Govind Ballabh Pant Hospital

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

To determine the prevalence and natural history of gastric varices, we prospectively studied 568 patients (393 bleeders and 175 nonbleeders) with portal hypertension (cirrhosis in 301 patients, noncirrhotic portal fibrosis in 115 patients, extrahepatic portal vein obstruction in 117 patients and hepatic venous outflow obstruction in 35 patients). Primary (present at initial examination) gastric varices were seen in 114 (20%) patients more were present in bleeders than in nonbleeders (27% vs. 4%, respectively; p < 0.001). Secondary (occurring after obliteration of esophageal varices) gastric varices developed in 33 (9%) patients during follow–up of 24.6 ± 5.3 mo. Gastric varices (compared with esophageal varices) bled in significantly fewer patients (25% vs. 64%, respectively). Gastric varices had a lower bleeding risk factor than did esophageal varices (2.0 ± 0.5 vs. 4.3 ± 0.4, respectively) but bled more severely (4.8 ± 0.6 vs. 2.9 ± 0.3 transfusion units per patient, respectively). Once a varix bled, mortality was more likely (45%) in gastric varix patients. Gastric varices were classified as gastroesophageal or isolated gastric varices. Type 1 gastroesophageal varices (lesser curve varices) were the most common (75%). After obliteration of esophageal varices, type 1 gastroesophageal varices disappeared in 59% of pateints and persisted in the remainder; bleeding from perisistent gastroesophageal varices was more common than it was from gastroesophageal varices that were obliterated (28% vs. 2%, respectively; p < 0.001). Type 2 gastroesophageal varices, which extend to greater curvature, bled often (55%) and were associated with high mortality. Type 1 isolated gastric varices patients had only fundal varices, with a high (78%) incidence of bleeding. Type 2 isolated gastric varices were mainly (86%) ectopic, secondary gastric varices that bled only rarely (9%). Sclerotherapy was more effective in controlling acute bleeding and obliterating varices in gastroesophagael varices than in isolated gastric varices; the latter often required surgery. In conclusion, gastric varices are a common and serious complication of portal hypertension. Our classification was helpful in understanding the natural history and management of gastric varices.

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the “APASL ACLF Research Consortium (AARC)” was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the ‘Golden Therapeutic Window’, extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.

Insulin resistance is a hallmark of obesity, diabetes, and cardiovascular diseases, and leads to many of the abnormalities associated with metabolic syndrome. Our understanding of insulin resistance has improved tremendously over the years, but certain aspects of its estimation still remain elusive to researchers and clinicians. The quantitative assessment of insulin sensitivity is not routinely used during biochemical investigations for diagnostic purposes, but the emerging importance of insulin resistance has led to its wider application research studies. Evaluation of a number of clinical states where insulin sensitivity is compromised calls for assessment of insulin resistance. Insulin resistance is increasingly being assessed in various disease conditions where it aids in examining their pathogenesis, etiology and consequences. The hyperinsulinemic euglycemic glucose clamp is the gold standard method for the determination of insulin sensitivity, but is impractical as it is labor- and time-intensive. A number of surrogate indices have therefore been employed to simplify and improve the determination of insulin resistance. The object of this review is to highlight various aspects and methodologies for current and upcoming measures of insulin sensitivity/resistance. In-depth knowledge of these markers will help in better understanding and exploitation of the condition.

Diabetes is a dreadful disease identified by escalated levels of glucose in the blood. Machine learning algorithms help in identification and prediction of diabetes at an early stage. The main objective of this study is to predict diabetes mellitus with better accuracy using an ensemble of machine learning algorithms. The Pima Indians Diabetes dataset has been considered for experimentation, which gathers details of patients with and without having diabetes. The proposed ensemble soft voting classifier gives binary classification and uses the ensemble of three machine learning algorithms viz. random forest, logistic regression, and Naive Bayes for the classification. Empirical evaluation of the proposed methodology has been conducted with state-of-the-art methodologies and base classifiers such as AdaBoost, Logistic Regression,Support Vector machine, Random forest, Naïve Bayes, Bagging, GradientBoost, XGBoost, CatBoost. by taking accuracy, precision, recall, F1-score as the evaluation criteria. The proposed ensemble approach gives the highest accuracy, precision, recall, and F1_score value with 79.04%, 73.48%, 71.45% and 80.6% respectively on the PIMA diabetes dataset. Further, the efficiency of the proposed methodology has also been compared and analysed with breast cancer dataset. The proposed ensemble soft voting classifier has given 97.02% accuracy on the breast cancer dataset.

OBJECTIVE: To evaluate the efficacy and safety of perampanel 2, 4, and 8 mg/day added to 1-3 concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. METHODS: During this double-blind, placebo-controlled trial, patients with persisting seizures on 1-3 AEDs were randomized to perampanel 2, 4, and 8 mg/day or placebo following a 6-week baseline phase. Perampanel was titrated weekly by 2 mg/day and maintained at the dose achieved for 13 weeks. Primary endpoints were median percent change in seizure frequency and 50% responder rate. Analysis of covariance was performed on all treated patients with any seizure data (recorded in daily diaries) in the double-blind phase. RESULTS: A total of 706 patients were randomized and received trial medication; 623 completed the trial. Median percent change in seizure frequency-the primary efficacy endpoint-was -10.7%, -13.6%, -23.3%, and -30.8% for placebo, perampanel 2, 4, and 8 mg/day, respectively. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0026) and 8 mg/day (p < 0.0001). The corresponding 50% responder rates were 17.9%, 20.6%, 28.5%, and 34.9%. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0132) and 8 mg/day (p = 0.0003). An apparent dose response was suggested for dizziness, which was the most frequent treatment-emergent adverse event. CONCLUSIONS: This trial demonstrated that adjunctive perampanel effectively reduced seizure frequency and possessed a favorable tolerability profile in patients ≥12 years with partial-onset seizures (with or without secondary generalization), with a minimum effective dose of 4 mg/day. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 4 and 8 mg/day doses of adjunctive perampanel are effective and tolerated in reducing partial-onset seizures.

BACKGROUND AND METHODS: We compared propranolol therapy and endoscopic ligation for the primary prevention of bleeding from esophageal varices. This prospective, controlled trial included consecutive eligible patients who had large varices (>5 mm in diameter) that were at high risk for bleeding. The patients were assigned to either propranolol therapy, at a dose sufficient to decrease the base-line heart rate by 25 percent, or variceal ligation, to be performed weekly until the varices were obliterated or so reduced in size that it was not possible to continue treatment. RESULTS: Of the 89 patients, 82 of whom had cirrhosis of the liver, 44 received propranolol and 45 underwent variceal ligation. The mean (+/-SD) duration of follow-up in each group was 14+/-9 and 13+/-10 months, respectively. The mean time required to achieve an adequate reduction in the heart rate was 2.5+/-1.7 days; the mean number of sessions needed to complete variceal ligation was 3.2+/-1.1. After 18 months, the actuarial probability of bleeding was 43 percent in the propranolol group and 15 percent in the ligation group (P=0.04). Twelve patients in the propranolol group and four in the ligation group had bleeding. Three of the four in the ligation group had bleeding before their varices had been obliterated. Nine patients in the ligation group had recurrent varices, a mean of 3.7 months after the initial treatment. Five patients in each group died; bleeding from the varices was the cause of death of four patients in the propranolol group and of three in the ligation group. There were no serious complications of variceal ligation; in the propranolol group, treatment was stopped in two patients because of side effects. CONCLUSIONS: In patients with high-risk esophageal varices, endoscopic ligation of the varices is safe and more effective than propranolol for the primary prevention of variceal bleeding.

OBJECTIVES: Hepatic encephalopathy (HE) is associated with poor prognosis in cirrhosis. Drugs used in the treatment of HE are primarily directed at the reduction of the blood ammonia levels. Rifaximin and lactulose have shown to be effective in HE. We evaluated the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for treatment of overt HE. METHODS: In this prospective double-blind randomized controlled trial, 120 patients with overt HE were randomized into two groups: (group A lactulose plus rifaximin 1,200 mg/day; n=63) and group B (lactulose (n=57) plus placebo). The primary end point was complete reversal of HE and the secondary end points were mortality and hospital stay. RESULTS: A total of 120 patients (mean age 39.4±9.6 years; male/female ratio 89:31) were included in the study. 37 (30.8%) patients were in Child-Turcotte-Pugh (CTP) class B and 83 (69.2%) were in CTP class C. Mean CTP score was 9.7±2.8 and the MELD (model for end-stage liver disease) score was 24.6±4.2. At the time of admission, 22 patients (18.3%) had grade 2, 40 (33.3%) had grade 3, and 58 (48.3%) had grade 4 HE. Of the patients, 48 (76%) in group A compared with 29 (50.8%) in group B had complete reversal of HE (P<0.004). There was a significant decrease in mortality after treatment with lactulose plus rifaximin vs. lactulose and placebo (23.8% vs. 49.1%, P<0.05). There were significantly more deaths in group B because of sepsis (group A vs. group B: 7:17, P=0.01), whereas there were no differences because of gastrointestinal bleed (group A vs. group B: 4:4, P=nonsignificant (NS)) and hepatorenal syndrome (group A vs. group B: 4:7, P=NS). Patients in the lactulose plus rifaximin group had shorter hospital stay (5.8±3.4 vs. 8.2±4.6 days, P=0.001). CONCLUSION: Combination of lactulose plus rifaximin is more effective than lactulose alone in the treatment of overt HE.

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.

INTRODUCTION More than 600,000 people die of hepatocellular carcinoma (HCC) each year. Worldwide research on the disease needs to be intensified in both the medical and pharmaceutical fields, especially with a focus on providing help to areas where resources are limited. Treatment approaches depend on the stage of the disease at diagnosis and on access to complex treatment regimens. However, advanced disease is not curable, and management of advanced disease is expensive and only marginally effective in increasing quality-adjusted life years. The delivery of healthcare services for HCC can be improved by developing centers of excellence. Concentrating medical care in this way can lead to an increased level of expertise, so that resections are performed by surgeons who understand liver disease and the limitations of resection and other relevant procedures. Promising new agents are beyond the reach of those who would benefit most: in low-resource countries, sorafenib is out of the question for general use. For example, “snapshot” cost indications of monthly pharmacy prices for sorafenib are: $7300 in China, $5400 in the United States, $5000 in Brazil, €3562 in France, and $1400 in Korea (source: N Engl J Med. 2008;359:378–390; PMID 18650519). From a global perspective, therefore, the most urgent task is to prevent the occurrence of HCC. The only effective strategy is primary prevention of viral hepatitis, and in most countries this is already in place in the form of hepatitis B vaccination of newborns. Prevention of alcohol abuse and preventing the spread of hepatitis C virus (HCV) and metabolic syndrome are also relevant. Another important task is to prevent aflatoxin formation through proper care of crops and food storage. The next best approach is to increase awareness among the healthcare community to promote surveillance of patients who are at risk and achieve earlier diagnosis and resection or ablation of small lesions. Global Prevalence and Incidence HCC is the sixth most common malignancy worldwide. It is the fifth most common malignant disease in men and the eighth most common in women. It is the third most common cause of death from cancer, after lung and stomach cancer. HCC is the most common malignant disease in several regions of Africa and Asia. At least 300,000 of the 600,000 deaths worldwide occur in China alone, and the majority of the other 300,000 deaths occur in resource-challenged countries in sub-Saharan Africa. These devastating figures are most likely due to: Failure to recognize those at risk (with hepatitis B and/or C) High prevalence of risk factors in the population Lack of medical expertise and facilities for early diagnosis Lack of effective treatment after diagnosis Other important factors include poor compliance, with inadequate attendance or absent in surveillance programs and thus late presentation of patients with large tumors; low awareness of the benefits of HCC treatment and ways of preventing underlying liver disease; and a negative opinion among some physicians about screening. In Japan, the United States, Latin America, and Europe, hepatitis C is the major cause of HCC. The incidence of HCC is 2% to 8% per year in patients with chronic hepatitis C and established cirrhosis. In Japan, the mortality from HCC has more than tripled since the mid-1970s. HCV infection is responsible for 75% to 80% of cases and hepatitis B virus (HBV) for 10% to 15% of cases. HCV-related HCC has been linked to blood transfusions in the 1950s and 1960s, intravenous drug use, and the reuse of syringes and needles. In many (but not all) countries, the spread of HCV is declining, but due to migration the disease burden has not changed. In Asia, Africa, and in some eastern European countries, chronic hepatitis B is the prime cause of HCC, far outweighing the impact of chronic hepatitis C (Fig. 1). There are 300 million people infected with HBV, 120 million of whom are Chinese. In China and Africa, hepatitis B is the major cause of HCC; approximately 75% of the HCC patients have hepatitis B.FIGURE 1.: The worldwide geographic distribution of chronic hepatitis B virus infection (source: Centers for Disease Control, 2006).HCC Risk Factors HCC is associated with liver disease independently of the specific cause of the disease: Infectious: chronic hepatitis B or C. Nutritional and toxic: alcohol, obesity (nonalcoholic fatty liver disease), aflatoxin (cofactor with HBV), tobacco. Genetic: tyrosinosis, hemochromatosis (iron overload). However, iron overload as a cause per se and as a result of dietary intake (due to cooking in iron pots) is a subject of controversy. α1-antitrypsin deficiency. Immunologic: autoimmune chronic active hepatitis, primary biliary cirrhosis. The major risk factors for HCC are: Chronic HBV or HCV infection. Alcoholic cirrhosis. Nonalcoholic steatohepatitis. Diabetes (metabolic syndrome is the likely risk process). Cirrhosis by itself, of whatever cause. In Europe, North America, and Japan, HCC occurs mainly in patients with established cirrhosis. The risk of developing HCC in patients infected with HBV increases with: The viral load Male sex Older age The presence of cirrhosis Exposure to aflatoxins Location in sub-Saharan Africa, where patients develop HCC at a younger age The risk of developing HCC in patients infected with HCV and cirrhosis increases in combination with: Concurrent alcohol abuse Obesity/insulin resistance Previous or concurrent infection with HBV. Primary Care Physical findings: If the tumor is small: often without symptoms Physical signs may not be found at all Signs related to the chronic liver disease and/or underlying cirrhosis In more advanced cases: Palpable mass in the upper abdomen, or a hard, irregular liver surface Tenderness in the upper right abdominal quadrant Splenomegaly, ascites, jaundice (also symptoms of cirrhosis) Hepatic arterial bruit (heard over the tumor) Signs that should raise a suspicion of HCC in patients with previously compensated cirrhosis: Rapid deterioration of liver function New-onset (or refractory) ascites Acute intra-abdominal bleeding Increased jaundice Weight loss and fever New-onset encephalopathy Variceal bleeding Patients with late-stage HCC may present with: Right upper quadrant abdominal pain Symptoms and signs of underlying cirrhosis Weakness Abdominal swelling Nonspecific gastrointestinal symptoms Jaundice Loss of appetite Weight loss Anorexia Laboratory findings: Usually nonspecific Signs of cirrhosis: Thrombocytopenia Hypoalbuminemia Hyperbilirubinemia Coagulopathy Electrolyte disturbances Liver enzymes abnormal, but nonspecific Elevated α-fetoprotein (AFP; requires definitionsof levels and appropriate setting) Elevated alkaline phosphatase Follow-up to assess the patient after therapy—to be performed every 3 to 6 months: Physical examination Laboratory blood tests Computed tomography (CT), magnetic resonance imaging, and ultrasonography Referring to a specialist may help in: Confirming the diagnosis (and excluding possible alternatives—eg, liver diseases). Determining the extent of hepatic involvement and (remaining) liver function. Excluding extrahepatic disease. Choosing the best therapeutic option, including palliative care. If expert centers are within reach, it is generally recommended that HCC patients should be referred there, where care and options are optimally applied with all the expertise required from different areas of knowledge. Diagnosis Initial patient evaluation: Complete history Full physical examination Initial laboratory tests: Complete blood count Serum glucose Renal function and serum electrolytes AFP Albumin Prothrombin time Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin Hepatitis B surface antigen and anti-HCV (if not already known) Chest x-ray and/or CT scan Ascitic fluid cytology may also be considered, despite its low sensitivity—it is simple and practicable in Africa. Diagnostic Tests (Table 1) Sufficient to establish a diagnosis of HCC is a combined finding of: the classic appearance on one of the imaging modalities—that is, a large and/or multifocal hepatic mass with arterial hypervascularity; and elevated serum AFP, against a background of chronic (generally asymptomatic), generally cirrhotic-stage liver disease.TABLE 1: Tests Used to Diagnose Hepatocellular CarcinomaUltrasound Imaging, CT, or Magnetic Resonance Imaging Radiology and/or biopsy are the definitive diagnostic tools. Contrast-enhanced ultrasound may produce false-positive findings for HCC in patients with intrahepatic cholangiocarcinoma. AFP is an adjunctive diagnostic tool. A persistent AFP level of more than 400 ng/mL or a rapid increase in the AFP level may be a useful diagnostic criterion. In patients with lower AFP levels when radiology is not available, the diagnosis of HCC can only be made by clinical judgment. Even if options for treating HCC are absent or very limited, AFP testing and ultrasound imaging may be available. Cautionary Notes It is important to distinguish the use of AFP testing as a screening tool from its use as a diagnostic tool. Although it is considered to be a useful and feasible screening tool in China, others disagree. Its performance as a diagnostic tool is better. A positive AFP test (above 400 ng/mL, for example, can be considered diagnostic, but an AFP that is negative or below the predetermined cut-off point does not exclude HCC, as up to 40% of HCCs will never produce AFP. However, 90% of black African patients have raised AFP levels that are above the diagnostic level of 500 ng/mL in 70% of patients. However, this in turn may reflect the late presentation of these patients. In Western patients, AFP testing is less useful. Increased AFP and a mass are the diagnostic criteria of malignancy, but it is not possible to distinguish between HCC and cholangiocarcinoma. The incidence of cholangiocarcinoma is increasing, and cirrhosis is a risk factor. If the radiographic findings are conclusive, the diagnosis is certain; but if radiology is not conclusive, a biopsy is recommended to confirm the diagnosis. Cascades—A Resource-sensitive Approach A “cascade” is a hierarchical set of diagnostic, therapeutic, and management options for dealing with risk and disease, ranked by the resources locally available. A gold-standard approach is feasible in regions and countries where liver transplantation is available for the treatment of HCC. Elsewhere, resection and/or local ablation are available, but not liver transplantation. What is it still possible to do in the various settings in which transplantation or resection and/or local ablation are available? To answer this question, this guideline is structured on the basis of resource-sensitive cascades: for minimal-resource and medium-resource areas, the guideline discusses primary and secondary prevention, patient evaluation, and treatment options. For high-resource regions and countries, the guideline published by the American Association for the Study of Liver Diseases (AASLD) should be consulted. MINIMAL RESOURCES Minimal-resource regions are defined as those in which hardly any treatment options are available. The focus is on prevention and symptomatic treatment. At best, resection or local ablation may be available in some areas. Defining the criteria for referral to a specialist is a complex matter. As patients with advanced cases (and these are the majority of cases in resource-challenged countries) have no treatment options except supportive care, referral is generally futile. Only patients with early cases can benefit (imaging technology is required to identify early cases) and should be referred to specialists. All recommendations should focus on primary prevention and on the treatment of viral hepatitis and cirrhosis. Primary HCC Prevention Particularly when potentially curative treatment is unavailable, primary prevention is very important in reducing the risk of HCC (Table 2).TABLE 2: Options for Primary Prevention of Hepatocellular Carcinoma The vaccination prevention strategy against viral hepatitis (HBV) should be carried out worldwide; so far, it has been implemented in 152 countries. It is supported by nongovernmental organizations such as the Gates Foundation and the Global Alliance for Vaccines and Immunization. In Nigeria, vaccination costs less than a dollar; vaccines are also administered free for babies in public hospitals and immunization centers through the National Program on Immunization. Pakistan runs the World Health Organization's “Expanded Program of Immunization,” with free immunization for all newborns. Antiviral therapy should be recommended if needed: In many countries, the problem with antiviral therapy is management (drug resistance), compliance, and education. Costs may also be a problem, although several medications are reported to be relatively inexpensive. One year of lamivudine treatment costs $165 in Sudan; adefovir is inexpensive in India and China; and entecavir in China costs $5/d compared with $22/d in developed countries. Health education on viral hepatitis should emphasize the ways in which it is possible for the disease to spread in relation to local practices involving blood-blood contact, such as circumcision, scarification, tribal marks, and tattoos; in relation to the care of open sores and marks after multiple-use tooth extraction equipment; and in connection to the reuse of needles (or multiple-dose vials). Secondary HCC Prevention—Surveillance Screening should be encouraged in regions in which it is possible to offer curative treatment for HCC. There is little point in carrying out mass screening of a population if the resources for further investigation and treatment are lacking. Screening should only be undertaken if at least one of these management options is available: liver transplantation, resection, transarterial chemoembolization (TACE), or ablation techniques. Treatment with acetic acid (vinegar) is used in some places. One of the starting points for screening is to identify asymptomatic patients with HCC. If patients have cancer symptoms at diagnosis, the outcome is not good and treatment is not likely to be cost-effective. Treatment Options Appropriate treatment options that may or may not be beyond the scope of local medical facilities include: Partial liver resection Percutaneous ethanol injection (PEI) or radiofrequency ablation (RFA) TACE Traditional chemotherapy has no place in the management of HCC. Patients should be offered symptomatic treatment when it is needed and possible. MEDIUM RESOURCES Medium-resource regions are defined as those in which both resection and ablation are available for the treatment of HCC, but transplantation is not an option. In addition to primary HCC prevention (as discussed under “Minimal Resources” above), detailed recommendations can be provided on surveillance, diagnosis, and treatment. The delivery of healthcare services for HCC can be improved by developing centers of excellence—concentrating medical care can lead to an increased level of expertise, so that resections are performed by surgeons who understand liver disease and the limitations of each treatment modality. Secondary HCC Prevention—Surveillance When resection and/or local ablation are available for the treatment of HCC, there should be an emphasis on surveillance. Primary prevention—that is, hepatitis B vaccination of youngsters—is optimal in reducing the risk of HCC. Early diagnosis and treatment are essential for improving survival, but preventing recurrent HCC is still a major challenge. HCC surveillance may improve early detection of the disease. Generally, treatment options are broader when HCC is detected at an earlier stage. Finding early-stage disease is a prerequisite for improved prognosis. Screening should be encouraged in regions in which it is possible to offer curative treatment for HCC. The risk factors for HCC are well known, and this allows cost-effective surveillance. Screening for early detection of HCC is recommended for the groups of high-risk patients listed in Table 3.TABLE 3: Criteria for Hepatocellular Carcinoma ScreeningSurveillance involves establishing screening tests, screening intervals, diagnostic criteria, and recall procedures (Table 4).TABLE 4: Surveillance Techniques Depending on the clinical condition and the available resources, an ultrasound screening interval of 6 to 12 months is recommended. In advanced cases and in patients with cirrhosis, ultrasound screening should be performed every 4 to 6 months. Patient education is an essential prerequisite. Tertiary HCC Prevention—Recurrence Recurrent HCC may result from multicentric carcinogenesis or inadequate initial treatment. Prevention of HCC recurrence requires early diagnosis and complete removal of primary HCC lesions. Currently, there is no proof of the efficacy of tertiary prevention of HCC with any agent, including chemotherapy, HBV and HCV therapy, or interferon. There are no safe and effective chemotherapeutic agents available yet to prevent the recurrence of HCC. Molecular-targeted drugs seem to show promising clinical activity, but the median survival is not satisfactory and these agents are very costly. Anti-HBV oral nucleoside/nucleotide analogs are required for patients with ongoing active chronic hepatitis B with HCC as a complication and who are in Child-Pugh class A or B. Evaluation The management of HCC is changing. In the developed countries, HCC patients are increasingly being evaluated and managed at specialized centers by multidisciplinary teams consisting of hepatologists, oncologists, radiologists, surgeons, and pathologists. The Barcelona Clinic Liver Cancer (BCLC) staging system takes into account variables related to tumor stage, liver function, physical status, and cancer-related symptoms, and links these with treatment options and life expectancy. On the basis of the BCLC staging system, patients may be classified as having: Early HCC: single nodule or three nodules ≤3 cm. These patients may benefit from curative therapies. Intermediate HCC: multinodular. These patients may benefit from chemoembolization. Advanced HCC: multinodular with portal These patients may benefit from palliative new agents may be HCC: very poor life symptomatic treatment. a diagnosis of HCC has been liver function is one of the factors in the treatment performance and to be in liver function are: Child-Pugh Serum Prothrombin Hepatic encephalopathy hepatic A test result would confirm relevant portal which is important when resection is Treatment Options Treatment options depend on liver function, tumor and the presence or of or In most curative such as resection, or liver transplantation are not the options to Screening of is the only way of at a stage at which are of being of the treatment options are expensive and/or specialized and local ablation are the treatment options most likely to be used in patients with HCC surveillance in developing countries. resection and ablation can a in small Partial liver a curative approach for HCC. Only a of the patients for this option, due to advanced disease stage and/or liver function. can be due to tumor that the time or a is, a tumor in a liver that is to develop or These are safe and effective when resection is not an option, or when the patient is transplantation. is available, but requires at least and are effective for cm. is more effective than alcohol injection in cm. The of is more in all tumor is the of care for patients with good liver function and disease that is not to or but who have no extrahepatic no and no cancer Table a of benefits in HCC, and levels of developed by an expert American Association for the Study of Liver Diseases (AASLD) of and of in Hepatocellular Care Patients with Child-Pugh class C cirrhosis should be offered symptomatic treatment More such as and therapy, are available at specialized RESOURCES regions are defined as those in which liver transplantation is available for the treatment of HCC. For detailed of diagnostic and therapeutic options and of the of chemotherapy, the should be of hepatocellular

OBJECTIVE: Treatment of bleeding gastric varices (GVs) is still controversial, mainly because of anecdotal studies or inclusion of patients with GVs located at different sites that have variable incidences of bleeding. A prospective study was undertaken to compare the efficacy and safety of GV sclerotherapy using alcohol and GV obturation using cyanoacrylate glue. METHODS: Thirty-seven consecutive patients with portal hypertension and endoscopic evidence of isolated GVs, 17 presenting with histories of active bleeding, were randomized to receive endoscopic intervention either with alcohol (n = 17) or with cyanoacrylate glue (n = 20) injection. Variceal obliteration, rebleeding, or death was the endpoint. RESULTS: The glue was significantly more effective in achieving variceal obliteration than alcohol (100% vs 44%, p < 0.05). Furthermore, this could be achieved in a significantly shorter period (2.0 +/- 1.6 vs 4.7 +/- 3.2 wk, p < 0.05) and with a smaller volume of the agent. Cyanoacrylate glue injection could achieve arrest of acute GV bleeding more often than alcohol (89% vs 62%), and the need for rescue surgery was less; the difference was, however, not significant. Six patients died from uncontrolled GV bleeding, four being in the alcohol group. During a mean follow-up of 15.4 +/- 3.7 months there was no recurrence of GVs in either group. CONCLUSIONS: Our results show that cyanoacrylate is more effective and achieves GV obliteration faster than injection sclerotherapy with alcohol. It also appears to be more useful in controlling acute GV bleeding, with less of a need for rescue surgery.

BACKGROUND AND AIM: Hepatorenal syndrome (HRS) occurs in about 18% of cirrhotic patients with ascites and is characterized by intense renal vasoconstriction, low glomerular filtration rate and preserved tubular function and normal renal histology. The aim of the present study was to examine the effects of terlipressin on renal function, systemic hemodynamics and clinical outcome in patients with HRS. METHODS: The study was a randomized controlled single-blind trial. We randomly assigned 24 consecutive patients with HRS to treatment with terlipressin 1 mg i.v. at 12-h intervals (group A; n = 12) or placebo at 12-h intervals (group B; n = 12). The end-point of the study was improvement in renal functions defined as reversal of HRS and survival at 15 days. RESULTS: The two groups were comparable at baseline. After treatment with terlipressin, urine output significantly (P < 0.05) increased progressively in group A (day 4, 960 +/- 40 mL/24 h; day 8, 1068 +/- 56 mL/24 h) compared with group B (day 4, 451 +/- 40 mL/24 h; day 8, 291 +/- 45 mL/24 h). Creatinine clearance improved (P < 0.05) in group A (day 4, 20.2 +/- 2.1 mL/min; day 8, 35 +/- 2.8 mL/min) compared with group B (day 4, 11.3 +/- 1.3 mL/min; day 8, 9.3 +/- 1.7 mL/min). Serum creatinine decreased in group A but not in group B (day 8, 1.6 +/- 0.01 compared with 3.9 +/- 0.26, P < 0.05). Mean arterial pressure increased significantly (P < 0.05) in group A. Terlipressin administration was associated with transient self-limiting side-effects including crampy abdominal pain in two patients and cardiac arrhythmias in three patients. Five of the 12 patients survived in group A compared with none in group B at day 15 (P < 0.05) and all survivors had reversal of HRS. CONCLUSION: In patients with HRS, terlipressin significantly improved renal functions and systemic hemodynamics, and showed a trend towards better clinical outcome. The drug merits further evaluation with different dosages and longer schedules.

BACKGROUND AND AIM: Certain hepatitis B virus (HBV) genotypes have been alleged to be associated with the development of cirrhosis and hepatocellular carcinoma (HCC), and the response to interferon therapy in Taiwanese patients. We undertook to study the prevalence and significance of HBV genotypes in the Indian subcontinent. METHODS: One hundred and thirty histopathologically proven chronic HBV-infected patients, including 52 incidentally detected asymptomatic hepatitis B surface antigen (HBsAg)-positive subjects (IDAHS) with chronic HBV infection (group I), 48 cirrhotics (group II) and 30 hepatocellular carcinoma (HCC; group III) patients were studied. Hepatitis B virus genotypes were determined by using restriction fragment length polymorphism, and direct sequencing of the s gene including the 'a' determinant region. RESULTS: Only genotypes A (46%) and D (48%) were found in the chronic HBV-infected patients. A mixed infection with genotypes A and D was seen in 6% of patients. Genotype A was found in 42, 48 and 50%, and genotype D in 48, 50 and 47% of group I, II and III patients, respectively (P = NS). The patients who had mixed genotypes were significantly younger (P < 0.05). In group I (IDAHS) patients infected with genotype D, none had a histological activity index (HAI) of < four. Genotype D was significantly more common in group I patients with HAI > 4 as compared to genotype A (53 vs 32%, P < 0.05). Similarly, genotype D was associated with more severe liver diseases (61 vs 30%, P < 0.05). Genotype D was more prevalent in HCC patients of < 40 years of age, as compared to IDAHS (63 vs 44%, P = 0.06). CONCLUSIONS: (i) Hepatitis B virus genotypes A and D are prevalent in chronic liver disease patients of Indian origin; and (ii) HBV genotype D is associated with more severe diseases and may predict the occurrence of HCC in young patients.

BACKGROUND AND AIMS: Hepatorenal syndrome (HRS) is characterized by functional renal failure in end-stage liver disease. Terlipressin is the drug of choice for treating type 1 HRS (HRS-1). It is expensive and often not readily available. We, in an open label, randomized, pilot trial, compared the efficacy of terlipressin and noradrenaline on the renal functions and clinical outcome of patients with HRS-1 and also sought predictors of response. PATIENTS AND Forty consecutive patients with HRS-1 were randomized to receive noradrenaline 0.5-3.0 mg/h and METHODS: albumin (group A, N = 20) or terlipressin 0.5-2 mg, 6 hourly and albumin (group B, N = 20), until reversal of HRS (primary end point) or completion of 15 days of therapy (secondary end point). Systemic and renal parameters were monitored. Baseline parameters and delta creatinine at day 4 (DCD4) were used to predict response. RESULTS: The two groups were comparable at baseline. At similar time points, 10 (50%) patients in each group achieved primary end points. Patients in both groups had a significant (P < 0.05) decrease in serum creatinine from baseline (group A day 4 2.4 +/- 1.2 mg/dL, day 8 1.6 +/- 1.2 mg/dL, and day 15 1.0 +/- 0.4 mg/dL; group B day 4 2.5 +/- 1.5 mg/dL, day 8 1.8 +/- 0.9 mg/dL, and day 15 1.2 +/- 0.5 mg/dL) and progressive increase in creatinine clearance (group A day 4 26.5 +/- 12.8 mL/min and day 15 59.8 +/- 14.2 mL/min; group B day 4 31.4 +/- 21.4 mL/min and day 15 54.9 +/- 27.5 mL/min, P < 0.05). Median baseline plasma renin activity was reduced from 38.0 and 42.0 ng/mL/h to 3.0 and 8.0 ng/mL/h (P= 0.08) in groups A and B, respectively. Mean arterial BP and urine output significantly increased in both groups with therapy. Eleven (55%) patients in group A (10 responders) and an equal number in group B (8 responders) survived until day 15 (P= 0.798). Reversible cardiac ischemia was seen in one patient in each group. Noradrenaline therapy was significantly less expensive than terlipressin. On univariate analysis, the following baseline parameters predicted response to therapy: lower grade of encephalopathy, lower MELD score, higher creatinine clearance, higher mean arterial pressure (MAP), and lower plasma renin activity. However, on multivariate analysis only baseline creatinine clearance, MAP, and plasma renin activity were independent predictors of response. At day 4 of therapy, DCD4 was computed and a value of 0.15 mg/dL/day or more accurately predicted response. The sensitivity, specificity, positive predictive value, and negative predictive value for DCD4 0.15 mg/dL/day for predicting response to therapy were 90%, 75%, 78%, and 88%, respectively. CONCLUSIONS: Noradrenaline may be an effective and safe alternative to terlipressin in improving renal functions. Various baseline parameters and DCD4 can be used to predict response to therapy.

The Asian Pacific Association for the Study of the Liver (APASL) had set up a working party on portal hypertension in 2002 with a mandate to develop consensus on various aspects of portal hypertension. The first of these consensuses has been developed on extra-hepatic portal vein obstruction (EHPVO). It was discussed and prepared by the experts in this field from the Asian region and was presented at the annual meeting of the APASL, at Bali in August 2005. This article summarizes all the consensus statements approved by the APASL on various aspects of EHPVO.

UNLABELLED: Spontaneous reactivation of chronic hepatitis B (CHB) is an important cause of acute-on-chronic liver failure (ACLF). Antiviral drugs may help reduce the high morbidity and mortality in such patients, especially in places where liver transplant is not available. The aim was to evaluate the efficacy of tenofovir and to determine the predictors of mortality in patients with spontaneous reactivation of CHB with ACLF. Consecutive patients of ACLF due to spontaneous reactivation of CHB were randomized to receive either tenofovir or placebo. The primary endpoint was survival at 3 months. Of the 90 patients with ACLF of different etiologies, 27 (26%) were due to reactivation of CHB and were enrolled. The median baseline hepatitis B virus (HBV) DNA level was 9 × 10(5) IU/mL. Fourteen patients received tenofovir and 13 placebo. At 3 months the probability of survival was higher in the tenofovir than the placebo group (8/14 [57%] versus 2/13 [15%], respectively; P = 0.03). The cause of death in the 15 patients was progressive liver failure leading to multiorgan failure. Liver transplantation could not be offered due to its nonavailability. In the surviving patients, there was a significant improvement in the Child-Turcotte Pugh (CTP) and model for endstage liver disease (MELD) scores and significant decline in the HBV DNA levels in the tenofovir group, whereas these parameters did not change significantly in the placebo group. More than 2 log reduction in HBV DNA levels at 2 weeks was found to be an independent predictor of survival. CONCLUSION: Tenofovir significantly reduces HBV-DNA levels, improves CTP and MELD scores, and reduces mortality in patients with severe spontaneous reactivation of CHB presenting as ACLF. Reduction in HBV-DNA levels at 2 weeks should be a desirable goal and is a good predictor of survival.

Development of gastric varices is an important manifestation of portal hypertension. In segmental portal hypertension, gastric varices originate from short gastric and gastroepiploic veins. In generalized portal hypertension, intrinsic veins at cardia participate in the formation of gastric varices. Endoscopy and/or splenoportovenography and a high index of suspicion are required for the diagnosis of gastric varices. The incidence of gastric varices in patients with portal hypertension has been variably reported (2-70%), probably due to difficulties in diagnosis. In a small proportion of patients with gastric varices, chronic portal-systemic encephalopathy or significant variceal bleeding develops. Gastric varices can be classified, depending on their anatomical location, into gastroesophageal varices (a continuation of esophageal varices) or "isolated" gastric varices (fundal or ectopic varices). This distinction is necessary for management. Whereas surgery is recommended for bleeding fundal varices, in acute bleeding from gastroesophageal varices, sclerotherapy could be attempted successfully. In more than a quarter of patients, gastric varices disappear after obliteration of esophageal varices. Prophylactic sclerotherapy of gastric varices is not recommended.

Atherosclerosis is the root cause of the biggest killer of the 21st century. Mechanisms contributing to atherogenesis are multiple and complex. A number of theories-including the role of dyslipidemia, hypercoagulability, oxidative stress, endothelial dysfunction, and inflammation and infection by certain pathogens-have been propounded from time to time explain this complex phenomenon. Recently it has been suggested that atherosclerosis is a multifactorial, multistep disease that involves chronic inflammation at every step, from initiation to progression, and that all the risk factors contribute to pathogenesis by aggravating the underlying inflammatory process. A better understanding of the pathogenesis of atherosclerosis will aid in devising pharmaceutical and lifestyle modifications for reducing mortality resulting from coronary artery disease (CAD).A comprehensive literature search was conducted using the Web sites of the National Library of Medicine (http:// www.ncbl.nlm.nih.gov/) and PubMed Central, the US National Library of Medicine's digital archive of life sciences literature (http:// www.pubmedcentral.nih.gov/). The data were accessed from books and journals in which relevant articles in this field were published. The whole spectrum of coronary artery disease evolves through various events that lead to the formation and progression of atherosclerotic plaque and finally its complications. Atherosclerosis is the culprit behind coronary artery disease, cerebral vascular disease, and peripheral vascular disease. The pathogenic mechanisms are varied and complex. Of late, the role of lipoprotein (a), homocysteine, and inflammation and infection as prime culprits in pathogenesis of CAD is the subject of intense research and debate. The appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework to understand the clinical benefits of newer therapeutic strategies, and a better understanding of pathogenesis aids in formulating preventive and therapeutic strategies in reducing mortality resulting from CAD.An in-depth knowledge of the various pathogenic mechanisms involved in atherosclerosis can help in substantiating the current existing knowledge about the CAD epidemic. This knowledge will help clinicians to better manage the disease, which affects Indians in its most severe form.

A randomized, open-label comparative study of entecavir versus adefovir therapy was performed in subjects with chronic hepatitis B who had hepatic decompensation (Child-Turcotte-Pugh score ≥7). Adult subjects were randomized and treated (n = 191) with entecavir 1.0 mg or adefovir 10 mg daily for up to 96 weeks from the date of last subject randomization. Subjects were positive or negative for hepatitis B e antigen and experienced or naive for treatment with nucleos(t)ide analogues. The primary efficacy endpoint was the mean reduction in serum hepatitis B virus (HBV) DNA, as determined by polymerase chain reaction, at week 24, adjusted for baseline HBV DNA and lamivudine resistance status by linear regression analysis. Entecavir demonstrated superiority to adefovir for this endpoint (treatment difference 1.74 log(10) copies/mL [95% confidence interval -2.30, -1.18]; P < 0.0001). The entecavir group showed a greater change from baseline in HBV DNA at all time points through week 48 and a higher proportion of subjects who achieved HBV DNA < 300 copies/mL at weeks 24 (entecavir 49%; adefovir 16%; P < 0.0001) and 48 (entecavir 57%; adefovir 20%; P < 0.0001). Approximately two-thirds of subjects in both groups showed improvement/stabilization in Child-Turcotte-Pugh status. Model for End-Stage Liver Disease score change at week 48 was -2.6 for entecavir and -1.7 for adefovir. Adverse event rates were comparable between groups. Cumulative hepatocellular carcinoma rates were 12% for entecavir and 20% for adefovir. Cumulative death rates were 23% for entecavir and 33% for adefovir. Week 24 mortality rates were 12% for both groups. conclusion: Entecavir demonstrated superior virologic efficacy to adefovir in a population of patients with chronic hepatitis B who had hepatic decompensation. Biochemical and clinical benefits were also demonstrated. Entecavir was well tolerated, and early mortality rates were consistent with rates observed in similar populations treated with lamivudine.

Sepsis associated encephalopathy (SAE) is a common but poorly understood neurological complication of sepsis. It is characterized by diffuse brain dysfunction secondary to infection elsewhere in the body without overt CNS infection. The pathophysiology of SAE is complex and multifactorial including a number of intertwined mechanisms such as vascular damage, endothelial activation, breakdown of the blood brain barrier, altered brain signaling, brain inflammation, and apoptosis. Clinical presentation of SAE may range from mild symptoms such as malaise and concentration deficits to deep coma. The evaluation of cognitive dysfunction is made difficult by the absence of any specific investigations or biomarkers and the common use of sedation in critically ill patients. SAE thus remains diagnosis of exclusion which can only be made after ruling out other causes of altered mentation in a febrile, critically ill patient by appropriate investigations. In spite of high mortality rate, management of SAE is limited to treatment of the underlying infection and symptomatic treatment for delirium and seizures. It is important to be aware of this condition because SAE may present in early stages of sepsis, even before the diagnostic criteria for sepsis can be met. This review discusses the diagnostic approach to patients with SAE along with its epidemiology, pathophysiology, clinical presentation, and differential diagnosis.