Efficacy of Granulocyte Colony-stimulating Factor in the Management of Steroid-Nonresponsive Severe Alcoholic Hepatitis: A Double-Blind Randomized Controlled Trial.

Severe alcoholic hepatitis (SAH) is often a progressive disease with high mortality and limited steroid responsiveness. Management options of steroid nonresponsive SAH (day 7 Lille score > 0.45) are limited. We assessed the efficacy and safety of granulocyte colony-stimulating factor (G-CSF) in steroid nonresponders. A randomized, double-blind, single-center trial (NCT01820208) was conducted between March 2013 and June 2016 in patients with histologically proven SAH, nonresponsive to 40 mg/day of prednisolone were randomized to G-CSF (12 doses, 300 µg each in 28 days) or placebo. Responders were continued with prednisolone. Of the 430 patients with SAH, 132 received steroid therapy. Of these, 33 (25%) were nonresponders and were randomized to G-CSF or placebo (14 in each group after exclusions). The baseline characteristics of both groups were comparable. The 28-day mortality was comparable between the groups (21.4%, G-CSF; 28.6%, placebo; P = 0.69). At 90 days, in the G-CSF but not in the placebo group, the Model for End-Stage Liver Disease reduced from 24.6 ± 3.9 to 19.4 ± 3.7 (P = 0.002) and Maddrey's discriminant function from 74.8 ± 22.8 to 57.4 ± 31 (P = 0.26). Infections were less common (28% versus 71%; P < 0.001) with lower 90-day mortality (35.7% versus 71.4%; P = 0.04) in the G-CSF than in the placebo group. On Cox regression analysis, receiving G-CSF (hazard ratio, 0.37; SD, 0.14-0.98; P = 0.04), and high baseline serum creatinine (hazard ratio, 4.12; SD, 1.7-10.3; P = 0.002) predicted day-90 outcomes in steroid nonresponsive SAH. Patients tolerated G-CSF without any major adverse events. Conclusion: Approximately one-quarter of patients with SAH do not respond to corticosteroid therapy. Administration of G-CSF is safe and helps to reduce the disease severity and 90-day mortality in these patients.

Positive familial history for metabolic traits predisposes to early and more severe alcoholic cirrhosis: A cross-sectional study.

BACKGROUND & AIMS: Familial aggregation of metabolic traits in NAFLD is well documented. However, relevance of these traits in alcoholic cirrhosis is not well studied. We aimed to explore the association of family history of metabolic traits with age at diagnosis, severity and complications of alcoholic cirrhosis. METHODS: In a cross-sectional study, all consecutive patients with alcoholic cirrhosis presenting to our tertiary care centre were included. Family and personal history, demographic characteristics, medical history, anthropometric measurements and laboratory data were recorded. The amount and duration of alcohol consumption were also carefully recorded. RESULTS: Out of 1084 alcoholic cirrhotics (age 48.5 ± 10.1 years, all males), family history for metabolic traits was documented in 688 (63.5%) patients. These patients had younger age at diagnosis, increased incidence of jaundice, ascites, variceal bleed and hepatic encephalopathy with consequently higher MELD and CTP score. These patients developed cirrhosis despite shorter median duration (13 years, IQR 7-20 vs 21, IQR 18-25) and lesser amount of alcohol consumption (74 g/d, IQR 24-96 vs 144, IQR 100-148). Patients with both family and personal history of metabolic traits had a higher risk by 3.3 times (95% CI 2.2-4.8) of an early age at diagnosis, 13.2 times (95% CI 8.7-20.1) of progression to cirrhosis with lesser amount of alcohol consumption and 4.6 times (95% CI 3.1-6.9) with lesser duration of alcohol consumption. CONCLUSIONS: Positive family and personal history of metabolic traits predispose to alcoholic cirrhosis with an earlier age at onset and more severity despite lesser exposure to alcohol.

Impact of family history of metabolic traits on severity of non-alcoholic steatohepatitis related cirrhosis: A cross-sectional study.

BACKGROUND & AIMS: Familial aggregation of metabolic traits with fatty liver disease is well documented. However, there is scarcity of data regarding such association with non-alcoholic steatohepatitis (NASH)-related cirrhosis. This study was aimed to explore the association of family history of metabolic traits with severity of cirrhosis. METHODS: In a cross-sectional study, all consecutive patients with NASH-related cirrhosis presenting to our tertiary care centre were included. Family history, personal history, demographic characteristics, medical history, anthropometric measurements and laboratory data were recorded. RESULTS: Of the 1133 cirrhotics (68.1% males, age 51.4±10.9 years); 779 (68.8%) had family history for metabolic traits. These patients had lower age at diagnosis (45.4±10.6 vs 49.6±11.2 years), higher Child-Turcotte-Pugh (CTP) score (7.8±1.9 vs 6.6±1.5), higher model for end stage liver disease (MELD) score (12.9±6.1 vs 10.9±4.1) and more incidence of decompensation in the form of ascites (46.3% vs 25.7%), jaundice (12.1% vs 6.2%) and hepatic encephalopathy (26.1% vs 11.0%). Patients with family and personal history of metabolic traits, had an increased risk of an early diagnosis of cirrhosis at<45 years of age (OR: 3.1, 95% CI 2.1-4.4), CTP≥10 (OR: 4.6, 95% CI 2.3-9.1), MELD>15 (OR: 6.6, 95% CI 3.8-11.5) with ≥1 features of decompensation (OR: 4.2, 95% CI 2.9-6.1). Family history of diabetes alone, also had higher risk of cirrhosis with MELD>15 (OR: 4.3, 95% CI 2.4-5.3, P<.001). CONCLUSION: Family and personal history of metabolic traits are associated with early age at diagnosis of cirrhosis with more severity and decompensation and so, has a prognostic importance in NASH-related cirrhotics.

Characterization of body composition and definition of sarcopenia in patients with alcoholic cirrhosis: A computed tomography based study.

BACKGROUND: Alterations in body composition (BC) as loss of fat and muscle mass (sarcopenia) are associated with poor outcome in alcoholic cirrhosis (ALC). Prevalence of sarcopenia depends upon the method of assessment. Computed Tomography (CT) is a gold standard tool for assessing BC. AIM: To characterize BC and define sarcopenia in ALC patients using CT. METHODS: Single slice CT images at L3 vertebrae of healthy controls (HC) - organ transplant donors and ALC patients were analysed to give cross-sectional area of five skeletal muscles normalized for height -skeletal muscle index (SMI; cm2 /m2 ), area of subcutaneous (SAT;cm2 ) and visceral adipose tissue (VAT;cm2 ). Cut-offs for defining sarcopenia was established at 2SD below the mean of HC. HC were compared with Child A-compensated (C) and Child B+C-decompensated (DC) patients. RESULTS: Cut-offs of SMI derived from HC (n = 275; M: 50%; age 32.2 ± 9.8 years; BMI 24.2 ± 3.2 Kg/m2 ) were 36.54 in males and 30.21 in females. Sarcopenia was found in 12.8% of ALC patients [n = 148; C (31.8%): DC (68.2%); M: 100%; age 46.6 ± 9.7 years; BMI 24.5 ± 4.4]. Compared to HC, compensated patients had higher adiposity and comparable muscularity; decompensated patients had significantly lower muscle and also fat mass compared to both HC and compensated patients. HC vs C vs DC: SAT (140 ± 82 vs 177.3 ± 11 vs 112 ± 8.2); VAT (96.5 ± 6.5 vs 154.9 ± 8.7 vs 87.5 ± 6.5) and SMI (52.1 ± 0.9 vs 49.6 ± 1.2 vs 46 ± 0.9). CONCLUSIONS: Compensated ALC have increased adiposity and relatively preserved muscularity but decompensation leads to loss of both muscle and fat mass. Prevalence of sarcopenia, based on derived ethnic cut-offs was 12.8%.

Handgrip strength: Best practice for a rapid nutrition screening and risk stratification in male patients with alcoholic liver cirrhosis, a classification and regression tree analysis study.

BACKGROUND: Rapid nutrition screening (NS) is vital for apt management in patients with alcoholic liver cirrhosis (ALC). AIM: To identify a quick method of NS having high reliability and prognostic significance. METHODS: NS of patients with ALC was assessed using mid-upper arm circumference (MUAC), handgrip strength (HGS), fat-free mass index (FFMI), and the Royal Free Hospital-Global Assessment (RFH-GA). Baseline clinical and biochemical information were recorded along with 90-day survival data. The classification and regression tree method was used to classify HGS, MUAC, and FFMI values as well nourished (WN), moderately malnourished (MM), and severely malnourished (SM), and their concordance with RFH-GA categories was assessed using Kendall tau-b coefficient. The prognostic proficiency of each method was tested by Cox regression analysis. RESULTS: According to the RFH-GA, of 140 male patients with ALC, 13 of 140 (9.3%) were WN, 93 of 140 (66.4%) were MM, and 34 of 140 (26.8%) were SM. HGS has the strongest association with the RFH-GA (Kendall tau-b = 0.772; diagnostic accuracy -81.4%). HGS was found to be the independent predictor of 90-day mortality (26 of 140 [18.6%]; hazard ratio, 0.93; 95% CI, 0.88-0.98; P = 0.002) after adjusting for age, body mass index, and disease severity. The hazard of mortality was 8.5-times higher in patients with ALC with HGS < 22 kg as compared with those with HGS > 29. CONCLUSION: HGS is a reliable tool for rapid NS. HGS < 22 kg suggests a high risk for severe malnutrition and is strongly associated with short-term mortality in male patients with ALC.

Sarcopenia is the independent predictor of mortality in critically ill patients with cirrhosis.

Background: Sarcopenia is strongly associated with poor outcome in cirrhosis. There are little prospective data that sarcopenia influences outcomes in critically ill cirrhotics (CICs). Computed tomography (CT) is the gold standard for sarcopenia assessment in the intensive care unit (ICU), as it is independent of hydration status. Aim: This study aims to assess the prevalence of sarcopenia and study its impact on clinical outcomes in CICs. Methods: In this prospective observational study, CICs admitted to the liver ICU were enrolled, if meeting inclusion (age 18-70 years, abdominal CT scan within three months before ICU admission) and exclusion criteria (survival likely to be <24 h, coexisting chronic diseases). Clinical, hemodynamic, biochemical, and nutritional parameters, including length of stay (LOS), duration of mechanical ventilation (MV), development of new-onset infections (NOI), incidence of new-onset acute kidney injury (AKI), and overall survival, were recorded. CT images at the L3 level were analyzed using Slice-O-Matic V4.3 software to assess the skeletal muscle index (SMI) expressed as skeletal muscle area (cm2)/height (m2). Sarcopenia was defined if SMI was <50 cm2/m2 - males and <39 cm2/m2 - females. Data were analyzed using SPSS version 22. Results: Altogether 111 patients (M-83.8%; age 48.4±11.3 years; etiology: Alcohol - 56 [50.5%], non-alcoholic steatohepatitis - 27 [24.3%], viral - 12 [10.8%], and others - 16 [14.4%]; Child-Turcotte-Pugh - 11.9±1.8; model for end-stage liver disease - 27.8±7.3; sequential organ failure assessment - 10.5±4.1; APACHE - 23±8; and MV - 54 [48.6%]) were enrolled. Of these, 76 (68.5%) were sarcopenic and 35 (31.5%) non-sarcopenic. Sarcopenic CICs had higher overall mortality (72.4%) compared to non-sarcopenics (40%) (P=0.001, OR [95% CI] - 3.93 [1.69-9.12]), and higher prevalence of sepsis at ICU admission (53.9% vs. 31.4%, P=0.027, OR [95% CI] - 1.7 [1.0-2.92]) than non-sarcopenics. LOS, duration of MV, incidence of NOI, and development of new-onset AKI were comparable between groups. Multivariate binary logistic regression showed that sarcopenia, sepsis, and APACHE II score were independently associated with mortality. Conclusion: Two-thirds of CICs have sarcopenia at ICU admission, making them 1.7 times more susceptible to sepsis and increasing the risk of mortality by almost 4-fold in the ICU. Relevance for Patients: Almost 70% of patients with chronic liver disease admitted to the ICU have low muscle mass (sarcopenia). The presence of sarcopenia per se makes them highly prone to infections and increases the chances of death by almost 4-fold; thus, highlighting the importance of nutrition optimization in this patient group.

Effect of long-term aggressive nutrition therapy on survival in patients with alcohol-related cirrhosis: A randomized controlled trial.

BACKGROUND: The aim of this study was to assess the effect of long-term aggressive nutritional therapy on clinical outcomes and survival in patients with alcoholic liver cirrhosis (ALC). METHODS: Malnourished patients assessed by Royal Free Hospital-Subjective Global Assessment (RFH-SGA) were randomized to control group (CG) (35-40 kcal and 1.2 g protein/kg/day; diet alone) or intervention group (IG) (40-45 kcal and 1.5 g protein/kg/day; diet plus polymeric formula) for 3 months. Patients were followed up at 3 and 12 months. RESULTS: Malnourished patients (age 44.0 ± 9 years; M [100%]; Child A:B:C [%] = 11:39:50) were randomized to the CG (n = 50) or IG (n = 54); 21 patients in CG and 27 in IG completed 3 months of follow-up. The RFH-SGA improved in 7 (33.3%; p = 0.016) in IG vs. 3 (14.2%; p = 0.625) in CG. Over 3 months, increments (CG vs. IG) were seen in calories (1554 ± 972 to 1823 ± 398; p = 0.001 vs.1542 ± 603 to 2254 ± 372; p=0.001), protein (53.1 ± 18.4 to 72.5 ± 19.6; p = 0.001 vs. 53 ± 21 to 86.9 ± 18.8; p = 0.00), dry body weight (64 ± 10 to 66 ± 11; p = 0.04 vs. 60.8 ± 9.2 to 63.2 ± 10.7; p = 0.009), and mid-upper arm circumference (MUAC) (24.7 ± 3.3 to 25.5 ± 3.3; p = 0.116 vs. 23.5 ± 2.7 to 24.1 ± 2.9; p = 0.015), with better ascites resolution in IG (53.3%; p = 0.008) vs. CG (44.4%; p = 0.227). Median 12-month survival was comparable in both the groups (p = 0.864). Irrespective of the intervention group, energy intake > 25 kcal and protein > 0.8 g/kg/day significantly improved 12-month survival. CONCLUSION: Aggressive nutritional therapy improves nutritional status and resolves ascites, however fails to show long-term survival benefit, though higher calorie and protein intake has the potential to impact survival. TRIAL REGISTRATION: NCT02140294.

Identifying critically ill patients with cirrhosis who benefit from nutrition therapy: the mNUTRIC score study.

Background and Aim: Malnutrition increases risk of mortality in critically ill patients with cirrhosis. Modified Nutrition Risk in Critically ill (mNUTRIC) score is a validated tool to identify at risk patients who may benefit from goal-directed nutrition therapy. We aimed to study the association between mNUTRIC score and 28-day mortality in critically ill patients with cirrhosis. Methods: A prospective study was conducted in the liver intensive care unit of a quaternary teaching institute. Baseline and follow-up data pertaining to mNUTRIC score, clinical, hemodynamic, biochemical, nutritional parameters, mechanical ventilation, length of ICU stay, and development of sepsis were collected. Correlation between mNUTRIC score and its modulation by nutritional adequacy was determined. Results: One hundred and fifty patients were enrolled. Out of these, 116 (77%) had a high NUTRIC score (HNS) and 34 (23%) had a low NUTRIC score (LNS). Patients with HNS had higher mortality (54% vs. 10%; P = 0.008), longer mechanical ventilation (P = 0.02), and high incidence of sepsis (32% vs. 2.6%; P = 0.002) compared to LNS. The probability of survival increased with increase in nutritional adequacy (P < 0.01) in patients with HNS. Conclusion: mNUTRIC score is a useful tool for identifying nutrition risk in critically ill patients with cirrhosis. Goal-directed nutrition therapy in patients with HNS can significantly improve survival. Relevance for Patients: Critically ill patients with cirrhosis who are at a higher nutritional risk as identified by the mNUTRIC score may have a better survival benefit if higher calorie and protein adequacy are achieved in the ICU.

Sarcopenia in Cirrhosis: Fallout on Liver Transplantation.

BACKGROUND: Liver transplantation (LT) is a game changer in cirrhosis. Poor muscle mass defined as sarcopenia may potentially upset the LT scoreboard. AIM: To assess the prevalence and impact of sarcopenia on the intraoperative and early postoperative outcomes in Indian patients undergoing LT. METHODS: Pre LT, single-slice routine computed tomography images at L3 vertebra of 115 LT recipients were analyzed, to obtain cross-sectional area of six skeletal muscles normalized for height in m2 - skeletal muscle index (SMI; cm2/m2). SMI< 52.4 in males and <38.5 in females was called sarcopenia. The intraoperative, postoperative outcome parameters and 90-day mortality were compared between sarcopenics and nonsarcopenics. RESULTS: Sarcopenia was found in 47.8% of patients [M (90.4%); age, 46.3 ± 10; BMI, 24.5 ± 4.3 kg/m2; child A:B:C = 1%:22%:77%; MELD, 20.6 ± 6.3; etiology alcohol: nonalchohol = 53%:47%; Charlson Comorbidity Index (CCI) > 3:≤3 = 56.5%:43.5%]. Sarcopenics vs. Nonsarcopenics; early postoperative complications: [sepsis, 49(89%) vs. 33(55%), P = 0.001; neurologic complications, 16(29.6%) vs. 5(8.8%), P = 0.040; Clavien-Dindo Classification ≥3-24 (43.6%):15 (25.4%),P = 0.041; ancillary parameters (days), duration of ventilation [median (range)] 1.5(1-3) vs. 1 (1-2), P = 0.021; intensive care unit (ICU) stay 12 (8-16) vs. 10 (8-12), P = 0.024; time to ambulation 9 (7-11) vs. 6 (5-7), P = 0.001; drain removal 18.7 ± 7.3 vs. 14.4 ± 6.2, P = 0.001; need for tracheostomy 5 (9%) vs. 0 (%), P = 0.017; preoperative prevalence of acute kidney injury, comorbidities and requirement for dialysis, intraoperative blood loss & inotropic support were significantly higher in sarcopenics. Ninety-day mortality was comparable between sarcopenics 5 (9.09%) and nonsarcopenics 4 (6.6%) P = 0.63. SMI (OR: 0.83; 95% CI: 0.71-0.97, P = 0.016; Acute on chronic liver failure (ACLF) presentation 12.5 (1.65-95.2), P = 0.015 and intraoperative blood loss 3.74 (0.96-14.6), P = 0.046 were predictors of 90-day mortality. CONCLUSION: Almost 50% of LT recipients had sarcopenia, who had a higher incidence of postoperative sepsis, neurological complications, longer ICU stay and ventilatory support. Low SMI, ACLF presentation, and intraoperative blood loss were the independent predictors of early mortality.