Neil Rajoriya

Non-selective β-blockers are associated with improved survival in patients with ascites listed for liver transplantation

Objective Recent data have suggested that non-selective β-blockers (NSBB) are associated with increased mortality in patients with cirrhosis and refractory ascites. However, other evidence implies that NSBB may be beneficial in this setting by reducing bacterial translocation. Our aim was to determine whether NSBB use was a risk factor for mortality in patients with end-stage chronic liver disease and ascites awaiting liver transplantation. Design This was a single-centre retrospective study of 322 patients with ascites listed January 2007 to July 2011. Results NSBB patients (n=159) and non-NSBB patients (n=163) were comparable with regards to listing model for end-stage liver disease score (p=0.168), frequency of hepatocellular carcinoma (p=0.193) and refractory ascites (35.2% vs. 37.4%, p=0.681). 82 patients died, 221 patients were transplanted and 19 patients were removed from the list during a median follow-up duration of 72 days; the median time to death was 150 and 54 days in the NSBB and non-NSBB groups, respectively. In a multivariate competing risk Cox model, patients on NSBB had reduced mortality compared with propensity risk score-matched non-NSBB patients (HR 0.55; 95% CI 0.32 to 0.95, p=0.032). Similarly, in the subgroup of patients with refractory ascites (n=117), NSBB remained independently associated with less waitlist death (adjusted HR 0.35; 95% CI 0.14 to 0.86, p=0.022). Conclusions NSBB in patients with ascites and refractory ascites listed for liver transplantation are not detrimental, and instead are associated with reduced waitlist death. Our findings argue that NSBB are safe and may confer benefit in patients with ascites complicating end-stage liver disease.

CD161 Defines a Transcriptional and Functional Phenotype across Distinct Human T Cell Lineages

Summary The C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCRγδ+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell receptor (TCR) expression and cell lineage.

The evolving use of higher risk grafts is associated with an increased incidence of acute kidney injury after liver transplantation

BACKGROUND & AIMS The growing discrepancy between supply and demand for liver transplantation has necessitated a greater use of higher risk grafts. Donation after Circulatory Death (DCD) liver transplant recipients have an increased frequency of acute kidney injury (AKI). We hypothesised that other higher risk grafts might also impact negatively on renal function. Our aim was to examine the effect of the evolving use of higher risk grafts on the incidence of post liver transplant AKI. METHODS Single-centre study of 1152 patients undergoing first-single-organ liver transplantation for chronic liver disease 01/2000-12/2011. To assess the impact of the evolution of graft quality over time; donor/graft/recipient variables were compared over three 4-year periods. RESULTS Pretransplant recipient renal function improved during follow-up (p<0.001), and the median postoperative day-1 (p<0.001), -2 (p<0.001), and -3 (p<0.001) tacrolimus trough levels fell. The proportion of patients receiving a higher risk graft was 31.8% in 2000-2003, 40.9% in 2004-2007, and 59.1% in 2008-2011 (p<0.001). There was a progressive increase in AKI (2000-2003, OR 1.00; 2004-2007, OR 1.43; 2008-2011, OR 2.40, p<0.001). After adjusting for recipient variables increasing recipient warm ischaemic time (p=0.019), DCD transplantation (p<0.001), donor age ≥60 years (p=0.020), and donor body mass index ≥30 kg/m(2) (p<0.001) were independent predictors of AKI. CONCLUSIONS The increasing use of higher risk liver grafts is associated with an increased incidence of AKI. These findings support the need for therapies that minimise the hepatic ischaemia-reperfusion injury.

Neutrophil-to-lymphocyte ratio predicts mortality in patients listed for liver transplantation.

In the absence of overt infection, the systemic inflammatory response is increasingly recognised as a pathogenetic factor in the circulatory dysfunction of advanced cirrhosis. Our aim was to determine whether the neutrophil‐to‐lymphocyte ratio, a marker of systemic inflammation, is predictive of mortality in patients with end‐stage cirrhosis listed for liver transplantation.

Gamma Delta T-lymphocytes in Hepatitis C and Chronic Liver Disease.

Discovered 30 years ago, gamma delta (γδ) T-lymphocytes remain an intriguing and enigmatic T-cell subset. Although in humans they comprise a small fraction of the total circulating T-lymphocyte pool, they represent an important T-cell subset in tissues such as the liver, with roles bridging the innate and adaptive immune systems. The associations of γδ T-lymphocytes with chronic liver disease have been explored – however, there remain conflicting data as to whether these T-cells are pathogenic or protective. In patients with some forms of liver disease, their expansion in the periphery and especially in the liver may indeed help pathogen clearance, while in other conditions their presence may, in contrast, contribute to disease progression. γδ T-cells can also express CD161, a C-type lectin, and such cells have been found to be involved in the pathogenesis of inflammatory disease. CD161+ T-cells of diverse subsets are known to be enriched in the livers of patients with chronic hepatitis C. This article serves to provide a review of the γδ T-cell population and its role in hepatitis C and other chronic liver diseases, and also explores a potential role of the CD161+ γδ T-cells in liver diseases.

Palliative care access for hospitalized patients with end‐stage liver disease across the United States

Patients with end‐stage liver disease (ESLD) often have a high symptom burden. Historically, palliative care (PC) services have been underused in this population. We investigated the use of PC services in patients with ESLD hospitalized across the United States. We used the Nationwide Inpatient Sample to conduct a retrospective nationwide cohort analysis. All patients >18 years of age admitted with ESLD, defined as those with at least two liver decompensation events, were included in the analysis. A multivariate logistic regression model predicting referral to PC was created. We analyzed 55,208,382 hospitalizations from the 2006‐2012 Nationwide Inpatient Sample, with 39,349 (0.07%) patients meeting study inclusion. PC consultation was performed in 1,789 (4.5%) ESLD patients. The rate of PC referral in ESLD increased from 0.97% in 2006 to 7.1% in 2012 (P < 0.01). In multivariate analysis, factors associated with lower referral to PC were Hispanic race (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.66‐0.89; P < 0.01) and insurance coverage (OR, 0.74; 95% CI, 0.65‐0.84; P < 0.01). Factors associated with increased referral to PC were age (per 5‐year increase, OR, 1.05; 95% CI, 1.03‐1.08; P < 0.01), do‐not‐resuscitate status (OR, 16.24; 95% CI, 14.20‐18.56; P < 0.01), treatment in a teaching hospital (OR, 1.25; 95% CI, 1.12‐1.39; P < 0.01), presence of hepatocellular carcinoma (OR, 2.00; 95% CI, 1.71‐2.33; P < 0.01), and presence of metastatic cancer (OR, 2.39; 95% CI, 1.80‐3.18; P < 0.01). PC referral was most common in west coast hospitals (OR, 1.81; 95% CI, 1.53‐2.14; P < 0.01) as well as large‐sized hospitals (OR, 1.49; 95% CI, 1.22‐1.82; P < 0.01). Conclusion: From 2006 to 2012 the use of PC in ESLD patients increased substantially; socioeconomic, geographical, and ethnic barriers to accessing PC were observed. (Hepatology 2017;66:1585–1591).

Historical overview and review of current day treatment in the management of acute variceal haemorrhage

Variceal haemorrhage is one of the most devastating consequences of portal hypertension, with a 1-year mortality of 40%. With the passage of time, acute management strategies have developed with improved survival. The major historical treatment landmarks in the management of variceal haemorrhage can be divided into surgical, medical, endoscopic and radiological breakthroughs. We sought to provide a historical overview of the management of variceal haemorrhage and how treatment modalities over time have impacted on clinical outcomes. A PubMed search of the following terms: portal hypertension, variceal haemorrhage, gastric varices, oesophageal varices, transjugular intrahepatic portosystemic shunt was performed. To complement this, Google™ was searched with the aforementioned terms. Other relevant references were identified after review of the reference lists of articles. The review of therapeutic advances was conducted divided into pre-1970s, 1970/80s, 1990s, 2000-2010 and post-2010. Also, a summary and review on the pathophysiology of portal hypertension and clinical outcomes in variceal haemorrhage was performed. Aided by the development of endoscopic therapies, medication and improved radiological interventions; the management of variceal haemorrhage has changed over recent decades with improved survival from an often-terminating event in recent past.

A liver mass post-Fontan operation

### Learning Point for Clinicians This case report raises awareness of a rare devastating complication of congenital heart diseases that require correction via the “Fontan” operation. In these patients, liver cirrhosis and its complications are now being recognised including hepatocellular carcinoma. With recognition, strategies for early treatment /interventions in a complicated population can be devised. A 19-year-old female was referred for urgent investigation of jaundice. She had a history of complex congenital heart disease with situs invertus, left atrial isomerism and juxtaposed atrial appendages, azygous continuation of the inferior vena cava and malposition of the great arteries with tricuspid atresia. In 1990, she had a successful atrio-pulmonary connection (‘Modified Fontan’ operation). She was followed up closely thereafter by the Cardiology team. Eight years later, she had an oesophageal variceal haemorrhage requiring variceal band ligation. At the time, it was felt that her portal …

Reply to: HEP‐17‐1544

We read with interest the study by Rush et al.(1) identifying increased utilization of palliative care in hospitalized patients with end-stage liver disease (ESLD) in the United States. A few considerations should be made, including additional sensitivity analyses and interpretation of these findings from a public health perspective. First, the number of hospitalizations and palliative care consultations were analyzed instead of the number of patients. Analysis of these numbers could over-represent patients or hospitals with frequent palliative care utilization groups. This concern can be appropriately adjusted by using the hierarchical modeling analysis.(2) Because Rush et al. used the SAS v9.4 statistical software, PROC GLIMMIX procedure can fit continuous, binary, or count outcomes to adjust data at multiple levels (patient and hospital).(2) If the researchers used multilevel adjustment methods, it is essential that they clarify this step. Second, the researchers did not fully report the number of missing data points. Identifying the proportion of missing data might be necessary given that this study used the International Classification of Diseases, Ninth Edition code V66.7 (palliative care consultation). Rush et al.(1) cited the validity of using V66.7 code from a study using a small number of patients (100) with a different diagnosis (ischemic stroke) from their analysis (ESLD).(3) However, when evaluating more than 100,000 admissions and a variety of diagnostic subgroups, Hua et al.(4) found that the sensitivity for the V66.7 code was 61.11% in chronic liver disease. Third, Rush et al.(1) collapsed insurance covariate into yes versus no. However, patients under private insurance, when compared to those with Medicaid, are quite heterogenous in annual income and disease severity. Vasveebye Sonoo, M.D.1* Jay V. Kumar, M.D.1* Xibei Liu, M.D.2 Johnson Ukken, M.S. 3 Mary Froehlich, M.A.3 Ji Won Yoo, M.D. 1 1 Department of Internal Medicine University of Nevada Las Vegas School of Medicine, Las Vegas, NV 2 Department of Medicine University of Arizona College of Medicine, Tucson, AZ 3 University of Nevada Reno School of Medicine Reno, NV

Portal hypertension in polycystic liver disease patients does not affect wait-list or immediate post-liver transplantation outcomes

AIM To establish the impact of portal hypertension (PH) on wait-list/post-transplant outcomes in patients with polycystic liver disease (PCLD) listed for liver transplantation. METHODS A retrospective single-centre case controlled study of consecutive patients listed for liver transplantation over 12 years was performed from our centre. PH in the PCLD cohort was defined by the one or more of following parameters: (1) presence of radiological or endoscopic documented varices from our own centre or the referral centre; (2) splenomegaly (> 11 cm) on radiology in absence of splenic cysts accounting for increased imaging size; (3) thrombocytopenia (platelets < 150 × 109/L); or (4) ascites without radiological evidence of hepatic venous outflow obstruction from a single cyst. RESULTS Forty-seven PCLD patients (F: M = 42: 5) were listed for liver transplantation (LT) (single organ, n = 35; combined liver-kidney transplantation, n = 12) with 19 patients (40.4%) having PH. When comparing the PH group with non-PH group, the mean listing age (PH group, 50.6 (6.4); non-PH group, 47.1 (7.4) years; P = 0.101), median listing MELD (PH group, 12; non-PH group, 11; P = 0.422) median listing UKELD score (PH group, 48; non-PH group, 46; P = 0.344) and need for renal replacement therapy (P = 0.317) were similar. In the patients who underwent LT alone, there was no difference in the duration of ICU stay (PH, 3 d; non-PH, 2 d; P = 0.188), hospital stay length (PH, 9 d; non-PH, 10 d; P = 0.973), or frequency of renal replacement therapy (PH, 2/8; non-PH, 1/14; P = 0.121) in the immediate post-transplantation period. CONCLUSION Clinically apparent portal hypertension in patients with PCLD listed for liver transplantation does not appear to have a major impact on wait-list or peri-transplant morbidity.