Palmitic acid causes hepatocyte inflammation by suppressing the BMAL1-NAD+-SIRT2 axis.

Palmitic acid is the most abundant saturated fatty acid in circulation and causes hepatocyte toxicity and inflammation. As saturated fatty acid can also disrupt the circadian rhythm, the present work evaluated the connection between clock genes and NAD+ dependent Sirtuins in protecting hepatocytes from lipid-induced damage. Hepatocytes (immortal cells PH5CH8, hepatoma cells HepG2) treated with higher doses of palmitic acid (400-600µM) showed typical features of steatosis accompanied with growth inhibition and increased level of inflammatory markers (IL-6 IL-8, IL-1α and IL-1ß) together with decline in NAD+ levels. Palmitic acid treated hepatocytes showed significant decline in not only the protein levels of SIRT2 but also its activity as revealed by the acetylation status of its downstream targets (Tubulin and NF-ƙB). Additionally, the circadian expression of both SIRT2 and BMAL1 was inhibited in presence of palmitic acid in only the non-cancerous hepatocytes, PH5CH8 cells. Clinical specimens obtained from subjects with NASH-associated fibrosis, ranging from absent (F0) to cirrhosis (F4), showed a significant decline in levels of SIRT2 and BMAL1, especially in the cirrhotic liver. Ectopic expression of BMAL1 or activating SIRT2 by supplementation with nicotinamide riboside (precursor of NAD+) dampened the palmitic acid induced lipoinflammation and lipotoxicity more effectively in PH5CH8 cells as compared to HepG2 cells. Mechanistically, palmitic acid caused transcriptional suppression of SIRT2 by disrupting the chromatin occupancy of BMAL1 at its promoter site. Overall, the work suggested that SIRT2 is a clock-controlled gene that is transcriptionally regulated by BMAL1. In conclusion the activation of the BMAL1-NAD+-SIRT2 axis shows hepatoprotective effects by preventing lipotoxicity and dampening inflammation.

Liver volumetry in cirrhotic patients with or without hepatocellular carcinoma: Its correlation with Child-Pugh, model for end-stage liver diseases and indocyanine green dye test.

BACKGROUND AND OBJECTIVES: To evaluate the correlation between non-tumoral liver volume (NTLV) by computed tomography (CT) volumetry and indocyanine green retention at 15 minutes (ICG-r15%), Child-Pugh score (CTP) and model for end-stage liver diseases (MELD) score in cirrhotic patients having hepatocellular carcinoma (HCC) (group A) and in cirrhotics without HCC (group B). METHODS: As many as 111 consecutive patients with liver cirrhosis, who underwent triple-phase CT abdomen, were retrospectively included in our study. They were classified into group A (cirrhosis with HCC, n = 69) and group B (cirrhosis only, n = 42). Segmental liver volume, tumor and NTLV were calculated using Myrian XP-Liver segmentation software. In group B, NTLV was the same as the total liver volume (TLV). The correlation of NTLV with ICG-r15%, CTP and MELD scores was analyzed using appropriate correlation tests for each group. RESULTS: NTLV had a good and significant negative correlation with ICG-r15% (ρ = - 512; p < 0.001) in group A, but not in group B. It also had a significant negative correlation with CTP (ρ = - 251; p = 0.038) and MELD (ρ = - 323; p = 0.007) scores only in group A. Furthermore, ICG-r15% had a good and significant positive correlation with CTP and MELD scores in both groups (p < 0.05). CONCLUSION: NTLV showed a significant negative correlation with ICG-r15% in cirrhotic patients with HCC, but not in cirrhotic patients without HCC. Therefore, CT volumetry can be a valuable tool to predict the functional hepatic volume in patients of cirrhosis with HCC subjected for hepatectomy, where a facility of ICG-r15% is not available. However, further studies are needed to validate our findings in cirrhotic only patients.

Number needed to screen to prevent progression of liver fibrosis to cirrhosis at primary health centers: An experience from Delhi.

BACKGROUND: Early diagnosis has been a bottleneck in the care of chronic liver disease patients and can be addressed by Community-based screening for liver fibrosis using non-invasive diagnostic techniques. OBJECTIVES: The study aimed to determine the prevalence of liver fibrosis and the number needed to screen (NNS) to prevent the progression of fibrosis, among adults visiting urban Primary Health Centres (PHC). METHODS: A facility-based cross-sectional study was conducted from May 2018 to April 2019 in 72 randomly chosen PHCs using a mobile screening van. A pre-tested questionnaire was used to collect relevant history from adult patients and patient attenders. A venous blood sample was collected for biochemical markers and Transient Elastography was also done to measure Liver stiffness (LSM). LSM ≥6.0 kPa was taken as the cut-off for detecting liver fibrosis. Lifestyle modifications and alcohol cessations were considered as interventions for non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) respectively, to calculate NNS. RESULTS: 7624 participants were recruited in the study with a mean age of 46 ± 12 years. Around 35.5% of participants had liver fibrosis and 3% had cirrhosis. Nearly 4% had ALD and 30% had NAFLD. NNS for preventing progression of fibrosis for ALD and NAFLD was 12 and 29 respectively. NNS was least among obese, diabetes and hypertensive participants. CONCLUSION: One-third of adults visiting urban PHCs had significant liver fibrosis. Low NNS to prevent the progression of fibrosis to cirrhosis among alcohol users and other high-risk groups, substantiates the need for screening among these groups.

Paracentesis-Induced Circulatory Dysfunction With Modest-Volume Paracentesis Is Partly Ameliorated by Albumin Infusion in Acute-on-Chronic Liver Failure.

BACKGROUND AND AIMS: Paracentesis-induced circulatory dysfunction (PICD) is a serious complication of large-volume (>5 L) paracentesis in cirrhosis and is reduced with albumin infusion. There is a lack of data on PICD in acute-on-chronic liver failure (ACLF). Because ACLF patients have greater hemodynamic derangements than patients with decompensated cirrhosis, we investigated whether PICD could develop with modest-volume paracentesis (MVP) and the role of albumin infusion. APPROACH AND RESULTS: A total of 80 ACLF patients undergoing <5 L paracentesis were randomized to receive albumin (8 g/dL of ascitic fluid; n = 40) or no albumin (n = 40) and serially followed to detect PICD. Baseline characteristics were comparable between groups, including volume of ascitic tap (4.16 ± 0.23 versus 4.14 ± 0.27 L; P = 0.72) and plasma renin activity (PRA; 20.5 ± 7.03 versus 23.2 ± 8.24 ng/mL/hour; P = 0.12). PICD was more frequent in the no-albumin group than the albumin group (70% versus 30%; P = 0.001), with higher incidence of hepatic encephalopathy (50% versus 27.5%; P = 0.04), hyponatremia (67.5% versus 22.5%; P < 0.001), acute kidney injury (62.5% versus 30%; P = 0.001), and in-house mortality (62.5% versus 27.5%; P = 0.003). PRA of 25.15 ng/mL at day 3 had sensitivity and specificity of 71% and 68%, respectively, for development of PICD at day 6. Albumin infusion decreased the incidence of PICD at day 6 (odds ratio, 0.068; 95% confidence interval, 0.011-0.43; P = 0.005). CONCLUSIONS: PICD is common and develops even with MVP in ACLF patients. Albumin infusion decreases the incidence of PICD and mortality in patients with ACLF. Clinical trial identifier: NCT02467348.

Correlation of baseline Portal pressure (hepatic venous pressure gradient) and Indocyanine Green Clearance Test With Post-transarterial Chemoembolization Acute Hepatic Failure.

BACKGROUND: Liver failure (LF) is a serious complication of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). This could be influenced by the hemodynamic and functional status of the underlying cirrhotic liver. We evaluated baseline hepatic venous pressure gradient (HVPG) and indocyanine green (ICG) clearance as predictive factors for the development of LF in patients with liver cirrhosis undergoing TACE for HCC. METHODS: Forty-two patients with cirrhosis and HCC, referred for TACE, were clinically evaluated including the assessment of Child Turcotte Pugh score (CTP), Model for End-Stage Liver Disease (MELD), HVPG measurement, and ICG retention test. Predictors of development of hepatic failure after TACE were determined. RESULTS: In our study population, the mean age of the patients was 58 years, with mean CTP of 6.60 ± 1.149 and mean MELD score of 9.57 ± 2.923. The mean HVPG and ICG retention at 15 min was 13.57 ± 4.64 mmHg and 21.571 ± 12.434, respectively. Post-TACE Liver Failure (PTLF within 1 month after TACE) developed in 23.80% patients, whereas 76.19% patients did not have PTLF. The statistically significant preprocedure variables that might predict hepatic failure after TACE using univariate analysis were found to be high CTP, MELD score, ICG retention, HVPG, serum bilirubin, serum creatinine, alfa-fetoprotein levels, large tumor size, and low baseline serum albumin. On multivariate analysis, ICG was an independent factor predictive of hepatic failure after TACE. CONCLUSION: Pretreatment evaluation of routine liver function is of fundamental importance before TACE. Baseline ICG retention test (ICG-R15) is a marker indicating the state of liver function in patients undergoing TACE and is an independent predictor for PTLF. Our study concludes that with a cutoff of 25, ICG-R15 has 92.9% accuracy, 90% sensitivity, and 87.5% specificity to predict hepatic failure after TACE.