A randomized-controlled trial comparing 20% albumin to plasmalyte in patients with cirrhosis and sepsis-induced hypotension [ALPS trial].

BACKGROUND & AIMS: The choice of resuscitation fluid in patients with cirrhosis and sepsis-induced hypotension is unclear. 5% albumin was superior to normal saline in the FRISC study. We compared the efficacy and safety of 20% albumin, which has greater oncotic properties, to plasmalyte in reversing sepsis-induced hypotension. METHODS: Critically ill patients with cirrhosis underwent open-label randomization to receive either 20% albumin (0.5-1.0 g/kg over 3 hours; n = 50) or plasmalyte (30 ml/kg over 3 hours, n = 50). The primary endpoint of the study was the attainment of mean arterial pressure (MAP) above 65 mmHg at 3 hours. RESULTS: Baseline characteristics were comparable in albumin and plasmalyte groups; arterial lactate (6.16±3.18 mmol/L vs. 6.38±4.77 mmol/L; p = 0.78), MAP (51.4±6.52 mmHg vs. 49.9±4.45 mmHg; p = 0.17) and SOFA score (10.8±2.96 vs. 11.1±4.2; p = 0.68), respectively. Most patients were alcoholics (39%) and had pneumonia (40%). In the intention-to-treat analysis, albumin was superior to plasmalyte in achieving the primary endpoint (62% vs. 22%; p <0.001). A faster decline in arterial lactate (p = 0.03), a reduced need for dialysis (48% vs. 62%; p = 0.16), and a longer time to initiation of dialysis (in hours) (68.13±47.79 vs. 99.7± 63.4; p = 0.06) were seen with albumin. However, the 28-day mortality rate was not different (58% vs. 62%, p = 0.57) and treatment had to be discontinued in 11 (22%) patients in the albumin group due to adverse effects compared to no discontinuations in the plasmalyte group. CONCLUSION: In patients with cirrhosis and sepsis-induced hypotension, 20% albumin leads to a faster improvement in hemodynamics and lactate clearance than plasmalyte, while 28-day survival was similar. However, patients on 20% albumin need to be closely monitored as it was more often associated with pulmonary complications. CLINICAL TRIAL REGISTRATION: NCT02721238. LAY SUMMARY: The current randomized-controlled trial performed in critically ill patients with cirrhosis and sepsis-induced hypotension highlights that 20% albumin restores arterial pressure more quickly but causes more pulmonary complications than plasmalyte. The impact on renal functions was also modest. These effects did not result in improvement in survival at 28 days. Plasmalyte is safer and well-tolerated and can be considered for volume resuscitation in patients with cirrhosis and sepsis-induced hypotension.

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.

Early cirrhosis and a preserved bone marrow niche favour regenerative response to growth factors in decompensated cirrhosis.

BACKGROUND: Exogenous growth factor-mobilized bone marrow (BM) stem cells have shown a differential response in the management of decompensated cirrhosis (DC). This study was designed to evaluate potential clinical benefit of adding Erythropoietin (EPO) in granulocyte-colony stimulating factor (G-CSF)-mobilized stem cell therapy, possible mechanisms of regeneration and predictive factors of regenerative response. METHODS: Sixty consecutive DC patients received either G-CSF with EPO (Group A; n = 30) or G-CSF and placebo (Group B; n = 30) for 2 months and were carefully followed up for 1 year. Baseline and post-treatment liver biopsy, BM biopsy and BM aspirate were analysed for fibro-inflammatory and regenerative response and BM hematopoietic reservoir. RESULTS: Addition of EPO to G-CSF showed a significant improvement in Child-Pugh score (P = 0.03) and MELD score (P = 0.003) as compared to G-CSF alone, with reduction in mortality (16.6% vs 36.7%, P = 0.09). The combination arm also demonstrated a decreased incidence of acute kidney injury (P < 0.001), encephalopathy (P = 0.005) and refilling of ascites (P = 0.03). Compared to monotherapy, it increased CD163+ macrophages (P = 0.013), Ki67+ index (P < 0.001) with decrease in α-SMA levels (P < 0.001) in liver tissue. The response was better with grade 1 and 2 than with grade 3 ascites; Child B cirrhosis and MELD < 16. Non-responders had lower hematopoietic stem cells (HSCs) at baseline. On multivariate analysis, the liver disease severity (MELD < 16) and a relatively preserved BM (BM-HSCs > 0.4) predicted therapeutic response (AUROC = 0.82). CONCLUSIONS: Early DC (MELD < 16) patients with mild-moderate ascites and those with a healthy cellular baseline BM respond better to growth factor therapy. Addition of EPO to G-CSF provides better regenerative response than G-CSF monotherapy.

A double-blind randomized controlled trial to assess efficacy of bromocriptine in cirrhotic patients with hepatic parkinsonism.

BACKGROUND: Parkinsonism like features can be seen in cirrhotics, possibly related to alterations in brain dopamine metabolism, transport and receptor integrity at basal ganglia. Hepatic parkinsonism is often not suspected and only ammonia-reducing therapies are given to such patients. We investigated the efficacy and safety of bromocriptine, a dopaminergic agent, in patients with hepatic parkinsonism. PATIENTS AND METHODS: Cirrhotics were screened for the presence of extrapyramidal symptoms and were diagnosed as hepatic parkinsonism if any two of tremor, bradykinesia and/or rigidity were present, supported by MRI brain showing T1 hyperintensities in basal ganglia and substantia nigra. Patients were randomized to receive placebo (Gr A, n = 22) or bromocriptine (Gr B, n = 24) for 12 weeks. Complete, partial and non-response were defined as 30%, 10%-30% and <10% reduction,respectively, in Unified Parkinson's Disease Rating Scale motor score. RESULTS: Of 1016 cirrhotics, 50 (4.9%) had hepatic parkinsonism. Patients in two treatment groups were comparable for MELD score, arterial NH3 and frequency of portosystemic shunts. Bromocriptine therapy for 12 weeks resulted in improvement in rigidity, tremors, bradykinesia and gait compared to placebo with complete and partial response in seven vs none (29.1%, 0%, P < 0.01) and 12 vs one (50%, 4.5%, P < 0.01) patients. Prolonged and more severe motor symptoms were associated with non-response to bromocriptine therapy. There were no major side effects in either treatment group. CONCLUSIONS: Hepatic parkinsonism is seen in ~5% cirrhotics. Bromocriptine is a safe and effective therapy for these patients and is more effective in mild to moderate hepatic parkinsonism.

SX-Ella Stent Danis Effectively Controls Refractory Variceal Bleed in Patients with Acute-on-Chronic Liver Failure.

BACKGROUND AND AIMS: Almost 10% of bleeding episodes are refractory to combination of vasoactive agent and endotherapy, and are associated with a mortality up to 50%. Severity of liver disease and high portal pressure are mainly responsible for it. TIPS cannot be used in these patients due to high MELD score. We aimed to evaluate the efficacy of self-expandable DE stents for control of refractory variceal bleeds in patients with ACLF. METHODS: Acute-on-chronic liver failure patients (n = 88, mean age 47.3 ± 10.9 years) with refractory variceal bleeds received either DE stent (Gr. A, n = 35) or continued with repeat endotherapy and vasoactive drug (Gr.B, n = 53). Matching by propensity risk score (PRS) was done to avoid selection bias. Competing risk Cox regression analysis was done to identify event-specific, i.e., gastrointestinal bleed-related death. RESULTS: Majority (78.4%) of patients were alcoholic with MELD score of 45.9 ± 20.1. Control of initial bleeding was significantly more in the DE stent group as compared to controls in both pre-match (89 vs. 37%; p < 0.001) and PRS-matched cohorts (73 vs. 32%; 0.007). Further, bleed-related death was also significantly lower in DE group as compared to controls in both pre-match (14 vs. 64%; p = 0.001) and PRS-matched cohorts (6 vs. 56%; p = 0.001). In a multivariate competing risk Cox model, patients who underwent DE stenting had reduced mortality in both pre-match (p = 0.04, HR 0.36, 95% CI 0.13-0.96) and PRS-matched cohorts (p < 0.001, HR 0.21, 95% CI 0.08-0.51). CONCLUSIONS: Self-expandable DE stents are very effective in control of refractory variceal bleeding and reduced mortality in patients with severe liver failure.

Encephalopathy in Cirrhosis: Prevention and Management.

Hepatic encephalopathy (HE) is a major neuropsychiatric complication of cirrhosis. The clinical manifestations of HE ranges from mild confusion, disorientation to altered behaviour and coma in advanced stages. HE is an important cause of recurrent admissions in liver cirrhosis patients. HE is the most common cause of altered mentation in a patient of liver cirrhosis. Lactulose and rifaximin are approved treatment options for the treatment of HE. In patients who have localised neurological signs or are not improving with lactulose and rifaximin should be investigated for other causes of altered sensorium.

A Case Series of Amoebic Liver Abscess in Patients With COVID-19 Infection.

Background: Globally, amoebiasis is the second leading cause of death due to parasitic diseases. Amoebic liver abscess (ALA) as an opportunistic infection in recently recovered COVID 19 disease patients has not been reported earlier. Methods: We present here a case series of 13 patients of ALA admitted during the month of May 2021 in BLK hospital, New Delhi, and had recently recovered from COVID 19 disease. Results: Out of 13, eight patients had moderate, and one had severe COVID 19 disease. All these patients had received steroids for the management of COVID 19 disease. The remaining 4 (30%) patients had mild disease. The mean age of our patients was 50 years (37-81 years). Out of 13 patients, nine (70%) were male, 5 were diabetic, 2 were hypertensive, and none were alcoholic. The most common presentation was fever (11/13) followed by upper abdomen pain (10/13). The mean time of symptom (fever or pain abdomen) onset from COVID 19 positivity date was 19 days (range 15-23 days). A complication the in form of localized intraperitoneal rupture was common in these patients and was seen in more than 50% (7/13) of patients. All the patients were managed with IV Metronidazole and abscess aspiration. All the patients were discharged, and the mean hospital stay was 6.6 days. Conclusion: We report here an increase in the incidence of ALA in recently recovered COVID 19 patients and propose that it is most likely due to alteration in the immune state of these patients. It is important for physicians to investigate for liver abscess in patients who present again with fever and/or pain abdomen within 2 weeks of COVID 19 recovery.

Normative values of skeletal muscle indices for nutritional assessment and implications on definition of sarcopenia in Indian adult population.

INTRODUCTION: Sarcopenia is defined as both low muscle function (performance or strength) and low muscle mass. Although aging is the main cause of sarcopenia, it can also occur due to poor nutrition and chronic diseases like liver cirrhosis, chronic kidney disease, and diabetes. OBJECTIVE: To do the quantitative analysis of various normative skeletal muscle indices (to define sarcopenia) in the Indian population. METHODS: Sex-specific means, standard deviations (SD), and sarcopenia cutoffs (mean-2SD) of psoas muscle thickness (PMTH), psoas muscle area (PMA), psoas muscle index (PMI), erector spinae muscle area (ESMA), skeletal muscle radiation attenuation (SMRA), total skeletal muscle area (SMA), and total skeletal muscle index (SMI) were computed. RESULTS: A total of 2002 individuals (1308 males and 694 females) underwent CT evaluation. PMTH (mm/m) was observed to be 15.87±2.67 in males vs. 12.61±2.46 in females (p=0.0001); PMA (cm2) was 18.55±3.45 in males vs.13.52±2.80 in females (p=0.0001); PMI (cm2/m2) was 6.69±1.40 in males vs. 5.57±1.18 in females (p=0.0001); ESMA (cm2) was 45.74±6.01 in males vs. 35.37±5.63 in females (p=0.0001); ESMI (cm2/m2) was 16.5±2.55 in males vs. 14.62±2.6 in females (p=0.0001); SMRA was 55.80±3.91 Hounsfield unit (HU) in males vs. 52.36±3.67 HU in females (p=0.0001); SMA (cm2) was 147.73±11.77 in males vs. 106.33±12.00 in females (p=0.0001); and SMI (cm2/m2) was estimated to be 51.00±5.70 in males vs. 43.93±6.05 in females (p=0.0001). PMTH, PMI, ESMI, SMI, and SMRA cutoffs for sarcopenia at L3 were observed to be 10.53 mm/m, 3.89 cm2/m2, 11.40 cm2/m2, 39.59 cm2/m2, and 47.98 HU among males and 7.69, 3.20, 9.42, 31.83, and 45.01 among females, respectively; these values were consistent with previously reported cutoffs in Indian studies but not consistent with the cutoffs reported in other countries. CONCLUSION: Normative values of skeletal muscle indices for either sex among the Indian adult population would enable future studies on sarcopenia in various medical conditions.

Impact of Living Donor Liver Transplantation on COVID-19 Clinical Outcomes from a Quaternary Care Centre in Delhi.

Background and Aims: The anticipated fear of serious outcomes in coronavirus infected liver transplant recipients led to disruption of transplant services globally. The aim of our study was to analyze COVID-19 severity in transplant recipients and to compare the difference of COVID-19 clinical outcomes in early (<1 year) vs. late (>1 year) post-transplant period. Methods: 41 post-living donor liver transplant recipients with COVID-19 infection were studied retrospectively from 1st April 2020 to 28th February 2021. Results: The median age was 49.00 years with a male preponderance (80.49%). Fifteen patients had infection within 1 year of transplant and 26 were infected after 1 year of transplant. The overall median interval between transplantation and COVID-19 diagnosis was 816.00 days. Fever and malaise were the common presenting symptoms. The most common associated comorbidities were diabetes mellitus (65.85%) and hypertension (46.34%). The severity of illness was mild in 28 (68.29%), moderate in 4 (9.76%), severe in 6 (14.63%) and critical in 3 (7.32%). To identify associated risk factors, we divided our patients into less severe and more severe groups. Except for lymphopenia, there was no worsening of total bilirubin, transaminases, alkaline phosphatase, and gamma-glutamyl transferase in the more severe group. Eight (19.51%) patients required intensive care unit admission and three (7.32%) died, while none suffered graft rejection. In recipients with early vs. late post-transplant COVID-19 infection, there were similar outcomes in terms of severity of COVID-19 illness, intensive care unit care need, requirement of respiratory support, and death. Conclusion: Living donor liver transplantation can be performed during the COVID-19 pandemic without the fear of poor recipient outcome in cases of unfortunate contraction of severe acute respiratory syndrome coronavirus-2.

Oesophageal and gastric varices: historical aspects, classification and grading: everything in one place.

Variceal disease and its management are of the utmost importance in the treatment of portal hypertension. Current guidelines are universal for management of variceal disease in portal hypertension. Classification and grading systems are numerous and differ according to geographical location. In this exhaustive review, the historical aspects of variceal disease, its classification and the grading systems in use are discussed, with self-explanatory tables and timelines. A better and clear understanding of the evolution of portal hypertension and variceal disease is provided.

Cholangicarcinoma Presenting as a Sister Mary Joseph Nodule.

Sister Mary Joseph nodules represent metastatic cancer of the umbilicus. More than half of these cases are attributable to gastrointestinal malignancies including gastric, colonic, and pancreatic cancer. In addition, gynecologic (ovarian, uterine cancer), unknown primary tumors, and, rarely, bladder or respiratory malignancies may cause umbilical metastasis. We report the case of a Sister Mary Joseph nodule originating from a hilar cholangiocarcinoma. Umbilical nodules should prompt clinical evaluation, as these tumors are usually associated with poor prognosis.

CD4+CD25+CD127(low) Regulatory T Cells Play Predominant Anti-Tumor Suppressive Role in Hepatitis B Virus-Associated Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide and hepatitis B is one of the commonest causes. T regulatory cells (Tregs) are strong immunomodulators and are likely to play a major role in HCC development. HBV infection is reported to induce expansion of Tregs. We investigated the CD4+CD25+CD127(-ve)FoxP3+ Tregs in HBV-related HCC as compared to non-HBV-HCC. PATIENTS AND METHODS: Whole blood immunophenotyping was analyzed by multicolor flow cytometry in patients with HBV-related HCC (HBV-HCC, n = 17), non-HBV-HCC (n = 22; NASH = 16, alcohol-related = 6), and chronic hepatitis B infection (CHBV; n = 10). Tregs functionality was checked by in vitro suppression assays using CD4+ CD25+ CD127(low) Tregs. Levels of serum alpha-fetoprotein (AFP), expression of FoxP3, IL-10, PD1, TGF-ß, and Notch in Tregs, and liver explants were analyzed by flow cytometry, immunohistochemistry, and quantitative RT-PCR. RESULTS: CD4+CD25+(hi) and Foxp3 expression in CD4+CD25+(hi)CD127(low) was significantly increased (P = 0.04, P = 0.007) in HBVHCC compared to non-HBVHCC and CHBV patients. HBVHCC also showed high IL-10 and TGF-ß secreting CD4 + CD25 + (hi)Tregs. The PD1 expression in CD4 + CD25+(hi) was significantly decreased in the HBVHCC than non-HBVHCC. In HBVHCC, AFP levels were significantly high (median 941, range 2-727940) than non-HBVHCC (median 13.5, range 2-18,900). In HBVHCC, patients with high AFP (range; 3982-727940 ng/ml) showed positive correlation with Foxp3 expression in CD4+CD25+(hi) CD127(low) (r = 0.857, P = 0.014). Reduced PD1 expression in HBVHCC also had negative correlation with FOXP3 in CD4+CD25+(hi) CD127(low) (r = -0.78, P = 0.04). However, AFP levels in non-HBVHCC showed negative correlation with (R = -0.67, P = 0.005) with CD4+CD25+(hi) Tregs. CONCLUSION: Our results demonstrate that CD4+ CD25+(hi) Tregs from HBVHCC patients have decreased expression of PD1, resulting in higher IL-10 and TGF-ß secretion. Increased suppressive ability of Tregs in HBV-related HCC confers increased anti-tumor suppressive response than in non-HBV-HCC. Modulation of Tregs and PD1 may serve as useful therapeutic targets.

Unique presentation of giant metastatic microcystic serous adenocarcinoma of the pancreas.

Tumors of the pancreas that contain substantial cystic components include mainly mucinous cystic neoplasm, intraductal papillary mucinous neoplasm, solid pseudopapillary tumor, and cystadenomas (which encompass microcystic, macrocystic/oligocystic, and rare solid serous adenomas). Microcystic adenoma of the pancreas is a tumor that is benign in nature. Malignant transformation in the tumor with metastases is rare and only about 26 cases have been reported so far. Here we present a giant microcystic adenoma of the pancreas, possibly the largest ever malignant type in this group ever reported in the literature with extensive metastases to the liver and causing extensive compression and encasement on surrounding structures.