Hitendra Garg

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.

Granulocyte Colony–Stimulating Factor Mobilizes CD34+ Cells and Improves Survival of Patients With Acute-on-Chronic Liver Failure

BACKGROUND & AIMS Acute-on-chronic liver failure (ACLF) develops in patients with chronic liver disease and has high mortality. Mobilization of bone marrow-derived stem cells with granulocyte colony-stimulating factor (G-CSF) could promote hepatic regeneration. METHODS Consecutive patients with ACLF were randomly assigned to groups given 5 μg/kg G-CSF subcutaneously (12 doses; group A, n = 23) or placebo (group B, n = 24) plus standard medical therapy. We assessed survival until day 60; Child-Turcotte-Pugh (CTP), Model for End-Stage Liver Disease (MELD), and Sequential Organ Failure Assessment (SOFA) scores; and the development of other related complications. RESULTS After 1 week of treatment, group A had higher median leukocyte and neutrophil counts than group B (P < .001). Sixteen patients in group A (69.6%) and 7 in group B (29%) survived; the actuarial probability of survival at day 60 was 66% versus 26%, respectively (P = .001). Treatment with G-CSF also reduced CTP scores in group A by a median of 33.3% compared with an increase of 7.1% in group B (P = .001), along with MELD (median reduction of 15.3% compared with an increase of 11.7% in group B; P = .008) and SOFA scores (median reduction of 50% compared with an increase of 50% in group B; P = .001). The percentages of patients who developed hepatorenal syndrome, hepatic encephalopathy, or sepsis were lower in group A than in group B (19% vs 71% [P = .0002], 19% vs 66% [P = .001], and 14% vs 41% [P = .04], respectively). After 1 month of treatment, G-CSF increased the number of CD34(+) cells in the liver (by 45% compared with 27.5% in group B; P = .01). CONCLUSIONS G-CSF therapy more than doubles the percentage of patients with ACLF who survive for 2 months; it also significantly reduces CTP, MELD, and SOFA scores and prevents the development of sepsis, hepatorenal syndrome, and hepatic encephalopathy.

Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure.

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 × 105 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. (HEPATOLOGY 2011;.)

Clinical profile and predictors of mortality in patients of acute-on-chronic liver failure

BACKGROUND Acute-on-chronic liver failure (ACLF) is characterised by acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in patients with previously diagnosed or undiagnosed chronic liver disease. We studied the clinical, biochemical and etiological profiles of ACLF patients investigating variables which could predict mortality. METHODS Consecutive ACLF patients were enrolled and given standard intensive care management. They were monitored for predictors of 90-day mortality. RESULTS 91 patients were included; besides jaundice (median bilirubin 23.1mg/dL) and coagulopathy, acute onset ascites with or without encephalopathy was the presenting symptom in 92%. In all patients a first diagnosis of chronic liver disease was made, mainly due to hepatitis B (37%) or alcohol (34%). Reactivation of chronic hepatitis B and alcoholic hepatitis were the common acute insults. The 90-day mortality was 63%. On multivariate analysis, hepatic encephalopathy, low serum sodium, and high INR were found to be independent baseline predictors of mortality. Amongst all severity scores studied, MELD, SOFA and APACHE-II scores had AUROCs of >0.8 which was significantly higher than that of Child-Turcotte-Pugh. CONCLUSIONS ACLF has very high mortality. Hepatic encephalopathy, low serum sodium and high INR predict poor outcome. Mortality can also be predicted by baseline MELD, SOFA or APACHE-II scores.

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.

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.

Propofol sedation during endoscopy in patients with cirrhosis, and utility of psychometric tests and critical flicker frequency in assessment of recovery from sedation.

BACKGROUND AND STUDY AIMS Patients with cirrhosis who undergo endoscopy under sedation could be at increased risk of complications. We assessed the utility of the critical flicker frequency (CFF) in the recovery of cognitive function. PATIENTS AND METHODS This was a prospective study in patients with cirrhosis who underwent endoscopy under sedation with propofol in a tertiary care center. The main outcome was deterioration in cognitive function as measured by the number connection test A and B (NCT-A, -B), digit symbol test (DST), serial dotting test (SDT), and line tracing test (LTT) before and 2 h after endoscopy. CFF was recorded before and then every 30 min after endoscopy for the next 2 h. RESULTS In the 108 patients there was no deterioration in results of the psychometric tests after the endoscopy (NCT-A 65.2 ± 44.4 vs. 62.4 ± 43.6 s, P = 0.01; NCT-B 110.4 ± 34.7 vs. 109.6 ± 44.6 s, P = 0.45; DST 26.2 ±1 0.0 vs. 26.7 ± 9.9, P = 0.25; SDT 88.6 ± 47.5 vs. 84.3 ± 44.1 s, P = 0.02; LTT 116.6 ± 55.2 vs. 115.4 ± 51.3 s, P = 0.47.) Patients with minimal hepatic encephalopathy (MHE; n = 64) did not show any deterioration in cognitive function at 2 h (NCT-A 87.7 ± 45.4 vs. 84.3 ± 44.9 s, P = 0.06; NCT-B 134.8 ± 65.4 vs. 132.7 ± 58.8 s, P = 0.46; DST 21.4 ± 8.9 vs. 22.2 ± 8.8, P = 0.09; SDT 107.1 ± 53.0 vs. 102.7 ± 48.5 s, P = 0.03; and LTT 131.5 ± 62.2 vs. 129.6 ± 57.2 s, P = 0.46). There was a significant difference between CFF at baseline and at 30 min and 1 h but no difference thereafter in non-MHE patients, MHE patients, and in controls. A total of 30 patients (28 %) had CFF < 38 Hz. In these patients, CFF at 2 h did not significantly differ from baseline CFF (35.9 ± 1.5 vs. 36.1 ± 2.0 Hz; P = 0.19). A total of 10 patients (9 %) had transient hypoxemia and 18 (17 %) had hypotension during the procedure. The endoscopy was completed in all patients. CONCLUSIONS Propofol is safe in patients with cirrhosis and the CFF is a useful tool for the assessment of recovery from sedation in these patients.

Altered Frequencies of Dendritic Cells and IFN‐γ‐secreting T Cells with Granulocyte Colony‐Stimulating Factor (G‐CSF) Therapy in Acute‐on‐Chronic Liver Failure

Acute‐on‐chronic liver failure (ACLF) is a serious hepatic ailment with impaired immunity and poor treatment options resulting high mortality. Treatment with granulocyte colony‐stimulating factor (G‐CSF) mobilizes CD34+ cells in ACLF patients; however its effect on impaired immune responses remains to be elucidated. To analyse the effect of G‐CSF in immune modulation in ACLF.

Hepatic and systemic hemodynamic derangements predict early mortality and recovery in patients with acute-on-chronic liver failure

Acute‐on‐chronic liver failure (ACLF) is a clinical entity where there is a potential for reversibility of hepatic dysfunction once the acute hepatic insult resolves. The portal and systemic hemodynamics in ACLF patients to study its relevance in determining the clinical outcomes was studied.