Journal of Clinical & Experimental Hepatology

Journal of Clinical and Experimental Hepatology (JCEH): Well Begun is Half-done

Radha K Dhiman — 2012-03-01

The Outgoing President of INASL: An Officer, an Academician and a Gentleman

Pankaj Puri — 2012-03-01

Back from the Future: Treating Hepatitis C Virus with Conventional Interferon

Pankaj Puri, Vivek A Saraswat — 2012-03-01

Battle in Search for Simple Reliable Non-invasive Marker of Liver Fibrosis

Anil Arora, Praveen Sharma — 2012-03-01

Treatment of Chronic Hepatitis due to Hepatitis C Virus (CH-C) in India: A Randomized Controlled Trial Comparing Daily Interferon-alfa-2b and Ribavirin with Daily Interferon-alfa-2b and Glycyrrhizin—A Multicenter Study

2012-03-01

Background and Aim: Pegylated-interferon-alfa (PEG-IFN-α) with ribavirin is an established treatment in chronic hepatitis due to hepatitis C virus (HCV) (CH-C). Such treatment is expensive and in resource-poor countries such as India, alternative less expensive therapy is needed. Methods: Multicenter randomized controlled trial comparing two treatment regimens (interferon-alfa-2b [IFN-α-2b] 3 million unit/day [MU/day] and ribavirin 1000 mg/day [I+R] vs IFN-α-2b 3 MU/day and glycyrrhizin 250 mg [I+G]) in CH-C. Viral, host characteristics and therapeutic responses were assessed (ICMR—6 months trial for chronic hepatitis—CTRI/2008/091/000105). Results: One hundred and thirty-one patients meeting the inclusion criteria were randomized to I + G (n=64) or I+R (n=67) during the period February 2002 to May 2005. About 85% (I+G=53, I+R=58) completed 6 months of treatment and 89% of them (I+G=46, I+R=53) completed 6 months of follow-up after completion of treatment. Hepatitis C virus genotype 3 was the major type detected (71% patients). The mean log10 viral load (copies/mL), histological activity index, and fibrosis stage for all patients were 5.1 ± 0.98, 5 ± 2, and 2± 1.5, respectively. Sustained viral response (SVR) was significantly higher in I + R group than in I + G group (65.7% vs 46.9%, OR=2.2, P = 0.03). Treatment with I + G was associated with significantly lower frequencies of leukopenia (2% vs 17%, P <0.01) and anemia (8% vs 40%, P <0.001) as compared to treatment with I + R. Conclusion: Genotype 3 HCV infection with low viral load is prevalent in India. Daily IFN with ribavirin showed significantly better responses. Leukopenia and anemia were significantly more in ribavirin group. Responses observed with IFN + ribavirin were similar to the reported response rates with PEG-IFN suggesting that this modality may be considered as a cheaper alternative of treatment for chronic hepatitis C.

Comparison of Circulating Endothelial Cell/Platelet Count Ratio to Aspartate Transaminase/Platelet Ratio Index for Identifying Patients with Cirrhosis

2012-03-01

Background/Objectives: Circulating endothelial cells (CECs) are indicative of vascular injury and correlate with severity of vascular diseases. A pilot study showed that the ratio of CEC to platelet count (CEC/PC) was effective in predicting cirrhosis. Therefore, we evaluated CEC/PC in a larger cohort of patients, correlated it with cirrhosis, and compared its operating characteristics with previously described biomarker for cirrhosis, the AST/platelet ratio index (APRI). Methods: Fifty-three patients with cirrhosis, 20 matched healthy controls, and 9 patients with noncirrhotic liver disease were recruited. Peripheral blood sample was collected and analyzed to enumerate nucleated CEC CD146+, CD105+, CD45– using a commercial assay. Results: Median CEC counts were significantly higher in patients with cirrhosis (62 cells/4 mL, interquartile range [IQR]: 43.5–121) as compared with controls (31 cells/4 mL, IQR: 22.2–40). The CEC/PC was also significantly elevated in cirrhotics (0.69, IQR: 0.39–1.48) compared with controls (0.12, IQR: 0.09–0.20) and noncirrhotics (0.21, IQR: 0.08–0.43). Receiver operator characteristic (ROC) analysis revealed that CEC cutoff value of ≥37 cells/4 mL showed sensitivity of 81% and specificity of 75% for differentiating cirrhosis from controls (area under the curve [AUC]: 0.80; 95% confidence interval [CI] 0.67–0.91). The CEC/PC ratio cutoff value of ≥0.23 showed sensitivity of 91% and specificity of 82% (AUC: 0.92; 95% CI 0.83–0.99). The APRI cutoff value of ≥0.4 showed sensitivity of 94% and specificity of 85% for differentiating cirrhosis from control patients (AUC: 0.96; 95% CI 0.90–1.0). A product of CEC and APRI, termed CAPRI (CEC-APRI), effectively distinguished patients with cirrhosis from controls; with cutoff value of ≥12.7, showing higher sensitivity of 98% and specificity of 85% (AUC: 0.98; 95% CI 0.96–1.0). Conclusion: The CEC/PC ratio is significantly elevated in patients with cirrhosis and demonstrates comparable operating characteristics to previously described APRI. Furthermore, CAPRI, compiled as product of CEC to APRI showed outstanding ability to distinguish patients with cirrhosis from controls, although larger studies are necessary for validation.

Human Interferon Regulatory Factor 2 Gene Expression is Induced in Chronic Hepatitis C Virus Infection—A Possible Mode of Viral Persistence

2012-03-01

Background: The interferon regulatory factors (IRFs) are a family of transcription factors known to be involved in the modulation of cellular responses to interferons (IFNs) and viral infection. While IRF-1 acts as a positive regulator, IRF-2 is known to repress IFN-mediated gene expression. The increase in the IRF-1/IRF-2 ratio is considered as an important event in the transcriptional activation of IFN-α gene toward development of the cellular antiviral response. Objective: This study was performed to assess the expression of IRF mRNAs along with the expression level of IFN-α, its receptor (IFNAR-1), and the signal transduction factor (STAT-1) in treatment naive hepatitis C virus (HCV)-infected subjects. Materials: Thirty-five chronically infected (CHC) patients and 39 voluntary blood donors as controls were included in the study. Quantification of HCV-RNA (ribonucleic acid) and genotyping were done by real-time polymerase chain reaction (PCR) and hybridization assays, respectively, using patient's serum/plasma. In both controls and patients, the serum level of IFN-α and IFN-α was measured by flow cytometry. Target gene expressions were studied by retro-transcription of respective mRNAs extracted from peripheral blood mononuclear cells (PBMCs) followed by PCR amplification and densitometry. Minus-strand HCV-RNA as a marker of viral replication in PBMCs was detected by an inhouse PCR assay. Results: Both IRF-1 and IRF-2 genes were significantly enhanced in CHC than in control subjects (P < 0.001). A significant positive correlation (r2 = 0.386, P <0.01) was obtained between higher IRF-2 gene expression and increasing level of HCV-RNA. Chronically infected subjects (13%) harboring replicating HCV in PBMCs showed no significant differences in gene expressions than the subjects without HCV in PBMCs. Conclusion: Our findings indicate that HCV modulates host immunity by inducing IRF-2 gene to counteract IRF-1-mediated IFN-α gene expression. Since the IRF-2 gene is known to encode oncogenic protein, the role of IRF-2 in CHC patients developing hepatocellular carcinoma warrants further studies.

Perioperative Bacterial Infections in Deceased Donor and Living Donor Liver Transplant Recipients

2012-03-01

Background: Deceased donor (DDLT) and living donor (LDLT) liver transplant (LT) is in vogue in several centers in India. Most centers are resorting to LDLT as a preferred surgery due to shortage of deceased donor liver. The risk of infection and its effect on survival in both groups of recipients from the Indian subcontinent are not known. The study was conducted to compare the bacterial infection rates among LDLT and DDLT recipients and their impact on survival at a tertiary referral center. Methods: Retrospective data on 67 LT recipients were reviewed. Data on pre-, per-, and postoperative bacterial infection rates and the common isolates were obtained. Results: Thirty-five patients had LDLT and 32 had DDLT. The prevalence of pre-operative bacterial infection and the isolates was similar in both groups. The perioperative bacterial infection rates were significantly higher in DDLT recipients (P < 0.01) (relative risk: 1.44 95% confidence interval 1.04–1.9). In both LDLT and DDLT, the common source was urinary tract followed by bloodstream infection. The common bacterial isolates in either transplant were Klebsiella followed by Escherichia coli, Pseudomonas spp. and nonfermenting gram-negative bacteria. Six patients (four LDLT; two DDLT) were treated for tuberculosis. Among the risk factors, cold ischemic time, and duration of stay in the intensive care unit was significantly higher for DDLT (p < 0.01). The death rates were not significantly different in the two groups. However, the odds for death were significantly high at 26.8 (p < 0.05) for postoperative bacterial infection and 1.8 (p < 0.001) for past alcohol. Conclusion: Liver transplant recipients are at high-risk for bacterial infection irrespective of type of transplant, more so in DDLT.

A Pharmacological Profile of Ribavirin and Monitoring of its Plasma Concentration in Chronic Hepatitis C Infection

Girish S Naik, Manoj G Tyagi — 2012-03-01

Chronic hepatitis C (CHC) infection, usually an asymptomatic infection, has long-term serious complications such as cirrhosis, hepatocellular carcinoma, and end-stage liver disease requiring liver transplantation (LT). Several novel drugs against hepatitis C which form part of ‘specifically targeted antiviral therapy for hepatitis C’ (STAT-C) have been developed. These include NS3/4A protease inhibitors telaprevir, boceprevir, and nucleoside/non-nucleoside polymerase inhibitors (NS5A) which hold promise for future therapy. Despite the development of new anti-hepatitis C virus (HCV) drugs, ribavirin (RBV) remains the single most important drug to prevent relapse and is frequently included among newer regimens being developed with novel small molecule anti-HCV drugs. The current approved treatment is a combination therapy of once weekly subcutaneous pegylated-interferon (PEG-IFN)-α plus body-weight-based oral RBV regimen. The most significant dose-dependent side effect of RBV is hemolytic anemia warranting dose reduction or discontinuation in severe cases compromising sustained virological response (SVR). Monitoring RBV plasma concentration has been challenging due to its peculiar pharmacokinetics and has been done to predict both efficacy and toxicity. Herein, we review the pharmacological profile of RBV and the monitoring of its plasma concentration, monitoring in renal impairment, post-LT, and human immunodeficiency virus (HIV)-HCV co-infection in patients being treated with combination therapy of PEG-IFN-α and RBV.

Gluing Gastric Varices in 2012: Lessons Learnt Over 25 Years

Vivek A Saraswat, Abhai Verma — 2012-03-01

Bleeding from gastric varices (GV) continues to pose a challenge to the endoscopist and no consensus has been reached on the best way for treating these patients. Gastric variceal obturation (GVO) with the tissue adhesive, N-2-butyl-cyanoacrylate (NBC), is considered the treatment of first-choice for this condition in most parts of the world. The liquid monomer polymerizes into a solid cast, obturating the vessel within 10–20 s of coming in contact with ionic solutions such as blood. Gastric variceal obturation achieves hemostasis in over 90% of patients with active bleeding, eradicates GV in over 80% of these patients, and re-bleeding occurs in 3–30%. These results are comparable with those of transjugular intrahepatic portosystemic shunting (TIPS; over 90% hemostasis in acute bleeding with re-bleeding in 15–30%). Though, there has been no direct comparison with GVO, balloon-occluded retrograde transvenous obliteration of GV (BRTO) achieves near 100% obliteration with recurrence in 0–10% and is superior to TIPS for hemostasis in active bleeding when used in combination with transcatheter sclerotherapy. Several complications have been described for GVO including thromboembolic complications which occur in 0.5–4.3% and may be devastating in some. Many of the complications and the variability in results of GVO can be attributed to variations in injection technique. The use of a standardized injection technique has been reported to achieve 100% hemostasis and obliteration with 6.9% re-bleeding and no embolic complications. Gastric variceal obturation with NBC continues to be the first-choice therapy for GV bleeding outside Japan. Adherence to a standard injection technique will maximize hemostasis and eradication of GV while minimizing complications of therapy.

Endoscopic Ultrasound (EUS) for Esophageal and Gastric Varices: How Can it Improve the Outcomes and Reduce Complications of Glue Injection

Vikram Bhatia — 2012-03-01

A large part of portal venous system and the paragastric and para-esophageal collateral circulation is within the reach of endoscopic ultrasound (EUS). The EUS is more sensitive than gastroscopy for the detection of gastric varices (GV), and can accurately distinguish GV from thickened gastric folds. Gastric varices are depicted by serpiginous, anechoic, Doppler-positive mural channels, with larger collateral channels visible outside the gastric wall. The EUS has also been used to monitor the completeness of GV obturation after glue injection. There are limited data that this strategy may be clinically beneficial to prevent GV re-bleed. The EUS has been used to deliver glue injections under real-time monitoring into the vascular channels, with or without steel coils as scaffolding for the glue. The potential advantages of this technique include a straight scope position, lack of hindrance from pooled blood in gastric fundus, smaller glue volume requirements, and precise intra-vascular placement of glue with avoidance of intramural injections, and reduced embolic complications.

HBsAg Quantification in Clinical Practice

Avnish K Seth — 2012-03-01

Several standardized commercial assays for quantification of hepatitis B surface antigen (qHBsAg) are now available. Studies on HBsAg kinetics from Asia and Europe have demonstrated that HBsAg levels are highest during the immune-tolerant phase, become lower during immune-clearance phase and are the lowest in hepatitis B ‘e’ antigen (HBeAg)-negative inactive low-replicative phase with a rise during HBeAg-negative chronic hepatitis B (CHB). Combined use of hepatitis B virus-deoxyribonucleic acid (HBV-DNA) and HBsAg levels may help in differentiating true inactive carrier state from HBeAg-negative CHB. Several retrospective studies have demonstrated a role for decline in HBsAg level for predicting response and nonresponse to therapy. In HBeAg-positive patients treated with pegylated-interferon (PEG-IFN), a lack of decline of qHBsAg at week 12 predicts nonresponders while a decline of qHBsAg at week 24 predicts responders to PEG-IFN. In HBeAg-negative patients, if at week 12, there is no decline in qHBsAg and the HBV-DNA decline is < 2 log, the patient is unlikely to respond, then stopping of PEG-IFN should be considered. With nucleos(t)ide analogs, the decline in HBsAg is lower than that with PEG-IFN and more marked in patients with HBeAg-positive chronic hepatitis, with elevated alanine aminotransaminase (ALT), thus suggesting that active immune response against HBV is required to lower HBsAg. In patients with HBeAg-negative chronic hepatitis, fall in HBsAg may help in developing stopping rules to reduce the need for lifelong therapy. Information provided by HBsAg is complementary to HBV-DNA and cannot replace the same. Prospective studies on HBsAg kinetics from all regions of the world are required to define optimum time of testing and cutoff levels before stopping rules can be recommended.

Post-liver Transplant Biliary Complications

Tegpal Atwal, Mariel Pastrana, Bimaljit Sandhu — 2012-03-01

Biliary tract complications remain a common source of morbidity and mortality in liver transplant (LT) recipients with an estimated incidence of 5–30% after orthotopic LT and a mortality rate of up to 10%. Biliary complications after LT may be related to various factors including hepatic artery thrombosis or stenosis, ischemia reperfusion injury, immunologic injury, infections, donor pool, and technical issues which include imperfect anastomosis and T-tube-related complications. Management of the detected biliary complications includes nonsurgical and surgical methods. A majority of these post transplant biliary complications can be treated with endoscopic retrograde cholangiography. If unsuccessful, a percutaneous intervention or surgery may be required. In this article, we review the incidence, clinical presentation, and management of the main types of biliary complications.

Onset of Type 1 Diabetes Mellitus During Pegylated-interferon Alfa and Ribavirin Therapy for Chronic Hepatitis C Virus Infection

Raghini Ranganathan, Krishnaveni Janarthanan, Senthilkumar Rajasekaran — 2012-03-01

A 16-year-old female was treated with pegylated-interferon (PEG-IFN) alfa (a)-2b and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection. She attained rapid virological response. She presented with diabetic ketoacidosis after 41 weeks of therapy. Anti-glutamic acid decarboxylase antibodies and islet cell antibodies were negative. Her fasting serum C-peptide level was <0.1 ng/mL, and the treatment course was completed. This case underlines the importance of periodic plasma glucose monitoring in patients during and after PEG-IFN and ribavirin therapy.

Association of Bell's Palsy with Hepatitis E Virus Infection: A Rare Entity

Ashish K Jha, Sandeep Nijhawan, Subhash Nepalia, Arya Suchismita — 2012-03-01

Hepatitis E virus (HEV) infection is a common cause of acute hepatitis in India and other developing countries. The data regarding the neurologic manifestation of HEV infection are limited. The neurologic disorders including Guillain–Barré syndrome, polyradiculopathy, neuralgic amyotrophy, encephalitis, bilateral brachial neuritis, ataxia/proximal myopathy, and acute transverse myelitis have been described. Bell's palsy and other cranial nerve involvement in hepatitis A virus (HAV) and HEV infection are rare. We present the second case of Bell's palsy associated with HEV.

Hepatocellular Carcinoma Presenting as Budd–Chiari Syndrome

2012-03-01

Multiple Choice Questions

2012-03-01

It is Patatin-like Phospholipase Domain-containing 3 Gene (PNPLA3)—All the Way

Ajay K Duseja — 2012-03-01

Answers to Multiple Choice Questions

2012-03-01