleeding but can be used when medical and endoscopic treatments fail, either in the acute situation or to prevent variceal rebleeding. However, careful selection of patients is mandatory before the TIPS procedure. Clinical followup is essential to detect and treat complications that may result from TIPS stenosis, which can be minimized by using covered stents. Followup is also required to monitor for worsening portosystemic encephalopathy. In severe cases of encephalopathy, reduction or occlusion of the shunt may be warranted. n nThe current first line pharmacologic and endoscopic therapies fail to control bleeding in approximately 10–15% of patients. Rescue therapies, which include balloon tamponade or TIPS, have many limitations and are contraindicated in some cases. A novel, emerging therapy is reviewed by F. Maufa and F. H. Al-Kawas. Placement of a fully covered self-expandable metallic stent can be used to control bleeding in cases of refractory esophageal hemorrhage. The removable stent can be left in place for as long as two weeks, allowing for improvement in liver function while a more definitive treatment can be planned semielectively. n nPortal hypertension in children represents a particular challenge in both diagnosis and management. A. Costaguta and F. Alvarez describe the progress that has been achieved recently in the treatment of children with portal hypertension. Two main factors influence therapeutic decisions: the age of the patient and the etiology of the liver disease. In this special issue, one can find a summary of the current knowledge and an expert opinion on the subject. n nFinally, nonneoplastic portal vein thrombosis (PVT) can be found in up to 25% of individuals with liver cirrhosis. The major risk factor of having PVT is severe liver disease and portal hypertension. Recently, it was found that procoagulant imbalance in individuals with advanced liver disease contributes to the development of PVT. The clinical impact of PVT on liver function is not clear. Nevertheless, it is a predictive factor for mortality among cirrhotics, independent of MELD score. PVT may be the cause of various life-threatening conditions. It increases portal hypertension and the risk of variceal bleeding. It may also extend into the superior mesenteric vein causing intestinal ischemia. The optimal management of PVT in individuals with cirrhosis is currently not addressed in any consensus publication or practice guidelines. G. Huard and M. Bilodeau explore the different aspects of PVT management including the potential risks and benefits of anticoagulation. n nThis special issue provides an excellent overview of one of the more complicated topics in the field of liver disease. It covers current concepts of the clinical and pathophysiological aspects of portal hypertension, management of the condition, along with emerging diagnostic and therapeutic modalities, and clinical controversies. We would like to congratulate the authors for their superb scientific manuscripts. n n nNir Hilzenrat n nAverell H. Sherker