Archana Rastogi

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL)

The Asian Pacific Association for the Study of the Liver (APASL) set up a working party on acute-on-chronic liver failure (ACLF) in 2004, with a mandate to develop consensus guidelines on various aspects of ACLF relevant to disease patterns and clinical practice in the Asia-Pacific region. Experts predominantly from the Asia–Pacific region constituted this working party and were requested to identify different issues of ACLF and develop the consensus guidelines. A 2-day meeting of the working party was held on January 22–23, 2008, at New Delhi, India, to discuss and finalize the consensus statements. Only those statements that were unanimously approved by the experts were accepted. These statements were circulated to all the experts and subsequently presented at the Annual Conference of the APASL at Seoul, Korea, in March 2008. The consensus statements along with relevant background information are presented in this review.

From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

Sequential progression from chronic liver disease to fibrosis and to cirrhosis culminates in neoplasia in hepatocellular carcinoma (HCC). The preneoplastic setting of the cirrhotic background provides a conducive environment for cellular transformation. The role of classical inflammation in cirrhosis is widely known, but the exact mechanism linking inflammation and cancer remains elusive. Recent studies have elucidated roles for NF-κB, STAT3 and JNK as possible missing links. In addition, the “inflammasome” (a multiprotein complex and sensor of cellular damage) is a recently identified player in this field. The hallmarks of cirrhosis include necroinflammation, deposition of extracellular matrix and shortening of telomeres, leading to senescence and regeneration. Additionally, the accumulation of genetic/epigenetic changes propels atypical cells toward a malignant phenotype. This review provides recent information on the classical inflammatory pathway, together with a spotlight on inflammasomes and the immunomodulatory role of cellular senescence during the progression from cirrhosis to HCC. Moreover, lacunae in the current knowledge were identified and key questions raised on whether the observed adaptive responses are beneficial or detrimental to tissue homeostasis in a complex organ like liver.

Histopathological features and accuracy for diagnosing biliary atresia by prelaparotomy liver biopsy in developing countries

Background and Aim:  A major challenge in neonatal cholestasis (NC) is to differentiate biliary atresia (BA) from other non‐atretic causes. In developing countries there are considerable problems of late referral of NC cases and performing surgery without prelaparotomy liver biopsy that contributes to a high proportion of negative laparotomy and increased morbidity. We evaluated the hepatic histopathology for presence of features that correlate best with the diagnosis of BA and assessed the accuracy of percutaneous liver biopsy.

Controlled attenuation parameter for non‐invasive assessment of hepatic steatosis: Does etiology affect performance?

Hepatic steatosis is an important parameter to assess in chronic liver disease patients. The controlled attenuation parameter (CAP) assesses liver steatosis using transient elastography.

Combination of Granulocyte Colony-Stimulating Factor and Erythropoietin Improves Outcomes of Patients With Decompensated Cirrhosis

BACKGROUND & AIMS Patients with decompensated cirrhosis have significantly reduced survival without liver transplantation. Granulocyte colony-stimulating factor (G-CSF) has been shown to increase survival in patients with acute-on-chronic liver failure, and erythropoietin promoted hepatic regeneration in animal studies. We performed a double-blind, randomized, placebo-controlled trial to determine whether co-administration of these growth factors improved outcomes for patients with advanced cirrhosis. METHODS In a prospective study, consecutive patients with decompensated cirrhosis seen at the Institute of Liver and Biliary Sciences, New Delhi (from May 2011 through June 2012) were randomly assigned to groups given subcutaneous G-CSF (5 μg/kg/d) for 5 days and then every third day (12 total doses), along with subcutaneous darbopoietin α(40 mcg/wk) for 4 weeks (GDP group, n = 29), or only placebos (control group, n = 26). All patients also received standard medical therapy and were followed for 12 months. Histology was performed on liver biopsies. The primary end point was survival at 12 months. RESULTS Baseline characteristics of patients were comparable; alcohol intake was the most common etiology of cirrhosis. A higher proportion of patients in the GDP group than controls survived until 12 months (68.6% vs 26.9%; P = .003). At 12 months, Child-Turcotte Pugh scores were reduced by 48.6% in the GDP group and 39.1% in the control group, from baseline (P = .001); Model for End Stage Liver Disease scores were reduced by 40.4% and 33%, respectively (P = .03). The need for large-volume paracentesis was significantly reduced in GDP group, compared with controls (P < .05). A lower proportion of patients in the GDP group developed septic shock (6.9%) during follow-up compared with controls (38.5%; P = .005). No major adverse events were observed in either group. CONCLUSIONS In a single-center randomized trial, a significantly larger proportion of patients with decompensated cirrhosis given a combination of G-CSF and darbopoietin α survived for 12 months more than patients given only placebo. The combination therapy also reduced liver severity scores and sepsis to a greater extent than placebo. Clinicaltrials.gov ID: NCT01384565.

Insulin resistance in chronic hepatitis B virus infection.

OBJECTIVES:Chronic hepatitis C virus infection is associated with insulin resistance (IR), and both host and viral factors are important in its development. The association and the predictors of IR in chronic hepatitis B virus (CHBV) infection remain unclear.METHODS:A total of 69 CHBV-infected subjects were examined to study the relationship between histological findings and anthropometric and biochemical data, including IR determined by the homeostasis model assessment (HOMA–IR). To assess the influence of CHBV infection on IR independent of any effect of hepatic fibrosis, overweight, or sex we also compared fasting serum insulin, C-peptide, HOMA–IR, HOMA-β (measure of β-cell function) and C-peptide–insulin ratio (to distinguish impaired insulin degradation (low ratio) from insulin hypersecretion (normal ratio)) levels between the subset of 14 male normal weight (body mass index, BMI<23) CHBV patients with stage 0 or 1 hepatic fibrosis and 50 male normal weight healthy controls matched by age and anthropometry (BMI and waist circumference).RESULTS:A total of 31 (44.9%) CHBV-infected patients were overweight (BMI>23 kg/m2) and 18 (26.1%) were obese (BMI>25 kg/m2). IR was seen in 34 (49.3%) patients. BMI (Spearmans coefficient=−0.436; P<0.001) and serum triglyceride levels (Spearmans coefficient=−0.307; P=0.010) were univariate predictors of IR. In multiple linear regression analysis, only BMI (P<0.001) was an independent predictor of HOMA–IR. The subgroup of CHBV-infected patients and the controls had comparable levels of all markers of IR, including fasting glucose, insulin, C-peptide, and HOMA–IR.CONCLUSIONS:IR in CHBV-infected patients is a reflection of the host metabolic profile and CHBV infection is not in itself correlated with IR.

Steatosis in chronic hepatitis B: Prevalence and correlation with biochemical, histologic, viral, and metabolic parameters

BACKGROUND AND AIMS Hepatic steatosis (HS) is highly prevalent in chronic hepatitis C and is an important variable predicting progression of histological injury, insulin resistance, and reduced response to antiviral therapy. There are limited data on HS in patients with chronic hepatitis B (CHB). This is relevant since response to current antiviral therapies for CHB is rather limited. We investigated the spectrum and predictors of HS in CHB patients. MATERIALS AND METHODS Liver biopsies of consecutive patients of chronic Hepatitis B Virus (HBV) infection were studied and were categorized as: Group I - hepatosteatosis (>5%) and Group II - no steatosis (£5%). Anthropometric, histological, biochemical, virological, and metabolic determinants were compared. Logistic regression analysis was applied to identify variables that were independently associated with the presence of steatosis. RESULTS Of the 350 patients, 118 (33.7%) liver biopsies showed steatosis (Group I); 65 (55.1%) had mild (6 to <25%) and 53 (44.9%) had moderate to severe steatosis ((3)25%). Patients in group I, compared with group II, were older (35.5 ± 10.5 vs 27.9 ± 14.0 years, P < 0.01), predominantly male (M: F, 10.8: 1 vs 4.8: 1, P = 0.035), obese (75.0% vs 23.4%, P P < 0.01), with higher triglycerides (138.8 ± 62.1 vs 88.0 ± 27.9, P = 0.02), with higher cholesterol (171.9 ± 43.5 vs 139.3 ± 37.6, P = 0.017), and with higher serum insulin (13.1 ± 9.1 vs 9.1 ± 6.0, P < .027) levels. HBV DNA level was significantly lower in group I than group II; however, HBV genotype did not influence HS. By multivariate regression analysis, only high serum triglyceride level was independent parameter associated with HS. CONCLUSIONS Steatosis is seen in one-third cases with HBV-related chronic liver disease and is associated with host metabolic factors, especially serum triglyceride levels, whereas HBV DNA level negatively correlated with HS.

Hepatic venous pressure gradient as a predictor of fibrosis in chronic liver disease because of hepatitis B virus.

Background: Liver biopsy has been considered to be a gold standard for assessing hepatic fibrosis. Sample variability, interobserver variability and step‐wise evaluation limit its use. Hepatic venous pressure gradient (HVPG) correlates with hepatic fibrosis in chronic liver disease (CLD) because of hepatitis C.

Clinicopathological characteristics and metabolic profiles of non-alcoholic fatty liver disease in Indian patients with normal body mass index: Do they differ from obese or overweight non-alcoholic fatty liver disease?

Background: Obesity is an important risk factor for non-alcoholic fatty liver disease (NAFLD); however, NAFLD does occur in lean subjects. This study was aimed to evaluate the magnitude, clinical, pathological, and metabolic profiles of NAFLD in normal body mass index (BMI) subjects (defined as lean NAFLD) in comparison to overweight or obese NAFLD and lean healthy control. Materials and Methods: 336 subjects (205 consecutive NAFLD, and 131 healthy controls) were studied. Results: Among 205 NAFLD patients, 27 (13.2%) were lean, while 141 (68.8%) and 37 (18%) patients were obese and overweight, respectively. The lean NAFLD compared to obese NAFLD had significantly lesser degree of fasting hyperinsulinemia (P < 0.001), homeostasis model assessment insulin resistance (HOMA-IR, P < 0.001), and lower prevalence of diabetes mellitus (P = 0.01) and metabolic syndrome (P < 0.001). The profiles of serum lipids were similar between all 3 BMI categories, and 89% of lean NAFLD were dyslipidemic. Compared to obese subjects, patients with lean NAFLD had less hepatic necro-inflammation (P = 0.05) and fibrosis (P < 0.001). However, the proportion of steatohepatitis and advanced fibrosis were similar between all BMI categories. The profiles of overweight NAFLD were similar to those of lean NAFLD, except for higher HOMA-IR, uric acids and male gender in overweight group. Despite being lean, the mean BMI of lean NAFLD were still higher than unselected lean healthy controls (P = 0.02). Conclusions: Lean NAFLD patients have less severe disease, minor, or no insulin resistance, but are frequently dyslipidemic and have BMI higher than lean healthy control.

Cirrhosis histology and Laennec staging system correlate with high portal pressure

To correlate cirrhosis histology and Laennec fibrosis scoring with portal pressure, as determined by hepatic venous pressure gradient (HVPG).